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Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency(CAH1)

MedGen UID:
424833
Concept ID:
C2936858
Congenital Abnormality
Synonyms: 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia; Congenital adrenal hyperplasia due to 21-hydroxylase deficiency; CYP21 deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): CYP21A2 (6p21.33)
 
Monarch Initiative: MONDO:0008728
OMIM®: 201910
Orphanet: ORPHA90794

Disease characteristics

21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21-OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth. [from GeneReviews]
Authors:
Saroj Nimkarn  |  Prasanna K Gangishetti  |  Mabel Yau, et. al.   view full author information

Additional descriptions

From OMIM
Congenital adrenal hyperplasia (CAH) results from a deficiency in one or another of the enzymes of cortisol biosynthesis. In about 95% of cases, 21-hydroxylation is impaired in the zona fasciculata of the adrenal cortex so that 17-hydroxyprogesterone (17-OHP) is not converted to 11-deoxycortisol. Because of defective cortisol synthesis, ACTH levels increase, resulting in overproduction and accumulation of cortisol precursors, particularly 17-OHP, proximal to the block. This causes excessive production of androgens, resulting in virilization. Slominski et al. (1996) presented evidence that the CYP21A2, CYP11A1 (118485), CYP17 (609300), and ACTHR (202200) genes are expressed in skin (see 202200). The authors suggested that expression of these genes may play a role in skin physiology and pathology and that cutaneous proopiomelanocortin activity may be autoregulated by a feedback mechanism involving glucocorticoids synthesized locally.  http://www.omim.org/entry/201910
From MedlinePlus Genetics
In both the salt-wasting and simple virilizing forms of this disorder, females typically have external genitalia that do not look clearly male or female. Males usually have male-typical genitalia but the testes may be small.

Females with the non-classic type of 21-hydroxylase deficiency have female-typical genitalia. As affected females get older, they may experience hirsutism, male pattern baldness, irregular menstruation, and decreased fertility. Males with the non-classic type may have early beard growth and small testes. Some individuals with this type of 21-hydroxylase deficiency have no symptoms of the disorder.

Approximately 75 percent of individuals with classic 21-hydroxylase deficiency have the salt-wasting type. Hormone production is extremely low in this form of the disorder. Affected individuals lose large amounts of sodium in their urine, which can be life-threatening in early infancy. Babies with the salt-wasting type can experience poor feeding, weight loss, dehydration, and vomiting. Individuals with the simple virilizing form do not experience salt loss.

Males and females with either classic form of 21-hydroxylase deficiency tend to have an early growth spurt, but their final adult height is usually shorter than others in their family. Additionally, affected individuals may have a reduced ability to have biological children (decreased fertility). Females may also develop excessive body hair growth (hirsutism), male pattern baldness, and irregular menstruation.

There are three types of 21-hydroxylase deficiency. Two types are classic forms, known as the salt-wasting and simple virilizing types. The third type is called the non-classic type. The salt-wasting type is the most severe, the simple virilizing type is less severe, and the non-classic type is the least severe form.

21-hydroxylase deficiency is an inherited disorder that affects the adrenal glands. The adrenal glands are located on top of the kidneys and produce a variety of hormones that regulate many essential functions in the body. In people with 21-hydroxylase deficiency, the adrenal glands produce excess androgens, which are male sex hormones.  https://medlineplus.gov/genetics/condition/21-hydroxylase-deficiency

Clinical features

From HPO
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Renal salt wasting
MedGen UID:
375868
Concept ID:
C1846347
Finding
A high concentration of one or more electrolytes in the urine in the presence of low serum concentrations of the electrolyte(s).
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Abnormal thorax morphology
MedGen UID:
867424
Concept ID:
C4021797
Anatomical Abnormality
Any abnormality of the thorax (the region of the body formed by the sternum, the thoracic vertebrae and the ribs).
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.
Adrenogenital syndrome
MedGen UID:
86215
Concept ID:
C0302280
Disease or Syndrome
Adrenogenital syndrome is also known as congenital adrenal hyperplasia, which results from disorders of steroid hormone production in the adrenal glands leading to a deficiency of cortisol. The pituitary gland reacts by increased secretion of corticotropin, which in turn causes the adrenal glands to overproduce certain intermediary hormones which have testosterone-like effects.
Adrenal hyperplasia
MedGen UID:
301220
Concept ID:
C1621895
Disease or Syndrome
Enlargement of the adrenal gland.
Elevated circulating 21-deoxycortisol concentration
MedGen UID:
1052516
Concept ID:
CN377347
Finding
The concentration of 21-deoxycortisol in the blood circulation is above the upper limit of normal.
Gynecomastia
MedGen UID:
6694
Concept ID:
C0018418
Disease or Syndrome
Abnormal development of large mammary glands in males resulting in breast enlargement.

