Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort.

INTRODUCTION: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (two or more affected members in a family) has been evidenced in 50 to 75% of patients with CDGP and the inheritance often is consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood.

OBJECTIVE: To characterize the clinical and genetic features of a CDGP cohort.

METHODS: Fifty-nine patients with CDGP (48 boys and 11 girls) underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel designed to capture 36 known and candidate genes implicated with pubertal development.

RESULTS: All patients had spontaneous or induced pubertal development (transient hormonal therapy) prior of 18 years of age. The mean clinical follow-up time was 46 months ± 28 months. Male predominance (81%), short stature (91%) and family history of delayed puberty (59%) were the main clinical features of this CDGP cohort. Genetic analyses revealed 15 rare heterozygous missense variants in 15 patients with CDGP (25%) in seven different genes (IGSF10, GHSR, CHD7, SPRY4, WDR11, SEMA3A and IL17RD). IGSF10 and GHSR were the most prevalent affected genes in this group.

CONCLUSIONS: Several rare dominant variants in genes implicated with GnRH migration and metabolism were identified in one quarter of the patients with familial or sporadic CDGP, suggesting genetic heterogeneity in this frequent pediatric condition.