PROKR2 mutations in autosomal recessive Kallmann syndrome

Abstract

Objective: To investigate the inheritance pattern of two missense PROKR2 changes within a single family.

Design: This is a descriptive study.

Setting: Tertiary referral center.

Patient(s): The proband and his brother, both with congenital hypogonadotropic hypogonadism and anosmia (Kallmann syndrome).

Intervention(s): Clinical and biochemical evaluation of Kallmann syndrome. Sequence analysis of the coding exons and exon-intron boundaries of KAL1, FGFR1, FGF8, PROK2, and PROKR2 from polymerase chain reaction (PCR)-amplified genomic DNA. Recombinant human FSH treatment of the proband.

Main outcome measure(s): Phenotypic and genotypic features, and inhibin B response to recombinant human FSH.

Result(s): The proband and his brother were homozygous for two variants in PROKR2; a novel mutation c.701G>A (p.G234D), and a polymorphism c.802C>T (p.R268C). Recombinant human FSH therapy of the proband increased serum inhibin B from <16 to 136 ng/L. The heterozygous parents were fertile and had six children.

Conclusion(s): These findings are consistent with recessive mode of inheritance. PROKR2 signaling does not directly affect Sertoli cell function.