Variant Of Congenital Adrenal Hyperplasia Research Articles

Congenital Adrenal Hyperplasia: A Review of Current Knowledge and Future Directions

Introduction: Congenital adrenal hyperplasia (CAH) is a group of diseases in which genetic defects occur that disturb the synthesis of cortisol. The most common variant of CAH (95%-99%) is caused by 21-hydroxylase deficiency as a result of mutations in the CYP21A2 gene and is one of the most common monogenic diseases. CAH is characterized by androgen overproduction along with variable degrees of cortisol and aldosterone deficiency. Age at diagnosis can provide some information about the underlying mutations, with those diagnosed at birth/early infancy being at greater risk of developing serious enzyme defects. Classic and non-classical forms of this disorder have been described in the literature. CAH diagnosis is based on the clinical presentation, hormonal panel, Adrenocorticotropic Hormone (ACTH) stimulation test, and genetic testing. The main goals of treatment for congenital adrenal hyperplasia are glucocorticoid/mineralcorticoid supplementation, control of high adrenal androgen levels, fertility control, genetic counseling, and optimization of patients’ quality of life. Purpose of the work: This study aims to review and characterize the clinical and pathophysiological aspects of congenital adrenal hyperplasia. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2 Results: Congenital adrenal hyperplasia is a heterogeneous group of genetic disorders that can lead to serious and even fatal complications in the form of adrenal crisis. Therefore, screening tests and early diagnosis are crucial and can save the lives of newborns. Treatment should be individualized and allow patients to achieve normal growth, sexual development, fertility and a better quality of life.

An interesting case of masculine voice in a girl: A case report of 11 beta hydroxylase deficiency

A 7-year-old girl presented to our outpatient department (OPD) with masculine voice, hyperpigmentation of skin, and genital ambiguity. On clinical examination, she had hypertension, hyperpigmentation of skin, pubarche, clitoromegaly, and low-pitched voice. Karyotype was 46 XX and ultrasound showed bilateral enlarged adrenals, uterus, and ovaries. Hormonal workup revealed elevated levels of 17-?-hydroxyprogesterone, testosterone, 11-deoxycortisol, and deoxycorticosterone. Due to the presence of hypertension, genital ambiguity and elevated 11-deoxycortisol, a diagnosis of 11-?-hydroxylase deficiency variant of Congenital Adrenal Hyperplasia was made. The child was started on hydrocortisone and amlodipine after which her symptoms such as hyperpigmentation improved.

A child with hypertension and ambiguous genitalia \u2013 an uncommon variant of congenital adrenal hyperplasia: a case report

BackgroundDeficiency in 11β-hydroxylase as a cause of congenital adrenal hyperplasia is uncommon. It should be considered in the differential diagnosis of hypertension with virilization in any prepubescent child.Case presentationA 12-year-old Asian boy from eastern Nepal presented with pain in his abdomen and hypertension. He was raised as a male but had absent testicles since birth and had precocious puberty. Plasma testosterone, follicle-stimulating hormone, and luteinizing hormone were below baseline level. Basal 17-hydroxyprogesterone was elevated. Magnetic resonance imaging of his pelvis showed presence of Müllerian structures and karyotyping revealed 46,XX genotype. A clinical diagnosis of 11β-hydroxylase deficiency was made in view of hypertension with severe virilization in a 46,XX individual. Our patient’s legal guardian was unwilling for our patient to change gender and because our patient is underage, the condition was well explained to his parents. He was managed with steroids and antihypertensive drugs. He was on regular follow-up; after 2 years there was no hypertension but he developed true puberty with functional ovaries. He was prescribed leuprolide (gonadotropin-releasing hormone analogue), letrozole (aromatase inhibitor), and a continuation of antihypertensive drugs.ConclusionsThis case highlights the importance of a thorough physical examination of the external genitalia at birth and appropriate referral, and addresses issues in the management of such a disorder. Ethical issues pertaining to consent and who is entitled to give it should be clear so that the affected individual will have optimal psychological development and quality of life.

3 Beta-hydroxysteroid Dehydrogenase Deficiency Presenting as Adrenal Crisis in an Infant

Ambiguous genitalia is a birth defect where the external genitals do not have the typical appearance of either a boy or girl. An 8-week-old infant presented with persistent vomiting, failure to thrive, and genital ambiguity. On the basis of clinical presentation, a salt-losing variety of congenital adrenal hyperplasia (CAH) was suspected. Hormonal levels were tested and 3 beta-hydroxysteroid dehydrogenase II (HSD3B2) deficiency, a rare CAH variant was suspected. This was confirmed by molecular analysis of the HSD3B2 gene from the affected baby. It revealed the presence of the homozygous P222Q mutation which was found to be heterozygous in both parents.

