21-hydroxylase deficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mehrian Jafarizade, M.D [2] Ahmad Al Maradni, M.D. [3]

21-hydroxylase deficiency is the most common type of congenital adrenal hyperplasia. Congenital adrenal hyperplasia was first discovered by Luigi De Crecchio, an Italian pathologist in 1865. Gene responsible for 21-hydroxylase deficiency is CYP21A. This disease may be classified into two subtypes: classic and non-classic forms. In patients with 21-hydroxylase deficiency, there is a defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol which results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion. Symptom of 21-hydroxylase deficiency ranges from severe to mild or asymptomatic forms, depending on the degree of 21-hydroxylase enzyme deficiency. In classic type, main symptoms can be severe hypotension due to adrenal crisis, ambiguous genitalia in females, and no symptoms or larger phallus in males. In non-classic types, infants and male patients may have no symptoms and females may show virilization symptoms after puberty. 17-hydroxyprogesterone level and cosyntropin stimulation test can be used to diagnosis. Medical therapy for classic type of 21-hydroxylase deficiency includes maternal administration of dexamethasone, for genetically diagnosed intranatal patients; also hydrocortisone and fludrocortisone may be used in children and adults. Treatment for non-classic type of 21-hydroxylase deficiency in children includes hydrocortisone until puberty and in women oral contraceptive pills for regulating menstrual cycle.

Congenital adrenal hyperplasia was first discovered by Luigi De Crecchio, an Italian pathologist in 1865. Explanation of hormonal aspects and molecular characteristics remained unclear until 1980. From 1980 scientists started to describe enzymes and molecular basis of 21-hydroxyase deficiency.

21-hydroxylase deficiency may be classified into two types based on severity and time of onset: classic and non-classic forms. Classic form includes two subtypes salt-wasting and non-salt wasting 21-hydroxylase deficiency.

In patients with 21-hydroxylase deficiency, there is a defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol which results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion. The resulting adrenal stimulation leads to increased production of androgens. More than 95% of all cases of CAH are caused by 21-hydroxylase deficiency. The clinical manifestation of congenital adrenal hyperplasia is closely related to the type and severity of disease. The severity of disease relates to the mutation type which is causes enzyme inactivity or hypo activity. There is a lack of enzyme in classic type of 21-hydroxylase deficiency; while in the non-classic form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production. Responsible gene for 21-hydroxylase deficiency is CYP21A. This gene is located within the human leucocyte antigen class III region of chromosome 6. Meiotic recombination events occurs in this genomic region as a result of the high degree of sequence homology between CYP21A2 and its pseudogene CYP21A1. Approximately 70% of CYP21A2 disease is due to gene conversion and micro-deletions in CYP21A1 gene.

Causes of 21-hydroxylase deficiency include mutations in CYP21A1 and CYP21A2 gene on chromosome 6. Approximately 70% of CYP21A2 disease is due to gene conversion and microdeletions in CYP21A1 gene; around 25% to 30% are chimeric genes due to large deletions. Less common causes are due to de novo mutations because of high variability of the CYP21A2 locus. Also chromosome 6 uniparental disomy is rare cause of 21-hydroxylase deficiency with an unknown prevalence.

21-hydroxylase deficiency must be differentiated from 11-β hydroxylase deficiency, 17-α hydroxylase deficiency, androgen insensitivity syndrome, 3β-Hydroxysteroid Dehydrogenase, polycystic ovarian syndrome, hyperprolactinemia, cushing syndrome, and adrenal tumor.