Recent clinical studies

Etiology

Fraga NR, Minaeian N, Kim MS
Pediatr Rev 2024 Feb 1;45(2):74-84. doi: 10.1542/pir.2022-005617. PMID: 38296783
Lee SC, Baranowski ES, Sakremath R, Saraff V, Mohamed Z
Front Endocrinol (Lausanne) 2023;14:1198519. Epub 2023 Nov 20 doi: 10.3389/fendo.2023.1198519. PMID: 38053731Free PMC Article
Maher JY, Gomez-Lobo V, Merke DP
Rev Endocr Metab Disord 2023 Feb;24(1):71-83. Epub 2022 Nov 18 doi: 10.1007/s11154-022-09770-5. PMID: 36399318Free PMC Article
Jha S, Turcu AF
Endocrinol Metab Clin North Am 2021 Mar;50(1):151-165. Epub 2021 Jan 9 doi: 10.1016/j.ecl.2020.10.008. PMID: 33518183Free PMC Article
Simonetti L, Bruque CD, Fernández CS, Benavides-Mori B, Delea M, Kolomenski JE, Espeche LD, Buzzalino ND, Nadra AD, Dain L
Hum Mutat 2018 Jan;39(1):5-22. Epub 2017 Nov 6 doi: 10.1002/humu.23351. PMID: 29035424

Diagnosis

Fraga NR, Minaeian N, Kim MS
Pediatr Rev 2024 Feb 1;45(2):74-84. doi: 10.1542/pir.2022-005617. PMID: 38296783
Lee SC, Baranowski ES, Sakremath R, Saraff V, Mohamed Z
Front Endocrinol (Lausanne) 2023;14:1198519. Epub 2023 Nov 20 doi: 10.3389/fendo.2023.1198519. PMID: 38053731Free PMC Article
Maher JY, Gomez-Lobo V, Merke DP
Rev Endocr Metab Disord 2023 Feb;24(1):71-83. Epub 2022 Nov 18 doi: 10.1007/s11154-022-09770-5. PMID: 36399318Free PMC Article
Adriaansen BPH, Schröder MAM, Span PN, Sweep FCGJ, van Herwaarden AE, Claahsen-van der Grinten HL
Front Endocrinol (Lausanne) 2022;13:1064024. Epub 2022 Dec 12 doi: 10.3389/fendo.2022.1064024. PMID: 36578966Free PMC Article
Jha S, Turcu AF
Endocrinol Metab Clin North Am 2021 Mar;50(1):151-165. Epub 2021 Jan 9 doi: 10.1016/j.ecl.2020.10.008. PMID: 33518183Free PMC Article

Therapy

Auchus RJ, Hamidi O, Pivonello R, Bancos I, Russo G, Witchel SF, Isidori AM, Rodien P, Srirangalingam U, Kiefer FW, Falhammar H, Merke DP, Reisch N, Sarafoglou K, Cutler GB Jr, Sturgeon J, Roberts E, Lin VH, Chan JL, Farber RH; CAHtalyst Adult Trial Investigators
N Engl J Med 2024 Aug 8;391(6):504-514. Epub 2024 Jun 1 doi: 10.1056/NEJMoa2404656. PMID: 38828955Free PMC Article
Fraga NR, Minaeian N, Kim MS
Pediatr Rev 2024 Feb 1;45(2):74-84. doi: 10.1542/pir.2022-005617. PMID: 38296783
Lee SC, Baranowski ES, Sakremath R, Saraff V, Mohamed Z
Front Endocrinol (Lausanne) 2023;14:1198519. Epub 2023 Nov 20 doi: 10.3389/fendo.2023.1198519. PMID: 38053731Free PMC Article
Maher JY, Gomez-Lobo V, Merke DP
Rev Endocr Metab Disord 2023 Feb;24(1):71-83. Epub 2022 Nov 18 doi: 10.1007/s11154-022-09770-5. PMID: 36399318Free PMC Article
Adriaansen BPH, Schröder MAM, Span PN, Sweep FCGJ, van Herwaarden AE, Claahsen-van der Grinten HL
Front Endocrinol (Lausanne) 2022;13:1064024. Epub 2022 Dec 12 doi: 10.3389/fendo.2022.1064024. PMID: 36578966Free PMC Article

