Case Report Kallmann's Syndrome: Clues to Clinical Diagnosis

Case Report Kallmann's Syndrome: clues to clinical diagnosis

H John1* and C Schmid2

Departments of 1Urology and 2Medicine (Division of Endocrinology), ZuÈrich University Hospital, Switzerland

Hypogonadotropic patients may visit pediatricians, general practitioners, endocrinologists or urologists, presenting with microphallus, cryptochidism or pubertas tarda and delayed bone maturation. Congenital hypogonadotropic hypogonadism is characterized, apart from small testes, by the constellation of low serum levels of testosterone, LH and FSH. Kallman's syndrome is characterized by congenital hypogonadotropic hypogonadism with midline defects such as anosmia (a de®ciency of the sense of smell).1 The ®rst case report dates back to 1856,2 and genetic defects causing the syndrome have been recently described.3 The diagnosis can be clinically suspected and is established by con®rming hormonal studies. International Journal of Impotence Research (2000) 12, 121±123.

Case Reports Case 2

Case 1 A 24-year-old patient consulted a general practi- tioner (the ®rst to address the problem of delayed puberty) for upper airway disease. He presented A 26-year old man fell on his right hand. The X-ray with an unbroken voice and sparse axillary and of the wrist (Figure 1) not only demonstrated the pubic body hair. He had a microphallus and fracture of the ®fth metacarpus but also an open testicular volumes of 2 ml, and a bone age of 17 epiphyseal line, thus revealing markedly delayed years. He did not smell garlic or curry. The sellar bone age. The patient's voice has not broken and he MRI was normal. Laboratory testing con®rms hypo- reported weak erections. At the age of three years he gonadotropic hypogonadism (Table 1). After the ®rst underwent orchiopexy on the left side for crypto- injection of 125 mg testosterone enanthate, priapism chidism. He never had a girlfriend and was known occurred. After one year of testosterone therapy, as an obliging and courteous person. Physical normal male sex features and libido are reached. examination shows eunuchoid proportions, de- The patient does not wish to be fertile. creased body hair with a female distribution and microphallus with a testicular volume of 2 ml on both sides. The patient did not smell offered coffee beans. Laboratory testing shows slight anemia Case 3 (hemoglobin of 13.8 g=dl) and low values of testosterone, FSH and LH (Table 1), con®rming hypogonadotropic hypogonadism. LH and FSH increased A 17-year-old male was referred by his family promptly within 30 and 50 minutes in response to physician for suspected hypogonadism and with intravenous GnRH, consistent with normal pituitary the differential diagnosis of constitutionally delayed function. Sperm analysis revealed cryptozoosper- puberty. He underwent hCG cycles and ®nally a mia. The MRI of the sella excluded a pituitary bilateral operation for maldescended testis when he tumor. Hormonal replacement therapy with trans- was eight years old. He had eunuchoid body dermal testosterone patches (Andropatch1) brought proportions, a microphallus and a total lack of smell serum testosterone levels and red blood cell indices (remarkably, his sister is found to lack unilaterally (hemoglobin of 16.2 g=dl) to values within the the sense of smell and, later on, turns out to have normal adult male range, and the voice of the primary amenorrhea, attributed to Kallmann's patient changed six months later. syndrome!). The laboratory values con®rmed in response to GnRH stimulation (Table 1). Other pituitary functions are normal and so is MR imaging. *Correspondence: H John, Department of Urology, ZuÈ rich The patient feels ®ne on testosterone replacement University Hospital, Switzerland. therapy, works as a farmer and is not yet married. Kallmann's syndrome H John and C Schmid 122 Table 1 Hormonal values and LH stimulation by 100 mg GnRH i.v. in four patients with Kallmann's syndrome

Age at Orchidopexy Total test FSH LH basal LH 300 LH 600 after Case diagnosis at the age of Anosmia (nmol=l) (U=l) (U=l) after GnRH (U=l) GnRH (U=l)

1263 2.7 < 2 2.5 9.0 9.9 224Ð 1.2 < 2 < 2 4.9 6.4 3178 1.2 < 2 2.5 6.6 6.6 4188 1.1 1.8 < 2 9.8 9.6

terone enanthate injections (250 mg i.m. every 3 or 4 weeks) which leads to a full male phenotype, apart from the testes, which remain small. He did not want hormonal treatment.

