Congenital adrenal hyperplasia (CAH) is a genetic disorder resulting from total or partial deficiency of an enzyme involved in cortisol and aldsosterone biosynthesis. In 95% of the cases of CAH, this enzyme is the 21-hydroxylase, which is responsible for the conversion of 17-hydroxyprogesterone to 11-deoxycorticsol. The deficiency of this enzyme leads not only to loss of cortisol synthesis, but also to the accumulation of cortisol precursors, and increase in ACTH, and consequently, androgen levels. CAH has four different clinical forms, of which the salt wasting type (SW) is the most severe. This form is characterized by life threatening vomiting and dehydration, occurring within the first few weeks of life, due to severe salt imbalances. Excess exposure of the female fetus to androgen causes masculinization of the genital-urinary structures, leading to erroneous gender assignments. Adult women present with clitorimegaly, poorly developed vaginal labia, oligomenorrhea, and infertility. In boys, body growth is unusually fast, and puberty is premature. The other forms of the disease are the simple virilizing or SV type (characterized by virilization in prepubertal children), the non-classical CAH (a milder form portrayed by shortened stature, near syncope, premature development of pubic hair, hyperpigmentation, acne, menstrual disturbances in females, excess body hair and infertility), and the cryptic type (late onset, asymptomatic).
About 1 in 21,500 live births are affected by CAH. Prenatal diagnosis is now available for the disease. Diagnosis is made in the first trimester by chorionic villus sampling and in the second trimester by measuring hormones such as 17-hydroxyprogesterone in the amniotic fluid. Considering the lethal nature of the disease, neonatal screening is also peformed by measuring the hormonal levels on heelstick blood. Treatment involves administering glucocorticoids, like hydrocortisone and prednisone, and mineralocorticoid analogues to improve the hormonal balance. Genital reconstructive surgery is also available to reconstruct the vagina, and reduce the size of clitoris in females.
The gene coding for 21-hydroxylase is located at 6p21.3. The functional gene, called CYP21 or CYP21B has 10 exons and codes for a protein with 494 amino acids (55.8KDa). A highly homologous pseudogene called CYP21P or CYP21A is also present, contiguous to the functional gene, rendering it easy for recombination events, and consequent mutations to occur.
Gad (2002) studied the CYP21 mutations in two Egyptian CAH patients. The first case was an infant girl, who presented with genital ambiguity. Her parents were first cousins, and two of her siblings, (a boy, and a girl with 'abnormal genitalia') had died in infancy. She had below normal serum sodium and greater than normal potassium levels. Her basal 17-hydroxyprogesterone level was highly increased (190 ng/ml). Ultrasonogrpahy of the internal genitalia was performed, showing intact Mullerian structures and ovaries. The second patient was a 5 day old infant. The boy's parents were double cousins, and they had three earlier children who died in infancy, as well as one twin miscarriage at 4 months gestation. The baby had an enlarged penis, and dark scrotal and genital skin. His serum sodium and potassium levels were abnormal too, although his basal 17-hydroxyprogesterone level was almost normal. PCR analysis of the patients' DNA using primers for four common Egyptian CYP21 mutations showed that both were homozygous for the I172N mutation. Their mothers were both heterozygous for the mutation. This mutation has been shown to have a wide spectrum of phenotypes, and is usually associated with the SV clinical form. However, both the cases that Gad (2002) studied belonged to the salt wasting type, indicating that this mutation can lead to the severe lethal phenotype too. Gad (2002) could not explain how the same mutation could lead to different biochemical phenotypes in relation to the basal hydroxyprogesterone levels in the two cases.
Arnaout (1992) determined the frequency of non-classical adrenal hyperplasia due to deficiencies of 3 beta-hydroxy-delta 5-steroid dehydrogenase, 21-hydroxylase, and 11 beta-hydroxylase among 65 women with hirsutism. All enzyme defects were identified by comparing the patients' hormonal responses to 0.25 mg intravenous bolus of alpha 1-24-ACTH with those of age-matched normal women. The hormones measured in plasma during the ACTH stimulation tests were progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, DHEA-sulfate, androstenedione, testosterone, 11-deoxycortisol, and cortisol. Similarly these hormones were measured after overnight 1 mg oral dexamethasone. Twelve women (18.5%) had 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency, 24 (37%) 21-hydroxylase deficiency, and 14 (21.5%) 11 beta-hydroxylase deficiency. Women with 21-hydroxylase deficiency also had evidence of a partial deficiency in 11 beta-hydroxylase activity (12 of the 24 patients). Similarly, most (11 of the 14) of the women with 11 beta-hydroxylase deficiency also had evidence of a deficiency in 3 beta-hydroxy-delta 5-steroid dehydrogenase activity. Among the 15 patients with no adrenal biosynthetic defect, eight had high plasma androgen concentrations, and seven had normal concentrations.
