The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics

Abstract

Kallmann syndrome (KS) consists of congenital, isolated, idiopathic hypogonadotropic hypogonadism (IHH) and anosmia.The gene responsible for the X-linked form of KS, KAL, encodes a protein, anosmin, that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus.In addition to X-linked pedigrees, autosomal dominant and recessive kindreds with KS have been reported.The relative importance of these autosomal vs. X-linked genes in producing KS, and the frequency of KAL mutations, are currently unknown because these are rare disorders and large series are unusual.We examined 101 individuals with IHH (Ϯ anosmia) and their families to determine their modes of inheritance, incidence of mutations in the coding sequence of KAL, genotype-phenotype correlations, and [in a subset (n ϭ 38)] their neuroendocrine phenotype.Of the 101 patients, 59 had true KS (IHH ϩ anosmia/hyposmia); whereas, in the remaining 42, no anosmia was evident in the patients or their families.Of the 59 KS patients, 21 were familial, whereas 38 were sporadic cases.Mutations in the coding sequence of KAL were identified in only 3 of 21 familial cases (14%) and 4 of 38 (11%) of the sporadic cases.Of the X-linked cases confirmed by mutational analysis, only 1 of 3 pedigrees appeared X-linked by inspection whereas the other 2 contained only affected brothers.Female members of known KAL mutation families (n ϭ 3) exhibited no reproductive phenotype and were not anosmic, whereas families with anosmic women (n ϭ 3) were not found to carry mutations in KAL.Mutations