Robert A. Schwartz, MD, MPH

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

Phytophotodermatitis (PPD) is a nonallergic contact dermatitis and thus is independent of the immune system, so prior sensitization is not required.^1-3 It sometimes is known by colorful names such as margarita photodermatitis, in which a slice of lime in a refreshing summer drink may be etiologic,^4,5 or berloque dermatitis, caused by exposure to perfumes containing bergapten (5-methoxypsoralen).^6,7 Phytophotodermatitis may develop when phototoxic agents such as furocoumarins, which protect plants from fungal pathogens, and psoralens are applied to the skin followed by exposure to UV light, more specifically in the UVA range of 320 to 400 nm. Thus, these chemicals produce a phototoxic rather than photoallergic reaction, leading to cellular damage. Furocoumarins and psoralens often are found in plants such as celery and figs as well as in citrus fruits such as limes, lemons, and grapefruits. Exposure may be cryptic, as the patient may not consider or mention the eruption as possibly caused by activities such as soaking one’s feet in a folk remedy containing fig leaves.^7,8 Once these phototoxic agents come in contact with the skin, the symptoms of PPD may arise within 24 hours of exposure, beginning as an acute dermatitis with erythema, edema, vesicles, or bullae accompanied by pain and itching.

Etiology

Phytophotodermatitis is caused by exposure to several different types of plants, including Ficus carica (common fig), the genus Citrus (eg, lime, lemon), or Pastina sativa (wild parsnip). Each of these contain furocoumarins and psoralens—phototoxic agents that cause cellular damage with epidermal necrosis and resultant pain when the skin is exposed to UVA light.^1-4 There are 2 types of photochemical reactions in PPD: type I reactions occur in the absence of oxygen, whereas oxygen is present in type II reactions. Both damage cell membranes and DNA, which then results in DNA interstrand cross-linking between the psoralen furan ring and the thymine or cytosine of DNA, activating arachidonic acid metabolic pathways to produce cell death.¹

Epidemiology

The incidence of PPD is unknown due to the high variability of reactions in individuals spanning from children to the elderly. It can be caused by many different wild and domestic plants in many areas of the world and can affect any individual regardless of age, race, gender, or ethnicity. Some individuals may be affected by hyperpigmentation without prominent inflammation.⁸ Diagnosis of PPD can be challenging, and an occupation and recreational history of exposure or recent travel with possible contact with plants may be required.

Occupational Dermatitis

Phytophotodermatitis also may be an occupational disease.^9-12 Occupational exposure may occur in soldiers during military drills and other activities, farm workers, chefs, gardeners, groundskeepers, food processors, bartenders, and florists. Wearing protective gloves when handling plants such as limes, lemons, grapefruit, celery, or parsnips may prevent occupational exposure. Exposure to hogweed, an invasive species originally introduced as an ornamental plant in Europe and the United States, can produce a dramatic acute photodermatitis from exposure to its sap, which contains the psoralens 5-methoxypsoralen and 8-methylpsoralen.^9-11

Recreational Dermatitis

Phytophotodermatitis may be caused by exposure to phototoxic agents during leisure activities. Recreational exposure can occur almost anywhere, including in the kitchen, backyard, park, or woods, as well as at the beach. One notable culprit in recreational PPD is cooking with limes, parsley, or parsnips—plants that often are employed as garnishes in dishes, allowing early exposure of juices on the hands. Individuals who garden recreationally should be aware of ornamental plants such as hogweed and figs, which are notorious for causing PPD.¹³ Children’s camp counselors should have knowledge of PPD, as children have considerable curiosity and may touch or play with attractive plants such as hogweed. Children enjoying sports in parks can accidentally fall onto or be exposed to wild parsnip or hogweed growing nearby and wake up the next day with erythema and burning.¹⁴ Photoprotection is important, but sunscreens containing carrot extract can produce PPD.¹⁵ Widespread PPD over 80% of the body surface area due to sunbathing after applying fig leaf tea as a tanning agent has been described.¹⁶ Eating figs does not cause photosensitization unless the juice is smeared onto the skin. Margarita dermatitis and “Mexican beer dermatitis” can occur due to limes and other citrus fruits being used as ingredients in summer drinks.⁵ Similarly, preparing sangria may produce PPD from lime and lemon juices.¹⁷ In one report, hiking in Corsica resulted in PPD following incidental contact with the endemic plant Peucedanum paniculatum.¹⁸

Perfume (Berloque) Dermatitis

Perfume dermatitis, or berloque dermatitis, is a type of PPD for which the name is derived from the German word berlock or the French word berloque meaning trinket or charm; it was first described in 1925 by Rosenthal⁷ with regard to pendantlike streaks of pigmentation on the neck, face, arms, or trunk. The dermatitis develops due to bergapten, a component of bergamot oil, which is derived from the rind of Citrus bergamia. Many perfumes contain bergamot oil, but the incidence of this condition has been diminished due to use of artificial bergamot oil.⁶

Clinical Manifestation

Phytophotodermatitis is first evident as erythematous patches that appear within 24 hours of initial exposure to a phototoxic agent and UVA light, sometimes with a burning sensation. Solar exposure within 48 hours of sufficient plant exposure is required. Perfuse sweating may enhance the reaction.¹⁹ Rarely, it first may be seen with the sudden appearance of asymptomatic hyperpigmentation. One may see the pattern of splash marks from lime or lemon juice (Figure 1). The acute dermatitis may be associated with adjacent cutaneous edema near the reaction site or along with the erythema and blister formation. Its severity is related to the intensity of sun exposure and amount of furocoumarins.² The most common etiologic plants are citrus fruits such as limes and lemons, but it also can be caused by celery, figs, parsley, parsnips, and even mustard.^1-3,12 Wild parsley may grow in grass, producing a bizarre pattern on the back in children who lay in the grass and then spend time in the sun. Phytophotodermatitis usually is followed by postinflammatory hyperpigmentation, which may be the principal or only finding in some individuals.⁸

Differential Diagnosis

Phytophotodermatitis may resemble other types of dermatitis, particularly other forms of contact dermatitis such poison ivy, and occasionally other environmental simulants such as jellyfish stings.^1-6,20,21 Photosensitizing disorders including porphyria cutanea tarda, pseudoporphyria, and lupus erythematosus must be distinguished from PPD.^22-24 Photosensitizing medications such tetracyclines, thiazide diuretics, sulfonamides, griseofulvin, and sulfonylureas should be considered. Airborne contact dermatitis may resemble PPD, as when poison ivy is burned and is exposed to the skin in sites of airborne contact.²⁰ Excessive solar exposure is popular, particularly among adolescents, so sunburn and sunburnlike reactions can be noteworthy.^25,26

Treatment

Phytophotodermatitis can be treated with topical steroids, sometimes adding an oral antihistamine, and occasionally oral steroids.^2-4 Localized pain or a burning sensation should respond to therapy. Alternatively, a cold compress applied to the skin can relieve the pain and pruritus, and the burn can be debrided and dressed daily with silver sulfadiazine plus an oral nonsteroidal anti-inflammatory drug. This eruption should be self-limited as long as it is recognized early and the cause avoided. Management of acute exposure includes prompt application of soap and water and avoidance of UV light exposure for 48 to 72 hours to prevent psoralen photoactivation.

Because PPD is essentially a chemical burn, a burn protocol and possible referral to a burn center may be needed, whether the reaction is acute or widespread.^{11,12,14,27,28} Surgical debridement and skin grafting rarely may be mandated.¹⁴ Postinflammatory hyperpigmentation may ensue as the dermatitis resolves but is not common.

The best approach for PPD is prevention (Figure 2). Individuals who are at risk should be aware of their surroundings and potential plants of concern and employ personal protective equipment to shield the skin from plant sap, which should be promptly removed if it comes in contact with the skin.

Phytophotodermatitis (PPD) is a nonallergic contact dermatitis and thus is independent of the immune system, so prior sensitization is not required.^1-3 It sometimes is known by colorful names such as margarita photodermatitis, in which a slice of lime in a refreshing summer drink may be etiologic,^4,5 or berloque dermatitis, caused by exposure to perfumes containing bergapten (5-methoxypsoralen).^6,7 Phytophotodermatitis may develop when phototoxic agents such as furocoumarins, which protect plants from fungal pathogens, and psoralens are applied to the skin followed by exposure to UV light, more specifically in the UVA range of 320 to 400 nm. Thus, these chemicals produce a phototoxic rather than photoallergic reaction, leading to cellular damage. Furocoumarins and psoralens often are found in plants such as celery and figs as well as in citrus fruits such as limes, lemons, and grapefruits. Exposure may be cryptic, as the patient may not consider or mention the eruption as possibly caused by activities such as soaking one’s feet in a folk remedy containing fig leaves.^7,8 Once these phototoxic agents come in contact with the skin, the symptoms of PPD may arise within 24 hours of exposure, beginning as an acute dermatitis with erythema, edema, vesicles, or bullae accompanied by pain and itching.

