Kallman syndrome 1 30000

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Idiopathic hypogonadotropic hypogonadism (IHH) or Kallman syndrome is characterized by hypogonadism. Most patients experience a delay in puberty although those with less severe defects may present with only infertility. Other findings include anosmia, small testes and occasionally renal agenesis, bimanual synkinesia, cleft lip and dental agenesis. When anosmia is not present, the condition is termed IHH. Testicular biopsies display a wide range of findings from germ cell aplasia to focal areas of complete spermatogenesis (Patrizio and Broomfield, 1999). The condition is inherited as a familial disorder in one-third of cases. Both X-linked and autosomal inheritance patterns have been described (Bhasin et al., 1998; Layman et al., 1998). In the X-linked recessive form, deletions occur in Kalig-1 (kallman-interval 1 or KAL1), a gene responsible for the migration of gonadotropin releasing hormone (GnRH) neurons to the pre-optic area of the hypothalamus during development (Bick et al., 1992). The KAL1 gene shares homology with other cell adhesion and axonal pathfinding molecules, further supporting the notion that a molecular defect in the gene causes the neuronal migration defect. The KAL protein is a secreted, diffusible molecule that easily incorporates into the extracellular matrix and is termed anosmin-1. Once incorporated into the extracellular matrix of the olfactory bulb, the KAL protein might promote the migration and target recognition of olfactory axons. As a consequence of mutations in this gene, there is failure of testicular stimulation by the anterior pituitary and hypothalamus and thus testis failure. Mutations in other genes have also been associated with the development of IHH including double-dose associated sex-reversal (DAX1) on the X chromosome (associated with congenital adrenal hyperplasia) (Guo et al., 1995), the GnRH receptor (Layman et al., 1998) and phosphatidylcholine (PC1) (associated with diabetes and obesity) (Jackson et al., 1997). In addition to the X-linked form,

Table 10.5. Recognized forms of Kallman syndrome

Descriptor

Inheritance

Gene identified

KAL1

X-linked

KALIG-1 (Xp22.3)

KAL2

Autosomal dominant

FGFR1 (8p11-12)

KAL3

Autosomal recessive

None

autosomal dominant (KAL2) and recessive (KAL3) transmission of Kallman syndrome has also been reported (Dode et al., 2003; Oliveira et al., 2001) (Table 10.5).

Phenotypically, Kallman patients with documented KAL1 mutations have apul-satile LH secretion, indicating complete lack of neuronal migration. In contrast, men with autosomal inheritance are more variably affected, generally with weakened but present LHRH-induced LH pulses. Although mental or intellectual disturbance was described in the original report of Kallman syndrome, more current analyses show that Kallman syndrome patients with mental disorders have large deletions on Xp that extend well beyond the KAL1 locus. Infertility can be treated with gonadotropin (LH and FSH) replacement over 12-18 months, which stimulates spermatogenesis and the presence of sperm in the ejaculate in 80% of men (Buchter et al., 1998). The clinical diagnosis of Kallman syndrome is confirmed by blood tests revealing a low total testosterone associated with low LH and low FSH levels in combination with normal prolactin.

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