Kallmann's Syndrome: Clues to Clinical Diagnosis

Kallmann's syndrome: clues to clinical diagnosis

H John1* and C Schmid2

1Department of Urology, ZuÈrich University Hospital, Switzerland; and 2Department of Medicine, Division of Endocrinology and Diabetes, ZuÈrich University Hospital, Switzerland

Five cases of Kallmann's syndrome are presented, out-patients with microtestes, hypogonadotropic hypogonadism and complete anosmia. The ®nal diagnosis was made only when they were aged between 17 and 26 (mean 21 years), although they had been seen by several physicians before: 3 for cryptorchidism and 3 for absence of spontaneous puberty; 2 had a positive family history, and 4 of the 5 patients or their parents admitted that they were aware of the fact that their sense of smell was completely absent, but they did not mention it spontaneously.

Keywords: cryptorchidism; hypogonadism; anosmia; gonadotropin releasing hormone

Introduction reported weak erections. At the age of 3 y he underwent orchidopexy on the left side for cryptorchidism. He never had a girlfriend and was Hypogonadotropic patients may visit pediatricians, known as an obliging and courteous person. Physi- general practitioners, endocrinologists or urologists cal examination shows eunuchoid proportions, presenting with microphallus, cryptorchidism or decreased body hair with a female distribution and pubertas tarda and delayed bone maturation. Con- microphallus with a testicular volume of 2 ml on genital hypogonadotropic hypogonadism is charac- both sides. The patient did not smell offered coffee terized, apart from small testes, by the constellation beans. Laboratory testing shows slight anemia of low serum levels of testosterone, luteinizing (hemoglobin of 13.8 g=dl) and low values of testos- hormone (LH) and follicle stimulating hormone terone, FSH and LH (Table 1), con®rming hypogo- (FSH). Kallmann's syndrome is characterized by nadotropic hypogonadism. LH and FSH increased congenital hypogonadotropic hypogonadism with promptly within 30 and 50 min in response to midline defects such as anosmia (a de®ciency of the intravenous GnRH, consistent with normal pituitary sense of smell).1 The ®rst case report dates back to function. Sperm analysis revealed cryptozoosper- 1856,2 and genetic defects causing the syndrome mia. The magnetic resonance imaging (MRI) of the have been recently described.3 The diagnosis can sella excluded a pituitary tumor. Hormonal replace- be clinically suspected and is established by ment therapy with transdermal testosterone patches con®rming hormonal studies. (Andropatch1) brought serum testosterone levels and red blood cell indices (hemoglobin of 16.2 g=dl) to values within the normal adult male range, and Case reports the voice of the patient changed 6 months later.

Case 1 Case 2

A 26-y old man fell on his right hand. The X-ray of the wrist (Figure 1) not only demonstrated the A 24-y old patient consulted a general practitioner fracture of the 5th metacarpus but also an open (the ®rst to address the problem of delayed puberty) epiphyseal line, thus revealing markedly delayed for upper airway disease. He presented with an bone age. The patient's voice has not broken and he unbroken voice and sparse axillary and pubic body hair. He had a microphallus, testicular volumes of 2 ml and a bone age of 17 y. He did not smell garlic or curry. The sellar MRI was normal. Laboratory *Correspondence: H John, Clinic of Urology, ZuÈ rich University Hospital, 8091 ZuÈ rich, Switzerland. testing con®rms hypogonadotropic hypogonadism E-mail: [email protected] (Table 1). After the ®rst injection of 125 mg testos- Received 1 January 2000; accepted 7 June 2000 terone enanthate, priapism occurred. After one year Clinical diagnosis of Kallmann's syndrome H John and C Schmid 270 Case 4

An 18-y old male is bothered by his low physical performance and by being called Mrs on the phone. His mother reports that he underwent bilateral orchidopexy at the age of 8 y. He has small testicles (1 ml each) and has not yet entered puberty. His mother also noticed that he lacks the sense of smell, a ®nding con®rmed by neurological examination. Laboratory tests reveal low levels of total testosterone and gonadotropins (Table 1). He is treated with testosterone 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 peptide treatment to induce fertility. 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 bone maturation). A bone CAT scan of the forearm of the patient reveals a density far below the reference values found in age- matched males, ie in the severely osteoporotic range.

Case 5 of testosterone therapy, normal male sex features and libido are reached. The patient does not wish to be fertile. A shy 17-y old boy consulted (after discussing his problem with his father) his general practitioner for absence of spontaneous puberty and, later on, an urologist. He had long extremities and was taller Case 3 than his father and brother, but had small testes (2 ml). Hemoglobin was low (11.6 g=dl), and so was total testosterone (initially < 0.1 nmol=l), as ex- A 17-y old male was referred by his family physician pected. A diagnosis of Kleinfelter's syndrome was for suspected hypogonadism and with the differen- considered, but cytogenetic analysis revealed a tial diagnosis of constitutionally delayed puberty. normal male (46, XY) karyotype, and serum gonado- He underwent human chorionic gonadotropin (hCG) tropins were low (Table 1). He was treated with cycles and ®nally a bilateral operation for maldes- testosterone injections. Investigations 5 years later cended testes when he was 8 y old. He had con®rmed hypogonadotropic hypogonadism, and eunuchoid body proportions, a microphallus and a moreover, showed an increase in LH in response to total lack of smell (remarkably, his sister is found to GnRH stimulation and complete anosmia. Family lack unilaterally the sense of smell and, later on, history revealed that his sister (who did not lack the turns out to have primary amenorrhea, attributed to sense of smell) had primary amenorrhea due to Kallmann's syndrome!). The laboratory values con- hypogonadotropic hypogonadism. She was initially ®rmed the diagnosis of hypogonadotropic hypogo- treated with sex hormones and, later on, became nadism and LH increases in response to GnRH pregnant after gonadotropin treatment for 2 years. stimulation (Table 1). Other pituitary functions are Our patient would still like to receive peptide normal and so is MR imaging. The patient feels ®ne treatment for fertility induction, after planned on testosterone replacement therapy, works as a marriage, if the treatment is reimbursed by his farmer and is not yet married. insurance.

