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2000-06-28-11 Congenital adrenal hyperplasia © Capelanes


Congenital adrenal hyperplasia

Angela Regina Capelanes, MD*, Philippe Jeanty, MD, PhD#

*Centro de Atendimento Materno-Fetal, Aracatuba Sao Paulo, Brazil;  #Nashville, TN


Synonyms:  None

Definition:  Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency (21-OHD) is the most common cause of ambiguous genitalia in females at birth[1];

 it is caused by enzymatic defects in the steroidogenesis of the adrenal glands and is characterized by impaired cortisol and aldosterone synthesis and overproduction

of androgens. The affected females usually present virilization and life-threatening problems[2].

Prevalence: Varies with geographic region, 20:10,000 in certain Eskimos, 20:10,000 in Switzerland, 0.66:10,000 in the United States Caucasians4.  

Etiology: Congenital adrenal hyperplasia is a autosomal recessive disorder[3],[4] caused by mutation CYP21 gene[5],[6], which is located on the short arm

of chromosome 6 in the HLA region2,[7]

Pathogenesis:  Congenital adrenal hyperplasia (CAH) represents several deficient syntheses of cortisol disorders in the adrenal cortex.

The defects in three steroidogenic enzymes, 21-hydroxylase, 11 b-hydroxylase, and 3 b-hydroxysteroid dehydrogenase, result in deficient

formation of cortisol, that cause increase in the release of ACTH. This leads to overproduction of adrenal androgens[8]. A large number of

patients also have aldosterone insufficiency, which causes the inability to conserve sodium and to excrete potassium that can lead to adrenal shock

and neonatal death. Affected female fetus can develop genital ambiguity[9].

Diagnosis: Excess androgen production from congenital adrenal hyperplasia is the most common cause of partial virilization at birth of a genotypic female

 with varying degrees of posterior labial fusion, clitoromegaly and absent vaginal introitus. Rarely, labial fusion arises secondary to maternal androgen ingestion

or an androgen-secreting tumor during pregnancy[10]. Rapid characterization of steroid 21-hydroxylase deficiencies is obtained using the allele-specific

polymerase chain reaction technique in affected children[11]. Two rounds of the polymerase chain reaction (PCR) are used to study the 21-hydroxylase

gene (CYP21). The primary PCR amplifies CYP21-specific DNA fragments, and the secondary PCR uses products from the primary PCR for analysis

of amplification-created restriction sites (ACRS) and direct DNA sequencing[12],[13],[14]. The prenatal diagnosis of steroid 21-hydroxylase deficiency can

 be obtained by chorionic villus sampling1 in high-risk families.

Sonographic findings: Ambiguous genitalia.

Differential diagnosis: Anomalies that cause ambiguous genitalia: partial androgen insensitivity syndrome, maternal androgen ingestion

or an androgen-secreting tumor during pregnancy[15].

Associated anomalies: Increased nuchal translucency has been associated with congenital adrenal hyperplasia[16].

Prognosis:   The prenatal treatment of affected female fetuses is generally efficient in minimizing virilization of external genitalia, in cases 
of congenital adrenal hyperplasia[17].

Recurrence risk:  Mendelian inheritance.

Management: The virilization of the fetus with 21-hydroxylase can be prevented by antenatal dexamethasone therapy1,2,[18]. Prenatal treatment 
of steroid 21- and 11 b-hydroxylase deficiency is safe and effective, reducing or eliminating virilization in the affected female, and influencing the
 postnatal life[19]. Determination of fetal sex is important for prenatal diagnosis of sex-related disorders as congenital adrenal hyperplasia and androgen
 insensitivity syndrome. A protocol has been developed to rapidly assess the fetal sex in chorionic villus through polymerase chain reaction rapidly[20].


[1] Theodoropoulou M, Barta C, Szoke M, Guttman A, Staub M, Niederland T, Solyom J,Fekete G, Sasvari-Szekely M.Prenatal diagnosis of
steroid 21-hydroxylase deficiency by allele-specific amplification.Fetal DiagnTher2001Jul-Aug;16(4):237-40.

