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Frontiers in Endocrinology 20223β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency is a rare form of congenital adrenal hyperplasia (CAH), with fewer than 200 cases reported in the world...
BACKGROUND
3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency is a rare form of congenital adrenal hyperplasia (CAH), with fewer than 200 cases reported in the world literature and few data on outcomes.
PATIENTS AND METHODS
We report a mixed longitudinal and cross-sectional study from a single Algerian center between 2007 and 2021. Virilization and under-masculinization were assessed using Prader staging and the external masculinization score (EMS), pubertal development staged according to the system of Tanner. Adrenal steroids were measured using mass spectrophotometry (LC-MS/MS). A genetic analysis of was performed using Sanger sequencing.
RESULTS
A 3βHSD2 defect was confirmed in 6 males and 8 females from 10 families (8 consanguineous), with p.Pro222Gln mutation in all but two siblings with a novel deletion: c.453_464del or p.(Thr152_Pro155del). Probable 3βHSD2 deficiency was diagnosed retrospectively in a further 6 siblings who died, and in two patients from two other centers. In the genetically confirmed patients, the median (range) age at presentation was 20 (0-390) days, with salt-wasting (n = 14) and genital anomaly (n = 10). The Prader stage for female patients was 2 (1-2) with no posterior fusion of the labia. The EMS for males was 6 (3-9). Median (range) values at diagnosis for 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxypregnenolone (17OHPreg) were elevated: 73.7 (0.37-164.3) nmol/L; 501.2(9.4-5441.3) nmol/L, and 139.7 (10.9-1500) nmol/l (NB >90 nmol/L diagnostic of 3βHSD2 defect). Premature pubarche was observed in four patients (3F:1M). Six patients (5F:1M) entered puberty spontaneously, aged 11 (5-13) years in 5 girls and 11.5 years in one boy. Testicular adrenal rest tumors were found in three boys. Four girls reached menarche at 14.3 (11-14.5) years, with three developing adrenal masses (surgically excised in two) and polycystic ovary syndrome (PCOS), with radiological evidence of ovarian adrenal rest tumor in one. The median IQ was 90 (43-105), >100 in only two patients and <70 in three.
CONCLUSIONS
The prevalence of 3βHSD2 deficiency in Algeria appears high, with p.Pro222Gln being the most frequent mutation. Mortality is also high, with significant morbidity from adrenal tumors and PCOS in adolescence and an increased risk of learning disability. The finding of adrenal tumors in older patients with 3βHSD2 indicates under-replacement, requiring effective hydrocortisone and fludrocortisone treatment rather than surgical removal.
Topics: Adolescent; Adrenal Gland Neoplasms; Adrenal Hyperplasia, Congenital; Aged; Algeria; Chromatography, Liquid; Cross-Sectional Studies; Female; Genotype; Humans; Male; Morbidity; Polycystic Ovary Syndrome; Retrospective Studies; Tandem Mass Spectrometry
PubMed: 35757411
DOI: 10.3389/fendo.2022.867073 -
Hormone Research in Paediatrics 2023The standard treatment for congenital adrenal hyperplasia (CAH) in children is still hydrocortisone. Improved strategies for timing of the dose during the day and the... (Review)
Review
BACKGROUND
The standard treatment for congenital adrenal hyperplasia (CAH) in children is still hydrocortisone. Improved strategies for timing of the dose during the day and the dose per square meter body surface area used in children of different ages and developmental phases have improved the situation and outcome for the patients. Neonatal screening enables an earlier diagnosis and initiation of treatment, prevents from adrenal crisis, and improves growth and development also for children with the less severe forms of CAH.
SUMMARY
This review describes the current treatment strategies for children with CAH and discusses some potential treatment options that have been developed with the primary aim to decrease the adrenal androgen production. Novel modified release glucocorticoid therapies are also discussed.
