Rare Rewritten is live! Check out how we are rewriting the wrongs.  View here

Back to Previous

Adrenal Hypoplasia Congenita (X-Linked)

X-linked adrenal hypoplasia congenita (X-linked AHC) is a rare disorder that is present from birth (congenital) and affects the development of the adrenal glands, which are hormone-producing glands located on top of each kidney. Adrenal glands produce a variety of hormones that regulate many essential functions in the body, including cortisol (which regulates our response to stress), aldosterone (which helps regulate blood pressure and salt balance in the body), and some sex hormones. In males, X-linked AHC causes a shortage of these hormones, resulting in adrenal insufficiency which typically begins in infancy and can cause vomiting, difficulty feeding, dehydration, low blood sugar (hypoglycemia), seizures and shock. If untreated, adrenal insufficiency is life-threatening. Due to a shortage of the adrenal sex hormones and low levels of some pituitary hormones, AHC can also cause hypogonadotropic hypogonadism, a condition that can cause under development of reproductive tissue, delayed puberty and infertility1.

X-linked AHC is caused by variants in the NR0B1 gene on the X chromosome. NR0B1 encodes the DAX-1 protein which is important in the development of the adrenal glands as well as the hypothalamic-pituitary-gonadal (HPG) axis. The onset and severity of AHC signs and symptoms can vary, even among affected members of the same family with the same NR0B1 gene variant. Among male patients, 60-70% will experience infantile-onset adrenal insufficiency, beginning before age 1 (average age 2-3 weeks), while 25-40% have childhood-onset adrenal insufficiency (between age 1-9 years)2,3. A relatively large study published in 2023 looked at 42 male patients with X-linked AHC and found that the first manifestation of disease was usually a salt-wasting crisis, a result of mineralocorticoid (aldosterone) deficiency, with other common early symptoms being vomiting and diarrhea, poor weight gain, and hyperpigmentation of the scrotum3. The same study found that 85% of male patients experienced delayed or arrested puberty due to hypogonadotrophic hypogonadism3.

 

Females with X-Linked AHC

Female carriers of X-linked AHC usually do not have symptoms, though in rare cases they can have mild features of disease. Delayed puberty is the most commonly reported sign of disease in females. One study in 1999 reported a family with X-linked AHC in which 3 females carried the disease variant on one X chromosome (heterozygotes), and all 3 of them experienced significantly delayed puberty, with menarche (first period) occurring at age 17-18 years4. It is hypothesized that the delay was a result of mild hypogonadotropic hypogonadism from AHC. None of these 3 females demonstrated evidence of adrenal insufficiency, nor did they experience infertility or menstrual irregularity following menarche.

Another case was reported in 1999 of a female who was found to be homozygous for X-linked AHC, meaning that due to a rare genetic event, she had an NR0B1 mutation on both of her X chromosomes5. While it might be expected that she would have the full phenotype of AHC disease like affected males, this patient only exhibited hypogonadotropic hypogonadism, without adrenal insufficiency. She had delayed puberty with amenorrhea (no period), a small uterus and ovaries, and a normal-appearing adrenal gland. Her brothers who had the same mutation on their X chromosomes both experienced adrenal insufficiency in addition to hypogonadotropic hypogonadism.

A case was reported in 2008 of a female carrier (heterozygote) of X-linked AHC who had adrenal insufficiency with a salt wasting crisis at 8 days of life6. Cellular testing revealed that X-inactivation was profoundly skewed in this patient, with expression of only the affected X chromosome in all blood cells (and complete inactivation of her normal X), which is thought to explain her disease severity. She remained pre-pubertal at the time that her case was reported, and as such it is unknown if she experienced hypogonadotropic hypogonadism in addition to her adrenal insufficiency.

The specific prevalence of delayed puberty or other signs and symptoms of X-linked AHC in female carriers is not known. Cases of symptomatic females are limited to few case reports, as outlined above, so at this time, it is widely accepted that most females with AHC are asymptomatic carriers.

This page was last updated in July, 2026. Please note that research into females with this condition is limited. Decisions regarding your own health should be made in consultation with your medical provider.

  1. X-linked adrenal hypoplasia congenita: MedlinePlus Genetics. Accessed July 14, 2026. https://medlineplus.gov/genetics/condition/x-linked-adrenal-hypoplasia-congenita/ 
  2. Achermann JC, Vilain EJ. NR0B1-Related Adrenal Hypoplasia Congenita. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed July 14, 2026. http://www.ncbi.nlm.nih.gov/books/NBK1431/ 
  3. Zheng W, Duan Y, Xia Y, et al. Clinical and genetic characteristics of 42 Chinese paediatric patients with X-linked adrenal hypoplasia congenita. Orphanet J Rare Dis. 2023;18:126. doi:10.1186/s13023-023-02737-y 
  4. Seminara SB, Achermann JC, Genel M, Jameson JL, Crowley WF Jr. X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females. J Clin Endocrinol Metab. 1999;84(12):4501-4509. doi:10.1210/jcem.84.12.6172 
  5. Merke DP, Tajima T, Baron J, Cutler GB. Hypogonadotropic Hypogonadism in a Female Caused by an X-Linked Recessive Mutation in the DAX1 Gene. N Engl J Med. 1999;340(16):1248-1252. doi:10.1056/NEJM199904223401605 
  6. Shaikh MG, Boyes L, Kingston H, et al. Skewed X inactivation is associated with phenotype in a female with adrenal hypoplasia congenita. J Med Genet. 2008;45(9):e1. doi:10.1136/jmg.2007.055129

​