Clinical Guidance

In X-linked AHC caused by a single-nucleotide variant in NR0B1 no clear correlation exists between the location or type of variant and the clinical phenotype, except as outlined below:

• Late-onset X-linked AHC can result from variants in the ligand-like binding region of NR0B1 around the hydrophobic core (e.g., , ) . Changes close to the repression helix domain can also present with late-onset X-linked AHC (e.g., , ) .

• Late-onset X-linked AHC may also occur as a result of nonsense variants at the amino-terminal region of NR0B1 (e.g., stop codons at position 37 or 39) . It has been proposed that translation reinitiation from a methionine at codon 83 produces an amino-terminally truncated protein with partially conserved function .

Source: GeneReviews — "NR0B1-Related Adrenal Hypoplasia Congenita"

Diagnostic Criteria

NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency), which 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).

Suggestive Findings

NR0B1-related adrenal hypoplasia congenita should be suspected in males with the of X-linked adrenal hypoplasia congenita (X-linked AHC) or Xp21 deletion and supportive and findings.

Clinical Findings

X-linked AHC and Xp21 deletion

Source: GeneReviews — "NR0B1-Related Adrenal Hypoplasia Congenita"

Differential Diagnosis

In males with salt-losing primary adrenal insufficiency and either a family history of X-linked adrenal insufficiency or other features of NR0B1-related X-linked AHC (e.g., hypogonadotropic hypogonadism), the likelihood of identifying a pathogenic NR0B1 variant is increased . In contrast, in males with salt-losing primary adrenal insufficiency with no family history of adrenal insufficiency and no other features of NR0B1-related X-linked AHC in whom other causes of primary adrenal insufficiency have been excluded (e.g., congenital adrenal hyperplasia), the likelihood of identifying a pathogenic NR0B1 variant is about 20%-40% [, , , ].

Source: GeneReviews — "NR0B1-Related Adrenal Hypoplasia Congenita"

Management Guidelines

Evaluations Following Initial Diagnosis

To assess the extent of disease and needs in an individual diagnosed with NR0B1-related adrenal hypoplasia congenita, the following evaluations are recommended under the care of an experienced pediatric endocrinologist.

All Individuals with NR0B1-Related Adrenal Hypoplasia Congenita (X-linked AHC or Xp21 Deletion) Assessment of adrenal function:

• If the presentation is predominantly mineralocorticoid insufficiency (salt loss), assess adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test). If function is reduced, appropriate glucocorticoid replacement is needed . If it is adequate, long-term follow up is necessary .

• If the presentation is predominantly glucocorticoid insufficiency, assess adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity). If function is reduced, fludrocortisone replacement is required as well as adequate salt supplementation in young children (age 1 year) . If it is adequate, long-term follow up is necessary .

Assessment for early puberty or hypogonadotropic hypogonadism:

Source: GeneReviews — "NR0B1-Related Adrenal Hypoplasia Congenita"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "NR0B1-Related Adrenal Hypoplasia Congenita"

Surveillance Guidelines

Primary Adrenal Insufficiency

If mineralocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity) is necessary. Monitoring should be fairly intense in the first two years of life (e.g., every 4 months) or at times of clinical concern. With age, mineralocorticoid sensitivity improves, but annual reviews would be appropriate and care needed during times of limited salt intake, fluid restriction, fluid loss (e.g., vomiting, diarrhea), or extreme heat. Clinical concern in the older child (e.g., postural hypotension or dizziness) needs investigation. If glucocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test) is necessary. Basal ACTH is a useful marker of impaired glucocorticoid function and should be measured together with cortisol during the first two years of life. If there are any concerns, a cosyntropin stimulation test should be performed, looking for an impaired cortisol response, not just an inadequate basal cortisol level. Annual reviews of basal ACTH/cortisol and possibly cosyntropin stimulation should be considered in a boy with a genuine X-linked AHC if glucocorticoid insufficiency has not yet developed. Any clinical concerns (e.g.

Source: GeneReviews — "NR0B1-Related Adrenal Hypoplasia Congenita"