Abdulkerim Kolkiran, Melike Ataseven Kulali, Tugba Dasar, Abdullah Sezer, Meliksah Keskin, Senay Savas-Erdeve, Erdal Kurnaz, Elifcan Tasdelen, Mustafa Tarik Alay, Berna Ucan, Mehmet Can Pence, Muhammed Erkan Emrahoglu, Ahmet Kablan, Firdevs Dinçsoy Bir, Hanife Saat, Ayse Derya Bulus, Nihan Solmaz
This study underscores genetic and clinical heterogeneity of HCH. Molecular diagnosis is essential for accurate identification, and continued reporting of clinical and molecular data will refine phenotypic spectrum and improve genotype-phenotype correlations.
INTRODUCTION: Hypochondroplasia (HCH) is mild, often under-recognized skeletal dysplasia caused by FGFR3 variants. It is characterized by disproportionate short stature and subtle radiographic findings, which can delay diagnosis. This study evaluated genetic, endocrine, and radiographic findings in patients with HCH.
METHODS AND RESULTS: We performed retrospective, single-center review of individuals with molecularly confirmed FGFR3 variants. Diagnosis was established by clinical exome and/or Sanger sequencing, and anthropometric, dysmorphologic, radiologic, and molecular data were extracted from medical records. Twenty-three patients (10 males, 13 females) were included. Short stature, frequently accompanied by skeletal abnormalities, was common. Most frequent radiologic findings were increased lumbar lordosis, lack of expected caudal widening of interpedicular distance, and scoliosis. Seven distinct FGFR3 genotypes were identified, with p.Asn540Ser and p.Asn540Lys being most prevalent.
DISCUSSION: Hypochondroplasia typically results from heterozygous FGFR3 variants, most commonly p.Asn540Ser or p.Asn540Lys substitutions. p.Asn540 appears central to disease pathogenesis and aligns with graded activation model, in which serine substitution is thought to increase receptor activation less than lysine substitution. Consistent with this, clinical findings in our cohort were milder in individuals with serine substitution than in those with lysine substitution. Clinical presentation usually includes mild-to-moderate disproportionate short stature with variable features such as macrocephaly, acanthosis nigricans, or craniosynostosis, and marked intra/interfamilial variability with mild radiographic dysplasia.
CONCLUSION: This study underscores genetic and clinical heterogeneity of HCH. Molecular diagnosis is essential for accurate identification, and continued reporting of clinical and molecular data will refine phenotypic spectrum and improve genotype-phenotype correlations.