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JCEM Case Reports Jun 2024A mutation in the steroidogenic acute regulatory protein () gene, which encodes a protein that plays a crucial role in steroid hormone synthesis, causes a severe form of...
A mutation in the steroidogenic acute regulatory protein () gene, which encodes a protein that plays a crucial role in steroid hormone synthesis, causes a severe form of congenital adrenal hyperplasia (CAH) known as lipoid CAH (LCAH). LCAH presents with primary adrenal insufficiency (PAI) as well as atypical genitalia. Individuals with LCAH require adrenal steroid hormone supplements for survival. Masculinization in males with deficiency varies from incomplete to normal virilization. Radiological examinations reveal enlarged and lipid-laden adrenals. A 10-year-old boy born of second-degree consanguinity presented with weight gain and hyperpigmentation for 1 year. He was diagnosed with PAI at age 7 months and treated with hydrocortisone and fludrocortisone. Dynamic adrenal gland testing revealed undetectable hormone reserves. Imaging detected hypoplastic adrenals and a small testis with testicular adrenal rests (TART). Genetic analysis indicated a novel homozygous pathogenic variant of in exon 7, c.814C > G(pArg272Gly) associated with LCAH (OMIM No. 201710). Testing revealed that asymptomatic family members and relatives were heterozygotes for the variant. The patient was diagnosed with nonclassic LCAH with hypoplastic adrenals and TART. Adequate hormone supplementation resulted in TART regression. This genetic variation is reported for the first time.
PubMed: 38803511
DOI: 10.1210/jcemcr/luae089 -
Scientific Reports May 2024Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and...
Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (r = - 0.83, P < 0.001) and progressive motility (r = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.
Topics: Humans; Male; Adrenal Hyperplasia, Congenital; Adult; Retrospective Studies; Infertility, Male; Ultrasonography; Risk Assessment; Semen Analysis; Testis; Young Adult; Adrenal Rest Tumor
PubMed: 38802468
DOI: 10.1038/s41598-024-62954-8 -
JCEM Case Reports Jun 2024We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite...
We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite supraphysiological glucocorticoid therapy. We used abiraterone acetate, an inhibitor of the 17-hydroxylase/17,20-lyase enzyme, to suppress adrenal androgen synthesis and allow physiological glucocorticoid and mineralocorticoid therapy, as a proof-of-concept, before proceeding to bilateral adrenalectomy. We report the patient's clinical course, the changes in adrenal steroids, and the immunohistochemistry of the adrenals.
PubMed: 38798742
DOI: 10.1210/jcemcr/luae077 -
Discovery Medicine May 202417α-hydroxylase/17,20-lyase deficiency (17OHD) is an autosomal recessive genetic disorder caused by a mutation of the cytochrome P450, family 17, subfamily A,...
Revealing a New Homozygous Variant in c.908G>A (p. Gly303Asp) by Genotyping a Chinese Patient with 46, XY 17a-Hydroxylase/17,20-Lyase Deficiency and Adrenal Space-Occupying Lesion.
BACKGROUND
17α-hydroxylase/17,20-lyase deficiency (17OHD) is an autosomal recessive genetic disorder caused by a mutation of the cytochrome P450, family 17, subfamily A, polypeptide 1 (). This study reports the case of a 22-year-old Chinese patient (46, XY) with 17OHD and a unilateral adrenal space-occupying lesion.
METHODS
The patient underwent serological, radiographic, genetic, and molecular analyses including whole-genome exome sequencing through high-throughput sequencing (HTS) technology to analyze the genetic conditions of both the patient and her parents. Additionally, chromosomal karyotype analysis was performed. The impact of the novel mutation on protein conformation was investigated by examining the three-dimensional structure of human using the SWISS-MODEL website tool (PDB code 3RUK).
RESULTS
The patient had a chromosomal karyotype 46, XY, and presented with hypertension, hypokalemia, and male pseudohermaphroditism. Furthermore, decreased levels of testosterone, dehydroepiandrosterone sulfate, and estradiol, along with increased levels of progesterone, luteinizing hormone, and follicle-stimulating hormone (FSH), were observed. DNA sequencing revealed a homozygous mutation (c.908G>A, p.G303A) in the fifth exon of the . Both parents carried a heterozygous c.908G>A mutation in the same exon, confirming the inheritance of the patient's exonic mutation.
CONCLUSION
For the first time, this study reports a novel homozygous mutation (c.908G>A in the fifth exon) in . Modeling analysis of suggested that the substitution of glycine with aspartic acid at position 303 induces alterations in the number, structure, and electrostatic potential of the protein's local binding sites. The p.G303A mutation may possess pathogenic properties. Our study expands the mutation spectrum of .
