This syndrome is also known as congenital adrenal hyperplasia. Various enzyme deficiencies, all inherited in an autosomal recessive fashion, comprise this syndrome. Because the adrenal gland produces steroids of either corticosteroids or mineralocorticoids, depending upon the enzyme defect, the patient will have various levels of hormone deficiencies. The pituitary gland, in turn, will attempt to stimulate the adrenal gland by secreting corticotropin. Since there is a primary enzyme defect, instead of the usual hormone produced, intermediary substances leading up to the enzyme block are produced. These substances can lead to virilization, or testoerone promoting-like changes.
Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency.
Lutfallah C, Wang W, Mason JI, Chang YT, Haider A, Rich B, Castro-Magana M, Copeland KC, David R, Pang S.
Department of Pediatrics, College of Medicine, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA.
J Clin Endocrinol Metab 2002 Jun;87(6):2611-22 Abstract quote
To define the hormonal criteria via genotypic proof for 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency in the adrenals and gonads, we investigated the type II 3beta-HSD genotype in 55 patients with clinical and/or hormonal presentation suggesting compromised adrenal with or without gonadal 3beta-HSD activity.
Fourteen patients (11 males and 3 females) had ambiguous genitalia with or without salt wasting and with or without premature pubarche. One female neonate had salt wasting only. Twenty-five children (4 males and 21 females) had premature pubarche only. Fifteen adolescent and adult females had hirsutism with or without menstrual disorder. The type II 3beta-HSD gene, including the promoter region up to -1053 base, all exons I, II, III, IV, and exon and intron boundaries, was sequenced in all subjects. Eight patients had a proven or predictably deleterious mutation in both alleles of the type II 3beta-HSD gene, and 47 patients had no apparent mutation in the gene. ACTH-stimulated (1 h post iv bolus of 250 microg Cortrosyn) serum 17-hydroxypregnenolone (Delta5-17P) levels and basal and ACTH-stimulated ratios of Delta5-17P to cortisol (F) in the genotypic proven patients were unequivocally higher than those of age-matched or pubic hair stage matched genotype-normal patients or control subjects (n = 7-30 for each group).
All other baseline and ACTH-stimulated hormone parameters, including dehydroepiandrosterone (DHEA) levels, ratios of Delta5-17P to 17-OHP and DHEA to androstenedione in the genotype-proven patients, overlapped with the genotype-normal patients or control subjects. The hormonal findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3beta-HSD deficiency congenital adrenal hyperplasia (numeric and graphic reference standards from infancy to adulthood are provided): ACTH-stimulated Delta5-17P levels in 1) neonatal infants with ambiguous genitalia at or greater than 378 nmol/liter equivalent to or greater than 5.3 SD above the control mean level [95 +/- 53 (SD) nmol/liter]; 2) Tanner I children with ambiguous genitalia at or greater than 165 nmol/liter equivalent to or greater than 35 SD above the control mean level [12 +/- 4.3 (SD) nmol/liter]; 3) children with premature pubarche at or greater than 294 nmol/liter equivalent to or greater than 54 SD above Tanner II pubic hair stage matched control mean level [17 +/- 5 (SD) nmol/liter]; and 4) adults with at or greater than 289 nmol/liter equivalent to or greater than 21 SD above the normal mean level [25 +/- 12 (SD) nmol/liter]. ACTH-stimulated ratio of Delta5-17P to F in 1) neonatal infants at or greater than 434 equivalent to or greater than 6.4 SD above the control mean ratio [88 +/- 54 (SD)]; 2) Tanner I children at or greater than 216 equivalent to or greater than 23 SD above the control mean ratio [12 +/- 9 (SD)]; 3) children with premature pubarche at or greater than 363 equivalent to or greater than 38 SD above the control mean ratio [20 +/- 9 (SD)]; and 4) adults at or greater than 4010 equivalent to or greater than 221 SD above the normal mean ratio [29 +/- 18 (SD)].
Conversely, the hormonal data in the genotype-normal patients suggest the following hormonal criteria are not consistent with 3beta-HSD deficiency congenital adrenal hyperplasia: ACTH-stimulated Delta5-17P levels in children with premature pubarche up to 72 nmol/liter equivalent to up to 11 SD above the control mean level, and in hirsute females up to 150 nmol/liter equivalent to up to 12 SD above the normal female mean level [28 +/- 10 (SD) nmol/liter]; and ACTH-stimulated Delta5-17P to F ratio in children with premature pubarche up to 67 equivalent to up to 5 SD above the control mean ratio, and in hirsute females up to 151 equivalent to up to 10 SD above the normal mean ratio [32 +/- 12 (SD)].