KEY MESSAGES
The long-term effects of the new adjunct therapies are unknown, and some are not suitable for use in children and adolescents. The effects of the new therapies on bone mineral density, gonadal functions, and long-term cognitive development are yet to be assessed. It is not known what levels of adrenal androgens are optimal for normal growth, puberty, and bone health. The basis of using glucocorticoids and mineralocorticoids in the treatment of CAH remains, and in some individuals, it may be beneficial to add therapies to reduce the androgen load during certain life stages.
Topics: Infant, Newborn; Adolescent; Child; Humans; Adrenal Hyperplasia, Congenital; Androgens; Glucocorticoids; Hydrocortisone; Mineralocorticoids
PubMed: 35086098
DOI: 10.1159/000522260 -
Frontiers in Endocrinology 2020
Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Child; Female; Hirsutism; Humans; Male; Patient-Centered Care; Polycystic Ovary Syndrome; Prognosis; Treatment Outcome; Young Adult
PubMed: 32296393
DOI: 10.3389/fendo.2020.00170 -
Current Opinion in Endocrinology,... Jun 2011Congenital adrenal hyperplasia (CAH) in children, the majority of which is due to 21-hydroxylase deficiency, represents a group of disorders in which there is impaired... (Review)
Review
PURPOSE OF REVIEW
Congenital adrenal hyperplasia (CAH) in children, the majority of which is due to 21-hydroxylase deficiency, represents a group of disorders in which there is impaired cortisol synthesis and abnormalities in adrenal hormonal profiles. There continues to be debate regarding the optimal management of and treatment for these children. This review will highlight the most recent advances in neonatal screening for CAH, as well as the timeliest recommendations for the treatment and management of 21-hydroxylase deficiency, both the classic and nonclassic forms of the disorder.
RECENT FINDINGS
Substantive advancements have been made with regard to neonatal screening for CAH, allowing for earlier diagnosis, while minimizing the morbidity and mortality associated with delayed detection. Although the achievement of normal growth and development remains the ultimate goal of treatment, recent studies have provided further insight into the management and refinement of therapy in these children.
SUMMARY
The optimal management and treatment for children with CAH is still unclear. Although there have been recent advances in the diagnosis and treatment of this group of disorders, there is still much to learn in order to optimize therapy for these individuals.
Topics: Adrenal Hyperplasia, Congenital; Humans; Infant, Newborn; Neonatal Screening; Steroid 21-Hydroxylase
PubMed: 21494138
DOI: 10.1097/MED.0b013e328346938c -
Endokrynologia Polska 2010Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive hereditary diseases. The impairment of cortisol... (Review)
Review
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive hereditary diseases. The impairment of cortisol synthesis leads to excessive stimulation of the adrenal glands by adrenocorticotropic hormone (ACTH), adrenal hyperplasia, and excessive androgen synthesis. The syndrome is characterised by a considerable correlation between the genotype and the phenotype with the type of CYP21A2 gene mutation affecting the severity of 21-hydroxylase deficiency. The clinical manifestations of CAH in adults result from adrenocortical and adrenomedullary insufficiency, hyperandrogenism, and the adverse effects of glucocorticosteroids used for the treatment of the condition. Non-classic CAH may sometimes be asymptomatic. In patients with classic CAH obesity, hyperinsulinaemia, insulin resistance, and hyperleptinaemia are more often seen than in the general population. These abnormalities promote the development of metabolic syndrome and its sequelae, including endothelial dysfunction, and cardiovascular disease. Long-term glucocorticosteroid treatment is also a known risk factor for osteoporosis. Patients with CAH require constant monitoring of biochemical parameters (17a-hydroxyprogesterone [17-OHP] and androstenedione), clinical parameters (body mass, waist circumference, blood pressure, glucose, and lipids), and bone mineral density by densitometry. The principal goal of treatment in adults with CAH is to improve quality of life, ensure that they remain fertile, reduce the manifestations of hyperandrogenisation in females, and minimise the adverse effects of glucocorticosteroid treatment. Patients with classic CAH require treatment with glucocorticosteroids and, in cases of salt wasting, also with a mineralocorticosteroid. Radical measures, such as bilateral adrenalectomy, are very rarely needed. Asymptomatic patients with non-classic CAH require monitoring: treatment is not always necessary. Medical care for patients with CAH should be provided by reference centres, as the management of such patients requires collaboration between an endocrinologist, diabetologist, gynaecologist, andrologist, urologist, and psychologist.