Topics: Humans; Steroid 17-alpha-Hydroxylase; Female; Adrenal Hyperplasia, Congenital; Homozygote; Young Adult; Asian People; Male; Genotype; Mutation, Missense; East Asian People
PubMed: 38798260
DOI: 10.24976/Discov.Med.202436184.94 -
Clinical Endocrinology May 2024Newborn screening (NBS) reduces the risk of mortality in congenital adrenal hyperplasia (CAH), mainly due to the salt-wasting form of 21-hydroxylase deficiency. There is...
BACKGROUND
Newborn screening (NBS) reduces the risk of mortality in congenital adrenal hyperplasia (CAH), mainly due to the salt-wasting form of 21-hydroxylase deficiency. There is limited knowledge regarding the results of NBS in non-CAH primary adrenal insufficiency (non-CAH PAI).
PATIENTS AND METHODS
Clinical and NBS for CAH data of neonates who were diagnosed with non-CAH PAI between January and December 2022 were examined.
RESULTS
Patients (n = 6, 4 females) were presented with severe hyperpigmentation (n = 6), hypoglycemia (n = 4), hyponatremia (n = 3), hyperkalemia (n = 1), respiratory distress syndrome (n = 1) between 3rd hour to 2 months of life. All had normal NBS results. The median first-tier 17-hydroxyprogesterone (17OHP) concentration in NBS for CAH was 0.14 ng/mL (range; 0.05-0.85). Molecular studies revealed biallelic mutations in the MC2R (n = 4; 3 homozygous, 1 compound heterozygous), MRAP (n = 1) and STAR (n = 1) genes. Glucocorticoid with or without mineralocorticoid replacement was initiated once the diagnosis of non-CAH PAI was established.
CONCLUSION
Neonates with non-CAH PAI have always normal NBS due to persistently low 17OHP, even when these newborn infants are severely symptomatic for adrenal insufficiency. Clinicians should be alert for signs of adrenal insufficiency in neonates, even if the patient has a 'normal' screening for CAH, so as not to delay diagnosis and treatment. This fact should be kept in mind particularly in countries where these conditions are more common than elsewhere.
PubMed: 38796770
DOI: 10.1111/cen.15080 -
F&S Science May 2024To investigate potential differences in pregnancy, delivery, and neonatal outcomes between 2 hyperandrogenic conditions in reproductive-aged women: polycystic ovary...
OBJECTIVE
To investigate potential differences in pregnancy, delivery, and neonatal outcomes between 2 hyperandrogenic conditions in reproductive-aged women: polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia (CAH).
DESIGN
Retrospective population-based study with data from the Health Care Cost and Utilization Project-Nationwide Inpatient Sample Database from 2004-2014.
SETTING
Not applicable.
PATIENT(S)
A total of 14,881 women with PCOS and 298 women with CAH.
INTERVENTION(S)
Not applicable.
MAIN OUTCOME MEASURE(S)
Gestational diabetes mellitus, placenta previa, pregnancy-induced hypertension (HTN), gestational HTN, preeclampsia, eclampsia, preeclampsia and eclampsia superimposed on HTN, preterm birth, preterm premature rupture of membrane, abruptio placenta, chorioamnionitis, mode of delivery, maternal infection, hysterectomy, blood transfusion, venous thromboembolism (deep vein thrombosis and pulmonary embolism during pregnancy, intrapartum, or postpartum), maternal death, chorioamnionitis, septicemia during labor, postpartum endometritis, septic pelvic, peritonitis, small for gestational age, congenital anomalies, and intrauterine fetal demise.
RESULT(S)
After adjusting for potential confounders, we found that women with PCOS were at increased risk of developing pregnancy-induced HTN (adjusted odds ratio [OR] = 1.76; 95% confidence interval [CI]: 1.12-2.77) and gestational diabetes (adjusted OR = 1.68; 95% CI: 1.12-2.52) when compared with women with CAH. Contrary women with CAH were at increased risk for delivery via cesarean section (adjusted OR = 0.59; 95% CI: 0.44-0.80) and small for gestational age neonates (adjusted OR = 0.32; 95% CI: 0.20-0.52).
CONCLUSION(S)
To our knowledge, this study is the first to directly compare obstetric and neonatal outcomes between patients with PCOS and CAH. Despite the similar phenotypes and some common hormonal and biochemical profiles, such as insulin resistance, hyperinsulinemia, and hyperandrogenism, our results suggest the existence of additional metabolic pathways implicated in the pathogenesis of pregnancy complications.