These findings help define newly proposed hormonal criteria to accurately predict inherited 3beta-HSD deficiency
Congenital adrenal hyperplasia: 11beta-hydroxylase deficiency.
SANITAS Ostseeklinik Boltenhagen and Division of Paediatric Endocrinology, Department of Paediatrics, University of Kiel, Kiel, Germany.
Semin Reprod Med 2002 Aug;20(3):249-54 Abstract quote
The most potent corticosteroids are 11beta-hydroxylated compounds.
In humans, two cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalyzing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed in high levels in the zona fasciculata and is regulated by adrenocorticotropic hormone (ACTH). CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. The substrate for P450c11 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency.
This disorder is characterized by androgen excess and hypertension and is autosomal recessively inherited. Classical and nonclassical forms of 11beta-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11beta-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). Molecular genetic studies of the CYP11B1 gene in 11beta-hydroxylase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. Molecular genetic studies have practical importance for the prenatal diagnosis of virilizing CAH forms.
Non-classical 21-hydroxylase deficiency in children: association of adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk of compound heterozygosity with severe mutations.
Ezquieta B, Cueva E, Varela J, Oliver A, Fernandez J, Jariego C.
Servicio de Bioquimica, Hospital Universitario La Paz, Madrid, Spain.
Acta Paediatr 2002;91(8):892-8 Abstract quote
AIM: To investigate the association between levels of 17-hydroxyprogesterone (17-OHP) and the risk of being compound heterozygous for severe mutations in children with non-classical 21-hydroxylase deficiency (NC21OHD).
METHODS: In 86 Spanish NC21OHD children (75 families) an analysis of the 21-hydroxylase (21-OH) gene was performed by CYP21B-specific polymerase chain reaction amplification, allele-specific oligonucleotide hybridization and Southern blotting. Familial analysis established how the alleles segregated, and allowed the selection of 21-OH-genotyped normal and carrier children, which proved useful in determining a more precise definition of the cut-off for diagnosis. Receiver operating characteristics (ROC) curve analyses were performed to determine the potential value of 17-OHP in predicting compound heterozygosity for severe mutations.
RESULTS: Thirty-four of the 86 children (39%) were found to carry one severe 21-OH mutation (7.3% deletions or conversions, 2.7% 655G, 2.7% Q318X, 1.3% 1172N, 1.3% R356W, and 3.3% double microconversions or small conversions involving single exons). The predominant mutation was V281L (56.7%). P453S and P30L were less frequent (3.3 and 2%). No patient showed two severe mutations. The degree of enzymic deficiency, as measured by basal or adrenocorticotropic hormone (ACTH)-stimulated 17-OHP levels in fully genotyped patients, but not clinical severity (age and number of symptoms at diagnosis), was found to be significantly greater in children with the severe/mild genotype. ROC curve analyses revealed a strong association between ACTH-17-OHP and genotype (area under the curve 0.908, SE 0.057).
CONCLUSION: ACTH-stimulated 17-OHP may predict the risk of severe mutations in compound heterozygosity in children (maximum predictive value 93% sensitivity and 83% specificity for a cut-off at 151 nmol l(-1)), although a certain overlap in individual values is observed and performance of molecular analysis should never be obviated in the genetic counselling of these patients.
CHARACTERIZATION RADIOLOGIC LABORATORY MARKERS GENERAL
Congenital adrenal hyperplasia: lessons from a multinational study.
Frisch H, Waldhauser F, Lebl J, Solyom J, Hargitai G, Kovacs J, Pribilincova Z, Krzisnik C, Battelino T; MEWPE-CAH Study Group.
Department of Paediatrics, University of Vienna, Austria.
Horm Res 2002;57 Suppl 2:95-101 Abstract quote
A study group of paediatric endocrinologists was established in Austria, Czech Republic, Hungary, Slovenia and Slovakia in order to investigate various aspects in children with congenital adrenal hyperplasia (CAH). Five hundred and ninety-eight patients with CAH who were diagnosed between 1969 and 1998 were included in order to analyze the following questions.
