Clinical, endocrinological, and molecular characterization of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: a single center experience

Abstract

PurposeIsolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified as Kallmann syndrome (KS) with anosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). This study was undertaken to investigate the clinical, endocrinological, and molecular characteristics in Korean patients with KS and nIHH.MethodsTwenty-six patients from 25 unrelated families were included. Their clinical, endocrinological, and radiological findings were analyzed retrospectively. Mutation analysis of the GNRH1, GNRHR, KISS1, KISS1R, PROK2, PROKR2, TAC3, TACR3, FGF8, FGFR1, and KAL1 genes was performed in all patients. CHD7 and SOX10 were analyzed in patients with CHARGE (Coloboma, Heart defects, choanae Atresia, Growth retardation, Genitourinary abnormality, Ear abnormality) features or deafness.ResultsOf the 26 patients, 16 had KS and 10 had nIHH. At diagnosis, mean chronologic age was 18.1 years in males and 18.0 years in females; height SDS were -0.67±1.35 in males, -1.12±1.86 in females; testis volume was 2.0±1.3 mL; and Tanner stage was 1.5. There were associated anomalies in some of the KS patients: hearing loss (n=6) and congenital heart disease (n=4). Absence or hypoplasia of the olfactory bulb/sulci was found in 84.62% of patients with KS. Molecular defects in KAL1, SOX10, and CHD7 were identified in 5 patients from 4 families (16.0%, 4/25 pedigrees). After sex hormone replacement therapy, there were improvement in sexual characteristics and the sexual function.ConclusionThis study described the clinical, endocrinological, and molecular genetic features in IGD patients in Korea. Although the mutation screening was performed in 10 genes that cause IGD, molecular defects were identified in relatively small proportions of the cohort.

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome

“…In an infant male with a micropenis or undescended testes, a magnetic resonance image (MRI) can be used as a primary diagnostic method . MRI in subjects with WS and SOX10 pathogenic variants frequently reveals hypoplasia or aplasia of the olfactory bulbs; in addition, inner ear or temporal bone abnormalities are often present . In older children, an MRI is often unnecessary and formal testing for anosmia or hyposomia can establish the diagnosis of Kallmann's syndrome .…”

“…method 53,54. MRI in subjects with WS and SOX10 pathogenic variants frequently reveals hypoplasia or aplasia of the olfactory bulbs; in addition, inner ear or temporal bone abnormalities are often present [55][56][57][58][59][60][61][62][63][64][65][66][67]. In older children, an MRI is often unnecessary and formal testing for anosmia or hyposomia can establish the diagnosis of Kallmann's syndrome 68.…”

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…Other noteworthy clinical signs in these patients with SOX10 mutations include abnormal iris pigmentation (124,126,127) and wisps/patches of white hair. In the few KS/CHH pedigrees so far described, transmission of SOX10 mutations is autosomal dominant but again, as with FGFR1 and CHD7, the penetrance of the various clinical signs is variable even among related individuals carrying the same SOX10 mutation (124)(125)(126)(127)(128)(129)(130).…”

“…SOX10 mutations associated with the KS phenotype are mainly missense loss-of-function or frameshift mutations present in the heterozygous state. To date, relatively few cases of KS linked to SOX10 mutations have been described (124)(125)(126)(127)(128)(129). However, their number may well increase rapidly, simply because this gene will be more frequently analyzed in patients with KS/nCHH as next-generation sequencing methods are adopted (see below) (129).…”

“…To date, relatively few cases of KS linked to SOX10 mutations have been described (124)(125)(126)(127)(128)(129). However, their number may well increase rapidly, simply because this gene will be more frequently analyzed in patients with KS/nCHH as next-generation sequencing methods are adopted (see below) (129). At the phenotypic level, this genetic form of KS is characterized by a high prevalence of neurogenic deafness associated Page 16 of 55 with semi-circular canal defects similar to those seen in CHH patients with CHD7 mutations (124)(125)(126)130).…”