Genetic testing reshapes the evaluation of children with short stature, allowing clinicians to identify specific molecular causes in many cases that were previously classified as idiopathic. A systematic review published in the European Journal of Endocrinology highlighted the increasingly important role of genetics in identifying the causes of short stature in children.

Researchers evaluated 134 studies published between 1990 and 2025 and found that modern genetic sequencing technologies offer a much higher diagnostic yield than conventional approaches, making it possible to identify the cause of the problem in up to 33.3% of patients. The findings also provided the scientific foundation for the development of a new international consensus on the genetic evaluation of short stature. Clinicians are increasingly identifying specific molecular causes instead of classifying many cases as idiopathic, helping guide treatment, prognosis, and long-term follow-up.

According to Alexander Augusto de Lima Jorge, MD, PhD, professor of endocrinology and metabolism at the University of São Paulo School of Medicine, São Paulo, Brazil, and one of the study authors, the benefits of establishing a genetic diagnosis extend well beyond assigning a clinical label.

Speaking with Medscape’s Portuguese edition, he said, “Identifying the underlying cause not only provides a diagnosis but also directly guides medical treatment, helps avoid unnecessary and burdensome testing, and enables appropriate genetic counseling regarding the risk of transmission to future children.”

From Single-Gene Testing to Exome Sequencing

This review highlights the advances made possible by next-generation sequencing (NGS) technologies.

Whereas traditional single-gene testing had a diagnostic yield of only 4.7%, targeted gene panels achieved a yield of 21.6%. The highest yield was observed with exome sequencing, which analyzes all protein-coding regions of the genome and identified the genetic cause of short stature in 33.3% of patients.

According to Jorge, this progress reflects two major developments.

“First, sequencing technologies now allow the simultaneous analysis of multiple regions of the genome, including through exome and whole-genome sequencing. Second, bioinformatics platforms have been developed that perform partially automated analyses to identify genetic variants most likely to be pathogenic in genes relevant to the patient’s clinical presentation.”

He added that combining these technologies with expanding knowledge of genetic disorders and increasingly refined diagnostic protocols has substantially improved specialists’ ability to establish a diagnosis.

Certain Clinical Features Increase Diagnostic Yield

One of the most significant findings of the review was the strong influence of phenotype on the diagnostic yield. When short stature is associated with other clinical features, the likelihood of identifying the genetic cause increases substantially.

Factors associated with a higher diagnostic yield included the following:

• Facial dysmorphism: 68.2% 
• Skeletal abnormalities: 61.1% 
• Syndromic features: 59.6% 
• Intellectual disability: 57.0% 
• Children born small for gestational age without an identified cause: 63.6% 
• Severe short stature (Z score < -2.5): 50.0% 

Even among children with isolated short stature and no other apparent clinical manifestations, exome sequencing established a diagnosis in 15.1% of cases.

Thais Milioni Luciano, MD, MSc, pediatric endocrinologist, and PhD researcher at the University of São Paulo in Ribeirão Preto, Brazil, and member on the telehealth and scheduling platform inki.com.br, noted that the findings help make the diagnostic evaluation more targeted.

“It is striking that in isolated short stature, only 10 genes account for more than half of all positive findings, whereas when short stature occurs as part of a syndromic condition, the 10 most frequently identified genes account for less than 30% of cases. These findings help guide diagnostic investigation more effectively.”

She also emphasized the impact of technological advances.

“One of the most notable findings is the substantial increase in diagnostic yield as testing becomes more comprehensive, with exome sequencing achieving a diagnostic yield of 33.3% compared with only 4.7% for single-gene testing.”

Molecular Diagnosis Is Already Changing Clinical Practice

According to Luciano, the evidence summarized in this review is robust enough to influence routine clinical practice.

“In addition to being a methodologically rigorous, peer-reviewed study published in a leading pediatric endocrinology journal, this is the first study to comprehensively evaluate the diagnostic performance of all major genetic testing approaches through a rigorous analysis of 134 studies published between 1990 and 2025,” she said.

She noted that the clinical implications extend well beyond identification of the underlying cause.

“The findings show that genetic testing does more than establish an etiologic diagnosis. It helps guide screening for comorbidities, such as cardiac and ophthalmologic complications, identifies patients who may benefit from targeted therapies, and prevents the use of treatments that are contraindicated in individuals with cancer predisposition syndromes.”

Jorge noted that exome sequencing can be considered early in diagnostic evaluation under certain circumstances.

“Depending on the patient’s medical history and findings on physical examination, exome sequencing may be among the first tests ordered. This is particularly true for patients with syndromic short stature who have not received a clinical diagnosis despite evaluation by an experienced physician.”

However, when laboratory and imaging studies help to further characterize the condition, genetic testing may be performed later in the diagnostic workup.

When the Results Change Treatment

The authors noted that identifying the genetic cause could substantially alter the treatment decisions.

“Each genetic diagnosis — and there are thousands of possibilities — has different clinical implications,” Jorge said.

One example is achondroplasia caused by pathogenic variants of FGFR3.

“We know that patients with achondroplasia caused by FGFR3 variants do not respond to growth hormone therapy. In contrast, C-type natriuretic peptide analogs are now used to improve body proportions, increase height, and potentially reduce associated complications,” he explained.

Jorge also highlighted the differences in response to growth hormone therapy.

“Patients with SHOX deficiency respond very well to growth hormone therapy when it is started before puberty. By contrast, patients with FGFR3-related achondroplasia respond very poorly.”

In some cases, genetic findings may indicate that treatment should be avoided.

“For children with short stature associated with disorders that markedly increase the risk of childhood cancer, such as Bloom syndrome, growth hormone therapy is generally contraindicated.”

Early Diagnosis Remains Critical

The review also renews the discussion on the optimal window of diagnosis and intervention, particularly for girls. According to Jorge, the therapeutic window narrows considerably after the onset of puberty.

“Menarche coincides with slowing growth as the growth plates progressively close, ultimately determining adult height. From the standpoint of promoting growth with somatropin, treatment is most effective when initiated before the first signs of puberty.”

He noted that puberty generally begins between 8 years and 13 years of age in girls, and between 9 years and 14 years of age in boys, underscoring the importance of early evaluation.

Although challenges related to access to genetic testing and the availability of specialists in medical genetics remain, researchers believe that incorporating these tools into routine clinical practice is inevitable.

“Genetic testing has moved beyond the research setting and is now becoming part of routine clinical care because its benefits for patients are undeniable,” Luciano said.

According to Jorge, the traditional concept of idiopathic short stature is gradually disappearing because an increasing number of cases, once considered idiopathic, have been found to have an identifiable genetic cause.

Roseane Santos is a Brazilian journalist with 35 years of experience who has worked for major national outlets like Universo Online, the daily newspaper Folha de S.Paulo, and Portal Terra and contributes to scientific publications from Albert Einstein Israelite Hospital and Brazil’s National Cancer Institute.

This story was translated from Medscape’s Portuguese edition.