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%).

Tests Available

Forms and Documents

Test Details

FGFR1
  • Confirmation of the clinical diagnosis
  • Identification of at-risk family members
  • Capillary Sequencing

Ordering

2402
3 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL)|Buccal Swabs

Billing

81405x1
No
Yes
  • 253.4 Other anterior pituitary disorders, Isolated or partial deficiency of an anterior pituitary hormone, other than growth hormone Prolactin deficiency
* For price inquiries please email zebras@genedx.com

References

  1. Hou et al., J Formos Med Assoc 98(6):448(1999)
  2. Pitteloud et al,. PNAS 103(16):6281 (2006)
  3. Oliveira et al., J Clin Endo Metab 86(4):1532 (2001)
  4. Sato et al., J Clin Endo Metab 89(3):1079 (2004)
  5. Albuisson et al., Hum Mut 25(1):98-9 (2005)
  6. Dode et al., Nat Genet 33(4):463 (2003)
  7. Hardelin et al., Hum Mol Genet 2(4)373-377 (1993)

Forms and Documents

Test Details

KAL1
  • Confirmation of the clinical diagnosis
  • Identification of at-risk family members
  • Capillary Sequencing

Ordering

2401
3 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL)|Buccal Swabs

Billing

81406x1
No
Yes
  • 253.4 Other anterior pituitary disorders, Isolated or partial deficiency of an anterior pituitary hormone, other than growth hormone Prolactin deficiency
* For price inquiries please email zebras@genedx.com

References

  1. Hardelin et al., Hum Mol Genet 2(4)373-377 (1993)
  2. Dode et al., Nat Genet 33(4):463 (2003)
  3. Albuisson et al., Hum Mut 25(1):98-9 (2005)
  4. Sato et al., J Clin Endo Metab 89(3):1079 (2004)
  5. Oliveira et al., J Clin Endo Metab 86(4):1532 (2001)
  6. Pitteloud et al,. PNAS 103(16):6281 (2006)
  7. Hou et al., J Formos Med Assoc 98(6):448(1999)

Forms and Documents

Test Details

CHD7, FGF8, FGFR1, GNRH1, GNRHR, KAL1, KISS1, KISS1R, NR0B1, NSMF (NELF), PROK2, PROKR2, TAC3, TACR3
  • 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
  • ExonArray CGH

Ordering

676
4 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL)|Buccal Swabs

Billing

81404x1, 81406x1, 81407x1, 81479x3
Yes
Yes
  • 255.2 Adrenogenital disorders, Adrenogenital syndromes,
  • 781.1 Disturbances of sensation of smell and taste Anosmia Parageusia Parosmia
  • 253.4 Other anterior pituitary disorders, Isolated or partial deficiency of an anterior pituitary hormone, other than growth hormone Prolactin deficiency
  • 257.2 Other testicular hypofunction, Defective biosynthesis of testicular androgen, Eunuchoidism: NOS hypogonadotropic Failure: Leydig's cell, adult seminiferous tubule, adult Testicular hypogonadism
* For price inquiries please email zebras@genedx.com

References

  1. Pallais et al., (2007) [Updated 2010 Oct 14]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1278/
  2. Silveira et al., (2010) Mol Cell Endocrinol 324(1-2):30-8.
  3. Brioude et al., (2010) Eur J Endocrinol 162:835-851.
  4. Raivio et al., (2007) N Engl J Med 357(9):863-73.
  5. Bennett (2004) Pharmacogenomics 5(4):433-8.
  6. Laitinen et al., (2011) Orphanet J Rare Dis 6:41.
  7. Sato et al., (2004) J Clin Endocrinol Metab 89(3):1079-1088.
  8. Trarbach et al., (2006) J Clin Endocrinol Metab 91(10):4006- 12.
  9. Kim et al., (2008) Am J Hum Genet 83(4):511-9.
  10. Cariboni et al., (2004) Hum Mol Genet 13(22):2781-91.
  11. Bianco & Kaiser (2009) Nat Rev Endocrinol 5(10):569-76.
  12. Shaw et al., (2011) J Clin Endocrinol Metab 96(3):E566-76.
  13. Trarbach et al., (2010) Clin Endocrinol 72(3):371-6.
  14. Falardeau et al., J Clin Invest. 2008 Aug;118(8):2822-31.
  15. Miura et al., (2004) J Hum Genet 49(5):265-8.
  16. Xu et al., (2011) Fertil Steril 95(5):1613-20.
  17. OMIM, Online Mendelian Inheritance in Man, (TM). McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), http://www.ncbi.nlm.
  18. Chan et al., (2011) J Clin Endocrinol Metab 96(11):E1771-81.
  19. Topaloglu et al., (2012) N Engl J Med 366(7):629-35.
  20. Niakan & McCabe (2005) Molec Genet Metab 86:70-83.
  21. Achermann et al., (2001) Mol Cell Endocrinol 185(1-2):17-25.
  22. Young et al., (2010) J Clin Endocrinol Metab 95(5):2287-95.
  23. Topaloglu et al., (2009) Nat Genet 41(3):354-8.