21-hydroxylase deficiency

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Other Names:

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency; CYP21 deficiency; 21 hydroxylase deficiency; Congenital adrenal hyperplasia due to 21-hydroxylase deficiency; CYP21 deficiency; 21 hydroxylase deficiency; Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency See More

Categories:

Newborn Screening

Subtypes:

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency; Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

This disease is grouped under:

Congenital adrenal hyperplasia

Summary Summary

21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH). CAH is a group of disorders that affect how the adrenal glands work. In 21-hydroxylase deficiency, a missing enzyme leads to overproduction of specific hormones made by the adrenal glands. There are three types of 21-hydroxylase deficiency that vary by the severity of symptoms. Infants with the more severe forms can experience excessive loss of salt in their urine, which can be life-threatening. Female infants may be born with genitalia that doesn't look male or female (ambiguous genitalia). Children with the less severe forms can have early puberty, excess hair growth, short stature as adults and decreased fertility.^[1]^[2]^[3]

21-hydroxylase deficiency is caused by genetic changes in the CYP21A2 gene and is inherited in an autosomal recessive pattern. Newborn screening is available in all 50 states of the US to test for this disorder at birth. The diagnosis is made based on the clinical symptoms, biochemical and genetic testing.^[4] Treatment is available and involves managing the symptoms through steroids and other medications.^[3]^[4] The long-term outlook for people with 21-hydroxylase deficiency depends on the severity of symptoms and the ability to manage the condition with medications.

Last updated: 4/11/2019

Symptoms Symptoms

The symptoms of 21-hydroxylase deficiency may be different from person to person. Some people may be more severely affected than others, even people who have the same form. Not everyone with 21-hydroxylase deficiency will have the same symptoms, and some may have few or no symptoms.

There are three forms of 21-hydroxylase deficiency: the classic salt wasting form, the simple virilizing form, and the non-classic form. Most patients with 21-hydroxylase deficiency will have the classic salt-wasting form or the simple virilizing form.^[3]

Infants with the severe classic salt wasting form develop symptoms within the first few weeks of life. These include:^[1]^[2]^[3]

Salt wasting crisis
- low sodium levels (hyponatremia)
- high potassium levels (hyperkalemia)
- high levels of renin in the blood (hyperreninemia)
- low blood volume (hypovolemic shock)
Ambiguous genitalia in female newborns babies (genitalia that is not typical female nor male appearing), with normal internal feminine reproductive organs (ovaries, uterus, and fallopian tubes); male babies usually have normal genitalia but may have small testes and an enlarged penis.

Salt wasting crises can be life-threatening and require immediate treatment.

Infants with the classic simple virilizing form may have:

Ambiguous external genitalia in female babies with normal internal reproductive organs; males are born with normal genitalia and may have small testes and an enlarged penis

Later in life both males and females with both classic forms of 21-hydroxylase deficiency may have:

Puberty starting in childhood (precocious puberty)
Excessive hair growth
Acne
Shorter than average adult height
Reduced fertility
Irregular periods (females)
Testicular enlargement and testicular tumors (males)

Females with the non-classic type of 21-hydroxylase deficiency have normal female genitalia, but when they get older, symptoms may include excessive hair growth (hirsutism), male pattern baldness, irregular periods and reduced fertility. Males with the non-classic type may have early beard growth, an enlarged penis, and small testes. The non-classical form is not considered a rare disease and some people with this form of 21-hydroxylase deficiency may not experience any signs or symptoms.

Last updated: 4/11/2019

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 11 |

Medical Terms	Other Names	Learn More: HPO ID
Percent of people who have these symptoms is not available through HPO
Abnormal thorax morphology	Abnormality of the chest	0000765
Adrenal hyperplasia	Enlarged adrenal glands	0008221
Adrenogenital syndrome		0000840
Autosomal recessive inheritance		0000007
Growth abnormality	Abnormal growth Growth issue [ more ]	0001507
Gynecomastia	Enlarged male breast	0000771
Hypertension		0000822
Hypoglycemia	Low blood sugar	0001943
Hypospadias		0000047
Recurrent fever	Episodic fever Increased body temperature, episodic Intermittent fever [ more ]	0001954
Renal salt wasting	Loss of salt in urine	0000127

Showing of 11 |

Do you have more information about symptoms of this disease? We want to hear from you.

Last updated: 2/1/2021

Cause Cause

21-hydroxylase deficiency is caused by genetic changes (mutations) in the CYP21A2 gene.^[2]

Last updated: 4/11/2019

Inheritance Inheritance

21-hydroxylase deficiency is inherited in an autosomal recessive pattern.^[2] All individuals inherit two copies of each gene. To have 21-hydroxylase deficiency, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have this.

