Rare Gastroenterology News

Disease Profile

21-hydroxylase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

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ICD-10

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Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency; CYP21 deficiency; 21 hydroxylase deficiency;

Categories

Newborn Screening

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. 

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.

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.

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

Cause

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

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]

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 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 guidelines for 21-hydroxylase deficiency.

    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

      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.

          References

          1. Congenital Adrenal Hyperplasia. National Organization of Rare Disorders (NORD). Updated 2018; . https://rarediseases.org/rare-diseases/congenital-adrenal-hyperplasia/.
          2. 21-hydroxylase deficiency. Genetics Home Reference (GHR). March, 2015; https://ghr.nlm.nih.gov/condition/21-hydroxylase-deficiency.
          3. 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.
          4. 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.
          5. Nimkarn A, Gangishetti PK, Yau M, New MI. 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia. GeneReviews. Updated Feb 4, 2016; https://www.ncbi.nlm.nih.gov/books/NBK1171/.
          6. 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.

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