Prognosis

Arriba M, Ezquieta B
Front Endocrinol (Lausanne) 2022;13:834549. Epub 2022 Mar 29 doi: 10.3389/fendo.2022.834549. PMID: 35422767Free PMC Article
Troger T, Sommer G, Lang-Muritano M, Konrad D, Kuhlmann B, Zumsteg U, Flück CE
J Clin Endocrinol Metab 2022 Jan 18;107(2):e487-e499. doi: 10.1210/clinem/dgab701. PMID: 34599587Free PMC Article
Carvalho B, Marques CJ, Santos-Silva R, Fontoura M, Carvalho D, Carvalho F
Exp Clin Endocrinol Diabetes 2021 Jul;129(7):477-481. Epub 2020 Mar 4 doi: 10.1055/a-1108-1419. PMID: 32131114
Reisch N
Endocrinol Metab Clin North Am 2019 Sep;48(3):619-641. doi: 10.1016/j.ecl.2019.05.011. PMID: 31345527
Falhammar H, Wedell A, Nordenström A
Endocrine 2015 Nov;50(2):306-14. Epub 2015 Sep 4 doi: 10.1007/s12020-015-0731-6. PMID: 26336836

Clinical prediction guides

Concolino P, Perrucci A, Carrozza C, Urbani A
Mol Diagn Ther 2023 Sep;27(5):621-630. Epub 2023 Aug 7 doi: 10.1007/s40291-023-00666-x. PMID: 37548905
Saho R, Dolzan V, Zerjav Tansek M, Pastorakova A, Petrovic R, Knapkova M, Trebusak Podkrajsek K, Suput Omladic J, Bertok S, Avbelj Stefanija M, Kotnik P, Battelino T, Pribilincova Z, Groselj U
Front Endocrinol (Lausanne) 2023;14:1134133. Epub 2023 Mar 17 doi: 10.3389/fendo.2023.1134133. PMID: 37008950Free PMC Article
Arriba M, Ezquieta B
Front Endocrinol (Lausanne) 2022;13:834549. Epub 2022 Mar 29 doi: 10.3389/fendo.2022.834549. PMID: 35422767Free PMC Article
Troger T, Sommer G, Lang-Muritano M, Konrad D, Kuhlmann B, Zumsteg U, Flück CE
J Clin Endocrinol Metab 2022 Jan 18;107(2):e487-e499. doi: 10.1210/clinem/dgab701. PMID: 34599587Free PMC Article
Carvalho B, Marques CJ, Santos-Silva R, Fontoura M, Carvalho D, Carvalho F
Exp Clin Endocrinol Diabetes 2021 Jul;129(7):477-481. Epub 2020 Mar 4 doi: 10.1055/a-1108-1419. PMID: 32131114

Recent systematic reviews

Hosomi SS, Salles IC, Bachega TASS
Arch Endocrinol Metab 2023 Mar 30;67(3):427-441. doi: 10.20945/2359-3997000000593. PMID: 37011374Free PMC Article
Navarro-Zambrana AN, Sheets LR
Horm Res Paediatr 2023;96(3):249-258. Epub 2022 Aug 16 doi: 10.1159/000526401. PMID: 35973409
Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R
Hum Reprod Update 2017 Sep 1;23(5):580-599. doi: 10.1093/humupd/dmx014. PMID: 28582566
Mercè Fernández-Balsells M, Muthusamy K, Smushkin G, Lampropulos JF, Elamin MB, Abu Elnour NO, Elamin KB, Agrwal N, Gallegos-Orozco JF, Lane MA, Erwin PJ, Montori VM, Murad MH
Clin Endocrinol (Oxf) 2010 Oct;73(4):436-44. doi: 10.1111/j.1365-2265.2010.03826.x. PMID: 20550539

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT Sheet, 2011
      American College of Medical Genetics ACT SHEET, Congenital Adrenal Hyperplasia, 2011
    • ACMG Algorithm, 2009
      American College of Medical Genetics Algorithm, Congenital Adrenal Hyperplasia, 2009
    • ACMG Algorithm, 2009
      American College of Medical Genetics and Genomics, Algorithm, Congenital Adrenal Hyperplasia (Elevated 17-OHP), 2009

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