Non-Classical Congenital Adrenal Hyperplasia

Also known as: 21-hydroxylase deficiency

Congenital adrenal hyperplasia results from a defect in the biosynthetic pathway of cortisol and / or aldosterone. Non-classical congenital adrenal hyperplasia (NCAH) is characterized by milder enzyme dysfunction and manifests most commonly in adolescence or early adulthood as a common cause of hyperandrogenism.

Presentation

Non-classical adrenal hyperplasia (NCAH) is a mild disorder with very varied symptoms that usually start to show in childhood. Some females and many males do not develop any symptoms at all.

NCAH does not cause the severe symptoms of virilisation and salt-wasting seen in classical congenital adrenal hyperplasia.

The disorder may be clinically indistinguishable from Polycystic Ovarian Syndrome (PCOS).

Common signs and symptoms of NCAH in both males and females are:

  • Premature development of pubic hair.
  • Hirsutism.
  • Acne.
  • Alopecia.

Other symptoms in females include:

  • Anovulation.
  • Menstrual dysfunction.
  • Decreased fertility.

Additional features in children include tall stature, accelerated linear growth velocity, and advanced skeletal maturation

Due to the nature of the hyperandrogenic symptoms, an ascertainment bias favours the diagnosis in females. Affected males are generally asymptomatic and usually identified following the diagnosis of a female family member.

Please click on the titles to open and close the following information sections.

Please click on the titles to open and close the following information sections.

  • In approximately 95% of cases, non-classical congenital adrenal hyperplasia (NCAH) is caused by mutations in the 21-hydroxylase gene (CYP21A2).  NCAH due to mutations in other steroidogenic enzyme genes, such as 11-beta-hydroxylase is rare.
  • The CYP21A2 gene is located at chromosome 6p21 within the HLA histocompatibility complex.
  • Functional analysis of mutations associated with NCAH generally indicates a 50-80% loss of enzymatic (21-hydroxylase) function – leading to cortisol deficiency, with or without aldosterone deficiency and androgen excess.
  • Clinical features of NCAH predominantly reflect androgen excess rather than adrenal insufficiency.
  • The carrier frequency is in the general population is estimated to be 1:100.
  • In Ashkenazi Jews the carrier frequency is approximately 1:3, with a disease incidence estimated at 1:27.
  • Higher prevalence has also been reported in Mediterranean, Middle-Eastern and Indian populations.
  • The short Synacthen test (Adrenocorticotropic hormone stimulation test) remains the gold standard to confirm decreased 21-hydroxylase activity. This is usually preceded by screening using morning 17-hydroxyprogesterone (17-OHP) concentrations, obtained in the follicular phase in reproductive-aged females.
  • Serum 17-hydroxyprogesterone levels are often normal in patients with NCAH (often elevated in patients with classic Congenital Adrenal Hyperplasia).

Gene Specific:

  • Genetic testing is not usually the first-line diagnostic route for individuals suspected of NCAH, however, it may be useful in patients considering future fertility.
  • Genetic testing can identify those individuals who are compound heterozygotes and may carry an allele encoding a severe defect in CYP21A2.
  • Many patients do not need treatment; treatment is recommended only for those with symptoms.
  • Clinical goals of treatment include normal linear growth velocity, normal rate of skeletal maturation, ‘on time’ puberty and appropriate weight status for children and adolescents.
  • For adolescent and adult women, goals of therapy include regularization of menstrual cycles, prevention of progressive hirsuitism and acne, and fertility.
  • For each patient with NCAH, the benefits of treatment should be weighed against the potential risks of acute adrenal insufficiency secondary to iatrogenic adrenal suppression due to glucocorticoid treatment.
  • Glucocorticoid treatment is indicated in children with androgen excess.
  • Adult women may need adjuvant anti-androgen therapy such as flutamide.
  • Patients with NCAH do not need stress doses of hydrocortisone unless they have iatrogenic suppression of their adrenal glands by glucocorticoid treatment.
  • If the main concern is infertility, ovulation induction is the treatment of choice.
  • If the main concern is hirsuitism, anti-androgens may be used.
  • Patients with non-classical congenital adrenal hyperplasia (NCAH) have a more favourable height prognosis than those with the classic form.
  • The fertility rate among untreated females is approximately 50%.
  • For patients exhibiting features of NCAH, suggested referral would be to a paediatrician or an endocrinologist, as appropriate (depending on the age of the patient). For Jewish patients, it is important to note the ancestry and higher prevalence of NCAH deficiency in the Jewish population.
CAH Parent And Patient Support Group

Patients and parents often feel alone in their journey in dealing with CAH. The CAH IS US support group was founded to help and offer support as well as give both parents and older patients the chance to meet, exchange ideas and share experiences.

Living With CAH

This support organisation is a sub group of CLIMB (Children Living with Inherited Metabolic Diseases). It exists to give support to families and people with the disorder, to increase awareness of the condition to the public and to the medical profession, and to raise funds to support research.

CARES Foundation

The Congenital Adrenal Hyperplasia Research Education & Support Foundation is committed to improving lives through proactively advancing research for better understanding of CAH, better treatments and a cure, as well as through education, advocacy, resources and support services.

GeneReviews: www.ncbi.nlm.nih.gov/pmc/articles/PMC2910408

OMIM: #210900

Written by: Dr Jacky Megitt, Jnetics researcher.
Approved by clinical specialist
Last review: 08.06.2018

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