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Lookup NU author(s): Dr Richard Quinton,
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OBJECTIVE The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmann's syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be Involved comprise KAL (associated with X-linked-KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient sample might provide new insights into the genetics of this rare disorder. Specifically, we wished to examine the following propositions. First, whether normosmic (nIHH) and anosmic (KS) forms of IHH were likely to be genetically discrete entities, on the basis of quantitative olfactory testing, analysis of autosomal pedigrees and the prevalence of developmental defects such as cryptorchidism and cleft palate. Second, whether mirror movements and/or unilateral renal agenesis were specific phenotypic markers for X-linked-KS. DESIGN AND PATIENTS We conducted a clinical study of 170 male and 45 female IHH patients attending the endocrinology departments of three London University teaching hospitals. Approximately 80% of data were obtained from case records and 20% collected prospectively. Parameters assessed included olfaction, testicular volume, family history of hypogonadism, anosmia or pubertal delay, and history or presence of testicular maldescent, neurological, renal or craniofacial anomalies. Where possible, the clinical information was correlated with published data on genetic analysis of the KAL locus. RESULTS Olfactory acuity was bimodally distributed with no evidence for a spectrum of olfactory deficit. Testicular volume, a marker of integrated gonadotrophin secretion, did not differ significantly between anosmic and normosmic patients, at 2-0 ml and 2-2 ml, respectively. Nevertheless, the prevalence of cryptorchidism was nearly three times greater in anosmic (70.3%, of which 75.0% bilateral) than in normosmic (23.2%, of which 43.8% bilateral) patients. Individuals with nIHH, eugonadal isolated anosmia and/or KS were observed to coexist within 6/13 autosomal IHH pedigrees. On three occasions, fertility treatment given to an IHH patient had resulted in the condition being transmitted to the resulting offspring. Mirror movements and unilateral renal agenesis were observed in 24/98 and 9/87 IHH patients, respectively, all of whom were identifiable as X-KS males on the basis of pedigree analysis and/or defective KAL coding sequence. Abnormalities of eye movement and unilateral sensorineural deafness were observed in 10/21 and 6/111 KS patients, respectively, but not in nIHH patients. DISCUSSION Patients with IHH are almost invariably either anosmic (KS) or normosmic (nIHH), rather than exhibiting intermediate degrees of olfactory deficit. Moreover, the prevalence of cryptorchidism is nearly three times greater in KS than in nIHH despite comparable testicular volumes, suggesting a primary defect of testicular descent in KS independent of gonadotrophin deficiency. Disorders of eye movement and hearing appear only to occur in association with KS. Taken together, these findings Indicate a clear phenotypic separation between KS and nIHH. However, pedigree studies suggest that autosomal KS is an heterogeneous condition, with incomplete phenotypic penetrance within pedigrees, and that some cases of autosomal KS, nIHH and even i
Author(s): Quinton R, Duke VM, Robertson A, Kirk JMW, Matfin G, de Zoysa PA, Azcona C, MacColl GS, Jacobs HS, Conway GS, Besser M, Stanhope RG, Bouloux PMG
Publication type: Article
Publication status: Published
Journal: Clinical Endocrinology
ISSN (print): 0300-0664
ISSN (electronic): 1365-2265
Publisher: Wiley-Blackwell Publishing Ltd.
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