Discussion

Kallmann's syndrome is the most frequent cause of isolated gonadotropin de®ciency due to insuf®cient secretion of GnRH. In its classical form, this congenital syndrome results in the absence of endogenous GnRH-induced LH pulsations, often cryptorchidism and microphallus, and includes hyposmia or anosmia. Kallmann's syndrome affects one of 10 000 males; females are six times less frequently affected. The most frequent form of the autosomal recessive disease is linked to the X chromosome and appears to be due to a defect in the embryonic migration of GnRH neurons and olfactory axons from the nose of the brain. As shown by our four case reports, the diagnosis of Kallmann's syndrome is often made with sub- stantial delay, despite clues in childhood such as anosmia, cryptochidism and failure to enter puberty timely. Bone maturation and formation of long- itudinal growth may occur at an age beyond 20 Figure 1 The X-ray of the wrist of a 26-y-old man with Kallmann's syndrome shows an open epiphyseal line (delay in years. At presentation, concomitant de®cits of other bone maturation). A bone CAT scan of the forearm of the patient pituitary hormones should be excluded by history, reveals a density far below the reference values found in age- clinical examination and laboratory ®ndings. The matched males, ie in the severely osteoporotic range. differential diagnosis includes, apart from constitutionally delayed puberty, neoplastic and in¯am- matory diseases but MRI imaging can rule out hypothalamic and pituitary tumors such as cran- iopharyngiomas or adenomas. Dynamic endocrine Case 4 testing using intravenous GnRH will usually increase both LH and FSH. The ®rst goal to achieve in therapy for hypogon- An 18-year-old male is bothered by his low physical adotropic hypogonadism is induction of puberty performance and by being called `Mrs' on the phone. and (in males) virilization. Testosterone replace- His mother reports that he underwent bilateral ment therapy can be performed by intramuscular orchiopexy at the age of eight years. He has small injections of testosterone esters of using transdermal testicles (1 ml each) and has not yet entered puberty. testosterone patches.4,5 This treatment successfully His mother also noticed that he lacks a sense of smell, substitutes for the lack of normal Leydig cell a ®nding con®rmed by neurological exam. Lab- function but will not induce spermatogenesis. oratory tests reveal low levels of testosterone and Gonadotropin (hMG hCG) and pulsatile GnRH gonadotropins (Table 1). He is treated with testos- therapy are used to induce fertility. In patients with

International Journal of Impotence Research Kallmann's syndrome H John and C Schmid 123 Kallmann's syndrome, GnRH is the treatment of References choice and GnRH may also work in other hypothalamic disorders, whereas in pituitary insuf®ciency, 1 Kallmann FJ, Shoenfeld WA, Barrerra SE. The genetic aspects administration of gonadotropins (hMG hCG) is of primary eunochoidism. Am J Ment D®c 1944; 48: 203 ± 236. 2 Maestre de San Juan A. Falta total de los nervios olfactorios required. Administration of GnRH to GnRH-de®- con anosmia en un individuo en quien existia una atro®a cient men simulates LH pulses observed in healthy congenita de los testiculos y miembro viril. Sigio Med 1856; men where pulses occur at a frequency of around 12 131: 211. per day. Intravenous or subcutaneous administra- 3 Franco B et al. A gene deleted in Kallmann's syndrome shares tion of GnRH with an infusion pump delivering 2 ± homology with neural cell adhesion and axonal path-®nding molecules. Nature 1991; 353; 529 ± 536. 40 mg GnRH per pulse every two hours was found to 4 Morales A, Johston B, Heaton JPW, Lundie M. Testosterone be effective in patients with Kallmann's syndrome. supplementation for hypogonadal impotence: assessment of Spermatogenesis can be induced in the majority of biochemical measures and therapeutic outcomes. J Urol 1997; these patients and fertility rates are above 50%.6,7 It 157: 849 ± 854. 5 Crowley WF, Whitcomb RW. Gonadotropin-releasing hor- may be dif®cult to estimate the prognosis for mone de®ciency in man: diagnosis and treatment with individual, eg for patients with orchiopexy at an exogenous gonadotropin-releasing hormone. Am J Obstet advanced age. The treatment by peptide hormones Gynecol 1990; 163: 1752 ± 1758. remains complicated and expensive but may be 6 Schopohl J. Comparison of gonadotropin-releasing hormone rewarding for those who can afford it and succeed in and gonadotropin therapy in male patients with idiopathic hypothalamic hypogonadism. Fertil Steril 1991; 56: 1143 ± fathering children. 1150.

International Journal of Impotence Research