Worldwide, the incidence of 21-hydroxilase deficiency, classic salt wasting type is 5 per 100,000 persons. Prevalence varies according to ethnicity and geographic area; ranges from a low of 3.57 per 100,000 persons in Chinese population  to a high of  per 100,000 persons with an average prevalence of 357 per 100,000 persons in Yupik Eskimos in Alaska. This disease usually affects individuals of the Ashkenazi Jews and Mediterranean race. The classic type affects approximately 6.25 in 100,000 live births. Non-classic type is one of the most common autosomal recessive disorders in humans and affects approximately 100 in 100,000 individuals, but in up to 1–2% among inbred populations, such as Eastern European (Ashkenazi) Jews. Incidence for 21-hydroxylase deficiency is more prevalent in some ethnic groups, particularly in remote geographic regions such as Alaskan Yupiks. The non-classic form is one of the most common autosomal recessive diseases. The prevalence of the non-classic form may differ from 100 in 100,000 to 1000 in 100,000, with a higher prevalence among Mediterraneans, Hispanics, and Eastern European Jews.

The most potent risk factors in the development of 21-hydroxylase deficiency is presence of family history of 21-hydroxylase deficiency, and being in certain ethnic groups, particularly Ashkenazi Jews and Yugoslavians and Yupik Inuits.

According to Endocrine Society Clinical Practice Guideline, screening for 21-hydroxylase deficiency by measuring 17-hydroxyprogesterone is recommended for all newborns. The Endocrine Society’s Clinical Practice Guideline recommends that genetic counseling be provided for individuals who are planning to conceive, and there is a family history of 21-hydroxylase deficiency.

If left untreated, patients with 21-hydroxylase deficiency may progress to develop complications. Common complications of 21-hydroxylase deficient congenital adrenal hyperplasia include short stature, adrenal crisis, infertility, and precocious puberty. The prognosis of to 21-hydroxylase deficiency is generally good with treatment.

Symptom of 21-hydroxylase deficiency ranges from severe to mild or asymptomatic forms, depending on the degree of 21-hydroxylase enzyme deficiency. There are three main clinical phenotypes: classic salt-wasting, classic non-salt-wasting (simple virilizing), and non-classic (late-onset). In classical type, main symptoms can be sever hypotension due to adrenal crisis, ambiguous genitalia in females, and no symptoms or larger phallus in males. In non-classic types, infants and male patients may have no symptoms and females may show virilization symptoms after puberty.

Patients with 21-hydroxylase deficiency usually appear underweight and dehydrated. Physical examination is usually remarkable for hypotension and virilization.

Laboratory findings consistent with the diagnosis of 21-hydroxylase deficiency differs in each disease type. 17-hydroxyprogesterone level and cosintropin stimulation test can be used to diagnosis.

On ultrasound, 21-hydroxylase deficiency is characterized by enlarged, wrinkled, and cerebriform adrenal glands. Also testicular masses may be seen in the setting of classic disease.

On abdominal CT scan, 21-hydroxylase deficiency is characterized by bilateral symmetric enlargement of the adrenal glands.

On abdominal MRI, 21-hydroxylase deficiency is characterized by bilateral symmetric enlargement of the adrenal glands.

Medical therapy for classic type of 21-hydroxylase deficiency includes maternal administration of dexamethasone, for genetically diagnosed intranatal patients, and hydrocortisone and fludrocortisone in may be used in children and adults. Treatment for non-classic type of 21-hydroxylase deficiency in children includes hydrocortisone until puberty and in women oral contraceptive pills for regulating menstrual cycle. Men with non-classic type of 21-hydroxylase deficiency are asymptomatic and they do not need treatment.

Surgery is not the first-line treatment option for patients with 21-hydroxylase deficiency. Surgical reconstruction of abnormal genitalia is usually reserved for severely virilized girls.

There are no primary preventive measures available for 21-hydroxylase deficiency.

Continued monitoring of hormone balance and careful readjustment of glucocorticoid dose is helpful in controlling fertility and preventing adrenal crisis in patient with 21-hydroxylase deficiency.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mehrian Jafarizade, M.D [2] Ahmad Al Maradni, M.D. [3]

Congenital adrenal hyperplasia was first discovered in 1865 by an Italian pathologist, Luigi De Crecchio. Explanation of hormonal aspects and molecular characteristics remained unclear until 1980. From 1980 scientists started to describe enzymes and molecular basis of 21-hydroxyase deficiency.