Left Ventricular Failure due to a Rare Variant of Congenital Adrenal Hyperplasia

"Hypertensive" variant of congenital adrenal hyperplasia is rare. The authors describe an interesting case of a 6-y-old boy who presented with an acute respiratory illness and progressive breathlessness since 1y. Genital hyperpigmentation was noticed since 2y of age; the onset of pubarche and increasing penile size at 4y. He was admitted in congestive cardiac failure with a blood pressure of 150/100mm Hg. Facial acne; slight facial, pubic hair and penile enlargement were additionally noted. Chest radiograph revealed cardiomegaly. Basal ACTH and 17-OHP levels were high. A diagnosis of congenital adrenal hyperplasia (11β-hydroxylase deficiency) was made due to hypertension with virilized genitalia. Cardiac failure was controlled with fluid restriction and diuretics; he was started on prednisolone, spironolactone and nifedipine. This case is presented for its rarity where hypertension can cause complication of cardiac failure, if diagnosis is delayed despite early features of pseudoprecocious puberty.

Impact of nasal continuous positive airway pressure for congenital adrenal hyperplasia with obstructive sleep apnea and bruxism

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders in humans. The most frequent CAH variant is 21-hydroxylase deficiency. Patients with 21-hydroxylase deficiency require long-term glucocorticoid replacement treatment. Although sleep disturbance is frequently observed under glucocorticoid replacement treatment, a case of obstructive sleep apnea(OSA) in patients with CAH has not been reported. A 43-year-old man with CAH who complained about sleep disturbance and sleep bruxism was diagnosed as obstructive sleep apnea (OSA) by polysomnography (PSG). Following the introduction of nasal continuous positive airway pressure (nCPAP), his sleep disturbance with symptoms also improved; in addition, he was able to reduce the dose of glucocorticoid replacement therapy without any adverse consequences on his sleep pattern. Physicians who treat a patient with CAH should know the possibility in the existence of OSA in their patients. Because symptoms with OSA in CAH patient may increase the dosage of long-term glucocorticoid treatment for the patient, which may induce several adverse effects including body weight gain on the patient.

Genetics of congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. It comprises a group of autosomal recessive disorders caused by the deficiency of one of four steroidogenic enzymes involved in cortisol biosynthesis or in the electron donor enzyme P450 oxidoreductase (POR) that serves as electron donor to steroidogenic cytochrome P450 (CYP) type II enzymes. The biochemical and clinical phenotype depends on the specific enzymatic defect and the impairment of specific enzyme activity. Defects of steroid 21-hydroxylase (CYP21A2) and 11beta-hydroxylase (CYP11B1) only affect adrenal steroidogenesis, whereas 17alpha-hydroxylase (CYP17A1) and 3beta-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency also impact on gonadal steroid biosynthesis. Inactivating POR gene mutations are the cause of CAH manifesting with apparent combined CYP17A1-CYP21A2 deficiency. P450 oxidoreductase deficiency (ORD) has a complex phenotype including two unique features not observed in any other CAH variant: skeletal malformations and severe genital ambiguity in both sexes.

Functional characterization of threeCYP21A2sequence variants (p.A265V, p.W302S, p.D322G) employing a yeast co-expression system

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase (CYP21A2) deficiency is the commonest inborn error in steroid hormone biosynthesis. Functional in vitro assessment of mutant activity generally correlates well with clinical phenotype and therefore has contributed greatly to phenotype prediction in this CAH variant. Three CYP21A2 sequence variants (g.1641C>T, p.A265V; g.1752G>C, p.W302S; and g.2012A>G, p.D322G) identified in patients with non-classic and simple virilizing CAH were characterized using a yeast co-expression system and a computational three-dimensional CYP21A2 model. Computational analysis of the mutants in the three-dimensional structural model predicted no relevant effect of p.A265V, while p.W302S and p.D322G were predicted to impact significantly on enzyme function. Consistent with these findings, in vitro mutant analysis revealed enzyme activity similar to wild-type for p.A265V, whereas p.W302S and p.D322G exerted activities compatible with simple virilizing and non-classical CAH, respectively. The results indicate that p.A265V is an allelic variant rather than a disease-causing amino acid change, whilst p.W302S and p.D322G could be confirmed as functionally relevant mutations. These findings emphasize the value of in vitro functional analysis of sequence variations in predicting genotype-phenotype correlations and disease severity.