Epidemiological data: There were significantly fewer males (43%) than females (57%), and the percentage of males did not increase during the observation period. Salt wasters (SW) totalled 64.7%, whereas 35.3% had simple virilizing (SV) CAH. Diagnosis was established significantly later in boys than in girls (median of 26 vs. 13 days for SW, p < 0.0001; 1,817 vs. 1,010 days for SV, p < 0.03). Mortality in the general population was significantly lower than in CAH siblings (1.8% vs. 7.0%, p < 0.0001) or in SW children (2.2% vs. 11.3%, p < 0.0001). According to our calculation with the present clinical diagnostic criteria in Central Europe, from 40 expected CAH patients/year, 2-2.5 SW, and one female and four male SV patients will not be diagnosed. Auxological data: Growth data from 341 patients were analyzed retrospectively. Percentiles were constructed in a longitudinal/cross-sectional study and pubertal growth was described in a longitudinal analysis. Growth of SW patients was impaired in early childhood (0-3 years), but followed a normal course until puberty. In contrast, SV children had a normal growth pattern during early childhood, but were above the standard thereafter. The pubertal growth spurt was of normal magnitude in boys and girls, but started too early. Final height was reduced compared with both standard and target heights. There was no correlation between final height and age of starting treatment or the year of birth. Bone age was accelerated in both CAH types, but more so in SV patients.
Molecular genetics: Three hundred and fifty-six patients were investigated for 11-14 of the most frequent mutations by direct allele-specific polymerase chain reaction (PCR) and/or PCR followed by sequence-specific oligonucleotide, single strand chain polymorphism and restriction fragment length polymorphism. In the group as a whole, we most frequently found the Intron 2 splice mutation (30.8%) or a deletion/conversion (28.5%). The Intron 2 mutation was most frequent in the Hungarian population, whereas deletions/conversions were found more frequently in Slovenians. The other mutations had a similar distribution to those seen in other populations. Genotype-phenotype correlation confirms previous reports.
Adrenal tumors associated with inadequately treated congenital adrenal hyperplasia.
Wang J, Bissada MA, Williamson HO, Yakout H, Bissada NK.
Department of Urology, Second Affiliated Hospital of Kunming Medical College, Kunming, Yunnan, China.
Can J Urol 2002 Jun;9(3):1563-4 Abstract quote
We describe a case of salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency complicated by a right adrenal adenoma. The development of adrenal adenoma or carcinoma in-patients with congenital adrenal hyperplasia (CAH) is rare; the etiology is not clear but is thought to be related to inadequate glucocorticoid therapy. Tumor formation is postulated to be a consequence of ACTH hypersecretion, which results from the lack of glucocorticoid synthesis.
Our patient underwent clitorectomy and multiple constructive procedures as a newborn baby; she was managed with hormone replacement for many years. However while she took adequate mineralocortocoid dosage, she chronically tended to take inadequate doses of glucocorticoid seeking to increase her muscle ability. She developed a 6.5 cm adrenal tumor. She was managed by a hand-assisted laparoscopic radical adrenalectomy.
The tumor was histologically consistent with adrenal adenoma. The importance of compliance with her medications was emphasized.
Hypertension in congenital adrenal hyperplasia and apparent mineralocorticoid excess.
Department of Pediatrics, Weill Cornell Medical College, New York Presbyterian Hospital, 525 E. 68th Street M622, New York, NY 10021, USA.
Ann N Y Acad Sci 2002 Sep;970:145-54 Abstract quote
Most often, low-renin hypertension in the child or adolescent has a clearly definable hormonal cause; thus while each of its numerous forms is moderately rare, a specific hormonal basis is to be expected. An endocrine evaluation is indicated after exclusion of cardiologic pathology or renovascular or portal abnormality in a hypertensive child.
The evaluation should include analysis of catecholamine and of thyroid hormone plasma levels, and plasma renin activity (PRA) level. Hormonal hypertension with high or normal renin conditions is rare.
Elevated blood pressure with high or normal renin levels may be in fact within normal range in the context of growth at upper percentile limits, possibly in conjunction with simple obesity. Diagnosis may be made at any age in most forms of low-renin hypertension.
GENERAL 21HYDROXYLASE DEFICIENCY
Nonclassic 21-hydroxylase deficiency.
Department of Endocrine Gynecology and Reproductive Medicine, Lille University Hospital, 6 rue du Professeur Laguesse, 59037 Lille Cedex, France.
Semin Reprod Med 2002 Aug;20(3):243-8 Related Articles, Links
Nonclassic 21-hydroxylase deficiency.
