Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia, a group of conditions that affect hormone production in the adrenal glands.¹ Adrenal glands sit on top of each kidney and are involved in producing important hormones that regulate many body functions. In CAH due to 21-hydroxylase deficiency, the 21-hydroxylase enzyme does not function properly. This causes the body to produce insufficient cortisol (a stress hormone) and aldosterone (a hormone that regulates water and salt balance in the body), and excess androgens (male sex hormones).^1,2

Deficiency of both cortisol and aldosterone can lead to an inability to retain salt and water, dehydration, low blood pressure, and a life‑threatening adrenal crisis known as a salt‑wasting crisis.^1,3 Too much androgen production can lead to virilisation, which is the development of male physical characteristics in females, as well as early (precocious) puberty in males and females.⁴

Symptoms can vary widely between individuals, but CAH due to 21-hydroxylase deficiency is broadly categorised into two types: ^1,5

• classic type – the more severe form. It is further divided into the salt-wasting form, which can be life-threatening if left untreated, and the simple virilising form, which does not involve salt-wasting
• non-classic type – a milder form that typically presents later in life and may or may not cause noticeable symptoms.

In Australia, CAH due to 21-hydroxylase deficiency is often detected shortly after birth via newborn bloodspot screening (NBS) programs. Additional testing is required to confirm the diagnosis. For individuals who are not screened at birth, CAH due to 21-hydroxylase deficiency often diagnosed after symptoms develop. Early diagnosis and timely, appropriate treatment of CAH due to 21-hydroxylase deficiency can help prevent life-threatening salt-wasting adrenal crisis and support normal growth and development.^4,6

Please note that this page addresses CAH due to 21-hydroxylase deficiency specifically. There are other forms of CAH, such as congenital lipoid adrenal hyperplasia, 3β-hydroxysteroid dehydrogenase deficiency, 17α hydroxylase deficiency, 11β-hydroxylase deficiency and p450 oxidoreductase deficiency, each caused by deficiencies in different enzymes, resulting in different sets of symptoms.¹

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

• ORPHA:315306 Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
• ORPHA:315311 Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

ICD-11: 5A71.01 Congenital adrenal hyperplasia

Symptoms of CAH due to 21‑hydroxylase deficiency vary between individuals and between the classic and non-classic forms. The classic form is further divided into the salt‑wasting and simple virilising types, which have different ranges of symptoms.

Symptoms of the classic type may present at birth in babies who are genetically female (who have 2 X chromosomes) due to virilisation, caused by excess androgen production. This can result in ambiguous genitalia (genitals that don’t typically look male or female) or in some cases, genitals with some male characteristics.^1,4-5 Symptoms are not obvious at birth in males, but if untreated, both males and females may have early puberty and rapid growth during childhood, followed by an earlier stop in growth (early arrest of growth), resulting in shorter adult height (short stature).^1,4-5

Most individuals with classic CAH have the salt-wasting form due to insufficient aldosterone. If not detected early and left untreated, this can lead to life-threatening adrenal crisis. This can present at an early age, causing symptoms in babies such as poor feeding, failure to thrive, vomiting and leading to coma and early death.^1,4-5 Those with the simple virilising form will not have issues regulating their salt and water levels, and will not be at risk of salt-wasting crisis.¹

For the non-classic type, symptoms tend to present later in life and are not life-threatening, as there is no associated salt-wasting. Females do not have ambiguous genitalia (no virilisation) at birth, but both males and females may display signs of hyperandrogenism (high androgen levels), such as early development of pubic hair, acne, irregular periods in females, faster-than-normal bone maturation, as well as rapid growth during childhood but early arrest of growth, resulting in short stature in adulthood.^1,4 Fertility may also be affected in some people.¹

Please speak to your medical team to learn more about the symptoms and complications 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 that is responsible for making the 21-hydroxylase enzyme. This enzyme is needed to produce cortisol and aldosterone in the adrenal glands. When this enzyme does not work properly, hormone production is disrupted, resulting in low or no cortisol and aldosterone being produced and consequently, a rise in androgen levels.⁴

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

Newborn 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:^2,4,5

• clinical evaluation – signs of virilisation (such as presence of ambiguous genitalia in females with 46;XX chromosomes, early signs of puberty in males with 46;XY chromosomes and other signs) 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, Addison’s disease, other diseases with androgen excess or any disorders of sex development.^1,6

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

There is currently no curative treatment for CAH due to 21-hydroxylase deficiency. Treatment of CAH due to 21-hydroxylase deficiency varies depending on the type and severity.¹

Treatment of the classic type of CAH due to 21-hydroxylase deficiency is life-long and involves a multidisciplinary care team.^4,6 Early diagnosis and timely, appropriate treatment of CAH due to 21-hydroxylase deficiency can help prevent life-threatening salt-wasting adrenal crisis and support normal growth and development.^4,6 Treatment of classic CAH typically involves glucocorticoid replacement therapy (to replace cortisol and suppress excess androgen production) and if necessary, mineralocorticoid therapy (to replace aldosterone).^1,5 Regular close monitoring is recommended to ensure the dose is appropriate, avoid effects of over- or under-treatment, and allow for adjustments as needed, particularly during growth, at different ages, and during illness or periods of stress.^5-7 Other interventions may include surgery, which may be considered to restore the functional anatomy in females with ambiguous genitalia; however, this decision involves careful consideration of multiple factors.⁷

Unlike the classic type, the non-classic type of CAH due to 21-hydroxylase deficiency is not life-threatening.¹ People with the non-classic type may not have any symptoms and hence may not require any treatment.^1,3 Treatment of the non-classic type of CAH due to 21-hydroxylase deficiency is aimed at managing symptoms as they present and may involve glucocorticoid treatment but may not be long-term.^1,7

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. For many rare diseases, treatment options may be limited. Participation in a clinical trial may provide access to new or emerging therapies.

Healthcare professionals involved in the 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.¹ The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.

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.

This may not be applicable to all rare diseases but for many, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness and is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. If this is relevant to you and you wish to find out more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline (with its subsequent corrigendum) is an update of the 2010 clinical practice guideline published by the Endocrine Society, United States of America; published in 2018. It contains recommendations for the clinical management of congenital adrenal hyperplasia with added considerations for patient safety, quality of life, cost, and utilisation.

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.

In addition, individuals, their parents, families and carers often develop extensive expertise on their specific rare disease. It is important to recognise that they can contribute valuable knowledge about their rare condition. Rare diseases often impact individuals differently, so it’s important to consider a person’s lived experience.

There may be special considerations for the emergency management of individuals living with CAH due to 21-hydroxylase deficiency:

• physical stress, such as illness, dehydration, surgery under general anaesthesia and major trauma, may trigger an adrenal crisis in individuals with classic CAH.⁴

The RARE Portal’s Primary adrenal insufficiency page (Emergency Management section) covers information about adrenal crisis in primary adrenal insufficiency, which may also be relevant for people with CAH.

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. For more information, please visit the RARE Portal’s Considerations for Participating in Health and Medical Research page.

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 research, including clinical trials,  with your medical team to determine suitability and eligibility.

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 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 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 on CAH due to 21-hydroxylase deficiency, or CAH in general, can be found at:

• healthdirect: Congenital adrenal hyperplasia
• Genetic and Rare Diseases (GARD) Information Center: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
• National Organization for Rare Disorders: Congenital Adrenal Hyperplasia

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.