Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia, a group of conditions that affect the adrenal glands. The adrenal glands sit on top of each kidney and is involved in producing important hormones that regulate many body functions. In CAH due to 21-hydroxylase deficiency, the 21-hydroxylase enzyme is not working properly. This causes the body to produce too much androgen (male sex hormone) and not enough cortisol (stress hormone) and aldosterone (hormone that regulates water and salt balance in the body).

Excessive androgen production can lead to virilisation, which is the development of male physical characteristics in females and premature puberty in males. Insufficient cortisol and aldosterone can result in inability to retain salt and water, dehydration, low blood pressure and life-threatening adrenal crisis (also known as salt-wasting crisis).

Symptoms can vary widely between individuals, but CAH due to 21-hydroxylase deficiency can typically be categorised into two types:

• classic type – more severe; can result in adrenal crisis and death if left untreated. It can sometimes be further divided into the salt-wasting form and simple virilising form
• non-classic type  – less severe; may or may not have symptoms

In Australia, CAH due to 21-hydroxylase deficiency is often detected shortly after birth via newborn bloodspot screening (NBS) programs. For individuals who are not screened at birth, CAH due to 21-hydroxylase deficiency is often diagnosed after symptoms develop. Early detection and management of CAH due to 21-hydroxylase deficiency is important to prevent life-threatening adrenal crisis, and to allow normal health, development and puberty.

Synonyms: Classic 21-OHD CAH

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:90794 Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

ICD-11: 5A71.01 Congenital adrenal hyperplasia

Rare diseases typically display a high level of symptom complexity. There is often a wide range of symptoms and the symptoms may vary between individuals in terms of its presentation, severity, duration and impact.

Please speak to your medical team to learn more about the symptoms of this condition.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

CAH due to 21-hydroxylase deficiency is a genetic condition. It is caused by disease-causing genetic changes (variants) in the CYP21A2 gene.

All individuals have two copies (alleles) of the CYP21A2 gene – one copy inherited from each parent. CAH due to 21-hydroxylase deficiency is an autosomal recessive condition, which means both copies of the CYP21A2 gene must have the disease-causing genetic variants. More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

Screening

In Australia, CAH due to 21-hydroxylase deficiency is usually detected via the newborn bloodspot screening (NBS) programs.  Shortly after birth and with parental consent, a nurse or midwife will collect the baby’s blood via a heel prick blood test. The healthcare provider will then send it to a specific laboratory to test for a range of rare conditions, including CAH due to 21-hydroxylase deficiency. If the test results suggest that there is a risk of the baby having one of screened conditions, laboratory staff will promptly get in touch with healthcare providers. The healthcare providers will then arrange for the baby to have further testing to confirm if the baby actually has the condition. The healthcare providers will also organise for the baby to receive urgent care if required. Depending on your state or territory, parents may or may not receive a notification if the test results are clear. You can find out more about NBS in your state or territory at Australian Government Department of Health, Disability and Ageing: Delivering newborn bloodspot screening programs.

Newborn bloodspot screening is a reliable way to check for certain rare conditions early in life. Although it’s extremely rare, cases can sometimes be missed. If you are concerned your baby may have a condition that they have already been screened for, you should contact a medical professional.

Diagnosis

A diagnosis of CAH due to 21-hydroxylase deficiency may be suspected based on an abnormal result from NBS but additional tests or a clinical examination will be required to confirm a diagnosis. For individuals who are not screened at birth, CAH due to 21-hydroxylase deficiency is often diagnosed after symptoms develop.

Diagnosis of CAH due to 21-hydroxylase deficiency may be made based on:

• clinical evaluation – signs of virilisation (such as presence of ambigious genitalia in females with 46;XX chromosomes, early signs of puberty in males with 46;XY chromosomes) and salt-wasting or adrenal insufficiency
• steroid hormone measurements – changes in serum steroid profile such as increased levels of serum 17-hydroxyprogesterone (17-OHP) and adrenal androgens and decreased cortisol levels; an ACTH stimulation test may also be performed
• genetic testing – presence of disease-causing genetic variants in the CYP21A2 gene

As part of the diagnostic process, doctors may do a differential diagnosis, which is to rule out other conditions that have similar symptoms, such as other forms of CAH, polycystic ovary syndrome (mainly for non-classical CAH), Addison’s disease, or any diseases with androgen excess.

Please speak to your medical team to learn more about the available pathways for diagnosis of this condition.

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities.

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

Healthcare professionals involved in the clinical care of individuals with CAH due to 21-hydroxylase deficiency may include general practitioners (GPs), paediatricians, geneticists, genetic counsellors, endocrinologists, urogynaecology specialists, psychologists and others. The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.

If you know of any relevant clinical care guidelines, please let us know via the  Contribute page.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

If you know of any relevant emergency management guidelines or information relevant to emergency care, please let us know via the  Contribute page.

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in any clinical trials with your medical team to determine suitability and eligibility.

Please note that RVA does not necessarily monitor or endorse each group/organisation’s operational governance and activities.

We are not aware of any registered rare disease organisations specifically for CAH due to 21-hydroxylase deficiency in Australia. If you are aware of any relevant Australian organisations, please let us know via the Contribute page.

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

CAH due to 21-hydroxylase deficiency varies between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease, including families and carers, often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many people find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information relevant to CAH due to 21-hydroxylase deficiency can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
• National Organization for Rare Disorders: Congenital Adrenal Hyperplasia
• CAH PeP Talk – Congenital Adrenal Hyperplasia Education  – contains a psychosocial education program developed for families with a diagnosis of Congenital Adrenal Hyperplasia (CAH)

Orphanet: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

GeneReviews^®: 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team. If you would like to see more information added to this page, please reach out via the Contact form. If you would like to share relevant resources for this condition, please visit the Contribute page.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.