Kallmann Syndrome

Kallmann syndrome (KS) is typically characterized by hypogonadotropic hypogonadism and anosmia. The presence of a defective sense of smell, whether partial (hyposmia) or complete (anosmia) distinguishes KS from normosmic idiopathic hypogonadotropic hypogonadism with a normal sense of smell (nIHH), which can be associated with mutations in the GnRHR and GPR54 genes. Due to hypothalamic GnRH deficiency, males with KS demonstrate cryptorchidism, testicular atrophy and microphallus at birth and then subsequent failure to undergo a normal puberty during adolescence. Females with KS usually present with primary amenorrhea or infertility. Mutations in at least two genes have been shown to be associated with KS. Mutation in the X-linked KAL1 gene is associated with the classic genital and olfactory features of Kallmann syndrome, and in some cases, renal agenesis in males only. This is known as Type 1 Kallmann syndrome (KAL1). Type 2 Kallmann syndrome (KAL2) is caused by mutation in the autosomal FGFR1 gene, a gene also responsible for several skeletal disorders including cleft lip and palate. Although premature skeletal fusion syndromes, i.e. craniosynostoses, have not been observed in patients with Kallmann syndrome, orofacial clefting and hypodontia can be seen in KAL2 patients. Both types show clinical variability and reduced penetrance, although this is much more significant in FGFR1-associated KS. Type 1 KS is the result of abnormal anosmin-1 protein production due to KAL1 gene mutation. Loss-of-function, or inactivating, mutation in the FGFR1 gene causes Type 2 KS, as opposed to gain-of-function, or activating mutations which are associated with craniosynostosis. Overall, about 25% of Kallmann syndrome cases are due to mutation in KAL1 (5-10%) or FGFR1 (8-16%).

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Test Details

CHD7, CYP19A1, DUSP6, ESR1, FEZF1, FGF17, FGF8, FGFR1, GNRH1, GNRHR, HS6ST1, IL17RD, KAL1, KISS1, KISS1R, LEP, LEPR, LHB, LHCGR, NR0B1, NR5A1, NSMF, POLR3B, PROK2, PROKR2, PROP1, SEMA3A, SEMA3E, SOX10, SPRY4, TAC3, TACR3, WDR11
  • Molecular confirmation of a clinical diagnosis
  • To assist with decisions about treatment and management of individuals with HH
  • Testing of at-risk relatives for specific known mutation(s) previously identified in an affected family member
  • Prenatal diagnosis for known familial mutation(s) in at-risk pregnancies
  • Next-Gen Sequencing
  • Deletion/Duplication Analysis

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References

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  11. Quaynor et al., (2011) Fertil Steril 96(6): 1424-1430 (PMID: 22035731)
  12. Bianco & Kaiser, (2009) Nat Rev Endocrinol 5(10):569-576 (PMID: 19707180)