The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human.

Despite recent advances in the understanding of the pathophysiology of Kallmann's syndrome (KS), the patterns of inheritance in the majority of cases of GnRH deficiency in human subjects remain unclear. To define further the genetic and phenotypic variability of this syndrome, detailed family histories were reviewed in 106 cases of GnRH deficiency with or without anosmia [i.e. KS or idiopathic hypogonadotropic hypogonadism (IHH)]. The great majority of cases appeared to be sporadic, with only 19 probands (18%) having at least 1 family member with GnRH deficiency. However, of the families in which the proband was the sole member affected by KS or IHH, 9 had individuals with isolated anosmia, and 8 had a strong history of delayed puberty. If these phenotypes were considered as alternative manifestations of the same genetic defect that presented as KS or IHH in the proband, 34% of the cases in the present series could be considered familial. In these families, the most likely modes of transmission were assessed in several ways, including analysis of probands with KS as a distinct subset, and separate determinations based upon whether the phenotypes of isolated anosmia and/or delayed puberty were considered relevant to the inheritance of KS or IHH. The proportion of familial cases that could be attributable to an X-linked mode of inheritance was no greater than 36% in any of these analyses. We conclude that 1) most cases of GnRH deficiency in humans are sporadic and, thus, could represent new mutations; 2) the X-linked form is the least common among familial cases of KS or IHH; 3) defects in at least two autosomal genes can results in GnRH deficiency; and 4) associated clinical defects may well represent clues to the nature and/or location of these autosomal genes.