ESPE Abstracts

Background: Micropenis may have various causes, like hormonal imbalances during fetal development, disorders affecting hormone production/action, and genetic factors. Determining the etiology may be challenging, especially in isolated cases and a thorough medical evaluation is typically necessary. The identification of genetic etiology is facilitated by the wide use of next-generation sequencing technologies. Here we report a patient presented with micropenis due to hypogonadotropic hypogonadism (HH) whose genetic etiology was explained by exome sequencing (ES).

Case report: A 10-year-old male patient presented with a complaint of a small penis. He was born at term with a birth weight of 3800 g. Parents were first-degree cousins. His paternal aunt had anosmia and infertility and his uncle had a history of in vitro fertilization (IVF). On physical examination, his weight, height, and body mass index were 40.9 kg (+1.1 SDS), 145.3 cm (+1.4 SDS), and 19.4 kg/m² (+0.9 SDS), respectively. Sense of smell was normal. The stretched penile length was 3.5 × 1.4 cm, and the testes were 1-2 ml. Testes were in the scrotum bilaterally and the scrotum was hypoplastic. Axillary hair was absent and pubic hair was Tanner stage 3. Systemic examination was otherwise normal. Bone age was 12.5 years. The DHEAS concentration was 222 µg/dL and the steroid profile by LCMS/MS was normal. Chromosomal analysis was 46, XY. LH, FSH, and total testosterone concentrations were 0.42 U/L, FSH 0.44 U/L, and 20.4 ng/dL, respectively. Anterior pituitary hormone concentrations were normal. In our patient evaluated for micropenis, and family history of infertility, ES disclosed a heterozygous likely pathogenic c.926G>A [p. (Arg309Gln)] variant in the KLB (NM_175737.4) gene. Segregation analysis showed that the father was heterozygous for this variant and he also had hypogonadism.

Conclusion: KLB (MIM*611135) encodes the β-klotho protein. The role of the FGF21/FGFR1/β-klotho pathway in GnRH neuron biology has been established before but KLB has not yet been associated with a phenotype in the OMIM database. Heterozygous KLB variants have been reported to cause HH in a small number of cases and our patient expands the phenotype in KLB -associated HH. Incomplete penetrance and variable expression may also be observed in these cases.