Etiology

Phytophotodermatitis is caused by exposure to several different types of plants, including Ficus carica (common fig), the genus Citrus (eg, lime, lemon), or Pastina sativa (wild parsnip). Each of these contain furocoumarins and psoralens—phototoxic agents that cause cellular damage with epidermal necrosis and resultant pain when the skin is exposed to UVA light.^1-4 There are 2 types of photochemical reactions in PPD: type I reactions occur in the absence of oxygen, whereas oxygen is present in type II reactions. Both damage cell membranes and DNA, which then results in DNA interstrand cross-linking between the psoralen furan ring and the thymine or cytosine of DNA, activating arachidonic acid metabolic pathways to produce cell death.¹

Epidemiology

The incidence of PPD is unknown due to the high variability of reactions in individuals spanning from children to the elderly. It can be caused by many different wild and domestic plants in many areas of the world and can affect any individual regardless of age, race, gender, or ethnicity. Some individuals may be affected by hyperpigmentation without prominent inflammation.⁸ Diagnosis of PPD can be challenging, and an occupation and recreational history of exposure or recent travel with possible contact with plants may be required.

Occupational Dermatitis

Phytophotodermatitis also may be an occupational disease.^9-12 Occupational exposure may occur in soldiers during military drills and other activities, farm workers, chefs, gardeners, groundskeepers, food processors, bartenders, and florists. Wearing protective gloves when handling plants such as limes, lemons, grapefruit, celery, or parsnips may prevent occupational exposure. Exposure to hogweed, an invasive species originally introduced as an ornamental plant in Europe and the United States, can produce a dramatic acute photodermatitis from exposure to its sap, which contains the psoralens 5-methoxypsoralen and 8-methylpsoralen.^9-11

Recreational Dermatitis

Phytophotodermatitis may be caused by exposure to phototoxic agents during leisure activities. Recreational exposure can occur almost anywhere, including in the kitchen, backyard, park, or woods, as well as at the beach. One notable culprit in recreational PPD is cooking with limes, parsley, or parsnips—plants that often are employed as garnishes in dishes, allowing early exposure of juices on the hands. Individuals who garden recreationally should be aware of ornamental plants such as hogweed and figs, which are notorious for causing PPD.¹³ Children’s camp counselors should have knowledge of PPD, as children have considerable curiosity and may touch or play with attractive plants such as hogweed. Children enjoying sports in parks can accidentally fall onto or be exposed to wild parsnip or hogweed growing nearby and wake up the next day with erythema and burning.¹⁴ Photoprotection is important, but sunscreens containing carrot extract can produce PPD.¹⁵ Widespread PPD over 80% of the body surface area due to sunbathing after applying fig leaf tea as a tanning agent has been described.¹⁶ Eating figs does not cause photosensitization unless the juice is smeared onto the skin. Margarita dermatitis and “Mexican beer dermatitis” can occur due to limes and other citrus fruits being used as ingredients in summer drinks.⁵ Similarly, preparing sangria may produce PPD from lime and lemon juices.¹⁷ In one report, hiking in Corsica resulted in PPD following incidental contact with the endemic plant Peucedanum paniculatum.¹⁸

Perfume (Berloque) Dermatitis

Perfume dermatitis, or berloque dermatitis, is a type of PPD for which the name is derived from the German word berlock or the French word berloque meaning trinket or charm; it was first described in 1925 by Rosenthal⁷ with regard to pendantlike streaks of pigmentation on the neck, face, arms, or trunk. The dermatitis develops due to bergapten, a component of bergamot oil, which is derived from the rind of Citrus bergamia. Many perfumes contain bergamot oil, but the incidence of this condition has been diminished due to use of artificial bergamot oil.⁶

Clinical Manifestation

Phytophotodermatitis is first evident as erythematous patches that appear within 24 hours of initial exposure to a phototoxic agent and UVA light, sometimes with a burning sensation. Solar exposure within 48 hours of sufficient plant exposure is required. Perfuse sweating may enhance the reaction.¹⁹ Rarely, it first may be seen with the sudden appearance of asymptomatic hyperpigmentation. One may see the pattern of splash marks from lime or lemon juice (Figure 1). The acute dermatitis may be associated with adjacent cutaneous edema near the reaction site or along with the erythema and blister formation. Its severity is related to the intensity of sun exposure and amount of furocoumarins.² The most common etiologic plants are citrus fruits such as limes and lemons, but it also can be caused by celery, figs, parsley, parsnips, and even mustard.^1-3,12 Wild parsley may grow in grass, producing a bizarre pattern on the back in children who lay in the grass and then spend time in the sun. Phytophotodermatitis usually is followed by postinflammatory hyperpigmentation, which may be the principal or only finding in some individuals.⁸

Differential Diagnosis

Phytophotodermatitis may resemble other types of dermatitis, particularly other forms of contact dermatitis such poison ivy, and occasionally other environmental simulants such as jellyfish stings.^1-6,20,21 Photosensitizing disorders including porphyria cutanea tarda, pseudoporphyria, and lupus erythematosus must be distinguished from PPD.^22-24 Photosensitizing medications such tetracyclines, thiazide diuretics, sulfonamides, griseofulvin, and sulfonylureas should be considered. Airborne contact dermatitis may resemble PPD, as when poison ivy is burned and is exposed to the skin in sites of airborne contact.²⁰ Excessive solar exposure is popular, particularly among adolescents, so sunburn and sunburnlike reactions can be noteworthy.^25,26

Treatment

Phytophotodermatitis can be treated with topical steroids, sometimes adding an oral antihistamine, and occasionally oral steroids.^2-4 Localized pain or a burning sensation should respond to therapy. Alternatively, a cold compress applied to the skin can relieve the pain and pruritus, and the burn can be debrided and dressed daily with silver sulfadiazine plus an oral nonsteroidal anti-inflammatory drug. This eruption should be self-limited as long as it is recognized early and the cause avoided. Management of acute exposure includes prompt application of soap and water and avoidance of UV light exposure for 48 to 72 hours to prevent psoralen photoactivation.

Because PPD is essentially a chemical burn, a burn protocol and possible referral to a burn center may be needed, whether the reaction is acute or widespread.^{11,12,14,27,28} Surgical debridement and skin grafting rarely may be mandated.¹⁴ Postinflammatory hyperpigmentation may ensue as the dermatitis resolves but is not common.

The best approach for PPD is prevention (Figure 2). Individuals who are at risk should be aware of their surroundings and potential plants of concern and employ personal protective equipment to shield the skin from plant sap, which should be promptly removed if it comes in contact with the skin.

Phytophotodermatitis (PPD) is a nonallergic contact dermatitis and thus is independent of the immune system, so prior sensitization is not required.^1-3 It sometimes is known by colorful names such as margarita photodermatitis, in which a slice of lime in a refreshing summer drink may be etiologic,^4,5 or berloque dermatitis, caused by exposure to perfumes containing bergapten (5-methoxypsoralen).^6,7 Phytophotodermatitis may develop when phototoxic agents such as furocoumarins, which protect plants from fungal pathogens, and psoralens are applied to the skin followed by exposure to UV light, more specifically in the UVA range of 320 to 400 nm. Thus, these chemicals produce a phototoxic rather than photoallergic reaction, leading to cellular damage. Furocoumarins and psoralens often are found in plants such as celery and figs as well as in citrus fruits such as limes, lemons, and grapefruits. Exposure may be cryptic, as the patient may not consider or mention the eruption as possibly caused by activities such as soaking one’s feet in a folk remedy containing fig leaves.^7,8 Once these phototoxic agents come in contact with the skin, the symptoms of PPD may arise within 24 hours of exposure, beginning as an acute dermatitis with erythema, edema, vesicles, or bullae accompanied by pain and itching.

Etiology

Phytophotodermatitis is caused by exposure to several different types of plants, including Ficus carica (common fig), the genus Citrus (eg, lime, lemon), or Pastina sativa (wild parsnip). Each of these contain furocoumarins and psoralens—phototoxic agents that cause cellular damage with epidermal necrosis and resultant pain when the skin is exposed to UVA light.^1-4 There are 2 types of photochemical reactions in PPD: type I reactions occur in the absence of oxygen, whereas oxygen is present in type II reactions. Both damage cell membranes and DNA, which then results in DNA interstrand cross-linking between the psoralen furan ring and the thymine or cytosine of DNA, activating arachidonic acid metabolic pathways to produce cell death.¹

Epidemiology

The incidence of PPD is unknown due to the high variability of reactions in individuals spanning from children to the elderly. It can be caused by many different wild and domestic plants in many areas of the world and can affect any individual regardless of age, race, gender, or ethnicity. Some individuals may be affected by hyperpigmentation without prominent inflammation.⁸ Diagnosis of PPD can be challenging, and an occupation and recreational history of exposure or recent travel with possible contact with plants may be required.