Ajlouni et al. (1996) reported three new patients with congenital adrenal hyperplasia due to a defect in 11-beta-hydroxylase enzyme with short fourth metatarsals. Gynecomastia was noted in one patient. Ajlouni et al. (1996) indicated that the relative rarity of 11-beta-hydroxylase deficiency and the association of skeletal abnormalities was suggestive for the possibility that this was more than a mere coincidental finding.
Taher et al. (2004) conducted a study aimed to display the spectrum of initial presentation and etiology among children with precocious puberty and to assess any association between the clinical features and the underlying cause of the condition. Forty-three girls and seven boys with precocious puberty were diagnosed at the Endocrine Clinic of Jordan University Hospital and at The National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan, between the 1984 and 2003. Mean age for the girls with precocious puberty was 4.1 years +/- 2.5 SD and for the boys was 2.4 years +/- 1.9 SD. Congenital adrenal hyperplasia was diagnosed in four boys and four girls, and hypothyroidism in three girls.
Al-Maghribi (2007) conducted a retrospective study on patients with congenital adrenal hyperplasia (CAH) over a period of 10 years (1996-2006) at the King Hussein Medical Center (KHMC) in Amman. The study included 73 Jordanian children (39 females and 34 males) with CAH. Patients were classified according to their symptoms into three groups; those with classical CAH (62 patients), non-classical CAH (six patients), and cryptic CAH (five patients). The enzymatic deficiency that underlies this condition was not 21-hydroxylase deficiency in all the patients; at least one patient suffered 3-beta hydroxysteroid dehydrogenase deficiency. Another group of seven patients was thought to have 11-beta hydroxylase deficiency. The diagnosis in 28 of the patients was made after one year of age, and most of these patients showed growth acceleration. Forty-one patients displayed salt loss at less than six months of age. Among the females with CAH, 27 had developed mental anomalies of the external genitalia and 14 were wrongly considered 'males' at birth due to severe virilization. Among the CAH sample, four patients had cerebral palsy and one of them died at 10 weeks of age. First and second cousin marriages were found in parents of 24 patients and 16 patients were siblings.
In a clinical study of 270 cases of hirsutism in Kuwait, Abdul Wahid (1989) found CAH to be causal in 1.5% of the cases.
Lubani et al. (1990) found 60 children with CAH diagnosed between 1978 and 1988, giving an estimated prevalence of 1 in 9,000 live births. In addition, there was presumptive evidence of CAH resulting in the death of 20 other children, giving a prevalence figure of 1 in 7,000. In 54 patients (90%), 21-hydroxylase deficiency was diagnosed; in three patients each, the diagnosis was 3-beta-hydroxysteroid dehydrogenase deficiency and 11-beta-hydroxylase deficiency.
Soliman et al. (1997) reported six children with congenital adrenal hyperplasia (CAH) who had late initiation of corticosteroid treatment and/or poor compliance and developed true precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis. These patients were treated with standard-dose hydrocortisone and fludrocortisone. Administration of depot leuprorelin (3.75 mg subcutaneously every 28 days) for 2 years or longer was effective in arresting the manifestations of puberty, decelerating the pretreatment growth velocity ([GV] 10.8 +/- 1.5 v3.65 +/- 0.95 cm/yr), increasing the predicted adult height ([PAHT] 147.5 +/- 7.8 v 153.4 +/- 8.3 cm), and decreasing the bone age to statural age ratio (1.26 +/- 0.13 v 1.16 +/- 0.09). Analysis of auxanological data during the first 2 years of life showed that linear growth was significantly accelerated and bone age was advanced in patients who developed CPP compared with 11 age-matched patients. Soliman et al. (1997) indicated that proper glucocorticoid replacement to achieve adequate control of hyperandrogenemia during early life might prevent development of CPP in these patients. They also added that gonadotropin-releasing hormone agonist (GnRHa) therapy can improve the final adult height, bringing it closer to that expected from the genetic potential.
Rajab et al. (2005) undertook a study to estimate the prevalence of commonly diagnosed autosomal recessive diseases in Oman from a hospital-based register in years 1993 to 2002. The study revealed that congenital adrenal hyperplasia was diagnosed in 55 patients, with an observed incidence of 1 in 10,000 births. Similarly, Sawardekar (2005) conducted a study to establish the prevalence of major congenital malformations in children born during a 10-year period in Nizwa Hospital. Of the 21,988 total births in the hospital, four children were born with congenital adrenal hyperplasia (21 OH deficiency). Sawardekar (2005) hinted for a possible genetic contribution in these children.