Age-specific changes in sex steroid biosynthesis and sex development

Normal male sex development requires the SRY gene on the Y chromosome, the regression of Müllerian structures via anti-Müllerian hormone (AMH) signalling, the development of the Wolffian duct system into normal male internal genital structures consequent to testosterone secretion by the testicular Leydig cells, and finally, sufficient activation of testosterone to dihydrotestosterone by 5alpha-reductase. All these events take place during weeks 8-12 of gestation, a narrow window of sexual differentiation. Recent studies in human fetal development have demonstrated the early fetal expression of the adrenocorticotrophic hormone (ACTH) receptor and all steroidogenic components necessary for the biosynthesis of cortisol. These findings provide compelling evidence for the assumed pathogenesis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, diminished feedback to the pituitary due to glucocorticoid deficiency, subsequent ACTH excess, and up-regulation of adrenal androgen production with subsequent virilization. Another CAH variant, P450 oxidoreductase deficiency, manifests with 46,XX disorder of sex development (DSD), i.e., virilized female genitalia, despite concurrently low circulating androgens. This CAH variant illustrates the existence of an alternative pathway toward the biosynthesis of active androgens in humans which is active in human fetal life only. Thus CAH teaches important lessons from nature, providing privileged insights into the window of human sexual differentiation, and particularly highlighting the importance of steroidogenesis in the process of human sexual differentiation.

Congenital adrenal hyperplasia and P450 oxidoreductase deficiency

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders, which are usually due to inactivating mutations in single enzymes involved in adrenal steroid biosynthesis. The characteristics of the biochemical and clinical phenotype depend on the specific enzymatic defect. In 21-hydroxylase and 11beta-hydroxylase deficiency only adrenal steroidogenesis is affected, whereas a defect in 3beta-hydroxysteroid dehydrogenase or 17alpha-hydroxylase also involves gonadal steroid biosynthesis. Recently, mutations in the electron donor enzyme P450 oxidoreductase were identified as the cause of CAH with apparent combined 17alpha-hydroxylase and 21-hydroxylase deficiency, thereby illustrating the impact of redox regulation enzymes on steroidogenesis. P450 oxidoreductase deficiency (ORD) has a complex phenotype including two unique features not observed in any other CAH variant, skeletal malformations and severe genital ambiguity in both sexes. Despite invariably low circulating androgens, females with ORD may present with virilized genitalia and mothers may suffer from virilization during pregnancy. This apparently contradictory finding may be explained by the existence of an alternative pathway in human androgen biosynthesis, with important implications for physiology and pathophysiology. This review discusses the biochemical and clinical presentation and the genetic and functional basis of the currently known CAH variants, with a specific focus on ORD.

A Male Twin Infant with Skull Deformity and Elevated Neonatal 17–Hydroxyprogesterone: A Prismatic Case of P450 Oxidoreductase Deficiency

We report on a male twin infant who presented with brachy‐turri‐cephaly, frontal bossing, large anterior fontanelle, low set and malformed ears, and mild arachnodactyly. He had normal male genitalia. There was no evidence for maternal virilization during pregnancy. The pattern of malformations resembled Antley–Bixler–Syndrome (ABS). However, sequencing analysis of the fibroblast growth factor receptor 2 gene (FGFR2) did not reveal mutations. The boy's twin sister did not show any somatic or endocrine abnormalities. In the boy, neonatal screening for congenital adrenal hyperplasia was positive with moderately elevated 17–hydroxyprogesterone. Sequence analysis of his CYP21 gene did not reveal any mutations. The short synacthen test revealed an exaggerated 17–hydroxyprogesterone and a blunted cortisol response. Urinary steroid profiling by gas chromatography‐mass spectrometry (GC‐MS) revealed a unique steroid metabolome suggestive of impaired activity of both 17–hydroxylase and 21–hydroxylase. Clinical and metabolic findings therefore were compatible with the recently described variant of congenital adrenal hyperplasia, P450 oxidoreductase deficiency (ORD). Subsequently, sequencing analysis of CPR, the gene encoding P450 oxidoreductase (OR), revealed a homozygous mutation in the patient, resulting in an amino acid exchange in position 284 of the OR protein (A284P). Both the female twin sister and the parents were heterozygous for the A284P mutation. P450 oxidoreductase deficiency represents a novel autosomal recessively inherited form of congenital adrenal hyperplasia. Its characteristic steroid metabolome can readily be detected by GC‐MS analysis of spot urine. Clinical features may include an ABS phenotype, ambiguous genitalia (virilization in girls, feminization in boys), and glucocorticoid deficiency. If required, hydrocortisone replacement should be provided.