Occupational Dermatitis

Phytophotodermatitis also may be an occupational disease.^9-12 Occupational exposure may occur in soldiers during military drills and other activities, farm workers, chefs, gardeners, groundskeepers, food processors, bartenders, and florists. Wearing protective gloves when handling plants such as limes, lemons, grapefruit, celery, or parsnips may prevent occupational exposure. Exposure to hogweed, an invasive species originally introduced as an ornamental plant in Europe and the United States, can produce a dramatic acute photodermatitis from exposure to its sap, which contains the psoralens 5-methoxypsoralen and 8-methylpsoralen.^9-11

Recreational Dermatitis

Phytophotodermatitis may be caused by exposure to phototoxic agents during leisure activities. Recreational exposure can occur almost anywhere, including in the kitchen, backyard, park, or woods, as well as at the beach. One notable culprit in recreational PPD is cooking with limes, parsley, or parsnips—plants that often are employed as garnishes in dishes, allowing early exposure of juices on the hands. Individuals who garden recreationally should be aware of ornamental plants such as hogweed and figs, which are notorious for causing PPD.¹³ Children’s camp counselors should have knowledge of PPD, as children have considerable curiosity and may touch or play with attractive plants such as hogweed. Children enjoying sports in parks can accidentally fall onto or be exposed to wild parsnip or hogweed growing nearby and wake up the next day with erythema and burning.¹⁴ Photoprotection is important, but sunscreens containing carrot extract can produce PPD.¹⁵ Widespread PPD over 80% of the body surface area due to sunbathing after applying fig leaf tea as a tanning agent has been described.¹⁶ Eating figs does not cause photosensitization unless the juice is smeared onto the skin. Margarita dermatitis and “Mexican beer dermatitis” can occur due to limes and other citrus fruits being used as ingredients in summer drinks.⁵ Similarly, preparing sangria may produce PPD from lime and lemon juices.¹⁷ In one report, hiking in Corsica resulted in PPD following incidental contact with the endemic plant Peucedanum paniculatum.¹⁸

Perfume (Berloque) Dermatitis

Perfume dermatitis, or berloque dermatitis, is a type of PPD for which the name is derived from the German word berlock or the French word berloque meaning trinket or charm; it was first described in 1925 by Rosenthal⁷ with regard to pendantlike streaks of pigmentation on the neck, face, arms, or trunk. The dermatitis develops due to bergapten, a component of bergamot oil, which is derived from the rind of Citrus bergamia. Many perfumes contain bergamot oil, but the incidence of this condition has been diminished due to use of artificial bergamot oil.⁶

Clinical Manifestation

Phytophotodermatitis is first evident as erythematous patches that appear within 24 hours of initial exposure to a phototoxic agent and UVA light, sometimes with a burning sensation. Solar exposure within 48 hours of sufficient plant exposure is required. Perfuse sweating may enhance the reaction.¹⁹ Rarely, it first may be seen with the sudden appearance of asymptomatic hyperpigmentation. One may see the pattern of splash marks from lime or lemon juice (Figure 1). The acute dermatitis may be associated with adjacent cutaneous edema near the reaction site or along with the erythema and blister formation. Its severity is related to the intensity of sun exposure and amount of furocoumarins.² The most common etiologic plants are citrus fruits such as limes and lemons, but it also can be caused by celery, figs, parsley, parsnips, and even mustard.^1-3,12 Wild parsley may grow in grass, producing a bizarre pattern on the back in children who lay in the grass and then spend time in the sun. Phytophotodermatitis usually is followed by postinflammatory hyperpigmentation, which may be the principal or only finding in some individuals.⁸

Differential Diagnosis

Phytophotodermatitis may resemble other types of dermatitis, particularly other forms of contact dermatitis such poison ivy, and occasionally other environmental simulants such as jellyfish stings.^1-6,20,21 Photosensitizing disorders including porphyria cutanea tarda, pseudoporphyria, and lupus erythematosus must be distinguished from PPD.^22-24 Photosensitizing medications such tetracyclines, thiazide diuretics, sulfonamides, griseofulvin, and sulfonylureas should be considered. Airborne contact dermatitis may resemble PPD, as when poison ivy is burned and is exposed to the skin in sites of airborne contact.²⁰ Excessive solar exposure is popular, particularly among adolescents, so sunburn and sunburnlike reactions can be noteworthy.^25,26

Treatment

Phytophotodermatitis can be treated with topical steroids, sometimes adding an oral antihistamine, and occasionally oral steroids.^2-4 Localized pain or a burning sensation should respond to therapy. Alternatively, a cold compress applied to the skin can relieve the pain and pruritus, and the burn can be debrided and dressed daily with silver sulfadiazine plus an oral nonsteroidal anti-inflammatory drug. This eruption should be self-limited as long as it is recognized early and the cause avoided. Management of acute exposure includes prompt application of soap and water and avoidance of UV light exposure for 48 to 72 hours to prevent psoralen photoactivation.

Because PPD is essentially a chemical burn, a burn protocol and possible referral to a burn center may be needed, whether the reaction is acute or widespread.^{11,12,14,27,28} Surgical debridement and skin grafting rarely may be mandated.¹⁴ Postinflammatory hyperpigmentation may ensue as the dermatitis resolves but is not common.

The best approach for PPD is prevention (Figure 2). Individuals who are at risk should be aware of their surroundings and potential plants of concern and employ personal protective equipment to shield the skin from plant sap, which should be promptly removed if it comes in contact with the skin.

Onychomadesis is an acute, noninflammatory, painless, proximal separation of the nail plate from the nail matrix. It occurs due to an abrupt stoppage of nail production by matrix cells, producing temporary cessation of nail growth with or without subsequent complete shedding of nails.^1-10 Onychomadesis has a wide spectrum of clinical presentations ranging from mild transverse ridges of the nail plate (Beau lines) to complete nail shedding.^4,11 Onychomadesis may be related to systemic and dermatologic diseases, drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids), nail trauma, fever, or infection,⁵ and a connection between onychomadesis and hand-foot-and-mouth disease (HFMD) was first described by Clementz et al¹² following outbreaks in Europe, Asia, and the United States.

Epidemiology

Onychomadesis has been observed in children of all ages including neonates. Neonatal onychomadesis is thought to be related to perinatal stressors and birth trauma, with possible exacerbation by superimposed candidiasis.¹⁰ Depending on the underlying cause, there may be involvement of a single nail or multiple nails. Nag et al¹ noted that onychomadesis was most commonly observed in nails of the middle finger (73.7%), followed by the thumb (63.2%) and ring finger (52.6%). Fingernails are more commonly involved than toenails.¹

Clementz et al¹² first proposed the association between onychomadesis and HFMD in 2000. Patients with a history of HFMD were found to be 14 times more likely to develop onychomadesis (relative risk, 14; 95% confidence interval, 4.57-42.86).⁴ A common pathogen for HFMD is coxsackievirus A6 (CVA6),^13,14 but the mechanism of onychomadesis in HFMD remains unclear.^5,7,13 Outbreaks of HFMD have been reported in Spain, Finland, Japan, Thailand, the United States, Singapore, and China.¹⁵ During an outbreak of HFMD in Taiwan, the incidence of onychomadesis following CVA6 infection was 37% (48/130) compared to 5% (7/145) in cases with non-CVA6 causative strains.¹⁶ There also have been observed differences in the prevalence of onychomadesis by age: a 55% (18/33) occurrence rate was noted in the youngest age group (range, 9–23 months), 30% (8/27) in the middle age group (range, 24–32 months), and 4% (1/28) in the oldest age group (range, 33–42 months), with an average of 4 nails shed per case.¹⁷ A study in Spain also found a high occurrence of onychomadesis in a nursery setting, with 92% (11/12) of onychomadesis cases preceded by HFMD 2 months prior.¹⁸

