Case Report: Infant With Congenital Adrenal Hyperplasia and 47,XXY

Congenital adrenal hyperplasia is a group of autosomal recessive disorders in which enzymes in the cortisol biosynthesis pathways are disrupted by gene mutations. The most common form of congenital adrenal hyperplasia, caused by 21-hydroxylase deficiency, is characterized by decreased cortisol and aldosterone synthesis and excessive androgen production. Adult height is often compromised in affected patients. Intellectual capability remains intact in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, based on previous studies. 47,XXY (KS) is a sex chromosomal aneuploidy that manifests with hypergonadotropic hypogonadism, tall stature, and variable intellectual and behavioral dysfunction. This clinical report describes an infant with 21-hydroxylase deficiency congenital adrenal hyperplasia and 47,XXY. The results of his neurodevelopmental, endocrine, neurological, and physical therapy evaluations during his first 22 months are included and were normal. This is the first published case investigating the neurodevelopmental profile of a patient with the combination of these two genetic disorders.

A Case of Congenital Adrenal Hyperplasia due to 3-Beta-Hydroxysteroid Dehydrogenase Deficiency Presented With Acute Liver Failure

Congenital adrenal hyperplasia (CAH) is a group of rare autosomal disorders characterized by a variety of defects in adrenal steroidogenesis. Most cases of CAH are due to an enzyme deficiency in either 21-hydroxylase or 11-beta-hydroxylase. A much rarer form of CAH due to 3-betahydroxysteroid dehydrogenase (3B-HSD) deficiency results in impaired synthesis of all steroid hormones. The clinical presentation of undervirilization in 46 XY patients, hyponatremia, hyperkalemia, and recurrent hypoglycemia in 3B-HSD deficiency cases is well described in the literature. We describe a neonate with 3B-HSD deficiency that presented with ambiguous genitalia and hypoglycemia and was found to have comorbid coagulopathy, cholestasis, and direct hyperbilirubinemia with liver failure that resolved with glucocorticoid and mineralocorticoid treatment. Prompt recognition of this disease is imperative for timely intervention.

CYTOGENETIC ANALYSIS OF PATIENTS WITH AMBIGUOUS GENITALIA

Objective: To determine the magnitude and classification of cases of ambiguous genitalia presenting to our setup. Study Design: Cross-sectional study. Place and Duration of Study: Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi Pakistan, from Aug 2018 to Feb 2019. Methodology: All the patients with ambiguous genitalia referred for cytogenetic analysis, were included in the study. The patients were subjected to a detailed history and physical examination. The record of radiological investigations was were obtained. Cytogenetic analysis was performed using the conventional G-banding technique. Hormonal testing included 17- hydroxyprogesterone (17-OHP) levels was also performed. Results: Fifty-one cases of ambiguous genitalia were studied. The median age was 15 months. Thirty-three patients (64.7%) had a 46XY karyotype, 17 (33.3%) had a 46XX karyotype while 1 (1.9%) had 45X/46, XY mosaic karyotype. Thirty patients (58.8%) were products of consanguineous marriage. Congenital adrenal hyperplasia was diagnosed in 12 cases (70.5%) of 46 XX karyotype and in 3 cases (9%) of 46XY karyotype. Conclusion: Ambiguous genitalia, currently categorized as disorders of sex development, are not uncommon in our populartion. Increased awareness and early diagnosis are crucial to prevent life threatening complications of congenital adrenal hyperplasia, to determine sex of rearing, and to counsel the parents or patients.

Meta analysis of variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2.

Context: CYP21A2 deficiency represents 95% of congenital adrenal hyperplasia cases (CAH), a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provides critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction. Objective: Analyze the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of the CYP21A2. Methods: SNVs of the CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of the CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors. Results: SNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews' correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD). Conclusion: From our analysis, we identified four predictors of CYP21A2 pathogenicity with good performance. These results can be used for future analysis to infer the impact of uncharacterized SNVs' in CYP21A2.

Meta Analysis of Variant Predictions in Congenital Adrenal Hyperplasia Caused by Mutations in CYP21A2

Context: CYP21A2 deficiency represents 95% of congenital adrenal hyperplasia cases (CAH), a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provides critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction. Objective: Analyze the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of the CYP21A2. Methods: SNVs of the CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of the CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors. Results: SNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews' correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD). Conclusion: From our analysis, we identified four predictors of CYP21A2 pathogenicity with good performance. These results can be used for future analysis to infer the impact of uncharacterized SNVs' in CYP21A2.

Disorders of Sex Development of Adrenal Origin

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.