Department of Endocrine Gynecology and Reproductive Medicine, Lille University Hospital, 6 rue du Professeur Laguesse, 59037 Lille Cedex, France.
The nonclassic form of adrenal hyperplasia (NCAH) has been increasingly recognized in adolescent or adult hyperandrogenic patients. It is now widely accepted that neither the clinical presentation nor the androgen plasma levels can be used for the screening or diagnosis of NCAH in hyperandrogenic women, especially those presenting with a phenotype like that in polycystic ovary syndrome.
Therefore, the measurement of a follicular morning level of serum 17-hydroxyprogesterone (17-HP) should be included in the initial investigation of all hyperandrogenic women, including those with premature pubarche. Levels of 17-HP lower than 2 ng/mL (6.0 nmol/L) and greater than 4 ng/mL (12.0 nmol/L) have good predictive negative and positive values, respectively. The adrenocorticotropic hormone test is useful only when the morning follicular unsuppressed 17-HP level falls between 2 and 4 ng/mL (6 to 12 nmol/L). Adrenal insufficiency and adrenal hyperplasia are more theoretical than real complications of NCAH. On the other hand, the polycystic ovary syndrome and infertility are frequently associated with NCAH.
For the treatment of hyperandrogenism, the conventional treatment by glucocorticoid therapy is challenged by cyproterone acetate, but it is still indicated when patients wish a pregnancy. It can be questioned whether the low risk of virilized female newborns in untreated women with NCAH justifies prenatal diagnosis and treatment.
Congenital adrenal hyperplasia: 21-hydroxylase deficiency in the newborn and during infancy.
Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Box 116, Hills Road, Cambridge CB2 2QQ, UK.
Semin Reprod Med 2002 Aug;20(3):229-42 Abstract quote
Congenital adrenal hyperplasia is a family of monogenic autosomal recessive disorders of steroidogenesis with protean clinical manifestations. The commonest form, 21-hydroxylase deficiency, is the most frequent cause of ambiguous genitalia in the newborn. The molecular features associated with abnormalities in the CYP21 gene are well characterized in relation to phenotypic manifestations.
The concordance between genotype and phenotype is sufficiently robust as to be relevant and useful in planning treatment strategies. Thus, the dose of glucocorticoid replacement in the early years of life can be tailored according to the predicted degree of 21-hydroxylase enzyme deficiency in the anticipation that this may avoid hitherto excessive steroid replacement during the critical early years of growth and development. The means to prevent genital virilization in affected females is clearly demonstrated by the success of early dexamethasone administration to pregnant mothers at risk.
Short-term outcome studies of children exposed to dexamethasone in utero indicate no significant adverse effects. Nevertheless, it is recommended that prenatal treatment programs to prevent a major congenital malformation of the urogenital system be conducted only as part of agreed national multicenter studies, which include a commitment to long-term outcome analyses.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL OVARY
Ovarian `Tumor' of the Adrenogenital Syndrome The First Reported Case
Hikmat A. Al-Ahmadie, M.D. ; Jerzy Stanek, M.D. , Ph.D. ; James Liu, M.D. ; Padma N. Mangu, M.D. ; Ted Niemann, M.D. ; Robert H. Young, M.D.
From the Departments of Pathology and Laboratory Medicine (H.A.A., J.S.), and Obstetrics and Gynecology (J.L., P.N.M.), University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology (T.N.), Ohio State University Hospitals, Columbus, Ohio; and the James Homer Wright Laboratories of the Massachusetts General Hospital (R.H.Y.), Harvard Medical School, Boston, Massachusetts, U.S.A.
Am J Surg Pathol 2001;25:1443-1450 Abstract quote
We report the case of a 36-year-old woman with congenital adrenal hyperplasia from 21-hydroxylase deficiency who had been receiving replacement therapy with corticosteroids since birth.
At the age of 35 years, she developed abrupt aggravation of her virilizing symptoms and underwent an adrenalectomy and partial left oophorectomy. Persistent virilization and high testosterone levels led to right oophorectomy and completion left oophorectomy 6 months later. Each adnexa contained ovarian or paraovarian soft brown masses that on microscopic examination were identical to the testicular tumor of the adrenogenital syndrome.
This represents the first reported case of this pathology (well known in the testis) in the ovary.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES SALT LOSING NEPRHOPATHY
Salt losing nephropathy simulating congenital adrenal hyperplasia in an infant.