Etiology

Local trauma to the nail bed is the most common cause of single-digit onychomadesis.⁴ Multiple-digit involvement suggests a systemic etiology such as fever, erythroderma, and Kawasaki disease; use of drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids); and viral infections such as HFMD and varicella at the infantile age (Table).^5,9,19 Most drug-related nail changes are the outcome of acute toxicity to the proliferating nail matrix epithelium. If onychomadesis affects all nails at the same level, the patient’s history of medication use and other treatments taken 2 to 3 weeks prior to the appearance of the nail findings should be evaluated. Chemotherapeutic agents produce nail changes in a high proportion of patients, which often are related to drug dosage. These effects also are reproducible with re-administration of the drug.²⁰ Onychomadesis also has been reported as a possible side effect of anticonvulsants such as valproic acid (VPA).²¹ One study evaluating the link between VPA and onychomadesis indicated that nail changes may be due to a disturbance of zinc metabolism.²² However, the pathomechanism of onychomadesis associated with VPA treatment remains unclear.²¹ Onychomadesis also has developed after an allergic drug reaction to oral penicillin V after treatment of a sore throat in a 23-month-old child.²³

Nail involvement has been reported in 10% of cases of inflammatory conditions such as lichen planus²¹; however, it may be more common but underrecognized and underreported. Grover et al⁹ indicated that lichen planus–induced severe inflammation in the matrix of the nail unit leading to a temporary growth arrest was the possible mechanism leading to nail shedding. Prompt systemic and intramatricial steroid treatment of lichen planus is required to avoid potential scarring of the nail matrix and permanent damage.⁹

Onychomadesis also has been reported following varicella infection (chickenpox). Podder et al¹⁹ reported the case of a 7-year-old girl who had recovered from a varicella infection 5 weeks prior and presented with onychomadesis of the right index fingernail with all other fingernails and toenails appearing normal. Kocak and Koçak⁵ reported onychomadesis in 2 sisters with varicella infection. There are few reported cases, so it is still unclear whether varicella infection is an inciting factor.¹⁹

One of the most studied viral infections linked to onychomadesis is HFMD, which is a common viral infection that mostly affects children younger than 10 years.¹ The precise mechanism of onychomadesis for these viral infection events remains unclear.^7,10,13 Several theories have been delineated, including nail matrix arrest from fever occurring during HFMD.⁶ However, this cause is unlikely, as fevers are typically low grade and present only for a few hours.^4,6,13 Direct inflammation spreading from skin lesions of HFMD around the nails or maceration associated with finger blisters could cause onychomadesis.^1,5,7 Haneke²⁴ hypothesized that nail shedding may be the consequence of vesicles localized in the periungual tissue, but studies have shown incidence without prior lesions on the fingers and no relationship between nail matrix arrest and severity of HFMD.^5,6,13 Bettoli et al²⁵ reported that inflammation secondary to viral infection around the nail matrix might be induced directly by viruses or indirectly by virus-specific immunocomplexes and consequent distal embolism. Osterback et al¹⁴ used reverse transcription–polymerase chain reaction to detect CVA6 in fragmented nails from 2 children and 1 parent following an HFMD episode, suggesting that virus replication could damage the nail matrix, resulting in onychomadesis. Cabrerizo et al¹⁸ also suggested that virus replication directly damages the nail matrix based on the presence of CVA6 in shed nails. Because fingernails with onychomadesis are not always of the fingers affected by HFMD, an indirect effect of viral infection on the nail matrix is more plausible.⁸ Additional studies are needed to clarify the virus-associated mechanism of nail matrix arrest.⁶ Finally, frequent washing of hands¹⁵ resulting in maceration, Candida infection, and allergic contact dermatitis² may be possible causes. It is unclear if onychomadesis following HFMD is related to viral replication, inflammation, or intensive hygienic measures, and further investigation is needed.^2,15

Clinical Characteristics

The ventral floor is the site of the germinal matrix and is responsible for 90% of nail production. As a result, more of the nail plate substance is produced proximally, leading to a natural convex curvature from the proximal to distal nail.¹¹ Beau lines are transverse ridging of the nail plates.⁶ Onychomadesis may be viewed as a more severe form of Beau lines, with complete separation and possible shedding of the nail plate (Figure).^3,4 In both cases, an insult to the nail matrix is followed by recovery and production of the nail plate at the nail matrix.⁴ In Beau lines, slowing or disruption of cell growth from the proximal matrix results in a thinner nail plate, leading to transverse depressions. Onychomadesis has a similar pathophysiology but is associated with a complete halt in the nail plate production.³

Diagnosis

The diagnosis of onychomadesis is made clinically.^3,10 Distinct nail changes can be detected by inspection and palpation of the nail plate,^3,11 which allows for differentiation between Beau lines and complete nail shedding. Additionally, any signs of nail trauma need to be noted, as well as pain, swelling, or pruritus, as these symptoms also can guide in determining the etiology of the nail dystrophy. Ultrasonography can confirm the diagnosis, as the defect can be identified beneath the proximal nail fold.^3,26 When it occurs after HFMD or varicella, onychomadesis tends to present in 28 to 40 days following infection.^4,6,10 Physicians should consider underlying associations. A review of viral illnesses within 1 to 2 months prior to development of nail changes often will identify the causative disease.⁴ Each patient should be evaluated for recent nail trauma; medications; viral infection; and autoimmune, systemic, and inflammatory diseases.

Treatment

Onychomadesis typically is mild and self-limited.^4,10 There is no specific treatment,¹⁰ but a conservative approach to management is recommended. Treatment of any underlying medical conditions or discontinuation of an offending medication may help to prevent recurrent onychomadesis.³ Supportive care along with protection of the nail bed by maintaining short nails and using adhesive bandages over the affected nails to avoid snagging the nail or ripping off the partially attached nails is recommended.⁴ In some cases, onychomadesis has been treated with topical application of urea cream 40% under occlusion²⁷ or halcinonide cream 0.1% under occlusion for 5 to 6 days,²⁸ but these treatments have not been universally effective.³ External use of basic fibroblast growth factor to stimulate new regrowth of the nail plate has been advocated.³ It is important to reassure patients that as long as the underlying causes are eliminated and the nail matrix has not been permanently scarred, the nails should grow back within 12 weeks or sooner in children. Thus, typically only reassurance and counseling of parents/guardians is required for onychomadesis in children.^1,2 However, the nails may be dystrophic or fail to regrow if there is poor peripheral circulation or permanent nail matrix damage.

Conclusion

Fortunately, onychomadesis is self-limited. Physicians should look for underlying causes of onychomadesis, including a history of viral infections such as HFMD and varicella as well as systemic diseases and use of medications. As long as any underlying disorder or condition has been resolved, spontaneous regrowth of healthy nails usually but not always occurs within 12 weeks or sooner in children.

Onychomadesis is an acute, noninflammatory, painless, proximal separation of the nail plate from the nail matrix. It occurs due to an abrupt stoppage of nail production by matrix cells, producing temporary cessation of nail growth with or without subsequent complete shedding of nails.^1-10 Onychomadesis has a wide spectrum of clinical presentations ranging from mild transverse ridges of the nail plate (Beau lines) to complete nail shedding.^4,11 Onychomadesis may be related to systemic and dermatologic diseases, drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids), nail trauma, fever, or infection,⁵ and a connection between onychomadesis and hand-foot-and-mouth disease (HFMD) was first described by Clementz et al¹² following outbreaks in Europe, Asia, and the United States.

Epidemiology

Onychomadesis has been observed in children of all ages including neonates. Neonatal onychomadesis is thought to be related to perinatal stressors and birth trauma, with possible exacerbation by superimposed candidiasis.¹⁰ Depending on the underlying cause, there may be involvement of a single nail or multiple nails. Nag et al¹ noted that onychomadesis was most commonly observed in nails of the middle finger (73.7%), followed by the thumb (63.2%) and ring finger (52.6%). Fingernails are more commonly involved than toenails.¹

Clementz et al¹² first proposed the association between onychomadesis and HFMD in 2000. Patients with a history of HFMD were found to be 14 times more likely to develop onychomadesis (relative risk, 14; 95% confidence interval, 4.57-42.86).⁴ A common pathogen for HFMD is coxsackievirus A6 (CVA6),^13,14 but the mechanism of onychomadesis in HFMD remains unclear.^5,7,13 Outbreaks of HFMD have been reported in Spain, Finland, Japan, Thailand, the United States, Singapore, and China.¹⁵ During an outbreak of HFMD in Taiwan, the incidence of onychomadesis following CVA6 infection was 37% (48/130) compared to 5% (7/145) in cases with non-CVA6 causative strains.¹⁶ There also have been observed differences in the prevalence of onychomadesis by age: a 55% (18/33) occurrence rate was noted in the youngest age group (range, 9–23 months), 30% (8/27) in the middle age group (range, 24–32 months), and 4% (1/28) in the oldest age group (range, 33–42 months), with an average of 4 nails shed per case.¹⁷ A study in Spain also found a high occurrence of onychomadesis in a nursery setting, with 92% (11/12) of onychomadesis cases preceded by HFMD 2 months prior.¹⁸