Landmark events in the understanding and discovery of adrenal hormones include the following:^{[1][2][3][4][5]}

• In 1563, Eustachius described the adrenal glands. The findings were later on published by Lancisi in 1714.
• In 1849, Thomas Addison, while searching for the cause of pernicious anemia, found a bronze colored growth associated with the adrenal glands. Then in 1855, Thomas Addison described clinical findings in 11 cases of adrenal disorders.
• In 1856, while conducting adrenalectomy experiments, Brown-Séquard found that the adrenal glands are necessary for life.
• In 1865, the Italian pathologist, Dr. Luigi De Crecchio was the first to describe 21-hydroxylase deficiency. Dr. Crecchio found large adrenal glands in a male autopsy, who had female internal organs.
• In 1896, William Osler prepared an extraction derived from pig adrenals and showed that it had clinical benefit in patients with Addison disease.
• In 1905, Bulloch and Sequeira described patients with congenital adrenal hyperplasia.
• In 1936, Selye described the concept of stress and its effect on pituitary–adrenal function.
• In 1937-1952, Kendall and Reichstein, described the basic structure of adrenocortical hormones.
• In 1943, Li and colleagues isolated adrenocorticotropic hormone from sheep pituitary.
• In 1950, Hench, Kendall, and Reichstein shared the Nobel Prize in Medicine for describing the anti-inflammatory effects of cortisone in patients with rheumatoid arthritis.
• In 1956, Conn described primary aldosteronism.
• In 1963 congenital adrenal hyperplasia was described as a complex disorder, caused by different enzyme deficiencies.
• In 1965, the diagnostic approach to congenital adrenal hyperplasia was established by measuring the levels of adrenal steroids in amniotic fluid.

• 1980 – present has been termed as the molecular era; highlights during this era are as follows:
  • Cloning and functional characterization of steroid hormone receptors was discovered.
  • Steroidogenic enzymes were described.
  • Adrenal transcription factors were reported.
  • Molecular basis for adrenal diseases was described.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mehrian Jafarizade, M.D [2], Ahmad Al Maradni, M.D. [3]

21-hydroxylase deficiency may be classified according to the severity of disease and time of onset into two forms, classic and non-classic. The classic form can be sub-divided into two sub-types, which are salt-wasting and non-salt wasting 21-hydroxylase deficiency.

21-hydroxylase deficiency my be classified by clinical manifestations in to two forms:

• Classical form, most severe form of 21-hydroxylase deficiency, presents during the neonatal period and early infancy. The classic form can be classified in to two subtypes based on aldosterone status:
  • Classic salt wasting, aldosterone deficient.
  • Classic non-salt wasting, normal aldosterone.
• Non-classic form or late-onset 21-hydroxylase deficiency, presents later during the adolescence period.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mehrian Jafarizade, M.D [2], Ahmad Al Maradni, M.D. [3]

The progression to 21-hydroxylase deficiency usually involves the defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol which results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion. The resulting adrenal stimulation leads to increased production of androgens due to shunting of the pathway to androgen synthesis. More than 95% of cases of congenital adrenal hyperplasia (CAH) are caused by 21-hydroxylase deficiency. The clinical manifestations of congenital adrenal hyperplasia is closely related to the type and severity of disease. The severity of disease relates to the type of mutation which causes enzyme inactivity or hypo-activity. There is a lack of enzyme in classic form of 21-hydroxylase deficiency; while in the non-classic form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production. The gene responsible for 21-hydroxylase deficiency is CYP21A. This gene is located within the human leucocyte antigen class III region of chromosome 6. Meiotic recombination occurs in this genomic region as a result of the high degree of sequence homology between CYP21A2 and its pseudogene CYP21A1. Approximately 70% of CYP21A2 genetic mutation is due to gene conversion and micro-deletions in CYP21A1 gene.

