European Journal of Endocrinology (EJE)International Guideline on Genetic Testing of Children with Short Stature

✅ Guideline Update

The European Journal of Endocrinology guideline is the first international consensus dedicated specifically to molecular genetic testing in children with short stature. The recommendations were developed by the International Growth Genetics Guideline Consortium using systematic review, meta-analysis, GRADE methodology, and multinational expert consensus. The guideline emphasizes that children with short stature should undergo thorough clinical evaluation before genetic testing and proposes a phenotype-based diagnostic algorithm to guide selection of genetic investigations. The document also addresses benefits, risks, diagnostic yield, genetic counseling, and test selection.

Clinical Considerations

• Genetic testing yield varies substantially by phenotype, ranging from 15.1% in idiopathic short stature to 50.8% in syndromic short stature and 69.8% in suspected skeletal dysplasia.
• Exome sequencing demonstrated a pooled diagnostic yield of 33.3%, exceeding single-gene testing (4.4%), chromosomal microarray (16.3%), and gene panels (21.6%).
• The guideline recommends genetic testing for children with neurodevelopmental disorders, congenital anomalies, disproportionate growth, severe short stature, skeletal abnormalities, or inheritance patterns suggestive of a monogenic disorder.
• All girls with unexplained short stature should undergo evaluation for Turner syndrome, including mosaic forms.
• Genetic counseling is recommended before testing and multidisciplinary collaboration between endocrinologists, geneticists, and laboratory specialists is strongly emphasized.
• The guideline advises against routine genetic testing when constitutional delay of growth and puberty or a strongly suspected polygenic origin is the likely explanation.

Practice Applications

• Assess clinical clues such as neurodevelopmental disorders, dysmorphism, body disproportion, microcephaly, macrocephaly, and family history before selecting genetic testing.
• Collaborate with genetics specialists for test selection, interpretation, counseling, and follow-up of variants.
• Consider exome or genome-based approaches when phenotypic features suggest an elevated likelihood of a genetic diagnosis.
• Reanalyze previously negative genetic data when new clinical features emerge or diagnostic technologies improve.
• Discuss both the benefits and limitations of testing, including incidental findings, variants of uncertain significance, and potential insurance implications.