Etiology

Local trauma to the nail bed is the most common cause of single-digit onychomadesis.⁴ Multiple-digit involvement suggests a systemic etiology such as fever, erythroderma, and Kawasaki disease; use of drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids); and viral infections such as HFMD and varicella at the infantile age (Table).^5,9,19 Most drug-related nail changes are the outcome of acute toxicity to the proliferating nail matrix epithelium. If onychomadesis affects all nails at the same level, the patient’s history of medication use and other treatments taken 2 to 3 weeks prior to the appearance of the nail findings should be evaluated. Chemotherapeutic agents produce nail changes in a high proportion of patients, which often are related to drug dosage. These effects also are reproducible with re-administration of the drug.²⁰ Onychomadesis also has been reported as a possible side effect of anticonvulsants such as valproic acid (VPA).²¹ One study evaluating the link between VPA and onychomadesis indicated that nail changes may be due to a disturbance of zinc metabolism.²² However, the pathomechanism of onychomadesis associated with VPA treatment remains unclear.²¹ Onychomadesis also has developed after an allergic drug reaction to oral penicillin V after treatment of a sore throat in a 23-month-old child.²³

Nail involvement has been reported in 10% of cases of inflammatory conditions such as lichen planus²¹; however, it may be more common but underrecognized and underreported. Grover et al⁹ indicated that lichen planus–induced severe inflammation in the matrix of the nail unit leading to a temporary growth arrest was the possible mechanism leading to nail shedding. Prompt systemic and intramatricial steroid treatment of lichen planus is required to avoid potential scarring of the nail matrix and permanent damage.⁹

Onychomadesis also has been reported following varicella infection (chickenpox). Podder et al¹⁹ reported the case of a 7-year-old girl who had recovered from a varicella infection 5 weeks prior and presented with onychomadesis of the right index fingernail with all other fingernails and toenails appearing normal. Kocak and Koçak⁵ reported onychomadesis in 2 sisters with varicella infection. There are few reported cases, so it is still unclear whether varicella infection is an inciting factor.¹⁹

One of the most studied viral infections linked to onychomadesis is HFMD, which is a common viral infection that mostly affects children younger than 10 years.¹ The precise mechanism of onychomadesis for these viral infection events remains unclear.^7,10,13 Several theories have been delineated, including nail matrix arrest from fever occurring during HFMD.⁶ However, this cause is unlikely, as fevers are typically low grade and present only for a few hours.^4,6,13 Direct inflammation spreading from skin lesions of HFMD around the nails or maceration associated with finger blisters could cause onychomadesis.^1,5,7 Haneke²⁴ hypothesized that nail shedding may be the consequence of vesicles localized in the periungual tissue, but studies have shown incidence without prior lesions on the fingers and no relationship between nail matrix arrest and severity of HFMD.^5,6,13 Bettoli et al²⁵ reported that inflammation secondary to viral infection around the nail matrix might be induced directly by viruses or indirectly by virus-specific immunocomplexes and consequent distal embolism. Osterback et al¹⁴ used reverse transcription–polymerase chain reaction to detect CVA6 in fragmented nails from 2 children and 1 parent following an HFMD episode, suggesting that virus replication could damage the nail matrix, resulting in onychomadesis. Cabrerizo et al¹⁸ also suggested that virus replication directly damages the nail matrix based on the presence of CVA6 in shed nails. Because fingernails with onychomadesis are not always of the fingers affected by HFMD, an indirect effect of viral infection on the nail matrix is more plausible.⁸ Additional studies are needed to clarify the virus-associated mechanism of nail matrix arrest.⁶ Finally, frequent washing of hands¹⁵ resulting in maceration, Candida infection, and allergic contact dermatitis² may be possible causes. It is unclear if onychomadesis following HFMD is related to viral replication, inflammation, or intensive hygienic measures, and further investigation is needed.^2,15

Clinical Characteristics

The ventral floor is the site of the germinal matrix and is responsible for 90% of nail production. As a result, more of the nail plate substance is produced proximally, leading to a natural convex curvature from the proximal to distal nail.¹¹ Beau lines are transverse ridging of the nail plates.⁶ Onychomadesis may be viewed as a more severe form of Beau lines, with complete separation and possible shedding of the nail plate (Figure).^3,4 In both cases, an insult to the nail matrix is followed by recovery and production of the nail plate at the nail matrix.⁴ In Beau lines, slowing or disruption of cell growth from the proximal matrix results in a thinner nail plate, leading to transverse depressions. Onychomadesis has a similar pathophysiology but is associated with a complete halt in the nail plate production.³

Diagnosis

The diagnosis of onychomadesis is made clinically.^3,10 Distinct nail changes can be detected by inspection and palpation of the nail plate,^3,11 which allows for differentiation between Beau lines and complete nail shedding. Additionally, any signs of nail trauma need to be noted, as well as pain, swelling, or pruritus, as these symptoms also can guide in determining the etiology of the nail dystrophy. Ultrasonography can confirm the diagnosis, as the defect can be identified beneath the proximal nail fold.^3,26 When it occurs after HFMD or varicella, onychomadesis tends to present in 28 to 40 days following infection.^4,6,10 Physicians should consider underlying associations. A review of viral illnesses within 1 to 2 months prior to development of nail changes often will identify the causative disease.⁴ Each patient should be evaluated for recent nail trauma; medications; viral infection; and autoimmune, systemic, and inflammatory diseases.

Treatment

Onychomadesis typically is mild and self-limited.^4,10 There is no specific treatment,¹⁰ but a conservative approach to management is recommended. Treatment of any underlying medical conditions or discontinuation of an offending medication may help to prevent recurrent onychomadesis.³ Supportive care along with protection of the nail bed by maintaining short nails and using adhesive bandages over the affected nails to avoid snagging the nail or ripping off the partially attached nails is recommended.⁴ In some cases, onychomadesis has been treated with topical application of urea cream 40% under occlusion²⁷ or halcinonide cream 0.1% under occlusion for 5 to 6 days,²⁸ but these treatments have not been universally effective.³ External use of basic fibroblast growth factor to stimulate new regrowth of the nail plate has been advocated.³ It is important to reassure patients that as long as the underlying causes are eliminated and the nail matrix has not been permanently scarred, the nails should grow back within 12 weeks or sooner in children. Thus, typically only reassurance and counseling of parents/guardians is required for onychomadesis in children.^1,2 However, the nails may be dystrophic or fail to regrow if there is poor peripheral circulation or permanent nail matrix damage.

Conclusion

Fortunately, onychomadesis is self-limited. Physicians should look for underlying causes of onychomadesis, including a history of viral infections such as HFMD and varicella as well as systemic diseases and use of medications. As long as any underlying disorder or condition has been resolved, spontaneous regrowth of healthy nails usually but not always occurs within 12 weeks or sooner in children.

Onychomadesis is an acute, noninflammatory, painless, proximal separation of the nail plate from the nail matrix. It occurs due to an abrupt stoppage of nail production by matrix cells, producing temporary cessation of nail growth with or without subsequent complete shedding of nails.^1-10 Onychomadesis has a wide spectrum of clinical presentations ranging from mild transverse ridges of the nail plate (Beau lines) to complete nail shedding.^4,11 Onychomadesis may be related to systemic and dermatologic diseases, drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids), nail trauma, fever, or infection,⁵ and a connection between onychomadesis and hand-foot-and-mouth disease (HFMD) was first described by Clementz et al¹² following outbreaks in Europe, Asia, and the United States.

