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A 26-year-old woman was referred by her general practitioner with primary amenorrhoea. She denied galactorrhoea or headaches. She had undergone ligation of a patent ductus arteriosus at 2 years of age and was noted in childhood to have a partial hearing defect in her right ear. On examination she was a phenotypically normal female with a BMI of 23.2 kg/m2. She had Tanner stage II breast and pubic hair development. Investigations revealed a normal full blood count, urea and electrolytes, with a glucose of 5 mmol/l, prolactin of 100 mU/l (normal < 400 mU/l). Hypogonadotrophic hypogonadism was confirmed with a low plasma oestradiol of 108 pmol/l (normal >130), luteinising hormone (LH) < 0.5 U/l and follicle-stimulating hormone (FSH) < 0.5 U/l. She had impaired responses to LHRH stimulation of LH < 0.5 U/l and FSH 0.6 U/l. Dynamic testing of pituitary function revealed a normal growth hormone, cortisol and prolactin response to insulin-induced hypoglycaemia. Thyroid function tests, pituitary magnetic resonance imaging, and karyotype were normal.
- What other clinical test would be useful?
- What is the diagnosis?
Test her sense of smell. This patient had an absent sense of smell to standard testing with coffee, lemon juice and varying concentrations of propionic acid.
In this case, the association of hypogonadotrophic hypogonadism, deafness and anosmia confirms the diagnosis of Kallmann's syndrome. Kallmann's syndrome is the commonest cause of isolated gonadotropin deficiency1 with a predominantly male predisposition. It can occur in a familial setting, though the majority of cases are sporadic.
Although the exact cause of Kallmann's syndrome remains to be identified, it is believed that there is a failure of migration of the LHRH neurones to the median eminence of the hypothalamus.2According to Rimon and Schimke,3 Kallmann's syndrome represents a complex spectrum of developmental anomalies which include midline cleavages of the embryonic forebrain, aplasia of the olfactory bulb and tract with midline dysplasia of the face causing abnormalities like cleft lip, cleft palate, congenital deafness and colour blindness. Other developmental abnormalities reported in association with Kallmann's syndrome include gut malrotation, renal agenesis and congenital heart defects.1
In 1960 Gauthier4 for the first time reported a case of a young woman with olfactogenital dysplasia (Kallmann's syndrome) who had died of an Ebstein anomaly. Since then there have been seven other case reports of Kallmann's syndrome in association with other cardiac abnormalities, these include right aortic arch, 2:1 atrioventricular block and Wenckebach phenomenon, atrial septal defect, and a complex case of transposition of the great vessels which required heart transplantation.1
Kallmann's syndrome is genetically heterogenous and may be inherited in an autosomal dominant or recessive pattern. In some forms of inheritance there is a defect in the KALIG-1 gene.2 It is speculated that this gene may have a direct effect on axonal outgrowth and is required for the normal migration of the embryonic cells that develop within the olfactory bulb and the hypothalamic nuclei that subsequently secrete gonadotropin-releasing hormone.2 The KALIG-1 gene may also be involved in the recognition mechanisms which occur between LHRH nuclei and olfactory nuclei, as well as in the modulation of migrating cardiac cells during embryonic development, which may account for the association of certain types of congenital heart defects with Kallmann's syndrome.2 This is supported by the demonstration of aorticopulmonary septal defects following the removal of areas within the occipital neural crest, the area from which the presumptive cardiac cells originate in chick embryos.5
Clinical features of Kallmann's syndrome
cleft lip and cleft palate
rarely, congenital heart defects, renal agenesis
To our knowledge there have been no reports of Kallmann's syndrome in association with patent ductus arteriosus. The significance of this and other cardiac defects in association with Kallmann's syndrome is unclear as it may represent a purely chance occurrence. However, it may also reflect a true association between Kallmann's syndrome and congenital heart defects, due to the putative mechanism outlined previously.