In 2003, the Hamad Medical Corporation, in partnership with the University Children's Hospital of Heidelberg built a comprehensive newborn screening program. Between December 2003 and July 2006, Lindner et al. (2007) investigated 25,214 neonates born in Qatar for inborn errors of metabolism and endocrine disorders. One neonate was diagnosed with congenital adrenal hyperplasia. This patient was suspected to have CAH due to the presence of ambiguous genitalia. Thus, although the screening result was received only at 10-days of age, treatment had already started at 7-days. The overall incidence of CAH was lesser than expected. However, Lindner et al. (2007) suspected that this could be due to the small sample size.
A two year and six months female suffering from failure to thrive, repeated chest infections, chronic cough and vomiting was reported by Banjar (2001). The subject was born to first cousin parents and had a sister who passed away from a chest infection at the age of 3 months. Laboratory examination demonstrated elevated levels of 17-OH progesterone, low dehydroepiandrosterone (DEHAS), 711 +1GEA homozygosity in intron 5 revealed through the CFTR analysis, and elevated levels of sweat chloride. This case represented a comorbidity of CF and CAH. Later on, the subject suffered from progressive bronchiectasis and became oxygen dependent at home, she was non compliant to treatment and passed away at the age of six years due to a severe chest infection.
Al-Zahrani (2002) reported a 5 and half year-old Saudi girl, was born to first-degree consanguineous parents, who presented at birth with severe bilateral congenital glaucoma and ambiguous genitalia. At the age of five years she lost vision in her left eye, and received anti-glaucoma treatment for her right eye. She had three other affected members in the family. Her 14-year-old brother had severe bilateral congenital glaucoma and lostvision in both eyes. In addition, her 10 and a half-year-old sister had ambiguous genitalia with large clitoris, no palpable gonads, and labioscrotal fusion. One of her first cousins had died at 4-months of age had ambiguous genitalia as well.
Al-Jurayyan (2011) conducted a retrospective study in the pediatric endocrine clinic at a university hospital Saudi Arabia during the period 1989-2008. Medical records of 81 children with ambiguous genitalia were reviewed. Fifty three (65%) of the patients were genetically females (46XX), with congenital adrenal hyperplasia being the common cause in 51 (97%) patients. Male genetic sex (46XY) was present in only 28 (35%) patients with a diversity of causes. Twenty-five (47%) of females were wrongly assigned as males, where only two (7%) males were wrongly assigned as females.
The distribution of mutations in the CYP21 gene causing 21-OHD was reported for the first time in the Tunisian population by Kharrat et al. (2004). A total of 51 unrelated Tunisian patients with CAH (10 males, 41 females) were selected for the study. Of these, 44 patients were diagnosed with the Salt Wasting (SW) form of the disease. At least 31 of the patients were from consanguineous families. PCR-RFLP was used to detect six point mutations in the CYP21 gene in these patients. In addition, non-selective amplification of exon 3 was also performed to detect large deletions, as was direct sequencing of the entire gene, to detect any uncommon mutations. Mutations in the CYP21 gene could be detected in 94.1% of the chromosomes. Of these, 36 patients had one of the mutations, nine patients were found to be heterozygous with two different mutations, whereas one patient was found to be homozygous for two different mutations. The most common mutation identified in the population was Q318X in exon 8 (35.3%), followed by large deletions of the gene (19.6%), IVS2-13A/C-G (17.6%), and I172N (10.8%). In fact, these four mutations accounted for 87% of the cases with the severe form of CAH. Kharrat et al. (2004) attributed the high frequency of the Q318X mutation in the Tunisian population to founder effect. They further went on to propose that this mutation be used for screening purposes in the Tunisian population. The Q318X mutation was also found to be linked to a 601 C-G polymorphism in the same gene. Novel mutations detected included W19X, frame shift mutation due to insertion of C in position 2699, R483W, and a small conversion DNA sequence from exon 5 to exon 8. All these new mutations were found in patients with the SW form of the disease, implying that the mutations completely destroyed the enzymatic activity.
Gatee et al. (1996) studied 102 women of Arab and Asian origins with hirsutism, polycystic ovary syndrome was diagnosed in 93 patients (91%) including 26 cases with hirsutism and regular menstrual periods. Late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency was identified in two cases, thus forming a prevalence of 8% in those who underwent adrenocorticotropin stimulation.
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