Epidemiology

Onychomadesis has been observed in children of all ages including neonates. Neonatal onychomadesis is thought to be related to perinatal stressors and birth trauma, with possible exacerbation by superimposed candidiasis.¹⁰ Depending on the underlying cause, there may be involvement of a single nail or multiple nails. Nag et al¹ noted that onychomadesis was most commonly observed in nails of the middle finger (73.7%), followed by the thumb (63.2%) and ring finger (52.6%). Fingernails are more commonly involved than toenails.¹

Clementz et al¹² first proposed the association between onychomadesis and HFMD in 2000. Patients with a history of HFMD were found to be 14 times more likely to develop onychomadesis (relative risk, 14; 95% confidence interval, 4.57-42.86).⁴ A common pathogen for HFMD is coxsackievirus A6 (CVA6),^13,14 but the mechanism of onychomadesis in HFMD remains unclear.^5,7,13 Outbreaks of HFMD have been reported in Spain, Finland, Japan, Thailand, the United States, Singapore, and China.¹⁵ During an outbreak of HFMD in Taiwan, the incidence of onychomadesis following CVA6 infection was 37% (48/130) compared to 5% (7/145) in cases with non-CVA6 causative strains.¹⁶ There also have been observed differences in the prevalence of onychomadesis by age: a 55% (18/33) occurrence rate was noted in the youngest age group (range, 9–23 months), 30% (8/27) in the middle age group (range, 24–32 months), and 4% (1/28) in the oldest age group (range, 33–42 months), with an average of 4 nails shed per case.¹⁷ A study in Spain also found a high occurrence of onychomadesis in a nursery setting, with 92% (11/12) of onychomadesis cases preceded by HFMD 2 months prior.¹⁸

Etiology

Local trauma to the nail bed is the most common cause of single-digit onychomadesis.⁴ Multiple-digit involvement suggests a systemic etiology such as fever, erythroderma, and Kawasaki disease; use of drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids); and viral infections such as HFMD and varicella at the infantile age (Table).^5,9,19 Most drug-related nail changes are the outcome of acute toxicity to the proliferating nail matrix epithelium. If onychomadesis affects all nails at the same level, the patient’s history of medication use and other treatments taken 2 to 3 weeks prior to the appearance of the nail findings should be evaluated. Chemotherapeutic agents produce nail changes in a high proportion of patients, which often are related to drug dosage. These effects also are reproducible with re-administration of the drug.²⁰ Onychomadesis also has been reported as a possible side effect of anticonvulsants such as valproic acid (VPA).²¹ One study evaluating the link between VPA and onychomadesis indicated that nail changes may be due to a disturbance of zinc metabolism.²² However, the pathomechanism of onychomadesis associated with VPA treatment remains unclear.²¹ Onychomadesis also has developed after an allergic drug reaction to oral penicillin V after treatment of a sore throat in a 23-month-old child.²³

Nail involvement has been reported in 10% of cases of inflammatory conditions such as lichen planus²¹; however, it may be more common but underrecognized and underreported. Grover et al⁹ indicated that lichen planus–induced severe inflammation in the matrix of the nail unit leading to a temporary growth arrest was the possible mechanism leading to nail shedding. Prompt systemic and intramatricial steroid treatment of lichen planus is required to avoid potential scarring of the nail matrix and permanent damage.⁹

Onychomadesis also has been reported following varicella infection (chickenpox). Podder et al¹⁹ reported the case of a 7-year-old girl who had recovered from a varicella infection 5 weeks prior and presented with onychomadesis of the right index fingernail with all other fingernails and toenails appearing normal. Kocak and Koçak⁵ reported onychomadesis in 2 sisters with varicella infection. There are few reported cases, so it is still unclear whether varicella infection is an inciting factor.¹⁹

One of the most studied viral infections linked to onychomadesis is HFMD, which is a common viral infection that mostly affects children younger than 10 years.¹ The precise mechanism of onychomadesis for these viral infection events remains unclear.^7,10,13 Several theories have been delineated, including nail matrix arrest from fever occurring during HFMD.⁶ However, this cause is unlikely, as fevers are typically low grade and present only for a few hours.^4,6,13 Direct inflammation spreading from skin lesions of HFMD around the nails or maceration associated with finger blisters could cause onychomadesis.^1,5,7 Haneke²⁴ hypothesized that nail shedding may be the consequence of vesicles localized in the periungual tissue, but studies have shown incidence without prior lesions on the fingers and no relationship between nail matrix arrest and severity of HFMD.^5,6,13 Bettoli et al²⁵ reported that inflammation secondary to viral infection around the nail matrix might be induced directly by viruses or indirectly by virus-specific immunocomplexes and consequent distal embolism. Osterback et al¹⁴ used reverse transcription–polymerase chain reaction to detect CVA6 in fragmented nails from 2 children and 1 parent following an HFMD episode, suggesting that virus replication could damage the nail matrix, resulting in onychomadesis. Cabrerizo et al¹⁸ also suggested that virus replication directly damages the nail matrix based on the presence of CVA6 in shed nails. Because fingernails with onychomadesis are not always of the fingers affected by HFMD, an indirect effect of viral infection on the nail matrix is more plausible.⁸ Additional studies are needed to clarify the virus-associated mechanism of nail matrix arrest.⁶ Finally, frequent washing of hands¹⁵ resulting in maceration, Candida infection, and allergic contact dermatitis² may be possible causes. It is unclear if onychomadesis following HFMD is related to viral replication, inflammation, or intensive hygienic measures, and further investigation is needed.^2,15

Clinical Characteristics

The ventral floor is the site of the germinal matrix and is responsible for 90% of nail production. As a result, more of the nail plate substance is produced proximally, leading to a natural convex curvature from the proximal to distal nail.¹¹ Beau lines are transverse ridging of the nail plates.⁶ Onychomadesis may be viewed as a more severe form of Beau lines, with complete separation and possible shedding of the nail plate (Figure).^3,4 In both cases, an insult to the nail matrix is followed by recovery and production of the nail plate at the nail matrix.⁴ In Beau lines, slowing or disruption of cell growth from the proximal matrix results in a thinner nail plate, leading to transverse depressions. Onychomadesis has a similar pathophysiology but is associated with a complete halt in the nail plate production.³

Diagnosis

The diagnosis of onychomadesis is made clinically.^3,10 Distinct nail changes can be detected by inspection and palpation of the nail plate,^3,11 which allows for differentiation between Beau lines and complete nail shedding. Additionally, any signs of nail trauma need to be noted, as well as pain, swelling, or pruritus, as these symptoms also can guide in determining the etiology of the nail dystrophy. Ultrasonography can confirm the diagnosis, as the defect can be identified beneath the proximal nail fold.^3,26 When it occurs after HFMD or varicella, onychomadesis tends to present in 28 to 40 days following infection.^4,6,10 Physicians should consider underlying associations. A review of viral illnesses within 1 to 2 months prior to development of nail changes often will identify the causative disease.⁴ Each patient should be evaluated for recent nail trauma; medications; viral infection; and autoimmune, systemic, and inflammatory diseases.

Treatment

Onychomadesis typically is mild and self-limited.^4,10 There is no specific treatment,¹⁰ but a conservative approach to management is recommended. Treatment of any underlying medical conditions or discontinuation of an offending medication may help to prevent recurrent onychomadesis.³ Supportive care along with protection of the nail bed by maintaining short nails and using adhesive bandages over the affected nails to avoid snagging the nail or ripping off the partially attached nails is recommended.⁴ In some cases, onychomadesis has been treated with topical application of urea cream 40% under occlusion²⁷ or halcinonide cream 0.1% under occlusion for 5 to 6 days,²⁸ but these treatments have not been universally effective.³ External use of basic fibroblast growth factor to stimulate new regrowth of the nail plate has been advocated.³ It is important to reassure patients that as long as the underlying causes are eliminated and the nail matrix has not been permanently scarred, the nails should grow back within 12 weeks or sooner in children. Thus, typically only reassurance and counseling of parents/guardians is required for onychomadesis in children.^1,2 However, the nails may be dystrophic or fail to regrow if there is poor peripheral circulation or permanent nail matrix damage.

Conclusion

Fortunately, onychomadesis is self-limited. Physicians should look for underlying causes of onychomadesis, including a history of viral infections such as HFMD and varicella as well as systemic diseases and use of medications. As long as any underlying disorder or condition has been resolved, spontaneous regrowth of healthy nails usually but not always occurs within 12 weeks or sooner in children.

Acne vulgaris typically is associated with adolescence and young adulthood; however, it also can affect neonates, infants, and small children.¹ Acne neonatorum occurs in up to 20% of newborns. The clinical importance of neonatal acne lies in its differentiation from infectious diseases, the exclusion of virilization as its underlying cause, and the possible implication of severe acne in adolescence.² Neonatal acne also must be distinguished from acne that is induced by application of topical oils and ointments (acne venenata) and from acneform eruptions induced by acnegenic maternal medications such as hydantoin (fetal hydantoin syndrome) and lithium.³

Neonatal Acne (Acne Neonatorum)

Clinical Presentation

Neonatal acne (acne neonatorum) typically presents as small closed comedones on the forehead, nose, and cheeks (Figure 1).⁴ Accompanying sebaceous hyperplasia often is noted.⁵ Less frequently, open comedones, inflammatory papules, and pustules may develop.⁶ Neonatal acne may be evident at birth or appear during the first 4 weeks of life⁷ and is more commonly seen in boys.⁸

Etiology

Several factors may be pivotal in the etiology of neonatal acne, including increased sebum excretion, stimulation of the sebaceous glands by maternal or neonatal androgens,⁴ and colonization of sebaceous glands by Malassezia species.² Increased sebum excretion occurs during the neonatal period due to enlarged sebaceous glands,² which may result from the substantial production of β-hydroxysteroids from the relatively large adrenal glands.^9,10 After 6 months of age, the size of the sebaceous glands and the sebum excretion rate decrease.^9,10