Sexual behavior in adolescent and adult females with congenital adrenal hyperplasia

As part of a comprehensive interview study, 34 female patients with congenital adrenal hyperplasia (CAH) plus 14 control sisters (ages 11–41 yr.) reported on their psychosexual development and sexual orientation (90 items). Fewer patients than sisters had ever experienced love relationships and sexual activities with male partners ( p<0.05 to 0.001). Twenty percent of the patients and none of the sisters wished for and/or had had homosexual relationships; in the patients >21 yr 44% expressed this interest ( p<0.07). For most items, patients with the salt-wasting variant of CAH (SW) differed more clearly from the sisters than the simple-virilizing patients (SV). For two scales “indicating” homosexual (HOM) and heterosexual orientation (HET) and for two indices of HOM/HET differences), the patients also revealed relatively stronger homosexual and/or weaker heterosexual interests than the sisters ( p<0.05 to 0.001). Here, too, the SW/sister differences were more clear-cut. These results corroborate earlier reports on both delays in reaching psychosexual milestones and increased rates of bisexual/homosexual fantasies and experiences in CAH women.

Late-Onset 21-Hydroxylase Deficiency Is an Allelic Variant of Congenital Adrenal Hyperplasia Characterized by Attenuated Clinical Expression and Different HLA Haplotype Associations

Three families with late-onset 21-hydroxylase deficiency were studied. Homozygous females presented with symptoms of mild hyperandrogenism such as acne, hirsutism, oligomenorrhea and menometrorrhagia. A homozygous male was asymptomatic and had reached normal adult height. The diagnosis of 21-hydroxylase deficiency was based upon markedly elevated responses of plasma 17-hydroxyprogesterone during a short (30-min) ACTH infusion test. The propositi of two of the families were diagnosed despite long-standing glucocorticoid therapy and adrenal suppression by using a prolonged (48-hour) ACTH infusion. Heterozygotes of late-onset 21-hydroxylase deficiency had mildly elevated 17-hydroxy-progesterone responses to ACTH. Late-onset 21-hydroxylase deficiency was inherited as an autosomal recessive trait with close linkage to the histocompatibility leukocyte antigens. The B14 haplotype was present in all affected members. One affected female had a daughter with classic, salt-losing 21-hydroxylase deficiency. Mixed heterozygosity of this patient for a classic and a late-onset 21-hydroxylase deficiency allele may have caused the classic phenotype in her daughter (homozygote for 2 classic alleles).

Late onset 21-hydroxylase deficiency is a genetic variant of the classic form of congenital adrenal hyperplasia (CAH)

Three young adult women with the diagnosis of idiopathic hirsutism had markedly abnormal elevations of serum 17-hydroxyprogesterone (17HP) in response to an ACTH stimulation test, indicating a mild degree of 21-hydroxylase deficiency. All three had oligoamenorrhea, exhibited no virilization and had reached a normal adult height. One had pubarche at 6 yrs. An ACTH stimulation test and HLA typing was performed on all available family members. Five of the 6 parents had elevations of 17HP comparable to those found in carriers of classic CAH. Two of the 3 propositi had HLA identical adult male siblings of normal height and masculinization with an identical abnormality in 17HP response to ACTH. One of the affected males developed intratesticular adrenal rest tumors that were reduced in size after dexamethasone therapy. Three HLA nonidentical sisters to the propositi were not affected. One patient married a CAH heterozygote and had two biochemically affected children (female 7 yrs and male 3 yrs) with normal heights, bone ages, and no signs of virilization, except for mildly increased terminal hair on the face and extremities of the daughter. We conclude that late onset congenital adrenal hyperplasia is a genetic variant of CAH with a milder enzymatic block and attenuated clinical expression. The affected gene is linked to the HLA locus. The presentation in females is that of mild masculinization. Males are asymptomatic but adrenal rest tumors in the testes may occur.

ABSENCE OF LINKAGE BETWEEN C-11 OH DEFICIENT CONGENITAL ADRENAL HYPERPLASIA AND HLA

A collaborative study revealed an unusually high frequency of congenital adrenal hyperplasia (CAH) due to C-11 OH deficiency in Israel. Seventeen families with 24 affected individuals were identified, mostly originating from North Africa. The diagnosis was based on clinical features and confirmed by the presence of high levels of urinary tetrahydro 11-deoxycortisol. Since both the C-11 and C-21 hydroxylating enzymes participate in the same adrenal biosynthetic pathways of steroids and 21-OH has been shown to be linked to HLA, we investigated the HLA antigens in our families. HLA antigens of the A, B and C loci were determined in 11 families which included 13 affected and 19 healthy children. Analysis of the data revealed that affected sibs did not share both haplotypes, and in addition, in several families unaffected siblings shared both haplotypes with the patients. Thus, no linkage between the C-11 OH variant of CAH and the HLA system was observed.