• 21-hydroxylase enzyme is involved in the synthesis of aldosterone in zona glomerulosa and cortisol in zona fasciculata. Lack of 21-hydroxylase enzyme leads to decrease in cortisol and aldosterone levels and the rest of synthesis pathways produce extra androgens and lead to hirsutism.
• More than 95% of all cases of congenital adrenal hyperplasia (CAH) are caused by 21-hydroxylase deficiency; the clinical manifestations of 21-hydroxylase deficiency is closely related to the type and severity of disease.
• The severity of disease relates to the type of mutation, which causes enzyme inactivity or hypo activity.
• There is a lack of enzyme in classic type of 21-hydroxylase deficiency; while in the non-classic form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production.

• In patients with 21-hydroxylase deficiency in zona fasciculata, there is a defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol which results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion.

• In patients with 21-hydroxylase deficiency in zona glomerulosa, there is a defective conversion of progesterone to 11-deoxycortisterone which results in decreased aldosterone synthesis.
• The lack of aldosterone causes large amounts of sodium loss in the urine. Urinary sodium concentrations are more than 50 mEq/L. As a result of high amount of sodium loss, blood volume and blood pressure can not be maintained in normal ranges.
• Due to mineralocorticoid deficiency, potassium and acid excretion are also impaired resulting in hyperkalemia and metabolic acidosis.
• There is significant water loss and symptoms of dehydration due to salt wasting within the first two week of life. In severe form of CAH, vomiting, severe dehydration, circulatory collapse and shockdevelops in the second or third week of life.

• In the androgen synthesis pathway, 21-hydroxylase enzyme does not have a direct role; therefore with extra amount of other products from blocked cortisol and aldosterone synthesis, androgen pathway have extra precursor metabolites resulting in androgen excess in the form of dehydroepiandrosterone and androstenedione accumulation.
• On the other hand, lack of cortisol removes the negative feedback on the pituitary gland, resulting in an increase in ACTH level and consequently more increase in androgen synthesis pathway. High androgen level in 21-hydroxylase deficient women during pregnancy causes ambiguous genitalia in female fetus; also in milder forms induces hirsutism and virilization in women. Adrenal androgens produce little effect on the genitalia of male infants with severe CAH. Excess androgen can cause precocious puberty in male child.

Below is the hormonal pathway of adrenal steroids and related enzymes, also the mechanism of 21 hydroxylase deficiency symptoms.^[1][2]

• Congenital adrenal hyperplasia subtypes are all autosomal recessive and monogenetic. The disease manifestation follows the allele that results in a more functional enzyme, and generally correlation between genotype and phenotype is good.^[4][5]

• The gene responsible for 21-hydroxylase deficiency is CYP21A. This gene is located within the human leucocyte antigen class III region of chromosome 6.

CYP21A gene has two types:

• An active gene called CYP21A2, which encodes 21-hydroxylase, a cytochrome P450 type II enzyme containing 495 amino acids.

• This gene is a non-functional pseudogene named CYP21A1 or CYP21P. This pseudogene produces an enzyme with no activity because it lacks eight bases from codons 110-112, which results in a stop codon.^[6]

• Meiotic recombination events occurs in this genomic region as a result of the high degree of sequence homology between CYP21A2 and its pseudogene CYP21A1.
  • Approximately 70% of disease associated with CYP21A2 is due to gene conversion and microdeletions in CYP21A1 gene.
  • Approximately 25% to 30% are chimeric genes due to large deletions.
  • Approximately 1% to 2% of cases are due to de novo mutations because of high variability of the CYP21A2 locus.
  • Chromosome 6 uniparental disomy is rare cause of 21-hydroxylase deficiency with an unknown prevalence.