Both maternal and neonatal androgens have been implicated in the stimulation of sebaceous glands in neonatal acne.² The neonatal adrenal gland produces high levels of dehydroepiandrosterone,² which stimulate sebaceous glands until around 1 year of age when dehydroepiandrosterone levels drop off as a consequence of involution of the neonatal adrenal gland.¹¹ Testicular androgens provide additional stimulation to the sebaceous glands, which may explain why neonatal acne is more common in boys.¹ Neonatal acne may be an inflammatory response to Malassezia species; however, Malassezia was not isolated in a series of patients,¹²  suggesting that neonatal acne is an early presentation of comedonal acne and not a response to Malassezia.^2,12

Differential Diagnosis

There are a number of acneform eruptions that should be considered in the differential diagnosis,³ including bacterial folliculitis, secondary syphilis,¹³ herpes simplex virus and varicella zoster virus,¹⁴ and skin colonization by fungi of Malassezia species.¹⁵ Other neonatal eruptions such as erythema toxicum neonatorum,¹⁶ transient neonatal pustular melanosis, and milia and pustular miliaria, as well as a drug eruption associated with hydantoin, lithium, or halogens should be considered.¹⁷ The relationship between neonatal acne and neonatal cephalic pustulosis, which is characterized by papules and pustules without comedones, is controversial; some consider them to be 2 different entities,¹⁴ while others do not.¹⁸

Treatment

Guardians should be reassured that neonatal acne is mild, self-limited, and generally resolves spontaneously without scarring in approximately 1 to 3 months.^1,2 In most cases, no treatment is needed.¹⁹ If necessary, comedones may be treated with azelaic acid cream 20% or tretinoin cream 0.025% to 0.05%.^1,2 For inflammatory lesions, erythromycin solution 2% and benzoyl peroxide gel 2.5% may be used.^1,20 Severe or recalcitrant disease warrants a workup for congenital adrenal hyperplasia, a virilizing tumor, or underlying endocrinopathy.¹⁹

Infantile Acne Vulgaris

Clinical Presentation

Infantile acne vulgaris shares similarities with neonatal acne^21,22 in that they both affect the face, predominantly the cheeks, and have a male predominance (Figure 2).^1,10 However, by definition, onset of infantile acne typically occurs later than acne neonatorum, usually at 3 to 6 months of age.^1,4 Lesions are more pleomorphic and inflammatory than in neonatal acne. In addition to closed and open comedones, infantile acne may be first evident with papules, pustules, severe nodules, and cysts with scarring potential (Figure 3).^1,2,5 Accordingly, treatment may be required. Most cases of infantile acne resolve by 4 or 5 years of age, but some remain active into puberty.¹ Patients with a history of infantile acne have an increased incidence of acne vulgaris during adolescence compared to their peers, with greater severity and enhanced risk for scarring.^4,23

Etiology

The etiology of infantile acne remains unclear.² Similar to neonatal acne, infantile acne may be a result of elevated androgens produced by the fetal adrenal glands as well as by the testes in males.¹¹ For example, a child with infantile acne had elevated luteinizing hormone, follicle-stimulating hormone, and testosterone levels.²⁴ Therefore, hyperandrogenism should be considered as an etiology. Other causes also have been suggested. Rarely, an adrenocortical tumor may be associated with persistent infantile acne with signs of virilization and rapid development.²⁵Malassezia was implicated in infantile acne in a 6-month-old infant who was successfully treated with ketoconazole cream 2%.²⁶

Differential Diagnosis

Infantile acne often is misdiagnosed because it is rarely considered in the differential diagnosis. When closed comedones predominate, acne venenata induced by topical creams, lotions, or oils may be etiologic. Chloracne also should be considered.¹⁴

Treatment

Guardians should be educated about the likely chronicity of infantile acne, which may require long-term treatment, as well as the possibility that acne may recur in severe form during puberty.¹ The treatment strategy for infantile acne is similar to treatment of acne at any age, with topical agents including retinoids (eg, tretinoin, benzoyl peroxide) and topical antibacterials (eg, erythromycin). Twice-daily erythromycin 125 to 250 mg is the treatment of choice when oral antibiotics are indicated. Tetracyclines are contraindicated in treatment of neonatal and infantile acne. Intralesional injections with low-concentration triamcinolone acetonide, cryotherapy, or topical corticosteroids for a short period of time can be used to treat deep nodules and cysts.² Acne that is refractory to treatment with oral antibiotics alone or combined with topical treatments poses a dilemma, given the potential cosmetic sequelae of scarring and quality-of-life concerns. Because reducing or eliminating dairy intake appears beneficial for adolescents with moderate to severe acne,²⁷ this approach may represent a good option for infantile acne.

Conclusion

Neonatal and infantile acne vulgaris may be overlooked or misdiagnosed. It is important to consider and treat. Early childhood acne may represent a virilization syndrome.

Acne vulgaris typically is associated with adolescence and young adulthood; however, it also can affect neonates, infants, and small children.¹ Acne neonatorum occurs in up to 20% of newborns. The clinical importance of neonatal acne lies in its differentiation from infectious diseases, the exclusion of virilization as its underlying cause, and the possible implication of severe acne in adolescence.² Neonatal acne also must be distinguished from acne that is induced by application of topical oils and ointments (acne venenata) and from acneform eruptions induced by acnegenic maternal medications such as hydantoin (fetal hydantoin syndrome) and lithium.³

Neonatal Acne (Acne Neonatorum)

Clinical Presentation

Neonatal acne (acne neonatorum) typically presents as small closed comedones on the forehead, nose, and cheeks (Figure 1).⁴ Accompanying sebaceous hyperplasia often is noted.⁵ Less frequently, open comedones, inflammatory papules, and pustules may develop.⁶ Neonatal acne may be evident at birth or appear during the first 4 weeks of life⁷ and is more commonly seen in boys.⁸

Etiology

Several factors may be pivotal in the etiology of neonatal acne, including increased sebum excretion, stimulation of the sebaceous glands by maternal or neonatal androgens,⁴ and colonization of sebaceous glands by Malassezia species.² Increased sebum excretion occurs during the neonatal period due to enlarged sebaceous glands,² which may result from the substantial production of β-hydroxysteroids from the relatively large adrenal glands.^9,10 After 6 months of age, the size of the sebaceous glands and the sebum excretion rate decrease.^9,10

Both maternal and neonatal androgens have been implicated in the stimulation of sebaceous glands in neonatal acne.² The neonatal adrenal gland produces high levels of dehydroepiandrosterone,² which stimulate sebaceous glands until around 1 year of age when dehydroepiandrosterone levels drop off as a consequence of involution of the neonatal adrenal gland.¹¹ Testicular androgens provide additional stimulation to the sebaceous glands, which may explain why neonatal acne is more common in boys.¹ Neonatal acne may be an inflammatory response to Malassezia species; however, Malassezia was not isolated in a series of patients,¹²  suggesting that neonatal acne is an early presentation of comedonal acne and not a response to Malassezia.^2,12

Differential Diagnosis

There are a number of acneform eruptions that should be considered in the differential diagnosis,³ including bacterial folliculitis, secondary syphilis,¹³ herpes simplex virus and varicella zoster virus,¹⁴ and skin colonization by fungi of Malassezia species.¹⁵ Other neonatal eruptions such as erythema toxicum neonatorum,¹⁶ transient neonatal pustular melanosis, and milia and pustular miliaria, as well as a drug eruption associated with hydantoin, lithium, or halogens should be considered.¹⁷ The relationship between neonatal acne and neonatal cephalic pustulosis, which is characterized by papules and pustules without comedones, is controversial; some consider them to be 2 different entities,¹⁴ while others do not.¹⁸

Treatment

Guardians should be reassured that neonatal acne is mild, self-limited, and generally resolves spontaneously without scarring in approximately 1 to 3 months.^1,2 In most cases, no treatment is needed.¹⁹ If necessary, comedones may be treated with azelaic acid cream 20% or tretinoin cream 0.025% to 0.05%.^1,2 For inflammatory lesions, erythromycin solution 2% and benzoyl peroxide gel 2.5% may be used.^1,20 Severe or recalcitrant disease warrants a workup for congenital adrenal hyperplasia, a virilizing tumor, or underlying endocrinopathy.¹⁹

Infantile Acne Vulgaris

Clinical Presentation

Infantile acne vulgaris shares similarities with neonatal acne^21,22 in that they both affect the face, predominantly the cheeks, and have a male predominance (Figure 2).^1,10 However, by definition, onset of infantile acne typically occurs later than acne neonatorum, usually at 3 to 6 months of age.^1,4 Lesions are more pleomorphic and inflammatory than in neonatal acne. In addition to closed and open comedones, infantile acne may be first evident with papules, pustules, severe nodules, and cysts with scarring potential (Figure 3).^1,2,5 Accordingly, treatment may be required. Most cases of infantile acne resolve by 4 or 5 years of age, but some remain active into puberty.¹ Patients with a history of infantile acne have an increased incidence of acne vulgaris during adolescence compared to their peers, with greater severity and enhanced risk for scarring.^4,23