Kari JA, Bamashmous HA, Al-Agha AE, Mosli HA.
Pediatrics Department, King Abdul-Aziz University Hospital, PO Box 80215, Jeddah 21589, Kingdom of Saudi Arabia.
Saudi Med J 2002 Jul;23(7):863-5 Abstract quote
Pseudo-hypoaldosteronism occurring predominately in male infants has been reported in association with a spectrum of urologic diseases including obstructive uropathy. This is thought to reflect tubule unresponsiveness to aldosterone.
We report a case, which was misdiagnosed as a case of congenital adrenal hyperplasia and treated inappropriately with hydrocortisone and fludrocortisone for 12-months before he had a urinary tract infection and was discovered to have obstructive uropathy on ultrasound. He presented with vomiting, dehydration, hyperkalemia, hyponatremia and metabolic acidosis. His initial 17 hydroxyprogestrone was high.
His electrolytes improved to normal after relieving the obstruction by vesicostomy and his treatment weaned slowly without complications. This case demonstrates the importance of urine culture and ultrasound examination in suspected cases of pseudo-hypoaldosteronism.
PROGNOSIS CHARACTERIZATION GENERAL
Long-term consequences of childhood-onset congenital adrenal hyperplasia.
White PC, Speiser PW.
Division of Pediatric Endocrinology and Professor of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Best Pract Res Clin Endocrinol Metab 2002 Jun;16(2):273-88 Abstract quote
Congenital adrenal hyperplasia (CAH) is a general term applied to several diseases caused by inherited defects of cortisol synthesis. The most common of these is steroid 21-mono-oxygenase (also termed 21-hydroxylase) deficiency (CAH-21OHD), found in approximately 1:10 000-1:15 000 live births.
Potentially lethal adrenal insufficiency is characteristic of about two-thirds to three-quarters of patients with the classic salt-wasting form of CAH-21OHD. Non-salt-wasting forms of CAH-21OHD may be diagnosed based in part on genital ambiguity in affected newborn females, and/or by later evidence of androgen excess in members of either sex. Non-classical CAH-21OHD may be detected in up to 1-3% of certain populations, and is often mistaken for idiopathic precocious pubarche in children or polycystic ovary syndrome in young women.
This chapter addresses issues relating to long-term consequences in adult life of CAH-21OHD diagnosed in early childhood or adolescence.
TREATMENT CHARACTERIZATION GENERAL HYDROCORTISONE
Effect of the dose of oral hydrocortisone on growth rate during long-term treatment of children with salt losing congenital adrenal hyperplasia.
Ciaccio M, Montiveros C, Rivarola MA, Belgorosky A.
Servicio de Endocrinologia, Hospital de Pediatria Garrahan, Combate de los Pozos 1881, 1245 Buenos Aires, Argentina.
Medicina (B Aires) 2002;62(6):551-4 Abstract quote
The effect of the dose of oral hydrocortisone on stature growth rate of patients with the salt losing form of congenital adrenal hyperplasia and adequate electrolyte balance was here assessed.
Thirty patients (21 girls and 9 boys) were followed longitudinally for 0.52 to 8.64 years, between chronological ages 0.35 and 8.64 years. Nine consecutive periods (Ps) of follow up were defined in order to compare two auxological parameters, height (H) at the end of a follow up P and delta H standard deviation score (SDS).
According to growth rate during a particular P, two types of Ps were defined: Ps with delta H SDS > -0.5 (Group 1, satisfactory growth rate) and Ps with delta H SDS = or < -0.5 (Group 2, poor growth rate). A cut off value of 18.5 mg/m2/day of oral hydrocortisone (95% CI upper limit of group 1) was defined to separate acceptable from excessive doses. In P2, mean (+/- SD) H SDS (-1.81 +/- 1.15) was significantly lower than in any of the other Ps (p < 0.001). In P1 and in P2, delta H SDS was negative, but it was positive in P3 and in P4. Hydrocortisone dose in P1 and in P2 was significantly higher than in the rest of the Ps. All patients in P1 and most patients in P2, but not in other Ps, received excessive doses. Predicted adult H, calculated in 9 patients was not statistically different from their respective target H.
It is concluded that, during the first year of life, our patients received an excess of oral hydrocortisone (> 18 mg/m2/day) and grew poorly, but they were able to recover, at least temporarily, when the dose was adjusted during the following years.
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