Adrenal Hypoplasia Congenita (AHC), X-linked

Loss-of-function mutations in the NR0B1 (DAX1) gene on chromosome Xp21 cause X-linked adrenal hypoplasia congenita (AHC). In males with X-linked AHC, the mature adult zone of the adrenal cortex fails to develop properly, resulting in a cortex that appears disorganized and contains large, cytomegalic cells that resemble cells in the fetal cortex. Typically, males with X-linked AHC develop salt-wasting primary adrenal failure in early infancy (~60%) or childhood (~40%), although later-onset cases presenting in adulthood have been described (Achermann et al., 2001; Mantovani et al., 2002). Individuals with mutations in the NROB1 gene also develop hypogonadotropic hypogonadism (HH), although the age of onset is variable. HH due to altered hypothalamic-pituitary-gonadal (HPG) activity may be observed in infancy, and greater than 10% of males with X-linked AHC have bilaterally undescended testicles. However, other individuals have normal HPG activity in infancy, and onset of HH is noted at the time of puberty. In rare cases, patients with DAX1 mutations have been reported with spontaneous onset of puberty, although pubertal development is incomplete. Most males have azoospermia and remain infertile even after treatment with gonadotropins (Mantovani et al., 2002), although a male with an NROB1 mutation was reported with preserved fertility (Merke et al., 1999). While mutations within the DAX1 gene result in isolated X-linked AHC, X-linked AHC may also occur as part of a contiguous gene deletion syndrome associated with mental retardation, glycerol kinase deficiency, and/or Duchenne muscular dystrophy, depending on the size of the deletion.

Most females who are heterozygous carriers of NROB1 mutations have normal adrenal function and no evidence of HH; however, several have been reported with delayed puberty (Seminara et al., 1999), and a female with a contiguous gene deletion including NROB1 had primary adrenal failure due to skewed X-inactivation (Shaikh et al., 2008). Additionally, one female was reported with a homozygous NROB1 mutation causing HH but apparently normal adrenal and ovarian function
(Merke et al., 1999).

Duplications of the NR0B1 gene and the surrounding genomic region, referred to as the dosage-sensitive sex reversal (DSS) region, do not cause X-linked AHC but instead result in a 46,XY disorder of sex development. Although most patients reported with duplications of the DSS region have complete gonadal dysgenesis causing XY sex reversal, partial gonadal dysgenesis with ambiguous genitalia has been described (Barbaro et al., 2008). Duplications of DAX1 in 46,XX individuals have no known clinical consequence, but the risk of transmission to 46,XY offspring is a significant consideration.

Tests Available

Forms and Documents

Test Details

NR0B1
  • To determine the etiology of primary adrenal insufficiency in a male, particularly in the presence of HH, an X-linked family history, and/or symptoms suggestive of a contiguous gene deletion syndrome
  • To determine etiology of 46,XY gonadal dysgenesis and ambiguous genitalia
  • Carrier testing for females with a family history of X-linked AHC
  • Prenatal diagnosis for at-risk pregnancies
  • Capillary Sequencing

Ordering

416
4 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL)|Dried Blood Spots|Buccal Swabs

Billing

81404x1
No
Yes
* For price inquiries please email zebras@genedx.com

References

  1. Morel et al., (January 2010) Studies of a cohort of 46,XY with DSD including steroid biosynthesis deficiencies Presented at Hormonal and Genetic Basis of Sexual Differentiation Disorder and Hot Topics in Endocrinology, Miami, FL
  2. Bardoni et al., (1994) Nat Genet 7:497-501
  3. Salvi et al., (2002) J Clin Endocrinol Metab 87:4094-4100
  4. Lin et al., (2006) J Clin Endocrinol Metab 91:3048-3054
  5. Muscatelli et al., (1994) Nature 372:672-676
  6. McCabe ERB (2007) Mol Cell Endocrinol 265- 266:179-182
  7. Ho et al., (2004) Mol Genet Metab 83:330-336
  8. Zhang et al., (1998) Am J Hum Genet 62:855-864
  9. Barbaro et al., (2008) Clin Genet 73:453-464
  10. Shaikh et al., (2008) J Med Genet 45:e1
  11. Seminara et al., (1999) J Clin Endocrinol Metab 84:4501- 4509
  12. Merke et al., (1999) NEJM 340:1248-1252
  13. Mantovani et al., (2002) J Clin Endocrinol Metab 87:44-48
  14. Achermann et al., (2001) Molec Cell Endocrinol 185:17-25

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.

Forms and Documents

Test Details

NR0B1
  • Full gene sequencing for male fetuses with a history of low maternal uE3, particularly in the presence of a family history suggestive of X-linked AHC
  • Mutation-specific testing for fetuses with a family history of known NR0B1 mutations
  • Capillary Sequencing

Ordering

663
2-3 weeks
20 mL Amniotic Fluid
20 mg CVS|2 T25 flasks of cultured amniocytes|2 T25 flasks of cultured chorionic villi|3 Ug DNA Concentration

Billing

81479x1, 81265x1
No
Yes
* For price inquiries please email zebras@genedx.com

References

  1. Achermann et al., (2001) Molec Cell Endocrinol 185:17-25.
  2. Mantovani et al., (2002) J Clin Endocrinol Metab 87:44-48.
  3. Merke et al., (1999) NEJM 340:1248-1252.
  4. Seminara et al., (1999) J Clin Endocrinol Metab 84:4501- 4509.
  5. Shaikh et al., (2008) J Med Genet 45:e1.
  6. Barbaro et al., (2008) Clin Genet 73:453-464.
  7. Zhang et al., (1998) Am J Hum Genet 62:855-864.
  8. Ho et al., (2004) Mol Genet Metab 83:330-336.
  9. McCabe ERB (2007) Mol Cell Endocrinol 265- 266:179-182.
  10. Muscatelli et al., (1994) Nature 372:672-676.
  11. Lin et al., (2006) J Clin Endocrinol Metab 91:3048-3054.
  12. Salvi et al., (2002) J Clin Endocrinol Metab 87:4094-4100.
  13. Bardoni et al., (1994) Nat Genet 7:497-501.
  14. Morel et al., (January 2010) Studies of a cohort of 46,XY with DSD including steroid biosynthesis deficiencies Presented at Hormonal and Genetic Basis of Sexual Differentiation Disorder and Hot Topics in Endocrinology, Miami, FL.