46,XY difference of sex development-adrenal insufficiency due to CYP11A1 deficiency

What it is

From: Orphanet

A rare, genetic, developmental defect during embryogenesis disorder characterized by severe, early-onset, salt-wasting adrenal insufficiency and ambiguous/female external genitalia (irrespective of chromosomal sex) due to mutations in the CYP11A1 gene. Milder cases may present delayed onset of adrenal gland dysfunction and genitalia phenotype may range from normal male to female in individuals with 46,XY karyotype. Imaging studies reveal hypoplastic/absent adrenal glands and biochemical findings include low serum cortisol, mineralocorticoids, androgens, and sodium, with elevated potassium levels.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal sex determination · Very frequent (99-80%)

Anomaly of primary or secondary sexual development or characteristics.

Abnormal urine potassium concentration · Very frequent (99-80%)

An abnormal concentration of potassium(1+) in the urine.

Abnormality of cholesterol metabolism · Very frequent (99-80%)

Any deviation from the normal concentration of cholesterol in the blood circulation.

Abnormality of prenatal development or birth · Very frequent (99-80%)

An abnormality of the fetus or the birth of the fetus, excluding structural abnormalities.

Absence of secondary sex characteristics · Very frequent (99-80%)

No secondary sexual characteristics are present at puberty.

Acidosis · Very frequent (99-80%)

Abnormal acid accumulation or depletion of base.

Adrenocorticotropic hormone excess · Very frequent (99-80%)

Overproduction of adrenocorticotropic hormone (ACTH), which generally leads secondarily to overproduction of cortisol by the adrenal cortex.

Agenesis of corpus callosum · Very frequent (99-80%)

Absence of the corpus callosum as a result of the failure of the corpus callosum to develop, which can be the result of a failure in any one of the multiple steps of callosal development including cellular proliferation and migration, axonal growth or glial patterning at the midline.

Ambiguous genitalia, male · Very frequent (99-80%)

Ambiguous genitalia in an individual with XY genetic gender.

Aplasia of the uterus · Very frequent (99-80%)

A congenital defect characterized by absence of the uterus. Aplasia refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue.

Cryptorchidism · Very frequent (99-80%)

Testis in inguinal canal. That is, absence of one or both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.

Decreased circulating aldosterone level · Very frequent (99-80%)

Abnormally reduced levels of aldosterone.

Decreased circulating androgen level · Very frequent (99-80%)

A reduction in the blood concentration of an androgen, that is, of a steroid hormone that controls development and maintenance of masculine characteristics. The androgens include testosterone and Dehydroepiandrosterone.

Decreased circulating cortisol level · Very frequent (99-80%)

Abnormally reduced concentration of cortisol in the blood.

Other findings in the same source

From: Orphanet

Additional reported features include Decreased testicular size (Very frequent (99-80%)); Delayed puberty (Very frequent (99-80%)); Delayed skeletal maturation (Very frequent (99-80%)); Failure to thrive (Very frequent (99-80%)); Feeding difficulties (Very frequent (99-80%)); Female external genitalia in individual with 46,XY karyotype (Very frequent (99-80%)); Gynecomastia (Very frequent (99-80%)); Hyperkalemia (Very frequent (99-80%)); Hypernatriuria (Very frequent (99-80%)); Hyponatremia (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

When it may begin

From: Orphanet

Infancy; Neonatal

Inheritance in the source

From: Orphanet

Autosomal dominant; Autosomal recessive

Frequency and the population described

From: Orphanet

Reported case(s): 9.0; Worldwide. This is a published case count, not prevalence. Point prevalence: <1 / 1 000 000; Worldwide; Class only.

Which doctor should you see?

The suggested department for discussing 46,XY difference of sex development-adrenal insufficiency due to CYP11A1 deficiency is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

Additional services that may be relevant, depending on the findings, include: Nephrology.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for 46,XY difference of sex development-adrenal insufficiency due to CYP11A1 deficiency. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.