Clinical characteristics: NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism.

Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD.

Diagnosis/testing: The diagnosis of NR0B1-related adrenal hypoplasia congenita is established in a male proband by detection of either a hemizygous pathogenic variant in NR0B1 or a non-recurrent Xp21 deletion that includes NR0B1.

Management: Treatment of manifestations: Episodes of acute adrenal insufficiency are usually treated in an intensive care unit with close monitoring of blood pressure, hydration, clinical status, and serum concentration of glucose and electrolytes. Once the initial acute episode has been treated, affected individuals are started on replacement doses of glucocorticoids and mineralocorticoids and – in younger children – oral supplements of sodium chloride. Steroid dosage must be increased during periods of stress (e.g., intercurrent illness, surgery, trauma); glucose and sodium may be needed. HH may be treated with increasing doses of testosterone to induce age-appropriate puberty and should be monitored by a pediatric endocrinologist. Treatment is usually initiated at around or just after the time puberty would be expected (age 12 years in boys).

Surveillance: If mineralocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal mineralocorticoid function is necessary. If glucocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal glucocorticoid function is necessary.

If puberty has not started by age 14 years, monitoring of serum concentrations of LH, FSH, testosterone, and inhibin B to evaluate for the possibility of HH is necessary. If puberty has started spontaneously, it is likely to arrest; thus, yearly routine monitoring of levels of LH, FSH, and testosterone is necessary.

Evaluation of relatives at risk: At birth: If the genetic status of an at-risk male relative has not been established prior to birth by prenatal molecular genetic testing, it is appropriate to monitor him with biochemical testing for evidence of adrenal insufficiency in the first few days of life in order to determine if he would benefit from prompt initiation of glucocorticoid and mineralocorticoid hormone replacement therapy to avoid a salt-losing adrenal crisis. Later in childhood: When the NR0B1 pathogenic variant in the family is known, it is reasonable to clarify the genetic status of at-risk asymptomatic maternal male relatives by molecular genetic testing as approximately 40% of affected males will not manifest adrenal insufficiency until childhood or later.

Genetic counseling: NR0B1-related adrenal hypoplasia congenita is inherited in an X-linked manner.

X-linked AHC: The risk to sibs depends on the genetic status of the mother: if the mother is heterozygous for an NR0B1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will typically not be affected but will be carriers. Most males with AHC are infertile.

Xp21 deletion: Although most mothers of an individual diagnosed with an Xp21 deletion are carriers, a proband may have the disorder as the result of a de novo contiguous gene deletion. The risk to the sibs of the proband depends on the genetic status of the mother: if the mother is heterozygous for the Xp21 deletion, the chance of transmitting the deletion in each pregnancy is 50%. Males who inherit the deletion will be affected; females who inherit the deletion will typically not be affected.

Once the NR0B1 pathogenic variant or Xp21 deletion has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.