People with autosomal recessive conditions inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive disorder typically do not have any signs or symptoms (they are unaffected). When two carriers of an autosomal recessive condition have children, each child has a:

25% (1 in 4) chance to have the disorder

50% (1 in 2) chance to be an unaffected carrier like each parent

25% (1 in 4) chance to be unaffected and not be a carrier

Last updated: 4/9/2019

Diagnosis Diagnosis

Babies born in the USA are screened at birth through newborn screening for the classic salt wasting and simple virilizing forms of 21-hydroxylase deficiency. For babies that test positive on the newborn screen for this disorder, additional biochemical and genetic testing is done to confirm the diagnosis.^[5] The less severe, non-classical form of 21-hydroxylase def is diagnosed based on the clinical symptoms, biochemical testing to look for excess hormone production. Genetic testing may also be helpful to determine the type and severity of 21-hydroxylase deficiency.^[6]

Last updated: 4/11/2019

Newborn Screening

An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
The Newborn Screening Coding and Terminology Guide created by the National Library of Medicine (NLM) at the National Institutes of Health (NIH) promotes and facilitates the use of electronic health data standards in recording and transmitting newborn screening test results. The Web site includes standard codes and terminology for newborn tests and conditions for which they screen, and links to related sites. Click on the links below to view details for the three types of congenital adrenal hyperplasia due to 21-hydroxylase.
Congenital adrenal hyperplasia (non-classical)
Congenital adrenal hyperplasia (salt-wasting)
Congenital adrenal hyperplasia (simple virilizing)

Treatment Treatment

Treatment for 21-hydroxylase deficiency depends on the severity of symptoms and the form of the condition. The goals of treatment are to manage to symptoms. Infants identified at birth with 21-hydroxylase deficiency are treated with hormones and steroids to prevent a salt-wasting crisis. In childhood and adulthood, other medications may be used to improve growth and fertility. Males should be monitored for the growth of testicular adrenal rest tumors, a benign tumor that can cause infertility. In some cases, females with ambiguous genitalia may be offered surgical correction. Some people with this condition have psychological issues and may benefit from therapy.^[5]^[4]

At least one organization has published clinical practice g uidelines for 21-hydroxylase deficiency.

Last updated: 4/11/2019

Prognosis Prognosis

The long-term outlook for people with 21-hydroxylase deficiency is dependent on the severity of the symptoms, the response to medications and the presence of any other medical conditions. In general, with early diagnosis and continuous lifetime treatment, the long-term outlook for people with this disorder is good. Long term complications of this condition may include fertility and mental health issues.^[4]

Last updated: 4/11/2019

Statistics Statistics

Approximately 1 in 10 to 15,000 people in the United States has congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency.^[1]^[3] The prevalence is higher is other parts of the world.

Last updated: 4/11/2019

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Find a Specialist Find a Specialist

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

ClinicalTrials.gov lists trials that are related to 21-hydroxylase deficiency. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Organizations Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Adrenal Insufficiency United
Toll-free: 1-855-AIUnite (248-6483)
E-mail: contact@aiunited.org
Website: http://aiunited.org/
Congenital Adrenal Hyperplasia Research Education and Support (CARES) Foundation
2414 Morris Ave, Suite 110
Union, NJ 07083
Toll-free: 866-227-3737
E-mail: contact@caresfoundation.org
Website: http://www.caresfoundation.org
National Adrenal Diseases Foundation (NADF)
P.O. Box 566
Lake Zurich, IL 60047
Telephone: +1-(847) 726-9010
E-mail: nadfmail@nadf.us
Website: https://www.nadf.us

Do you know of an organization? We want to hear from you.

Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provides information related to the health of children, adults, and families. Click on the link to view information on this topic.
The Genetic Alliance is an international coalition comprised of more than 600 advocacy, research and health care organizations representing millions of individuals with genetic conditions. Click on the link to view information on this topic.
Genetics Home Reference (GHR) contains information on 21-hydroxylase deficiency. This website is maintained by the National Library of Medicine.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
PubMed is a searchable database of medical literature and lists journal articles that discuss 21-hydroxylase deficiency. Click on the link to view a sample search on this topic.

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Rare Disease Day at NIH 2021
March 1, 2021

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References References

Congenital Adrenal Hyperplasia. National Organization of Rare Disorders (NORD). Updated 2018; . https://rarediseases.org/rare-diseases/congenital-adrenal-hyperplasia/.
21-hydroxylase deficiency. Genetics Home Reference (GHR). March, 2015; https://ghr.nlm.nih.gov/condition/21-hydroxylase-deficiency.
Parsa AA, New MI. Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. Jl Steroid Biochem Mol Biol. Jan 2017; 165(pt A):2-11. https://www.ncbi.nlm.nih.gov/pubmed/27380651.
Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP et al.. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society clinical practice guideline. Jl Clin Endo Metab. Nov 2018; 103(11):4043-4088. https://www.ncbi.nlm.nih.gov/pubmed/30272171.
Nimkarn A, Gangishetti PK, Yau M, New MI. 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia. GeneReviews. Updated Feb 4, 2016; http://www.ncbi.nlm.nih.gov/books/NBK1171/.
Concolino P, Costella A. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: A comprehensive focus on 233 pathogenic variants of CYP21A2 gene. Mol Diagn Ther. Jun 2018; 22(3):261-280. https://www.ncbi.nlm.nih.gov/pubmed/29450859.