• Gene mutations that completely inactivates CYP21A2 gene will result in the classic type and salt-wasting subtype.
• Gene mutations that maintain 1–2% of 21-hydroxylase activity will result in classic type and non-salt-wasting subtype. These patients have minimal aldosterone production that prevents a neonatal adrenal crisis.^[7]

Gross pathology findings in patients with 21 hydroxylase deficiency are:^[8][9]

• Enlarged adrenal glands
• Wrinkled surface of adrenal glands
• Cerebriform pattern in adrenal glands (pathognomonic sign)
• Normal ultrasound appearance

In 21-hydroxylase deficiency microscopic findings may include:

• Diffuse cortical hyperplasia with smaller cells
• The cell cytoplasm can be vacuolated, and often more basophilic.
• Rare mitotic figures may be present
• The hyperplastic cells typically lack features of cellular atypia.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mehrian Jafarizade, M.D [2], Ahmad Al Maradni, M.D. [3]

21-hydroxylase deficiency is caused by mutations in CYP21A1 and CYP21A2 genes found on chromosome 6. Approximately 70% of CYP21A2 disease is due to gene conversion and microdeletions in CYP21A1 gene; around 25% to 30% are chimeric genes due to large deletions. Less common causes are due to de novo mutations because of high variability of the CYP21A2 locus. Also, chromosome 6 uniparental disomy is rare cause of 21-hydroxylase deficiency with an unknown prevalence.

• Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no life-threatening causes of 21-hydroxylase deficiency.

Mutations in CYP21A1 and CYP21A2 gene on chromosome 6.

• Approximately 70% of disease associated with CYP21A2 is due to gene conversion and microdeletions in CYP21A1 gene.
• Approximately 25% to 30% are chimeric genes due to large deletions.

• Approximately 1% to 2% of cases are due to de novo mutations because of high variability of the CYP21A2 locus.
• Chromosome 6 uniparental disomy is a rare cause of 21-hydroxylase deficiency with an unknown prevalence.^{[1][2][1][3][4]}

• Mutation in CYPA21 gene

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

21-hydroxylase deficiency must be differentiated from 11-β hydroxylase deficiency, 17-α hydroxylase deficiency, androgen insensitivity syndrome, 3 beta-hydroxysteroid dehydrogenase deficiency, polycystic ovarian syndrome, hyperprolactinemia, cushing syndrome, and adrenal tumor.

21-hydroxylase deficiency classic form should be differentiated from other diseases that cause ambiguous genitalia, and non-classic form should be differentiated from the diseases that cause female hirsutism.

21-hydroxylase deficiency classic type must be differentiated from diseases that cause ambiguous genitalia:^[1][2]

21-hydroxylase deficiency non-classic type must be differentiated from diseases that cause virilization and hirsutism in female:^[2][3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Worldwide, the incidence of 21-hydroxylase deficiency, classic type (salt wasting) is 5 per 100,000 persons. Prevalence varies according to ethnicity and geographic area and ranges from a low of 3.57 per 100,000 persons in Chinese population to a high of 357 per 100,000 persons in Yupik Eskimos in Alaska. This disease usually affects Ashkenazi Jews and individuals of the Mediterranean race. The classic type affects approximately 6.25 in 100,000 live births. Non-classic type is one of the most common autosomal recessive disorders in humans and affects approximately 100 in 100,000 individuals, but among inbred populations, such as Eastern European (Ashkenazi) Jews the prevalence may reach up to 1000 per 100,000 individuals. Incidence for 21-hydroxylase deficiency is higher in some ethnic groups, particularly in remote geographic regions such as Alaskan Yupiks.

• Worldwide, the incidence of 21-hydroxylase deficiency classic type (salt-wasting) is 5 per 100,000 persons.
• Worldwide, the incidence of 21-hydroxylase deficiency classic simple type (non-salt wasting) is 16.6 per 100,000 persons.
• Worldwide, the incidence of 21-hydroxilase deficiency late-onset type type is 100 per 100,000 persons.^[1]

• Prevalence of 21- hydroxylase defieciency varies according to ethnicity and geographic area.
• Worldwide, the prevalence of 21 hydroxylase deficiency ranges from a low of 3.57 per 100,000 persons in Chinese population to a high of 357 per 100,000 persons in Yupik Eskimos in Alaska.^[2]
• The non-classic form is one of the most common autosomal recessive diseases. The prevalence of the non-classic form may vary from 100 in 100,000 to 1000 in 100,000, with higher prevalence among Mediterraneans, Hispanics, and Eastern European Jews.^[1][3]