Table 1 Hormonal values and LH stimulation by 100 mg GnRH i.v. in 4 patients with Kallmann's syndrome

Age at Orchidopexy Testosterone FSH LH basal LH 30 min LH 60 min Case diagnosis (y) at the age of Anosmia (nmol=l) (U=l) (U=l) after GnRH (U=l) after GnRH (U=l)

1263 2.7 < 2 2.5 9.0 9.9 224± 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 517Ð 0.7 < 2 < 2 3.0 3.2

International Journal of Impotence Research Clinical diagnosis of Kallmann's syndrome H John and C Schmid 271 Discussion syndrome, GnRH is the treatment of choice, and GnRH may also work in other hypothalamic dis- orders, whereas in pituitary insuf®ciency, adminis- As shown by our ®ve case reports, Kallmann's tration of gonadotropins (hMG (or rhFSH) hCG) is syndrome is the most frequent cause of isolated required. Adminstration of GnRH to GnRH-de®cient gonadotropin de®ciency due to insuf®cient secre- men simulates LH pulses observed in healthy men tion of GnRH. In its classical form, this congenital where pulses occur at a frequency of around 12 per syndrome results in the absence of endogenous day. Intravenous or subcutaneous administration of GnRH-induced LH pulsations, often cryptorchidism GnRH with an infusion pump delivering 2 ± 40 mg and microphallus, and includes hyposmia or anos- GnRH per pulse every 2 h was found to be effective mia. Kallmann's syndrome affects 1 in 10 000 males; in patients with Kallmann's syndrome. Spermato- females are six times less frequently affected. The genesis can be induced in the majority of these most frequent form of the autosomal recessive patients and fertility rates are above 50%.6,7 It may disease is linked to the X chromosome and appears be dif®cult to estimate the prognosis for the to be due to a defect in the embryonic migration of individual, eg for patients with orchiopexy at an GnRH neurons and olfactory axons from the nose to advanced age. The treatment by peptide hormones the brain. remains complicated and expensive but may be As shown by our four case reports, the diagnosis rewarding for those who can afford it and succeed in of Kallmann's syndrome is often made with sub- fathering children. stantial delay, despite clues in childhood such as anosmia, cryptorchidism and failure to enter puberty timely. Bone maturition and formation of longitudinal growth may occur at any age beyond References 20 y. At presentation, concomitant de®cits of other pituitary hormones should be excluded by history, clinical examination and laboratory ®ndings. The 1 Kallmann FJ, Schoenfeld WA, Barrerra SE. The genetic aspects differential diagnosis includes, apart from constitu- of primary eunuchoidism. Am J Ment De®c 1944; 48: 203 ± 236. tionally delayed puberty, neoplastic and in¯amma- 2 Maestre de San Juan A. Falta total de los nervios olfactorios con anosmia en un individuo en quien existia una atro®a congenital tory diseases but MRI imaging can rule out de los testiculos y miembro viril. Sigio Med 1856; 131: 211. hypothalamic and pituitary tumors such as cranio- 3 Franco B et al. A gene deleted in Kallmann's syndrome shares pharyngiomas or adenomas. Dynamic endocrine homology with neural cell adhesion and axonal path-®nding testing using intravenous GnRH will usually in- molecules. Nature 1991; 353: 529 ± 536. crease both LH and FSH. 4 Morales A, Johnston B, Heaton JPW, Lundie M. Testosterone supplementation for hypogonadal impotence: assessment of The ®rst goal to achieve in therapy for hypogo- biochemical measures and therapeutic outcomes. J Urol 1997; nadotropic hypogonadism is induction of puberty 157: 849 ± 854. and, in males, virilization. Testosterone replace- 5 John H, Trinkler F, Sulser T, Hauri D. Transdermal androgen ment therapy can be performed by intramuscular treatment in the impotent hypogonadal aging male. The Aging Male 1998; 1(Suppl 1): 35. injections of testosterone esters or using transdermal 6 Crowley WF and Whitcomb RW. Gonadotropin-releasing testosterone patches.4,5 This treatment successfully hormone de®ciency in man: diagnosis and treatment with substitutes for the lack of normal Leydig cell exogenous gonadotropin-releasing hormone. Am J Obstet function but will not induce spermatogenesis. Gynecol 1990; 163: 1752 ± 1758. Gonadotropin (hMG hCG) and pulsatile gona- 7 Schopohl J. Comparison of gonadotropin-releasing hormone and gonadotropin therapy in male patients with idio- dotropin releasing hormone (GnRH) therapy are pathic hypothalamic hypogonadism. Fertil Steril 1991; 56: used to induce fertility. In patients with Kallmann's 1143 ± 1150.

International Journal of Impotence Research