A wise medical precept is attributed to Theodore Woodward, MD (1914-2005): “When you hear hoofbeats, think of horses, not zebras.” Primary care pediatricians, however, often find themselves confronting so-called rare or uncommon diseases (“zebras”) in their offices. The pressing challenge is to know when to suspect them. How can one reconcile the need to dispel uncertainty with the use of diagnostic tests that can be costly and invasive? When can the desire to reassure parents mean delaying the detection of a potentially treatable condition?
“It may seem like wordplay, but it’s not uncommon to have a rare disease,” noted Alejandro Fainboim, MD, a specialist in rare diseases and head of the Multivalent Day Hospital at the Ricardo Gutiérrez Children’s Hospital in Buenos Aires, Argentina. “And pediatricians are the first line of defense in detecting these types of pathologies. To make the diagnosis, we have to consider them. And to consider them, we must be knowledgeable. That’s why sometimes, ignorance slows down the diagnosis,” Dr. Fainboim made his remarks during an online seminar organized for the press on the eve of Rare Disease Day, which is commemorated on February 29th.
There are more than 8000 rare diseases, which generally are defined as those affecting fewer than five people per 10,000. But collectively, one in every 13 people has one of these diseases, and one in every two diagnosed patients is a child. Dr. Fainboim emphasized that most of these rare diseases are severe or very severe, hereditary, degenerative, and potentially fatal. And although they are pediatric pathologies, some manifest later in adulthood.
“The major problem we pediatricians face is that we’re handed a model from adults to solve pediatric diseases. So, signs and symptoms are described that we won’t find early on, but we have to anticipate and learn to decode some that are hidden,” he remarked.
Diagnostic delays and repeated consultations with various doctors before identification are common. Dr. Fainboim added that in industrialized countries, the diagnosis of these diseases takes between 5 and 10 years, and in low-income countries, up to 30 years or more. However, “this has improved significantly in recent years,” he said.
Unnoticed Signs
Specialists who treat patients with rare diseases often feel that there were obvious signs that went unnoticed and should have aroused the suspicion of the primary care physician. An example is paroxysmal nocturnal hemoglobinuria, which affects 13-14 people per million inhabitants and can appear at any age, although the incidence is higher in the third decade of life.
“In my 50 years as a doctor, I’ve seen seven or eight patients with paroxysmal nocturnal hemoglobinuria,” said Elsa Nucifora, MD, a hematologist at the Italian Hospital of Buenos Aires, Argentina. But “the diagnosis is so easy” that doctors could make it if they “were to think instead of acting automatically because they’re in a hurry,” she added. The diagnosis should be considered “every time anemia occurs in a young person, with certain characteristics, instead of giving them iron like everyone else and ‘we’ll see later’…the diagnosis is in two or three steps, so it’s not complicated.”
Similar situations occur with more than 1000 neuromuscular diseases involving mutations in more than 600 genes, including spinal muscular atrophy and muscular dystrophies.
“What are the most common manifestations? The hypotonic infant, the child who walks late, who falls frequently, who can’t climb stairs, who later may have difficulty breathing, who loses strength: These are presentations often unrecognized by doctors not in the specialty,” said Alberto Dubrovsky, MD, director of the Department of Neurology and the Neuromuscular Diseases Unit at the Favaloro University Neuroscience Institute in Buenos Aires, Argentina, during the seminar. “And considering that these diseases are diagnosed based on genetic mutations that need to be known to search for and request them, we are faced with a truly complex scenario that requires subspecialization.”
In a study recently published in the Argentine Archives of Pediatrics, Dr. Dubrovsky and colleagues interviewed 112 families of Argentine patients with molecular diagnoses of spinal muscular atrophy types I, II, and III and found that in 75%-85% of cases, the first signs of the disease (such as hypotonia, developmental delay, inability to achieve bipedal standing, or frequent falls) were recognized by parents. For type I, the most severe and early onset, in only 17.5% of cases did a neonatologist or pediatrician first notice something. Of the 72 patients with types II and III, where routine checks are less frequent than in the first months of life, only one doctor detected the first signs of the disease before parents or other relatives.
In the same study, the median time elapsed between the first sign and confirmed molecular diagnosis was 2, 10, and 31.5 months for types I, II, and III, respectively. The delay “is primarily due to the lack of clinical suspicion on the part of the intervening physician, who often dismisses or misinterprets the signs reported by parents, as reflected in the alternative diagnoses invoked,” the authors wrote.
“I don’t even ask for suspicion of a specific rare disease because that requires specialization. What I ask for is a kind of recognition or realization that something is happening and then request a consultation with the specialist to ensure proper care,” said Dr. Dubrovsky.
In another study conducted among 70 Argentine patients under age 13 years who were diagnosed with Duchenne muscular dystrophy (one of the most severe forms of muscular dystrophy), 82% of the pediatricians who were initially consulted for any problem in motor agility that parents, other relatives, or teachers had detected dismissed the observation. “They’re told to wait, that it will mature a little more,” said Dr. Dubrovsky. This explains why the time to diagnosis in Argentina from the first signs is around 2 years. The delays are unfortunate because “today we have treatments capable of interfering with the disease’s progression slope, reducing its progression, or eventually stopping it,” he said.
“Do you mind that primary care pediatricians don’t notice or dismiss signs and symptoms strongly suggestive of one of these rare diseases? Does it frustrate you?” this news organization asked asked Dr. Dubrovsky. “Sometimes it does make me angry, but many times it’s understood that there can’t be highly trained specialists everywhere to realize and request diagnostic tests. One must consider the circumstances in each case, and that’s why we work in education,” he replied.