• 21-hydroxylase deficiency usually affects Ashkenazi Jews individuals of the Mediterranean race.
• The Ashkenazi Jews to Mediterranean race ratio is approximately 1:3.^[4][5]

21-hydroxylase deficiency is more prevalent in some ethnic groups, particularly in remote geographic regions (e.g. Alaskan Yupiks). Disease incidence for each region mentioned below:^[1][2][3]

• Alaska, Yupik Eskimos : 357/100,000
• France, La Reunion: 47.6/100,000
• Sweden: 10.2/100,000
• United States, Wisconsin: 9.1/100,000
• France, Lille: 7.7/100,000
• Japan: 5.6/100,000
• China: 3.6/100,000
• United States, Texas: 6.25/100,000
• Scotland: 5.9/100,000
• Italy: 5.6/100,000
• New Zealand: 4.3/100,000

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

The most potent risk factor in the development of 21-hydroxylase deficiency is presence of family history of 21-hydroxylase deficiency, and belonging to certain ethnic groups, particularly Ashkenazi Jews, Yugoslavians and Yupik Inuits.

The most potent risk factors in the development of 21-hydroxylase deficiency are:

• Presence of family history of 21-hydroxylase deficiency.
• Belonging to certain ethnic groups, particularly Ashkenazi Jews, Yugoslavians and Yupik Inuits.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

According to Endocrine Society Clinical Practice Guideline, screening for 21-hydroxylase deficiency should be done by measuring 17-hydroxyprogesterone and is recommended for all newborns. The Endocrine Society’s Clinical Practice Guideline recommends that genetic counseling should be provided for individuals who have a postive family history of 21-hydroxylase deficiency and are planning to conceive.

According to Endocrine Society Clinical Practice Guideline, screening for 21-hydroxylase deficiency by measuring 17-hydroxyprogesterone is recommended for all newborns.

• Blood sample on filter paper should be obtained via heel-prick, preferably between two and four days after birth.
• Screening programs should be done using a two-step protocol (initial immunoassay with further evaluation of positive tests by liquid chromatography or tandem mass spectrometry).
• Most affected neonates have 17-hydroxyprogesterone concentrations greater than 3500 ng/dL (normal level =105 nmol/L).^[1][2]

The Endocrine Society’s Clinical Practice Guideline recommends that genetic counseling be provided for individuals who are planning to conceive, and there is a family history of 21-hydroxylase deficiency.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

If left untreated, patients with 21-hydroxylase deficiency may progress to develop complications. Common complications of 21-hydroxylase deficient congenital adrenal hyperplasia include short stature, adrenal crisis, infertility, and precocious puberty. The prognosis of 21-hydroxylase deficiency is generally good with treatment.

• If left untreated, patients with 21-hydroxylase deficiency may progress to develop complications.
• Androgen excess in childhood leads to pseudoprecocious puberty, accelerated childhood growth with premature epiphyseal closure, which causes an overall short stature, and various metabolic abnormalities.
• Adults may also face fertility issues, both in classic and non-classic forms of 21-hydroxylase deficiency.
• Testicular adrenal rest tumors (nodular hyperplasia arising from cells that have many characteristics of adrenocortical cells and migrated with the testis during fetal development) may also occur and patients with 21-hydroxylase deficiency require monitoring for these tumors. These tumors indicate poor disease control and are usually reversible with optimum treatment.^[1][2]

Common complications associated with 21-hydroxylase deficiency include:^[1][2]

• Adrenal crisis
• Infertility
• Precocious puberty
• Virilization
• Dehydration
• Short stature

• The prognosis of 21-hydroxylase deficiency is generally good with treatment.
• A small percentage of children and adults with infancy or childhood onset 21 hydroxylase deficiency die of adrenal crisis, even after diagnosis and initiation of treatment.
• There may be no immediate worsening of symptoms if a person is well and has missed a dose or even several doses. However, glucocorticoid needs are increased during illness and stress.
• Missed doses during time of illness can lead (within hours) to hypotension, shock, and death.^[1][2]

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