In 1856, Maestre de San Juan observed the association of hypogonadism with olfactory system abnormalities.1 Later de Morsier described, under the term olfactogenital dysplasia, a series of patients with hypogonadism and anosmia who had various abnormalities of the olfactory system associated with multiple malformations.2,3 Kallmann first identified the inherited nature of this condition in 1944.4 Subsequently, the term Kallmann syndrome (KS) came to designate an inherited disorder characterized by the association of hypogonadotropic hypogonadism and anosmia.
The hypogonadism in KS is due to a reduced secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus.5 The degree of GnRH deficiency in KS patients is variable, ranging from complete deficiency, in which both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are low and there is no evidence of sexual maturation, to partial deficiency, in which FSH secretion predominates, allowing a certain degree of germinal-cell maturation in the testis but resulting in incomplete sexual development.6 Typical patients with KS have an eunuchoid habitus. Gynecomastia, micropenis, and cryptorchidism have been reported in some cases.7
The other cardinal feature of patients with KS is the presence of nonselective anosmia or hyposmia. Therefore, a precise determination of the olfactory threshold in patients with hypogonadotropic hypogonadism is of fundamental importance in confirming the diagnosis of KS.
Table 225-1 shows the complete spectrum of clinical features associated with KS. Additional features found in several patients with KS include synkinesia (mirror movements), pes cavus, high arched palate, and unilateral renal agenesis.8-11 Hardelin et al. demonstrated that these features represent pleiotropic effects of point mutations in the X-linked KS gene.12,13 Mirror movements occur in 85 percent of males with X-linked KS. When asked to perform unilateral intentional movements, patients with synkinesia move muscles of the contralateral side together with the primary movement. Synkinesia was suggested to arise from the lack of the fibers that typically cross within the corpus callosum and inhibit the contralateral uncrossed pyramidal tract.14 Danek et al. measured movement-related cortical potentials in families with X-linked KS and demonstrated a complete correlation between the presence of the KS phenotype and bilaterality of evoked motor responses.15 A recent neurophysiologic study concluded that patients with X-linked KS have a novel ipsilateral corticospinal tract, most likely resulting from a lack of decussation of the corticospinal tract at the level of the pyramids.16 However, both PET17 and functional MR imaging studies18 suggest that bilateral activation of the primary motor cortices could contribute to the presence of mirror movements.
Table 225-1: Clinical Features Associated with Kallmann Syndrome |Favorite Table|Download (.pdf) Table 225-1: Clinical Features Associated with Kallmann Syndrome
|Cardinal features found in most patients with Kallmann syndrome |
Pleiotropic effects of mutations in the KAL gene
Synkinesia (mirror movements)
Unilateral renal agenesis
High arched palate
Rare features observed in a few cases
Gaze-evoked horizontal nystagmus
Cleft lip and palate
Features found in patients with Xp22.3 deletions
(contiguous gene syndrome)
Additional neurologic symptoms described in some patients with KS include eye-movement abnormalities, cerebellar ataxia, gaze-evoked horizontal nystagmus,10,11 sensorineural deafness,9 spatial-attention abnormalities,19 spastic paraplegia,20 and mental retardation.8 Moreover, somatic defects, such as cleft lip and palate, and congenital heart defects have been described.9,11,21
Occasional patients with KS also manifest features of other distinct X-linked diseases such as ichthyosis, chondrodysplasia punctata, mental retardation, short stature, and ocular albinism. This combination of disorders results from deletions of the distal short arm of the human X chromosome, leading to a contiguous gene syndrome (see Chap. 65).22
Patients with KS usually present at puberty with a delay in the appearance of secondary sex characteristics. Laboratory tests reveal low serum concentrations of FSH and LH 6 and very low levels of testosterone in males or of estradiol in females. Differentiation between KS and delayed puberty requires a complete family history and a thorough assessment of olfactory function, which can be tested by the method proposed by Henkin and Bartter23 or by the Smell Identification Test.24 Sporadic cases of KS may be difficult to differentiate from idiopathic hypogonadotropic hypogonadism because of the variability in expression of anosmia in KS.25 Hypogonadotropic hypogonadism can also be due to central nervous system tumors, histiocytosis, radiation therapy, idiopathic hypopituitary dwarfism, Prader-Willi syndrome, Laurence-Moon-Biedl syndrome, chronic diseases, malnutrition, anorexia nervosa, or hypothyroidism. All of these disorders are easily distinguishable from KS.6
Treatment for KS is directed toward restoration of normal gonadal steroid levels to allow sexual maturation and induce fertility. The exogenous administration of testosterone is usually effective in inducing virilization. Achieving fertility, however, requires administration of gonadotropins or GnRH. Controversy exists regarding the effectiveness of gonadotropin versus GnRH replacement therapy in hypogonadotropic males, as reviewed elsewhere.26 Combined gonadotropin replacement by administration of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) appears to be the most common treatment for hypogonadotropic hypogonadism. Comparable results have been obtained with either subcutaneous or intramuscular administration. Subcutaneous applications, however, seem to be preferred because they are less painful and can be done by the patient.27 Response to gonadotropin therapy varies considerably among individuals.27 Although pulsatile subcutaneous administration of GnRH is the most physiological treatment,28 the need for a programmable infusion pump makes this therapy difficult to carry out and often decreases compliance. Hormonal replacement therapy, either by gonadotropins or GnRH, is required over many months, because shorter treatments usually fail to induce normal sexual development and spermatogenesis. The patient's compliance and his desire for fertility play a fundamental role in achieving successful treatment.