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URL of this page: https://medlineplus.gov/genetics/condition/x-linked-adrenal-hypoplasia-congenita/

X-linked adrenal hypoplasia congenita

Description

X-linked adrenal hypoplasia congenita is a disorder that is noticeable from birth (congenital) and affects the development of the adrenal glands, which are hormone-producing (endocrine) organs (glands) located on top of each kidney. These glands produce a variety of hormones that regulate many essential functions in the body, such as response to stress.

One of the main signs of this disorder is adrenal insufficiency, which occurs when the adrenal glands do not produce enough hormones. Adrenal insufficiency typically begins in infancy or childhood and can cause vomiting, difficulty with feeding, dehydration, extremely low blood glucose (hypoglycemia), and shock. If untreated, these complications are often life-threatening.

Individuals with X-linked adrenal hypoplasia congenita may also have a shortage of male sex hormones, which leads to underdeveloped reproductive tissues, undescended testicles (cryptorchidism), delayed puberty, and an inability to father children (infertility). Together, these characteristics are known as hypogonadotropic hypogonadism.

The onset and severity of these signs and symptoms can vary, even among affected members of the same family.

Frequency

X-linked adrenal hypoplasia congenita appears to be an uncommon condition. It has been reported to affect approximately 1 in 12,500 newborns, but this is likely an overestimate. The true prevalence of this condition is unknown.

Causes

Variants (also called mutations) in the NR0B1 gene cause X-linked adrenal hypoplasia congenita. The NR0B1 gene provides instructions to make a protein called DAX1. This protein plays an important role in the development and function of several endocrine tissues including the adrenal glands, two hormone-secreting glands in the brain (the hypothalamus and pituitary), and the gonads (ovaries in females and testes in males).  The hormones produced by these glands control many important body functions.

Some NR0B1 variants result in the production of an inactive version of the DAX1 protein, while other variants delete the entire gene. The resulting shortage of DAX1 disrupts the normal development and function of hormone-producing tissues in the body. The signs and symptoms of adrenal insufficiency and hypogonadotropic hypogonadism occur when endocrine glands do not produce the right amounts of certain hormones.

Rarely, the entire NR0B1 gene is deleted along with other neighboring genes, resulting in the development of X-linked adrenal hypoplasia with hypoplasia congenita and other diseases, such as Duchenne and Becker muscular dystrophy and glycerol kinase deficiency.

Learn more about the gene associated with X-linked adrenal hypoplasia congenita

Inheritance

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a variant must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females.  A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the altered gene, but usually does not experience signs and symptoms of the disorder. In rare cases, however, females who carry an NR0B1 gene variant may experience adrenal insufficiency or signs of hypogonadotropic hypogonadism such as underdeveloped reproductive tissues, delayed puberty, and an absence of menstruation.

Other Names for This Condition

  • Adrenal hypoplasia congenita
  • X-linked AHC

Additional Information & Resources

Genetic Testing Information

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Clinical Trials

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Achermann JC, Vilain EJ. NR0B1-Related Adrenal Hypoplasia Congenita. 2001 Nov 20 [updated 2018 Jan 25]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1431/ Citation on PubMed
  • Ahmad I, Paterson WF, Lin L, Adlard P, Duncan P, Tolmie J, Achermann JC, Donaldson MD. A novel missense mutation in DAX-1 with an unusual presentation of X-linked adrenal hypoplasia congenita. Horm Res. 2007;68(1):32-7. doi: 10.1159/000099835. Epub 2007 Feb 16. Citation on PubMed or Free article on PubMed Central
  • Choi HS, Kwon A, Chae HW, Suh J, Song KC, Lee JS, Kim HS. Identification of a novel point mutation in DAX-1 gene in a patient with adrenal hypoplasia congenita. Ann Pediatr Endocrinol Metab. 2021 Jun;26(2):126-129. doi: 10.6065/apem.2040088.044. Epub 2021 Jun 30. Citation on PubMed
  • Clipsham R, McCabe ER. DAX1 and its network partners: exploring complexity in development. Mol Genet Metab. 2003 Sep-Oct;80(1-2):81-120. doi: 10.1016/j.ymgme.2003.08.023. Citation on PubMed
  • Fujieda K, Okuhara K, Abe S, Tajima T, Mukai T, Nakae J. Molecular pathogenesis of lipoid adrenal hyperplasia and adrenal hypoplasia congenita. J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):483-9. doi: 10.1016/s0960-0760(03)00232-2. Citation on PubMed
  • Fujieda K, Tajima T. Molecular basis of adrenal insufficiency. Pediatr Res. 2005 May;57(5 Pt 2):62R-69R. doi: 10.1203/01.PDR.0000159568.31749.4D. Epub 2005 Apr 6. Citation on PubMed
  • Hammer GD, Parker KL, Schimmer BP. Minireview: transcriptional regulation of adrenocortical development. Endocrinology. 2005 Mar;146(3):1018-24. doi: 10.1210/en.2004-1385. Epub 2004 Dec 16. Citation on PubMed
  • Lalli E, Sassone-Corsi P. DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation. Mol Endocrinol. 2003 Aug;17(8):1445-53. doi: 10.1210/me.2003-0159. Epub 2003 May 29. Citation on PubMed
  • Ludbrook LM, Harley VR. Sex determination: a 'window' of DAX1 activity. Trends Endocrinol Metab. 2004 Apr;15(3):116-21. doi: 10.1016/j.tem.2004.02.002. Citation on PubMed
  • Mantovani G, De Menis E, Borretta G, Radetti G, Bondioni S, Spada A, Persani L, Beck-Peccoz P. DAX1 and X-linked adrenal hypoplasia congenita: clinical and molecular analysis in five patients. Eur J Endocrinol. 2006 May;154(5):685-9. doi: 10.1530/eje.1.02132. Citation on PubMed
  • Sehgal A, Stack J. Complex glycerol kinase deficiency: an X-linked disorder associated with adrenal hypoplasia congenita. Indian J Pediatr. 2005 Jan;72(1):67-9. doi: 10.1007/BF02760584. Citation on PubMed
  • Tabarin A. Congenital adrenal hypoplasia and DAX-1 gene mutations. Ann Endocrinol (Paris). 2001 Apr;62(2):202-6. Citation on PubMed
  • Wikiera B, Jakubiak A, Laczmanska I, Noczynska A, Smigiel R. Complex glycerol kinase deficiency - long-term follow-up of two patients. Pediatr Endocrinol Diabetes Metab. 2021;27(3):227-231. doi: 10.5114/pedm.2021.109681. Citation on PubMed

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