Children with rare genetic disorders often face years of uncertainty before receiving a diagnosis, leaving families without clear information about disease progression, treatment options, prognosis, or eligibility for clinical trials. Experts say that pediatricians are uniquely positioned to shorten this diagnostic journey by recognizing early signs of rare genetic syndromes and facilitating timely referral for specialist evaluation.

Speaking at the National Congress of the Italian Society of Pediatrics, Andrea Bartuli, MD, head of the Complex Operational Unit for Rare Diseases and Medical Genetics at Ospedale Pediatrico Bambino Gesù in Rome, Italy, outlined clinical features that should prompt suspicion of a rare genetic disorder and discussed the evolving role of genetic testing in diagnosis.

From Phenotype to Genotype

“In the past, diagnosing a disease relied solely on its clinical manifestations,” Bartuli explained. “With the introduction of genetic testing and the identification of mutations responsible for many diseases, the diagnostic process has become more complex. Observation of the phenotype leads to a suspected diagnosis, which is then confirmed by assessing the genes most likely to be involved.”

Today clinicians can sequence the entire exome and the collection of genes that may be responsible for a disease.

“We could therefore start with the genotype and then verify the phenotype,” Bartuli said. “However, even with these tools, the diagnosis may not fully explain the clinical manifestations or prognosis because different phenotypes can correspond to the same genotype, and the significance of some genetic variants remains uncertain or unknown.”

For this reason, careful clinical observation remains central to diagnosis.

“Observing clinical signs that may suggest a genetic syndrome is always a fundamental step in the diagnostic process,” Bartuli said.

Clinicians must also consider interindividual variability, the possibility that a patient may have two rare diseases simultaneously, which occurs in approximately 3% of cases, and the existence of disorders that have not yet been described.

However, the manifestations of genetic disorders are not always obvious or distinctive.

“For example, intellectual disability or autism without other associated clinical or physical abnormalities,” Bartuli continued. “These may be the only manifestations and can remain without a clear diagnosis.”

Before and After Birth

By the time a newborn reaches a pediatrician’s clinic, several prenatal screening and diagnostic evaluations are often performed.

These include ultrasound examinations to identify congenital malformations and increasingly common noninvasive prenatal tests that analyze fetal DNA circulating in maternal blood. Such tests can identify chromosomal abnormalities and screen for specific genetic variants that parents may harbor.

“In the first hours of life, all newborns undergo a thorough examination by a neonatologist and biochemical screening for more than 40 rare metabolic disorders,” Bartuli said.

Even so, some abnormalities may escape detection during prenatal or newborn screening, while others may emerge only as a child grows and develops. What clinical features should prompt a pediatrician to suspect a rare genetic syndrome?

“Above all, the simultaneous presence of multiple abnormalities,” Bartuli said. “Examples include a learning disability accompanied by facial features that differ from those of the parents, a congenital malformation, unusually rapid or delayed growth, or a head circumference that is substantially above or below average.”

Pregnancy history may also provide important information.

“The child’s prenatal history should always be considered,” he added. “Relevant findings include a sudden interruption in fetal growth, low birth weight, or unusually low or high volumes of amniotic fluid.”

When suspicion arises, referral to an experienced multidisciplinary center is essential.

“It is not enough to simply refer the patient to a geneticist,” Bartuli said. “On average, a child with a genetic syndrome is cared for by four to five different specialists.”

This story was translated from Univadis Italy, part of the Medscape Professional Network.