Etiology

The etiology of infantile acne remains unclear.² Similar to neonatal acne, infantile acne may be a result of elevated androgens produced by the fetal adrenal glands as well as by the testes in males.¹¹ For example, a child with infantile acne had elevated luteinizing hormone, follicle-stimulating hormone, and testosterone levels.²⁴ Therefore, hyperandrogenism should be considered as an etiology. Other causes also have been suggested. Rarely, an adrenocortical tumor may be associated with persistent infantile acne with signs of virilization and rapid development.²⁵Malassezia was implicated in infantile acne in a 6-month-old infant who was successfully treated with ketoconazole cream 2%.²⁶

Differential Diagnosis

Infantile acne often is misdiagnosed because it is rarely considered in the differential diagnosis. When closed comedones predominate, acne venenata induced by topical creams, lotions, or oils may be etiologic. Chloracne also should be considered.¹⁴

Treatment

Guardians should be educated about the likely chronicity of infantile acne, which may require long-term treatment, as well as the possibility that acne may recur in severe form during puberty.¹ The treatment strategy for infantile acne is similar to treatment of acne at any age, with topical agents including retinoids (eg, tretinoin, benzoyl peroxide) and topical antibacterials (eg, erythromycin). Twice-daily erythromycin 125 to 250 mg is the treatment of choice when oral antibiotics are indicated. Tetracyclines are contraindicated in treatment of neonatal and infantile acne. Intralesional injections with low-concentration triamcinolone acetonide, cryotherapy, or topical corticosteroids for a short period of time can be used to treat deep nodules and cysts.² Acne that is refractory to treatment with oral antibiotics alone or combined with topical treatments poses a dilemma, given the potential cosmetic sequelae of scarring and quality-of-life concerns. Because reducing or eliminating dairy intake appears beneficial for adolescents with moderate to severe acne,²⁷ this approach may represent a good option for infantile acne.

Conclusion

Neonatal and infantile acne vulgaris may be overlooked or misdiagnosed. It is important to consider and treat. Early childhood acne may represent a virilization syndrome.

Acne vulgaris typically is associated with adolescence and young adulthood; however, it also can affect neonates, infants, and small children.¹ Acne neonatorum occurs in up to 20% of newborns. The clinical importance of neonatal acne lies in its differentiation from infectious diseases, the exclusion of virilization as its underlying cause, and the possible implication of severe acne in adolescence.² Neonatal acne also must be distinguished from acne that is induced by application of topical oils and ointments (acne venenata) and from acneform eruptions induced by acnegenic maternal medications such as hydantoin (fetal hydantoin syndrome) and lithium.³

Neonatal Acne (Acne Neonatorum)

Clinical Presentation

Neonatal acne (acne neonatorum) typically presents as small closed comedones on the forehead, nose, and cheeks (Figure 1).⁴ Accompanying sebaceous hyperplasia often is noted.⁵ Less frequently, open comedones, inflammatory papules, and pustules may develop.⁶ Neonatal acne may be evident at birth or appear during the first 4 weeks of life⁷ and is more commonly seen in boys.⁸

Etiology

Several factors may be pivotal in the etiology of neonatal acne, including increased sebum excretion, stimulation of the sebaceous glands by maternal or neonatal androgens,⁴ and colonization of sebaceous glands by Malassezia species.² Increased sebum excretion occurs during the neonatal period due to enlarged sebaceous glands,² which may result from the substantial production of β-hydroxysteroids from the relatively large adrenal glands.^9,10 After 6 months of age, the size of the sebaceous glands and the sebum excretion rate decrease.^9,10

Both maternal and neonatal androgens have been implicated in the stimulation of sebaceous glands in neonatal acne.² The neonatal adrenal gland produces high levels of dehydroepiandrosterone,² which stimulate sebaceous glands until around 1 year of age when dehydroepiandrosterone levels drop off as a consequence of involution of the neonatal adrenal gland.¹¹ Testicular androgens provide additional stimulation to the sebaceous glands, which may explain why neonatal acne is more common in boys.¹ Neonatal acne may be an inflammatory response to Malassezia species; however, Malassezia was not isolated in a series of patients,¹²  suggesting that neonatal acne is an early presentation of comedonal acne and not a response to Malassezia.^2,12

Differential Diagnosis

There are a number of acneform eruptions that should be considered in the differential diagnosis,³ including bacterial folliculitis, secondary syphilis,¹³ herpes simplex virus and varicella zoster virus,¹⁴ and skin colonization by fungi of Malassezia species.¹⁵ Other neonatal eruptions such as erythema toxicum neonatorum,¹⁶ transient neonatal pustular melanosis, and milia and pustular miliaria, as well as a drug eruption associated with hydantoin, lithium, or halogens should be considered.¹⁷ The relationship between neonatal acne and neonatal cephalic pustulosis, which is characterized by papules and pustules without comedones, is controversial; some consider them to be 2 different entities,¹⁴ while others do not.¹⁸

Treatment

Guardians should be reassured that neonatal acne is mild, self-limited, and generally resolves spontaneously without scarring in approximately 1 to 3 months.^1,2 In most cases, no treatment is needed.¹⁹ If necessary, comedones may be treated with azelaic acid cream 20% or tretinoin cream 0.025% to 0.05%.^1,2 For inflammatory lesions, erythromycin solution 2% and benzoyl peroxide gel 2.5% may be used.^1,20 Severe or recalcitrant disease warrants a workup for congenital adrenal hyperplasia, a virilizing tumor, or underlying endocrinopathy.¹⁹

Infantile Acne Vulgaris

Clinical Presentation

Infantile acne vulgaris shares similarities with neonatal acne^21,22 in that they both affect the face, predominantly the cheeks, and have a male predominance (Figure 2).^1,10 However, by definition, onset of infantile acne typically occurs later than acne neonatorum, usually at 3 to 6 months of age.^1,4 Lesions are more pleomorphic and inflammatory than in neonatal acne. In addition to closed and open comedones, infantile acne may be first evident with papules, pustules, severe nodules, and cysts with scarring potential (Figure 3).^1,2,5 Accordingly, treatment may be required. Most cases of infantile acne resolve by 4 or 5 years of age, but some remain active into puberty.¹ Patients with a history of infantile acne have an increased incidence of acne vulgaris during adolescence compared to their peers, with greater severity and enhanced risk for scarring.^4,23

Etiology

The etiology of infantile acne remains unclear.² Similar to neonatal acne, infantile acne may be a result of elevated androgens produced by the fetal adrenal glands as well as by the testes in males.¹¹ For example, a child with infantile acne had elevated luteinizing hormone, follicle-stimulating hormone, and testosterone levels.²⁴ Therefore, hyperandrogenism should be considered as an etiology. Other causes also have been suggested. Rarely, an adrenocortical tumor may be associated with persistent infantile acne with signs of virilization and rapid development.²⁵Malassezia was implicated in infantile acne in a 6-month-old infant who was successfully treated with ketoconazole cream 2%.²⁶

Differential Diagnosis

Infantile acne often is misdiagnosed because it is rarely considered in the differential diagnosis. When closed comedones predominate, acne venenata induced by topical creams, lotions, or oils may be etiologic. Chloracne also should be considered.¹⁴

Treatment

Guardians should be educated about the likely chronicity of infantile acne, which may require long-term treatment, as well as the possibility that acne may recur in severe form during puberty.¹ The treatment strategy for infantile acne is similar to treatment of acne at any age, with topical agents including retinoids (eg, tretinoin, benzoyl peroxide) and topical antibacterials (eg, erythromycin). Twice-daily erythromycin 125 to 250 mg is the treatment of choice when oral antibiotics are indicated. Tetracyclines are contraindicated in treatment of neonatal and infantile acne. Intralesional injections with low-concentration triamcinolone acetonide, cryotherapy, or topical corticosteroids for a short period of time can be used to treat deep nodules and cysts.² Acne that is refractory to treatment with oral antibiotics alone or combined with topical treatments poses a dilemma, given the potential cosmetic sequelae of scarring and quality-of-life concerns. Because reducing or eliminating dairy intake appears beneficial for adolescents with moderate to severe acne,²⁷ this approach may represent a good option for infantile acne.

Conclusion

Neonatal and infantile acne vulgaris may be overlooked or misdiagnosed. It is important to consider and treat. Early childhood acne may represent a virilization syndrome.