PubMed: 38795844
DOI: 10.1016/j.xfss.2024.05.001 -
International Journal of Molecular... May 2024Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent...
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in , causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.
Topics: Animals; Adrenal Hyperplasia, Congenital; Disease Models, Animal; Steroid 21-Hydroxylase; Mice; Female; Male; Humans; Corticosterone; Aldosterone; Adrenal Glands; Mutation; Progesterone
PubMed: 38791102
DOI: 10.3390/ijms25105062 -
Current Issues in Molecular Biology May 2024Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has...
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has downstream effects. The most common variant of CAH, 21-hydroxylase deficiency (21OHD), is the result of pathogenic variants in the gene and is one of the most common monogenic disorders. However, the genetics of 21OHD is complex and challenging. The gene is located in the RCCX copy number variation (CNV), a complex, multiallelic, and tandem CNV in the major histocompatibility complex (MHC) class III region on chromosome 6 (band 6p21.3). Here, and its pseudogene are located 30 kb apart and share a high nucleotide homology of approximately 98% and 96% in exons and introns, respectively. This high-sequence homology facilitates large structural rearrangements, copy number changes, and gene conversion through intergenic recombination. There is a good genotype-phenotype correlation in 21OHD, and genotyping can be performed to confirm the clinical diagnosis, predict long-term outcomes, and determine genetic counseling. Thus, genotyping in CAH is clinically relevant but the interpretations can be challenging for non-initiated clinicians. Here, there are some concrete examples of how molecular diagnosis can sometimes require the use of multiple molecular strategies.
PubMed: 38785559
DOI: 10.3390/cimb46050291 -
Oxford Medical Case Reports May 2024We report the case of a 5-year-old boy diagnosed with congenital adrenal hyperplasia due to 11-hydroxylase deficiency, revealed by disorders of sex development (DSD) and...
We report the case of a 5-year-old boy diagnosed with congenital adrenal hyperplasia due to 11-hydroxylase deficiency, revealed by disorders of sex development (DSD) and acute pulmonary edema due to severe hypertension. We considered the diagnosis based on biological and radiological examinations. The sociocultural background and the delayed diagnosis had a significant impact on the therapeutic decisions. All babies should be screened for 11 beta-hydroxylase deficiency, there should be specialized and interdisciplinary medical centers, and early detection is essential to avoiding serious complications of this disease.
PubMed: 38784773
DOI: 10.1093/omcr/omae042 -
The Journal of Clinical Endocrinology... May 2024Small cohorts of youth with congenital adrenal hyperplasia (CAH) demonstrate increased risk of obesity and poor cardiometabolic health.
CONTEXT
Small cohorts of youth with congenital adrenal hyperplasia (CAH) demonstrate increased risk of obesity and poor cardiometabolic health.
OBJECTIVE
To determine the odds of cardiometabolic-related diagnoses in youth with CAH compared to matched controls in a cross-sectional analysis in a large, multisite database (PEDSnet).
DESIGN
Electronic health record data (2009-2019) were used to determine odds of cardiometabolic-related outcomes based on diagnosis, anthropometric and laboratory data using logistic regression among youth with CAH vs. controls.
SETTING
Six PEDSnet sites.
PATIENTS OR OTHER PARTICIPANTS
Youth with CAH and >1 outpatient visit in PEDSnet (n=1,647) were propensity-score matched on 8 variables to controls (n=6,588). A subset of youth with classic CAH (n=547, with glucocorticoid and mineralocorticoid prescriptions) were matched to controls (n=2,188).
INTERVENTION(S)
N/A.
MAIN OUTCOME MEASURE(S)
Odds of having cardiometabolic-related diagnoses among youth over 2 years with CAH compared to matched controls.
RESULTS
Outcomes were calculated for all individuals with CAH (median age at last visit 12.9 years [7.3, 17.6]) and a subset with classic CAH (median age at last visit 11.6 years [4.7, 17.5]) compared to their matched controls. All patients with CAH had higher odds of overweight/obesity (odds ratio [95% confidence interval] 3.63 [3.24,4.07]), hypertension (3.07 [2.60,3.64]), dysglycemia (1.95 [1.35,2.82], dyslipidemia (2.28 [1.79,2.91]) and liver dysfunction (2.30 [1.91,2.76]) compared to matched controls. Patients with classic CAH had higher odds of overweight/obesity (3.21 [2.61,3.93]), hypertension (8.22 [6.71,10.08]), and liver dysfunction (2.11 [1.55,2.89]) compared to matched controls.
CONCLUSIONS
Overall, youth with CAH are at increased risk of diagnoses related to worse cardiometabolic health.
PubMed: 38783717
DOI: 10.1210/clinem/dgae362