[2] Lee HH, Kuo JM, Chao HT, Lee YJ, Chang JG, Tsai CH, Chung BC.Carrier analysis and prenatal diagnosis of congenital adrenal hyperplasia

causedby 21-hydroxylase deficiency in Chinese.J Clin Endocrinol Metab 2000 Feb;85(2):597-600

[3] Lee HH, Kuo JM, Chao HT, Lee YJ, Chang JG, Tsai CH, Chung BC.Carrier analysis and prenatal diagnosis of congenital adrenal hyperplasia

 causedby 21-hydroxylase deficiency in Chinese.J Clin Endocrinol Metab 2000 Feb;85(2):597-600

[4] Buyse, ML. Birth Defects Enciclopedia. Pag 1603

[5] Ritzen EM, Lajic S, Wedell A.How can molecular biology contribute to the management of congenital adrenalhyperplasia?Horm

Res 2000;53 Suppl 1:34-7

[6] Pineda P, Fardella C, Poggi H, Torrealba I, Cattani A, Soto J, Foradori A. Molecular diagnosis of salt wasting congenital adrenal hyperplasia,

caused by deficit of 21-hydroxylase, in the Chilean population.Rev Med Chil 1997 Sep;125(9):987-92

[7] Pang S. Congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 1997 Dec;26(4):853-91 Relate

8 Kajic S, Bui TH, Holst M, Ritzen M, Wedell A.Prenatal diagnosis and treatment of adrenogenital syndrome. Preventvirilization of female

 fetuses.Lakartidningen 1997 Dec 10;94(50):4781-6

[9] Mathur R, Kabra M, Menon PS. Prenatal diagnosis and treatment of steroid 21-hydroxylase deficiency

(congenital adrenal hyperplasia).Indian J Pediatr 2000 Nov;67(11):813-8

[10] Klein VR, Willman SP, Carr BR.Familial posterior labial fusion.Obstet Gynecol 1989 Mar;73(3 Pt 2):500-3

[11] Mathur R, Kabra M, Menon PS.Diagnosis and management of congenital adrenal hyperplasia: clinical, molecular and prenatal aspects.

Natl Med J India 2001 Jan-Feb;14(1):26-31

[12] Ko TM, Kao CH, Ho HN, Tseng LH, Hwa HL, Hsu PM, Chuang SM, Lee TY. Congenital adrenal hyperplasia. Molecular characterization.

Reprod Med 1998 Apr;43(4):379-86

[13] Day DJ, Speiser PW, Schulze E, Bettendorf M, Fitness J, Barany F, White PC.Identification of non-amplifying CYP21 genes when using

 PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees.Hum Mol Genet 1996 Dec;5(12):2039-48

[14] Wedell A. Molecular approaches for the diagnosis of 21-hydroxylase deficiency and congenital adrenal hyperplasia. Clin Lab Med 1996 Mar;16(1):125-37

[15] Klein VR, Willman SP, Carr BR.Familial posterior labial fusion.Obstet Gynecol 1989 Mar;73(3 Pt 2):500-3

[16] Masturzo B, Hyett JA, Kalache KD, Rumsby G, Jauniaux E, Rodeck CH. Increased nuchal translucency as a prenatal manifestation of

congenital adrenal hyperplasia.Prenat Diagn 2001 Apr;21(4):314-6

[17] Lajic S, Wedell A, Bui TH, Ritzen EM, Holst M.Long-term somatic follow-up of prenatally treated children with congenitaladrenal hyperplasia.J

Clin Endocrinol Metab 1998 Nov;83(11):3872-80

[18] Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI. Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase

deficiencyJ Clin Endocrinol Metab 1995 Jul;80(7):2014-20

[19] New MI.Prenatal treatment of congenital adrenal hyperplasia. The United States experience.Endocrinol Metab Clin North Am 2001 Mar;30(1):1-13.

[20] Domenice S, Billerbeck AE, Rocha RO, Nishi MY, Medeiros MA, Bachega TA, Budunki

V, Mendonca BB. Protocol for rapid fetal sex determination in chorionic villus through

polimerase chain reaction.Rev Hosp Clin Fac Med Sao Paulo 1998 Mar-Apr;53(2):80-

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