Abstract
Kallmann syndrome (KS)/Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by hypogonadotropic hypogonadism and anosmia or hyposmia due to the abnormal migration of olfactory and gonadotropin releasing hormone producing neurons. Multiple genes have been implicated in KS/IHH. Sequential testing of these genes utilising Sanger sequencing is time consuming and not cost effective. The introduction of parallel multigene panel sequencing of small gene panels for the identification of causative gene variants has been shown to be a robust tool in the clinical setting. Utilizing multiplex PCR for the four gene KS/IHH panel followed by NGS, we describe herewith two cases of hypogonadotropic hypogonadism with a Prokineticin receptor 2 (PROKR2) gene and KAL1 gene mutation. The subject with a PROKR2 mutation had a normal perception of smell and normal olfactory bulbs on imaging. The subject with a KAL1 gene mutation had anosmia and a hypoplastic olfactory bulb.
Highlights
Idiopathic hypogonadotropic hypogonadism is associated with normosmia
Cole et al, has reported this mutation in a male patient with normosmic hypogonadotropic hypogonadism [5]. is mutation has been further con rmed by Sanger sequencing
Subject A2 was found to be positive for a reported homozygous KAL1 gene mutation c.1369C>T resulting in a change in amino acid arginine at codon 457 to a termination codon (p.Arg457Ter) (Figure 2(b))
Summary
Idiopathic hypogonadotropic hypogonadism is associated with normosmia. Kallmann syndrome (KS) is a unique disease phenotype of idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia [1]. His weight was 63 kg, height was 185 cm, upper and lower segment ratio of 0.7(87 cm/98 cm) He had a high pitched voice, intact olfactory perception, absent facial and axillary hair, pubic hair (Tanner’s stage 3), with bilateral descended prepubertal testes (2 ml in volume), stretched penile length of 7 cm and neurologic examination was essentially normal. On biochemical investigation, he was found to have an LH-0.69 mIU/ml (N-0.8–7.6 mIU/ml), FSH-0.77 mIU/ml (N-0.7–11.1 mIU/ml), Testosterone-103 ng/dl (N-270– 1030 ng/dl), suggestive of hypogonadotropic hypogonadism. MRI of the brain displayed a hypoplastic olfactory bulb consistent with Kallmann syndrome (Figure 1(b))
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