Topics: Adrenal Hyperplasia, Congenital; Adult; Female; Glucocorticoids; Humans; Metabolic Syndrome; Quality of Life; Steroid 21-Hydroxylase
PubMed: 20205117
DOI: No ID Found -
F1000Research 2019Congenital adrenal hyperplasia has traditionally been treated with daily oral doses of glucocorticoids and mineralocorticoid supplements. Such therapy does not precisely... (Review)
Review
Congenital adrenal hyperplasia has traditionally been treated with daily oral doses of glucocorticoids and mineralocorticoid supplements. Such therapy does not precisely replicate the adrenal cortex's circadian pattern. As a consequence, patients are intermittently overtreated or undertreated leading to growth suppression in children, excess weight gain and altered metabolism. Several new treatments are on the horizon. This article will summarize some new potential therapies as adjuncts to, or replacement for, standard therapy.
Topics: Adrenal Hyperplasia, Congenital; Child; Glucocorticoids; Humans
PubMed: 30984389
DOI: 10.12688/f1000research.17778.1 -
Frontiers in Endocrinology 2023Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21-OHD) is a rare autosomal recessive disorder caused by pathological variants in the gene....
OBJECTIVE
Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21-OHD) is a rare autosomal recessive disorder caused by pathological variants in the gene. After a high prevalence of classic 21-OHD CAH in the Romani population was reported in the Republic of North Macedonia, we decided to estimate the prevalence of 21-OHD in Croatia and, if high, assess the possible causes and estimate the frequency of particular variants.
DESIGN
Cross-sectional study.
METHODS
Data from a Croatian 21-OHD genetic database was reviewed, and only Romani patients were included in the study. genotyping was performed using allele-specific PCR, MLPA, and Sanger sequencing.
RESULTS
According to a survey conducted in 2017, Croatia had 22,500 Romani people and six of them had a salt-wasting (SW) form of 21-OHD. All were homozygous for the c.IVS2-13A/C-G pathological variant in intron 2 and descended from consanguineous families belonging to different Romani tribes. The calculated prevalence of 21-OHD in Croatian Romani is 1:3,750, while in the Croatian general population, it is 1:18,000. Three of the six Romani patients originated from two neighboring villages in North-western Croatia (Slavonia County), as well as the seventh patient who is of mixed Romani/Croatian descent and heterozygous for the c.IVS2-13A/C-G pathological variant (not included in the prevalence calculation).
CONCLUSION
A high prevalence of SW 21-OHD in the Croatian Romani population caused by the homozygous cIVS2-13A/C-G pathological variant was found. In addition to isolation and consanguinity, other possible reasons could be the heterozygous advantage of the gene pathological variant and the bottleneck effect as a result of the Romani Holocaust in World War II.
Topics: Humans; Adrenal Hyperplasia, Congenital; Steroid 21-Hydroxylase; Croatia; Prevalence; Cross-Sectional Studies; Roma; Genotype
PubMed: 37324261
DOI: 10.3389/fendo.2023.1170449 -
Archives of Disease in Childhood Dec 2019Steroid biosynthesis is a complex process in which cholesterol is converted to steroid hormones with the involvement of multiple enzymes and cofactors. Inborn conditions... (Review)
Review
Steroid biosynthesis is a complex process in which cholesterol is converted to steroid hormones with the involvement of multiple enzymes and cofactors. Inborn conditions affecting adrenal steroidogenesis are relatively common in paediatric practice and have serious implications on patient mortality and morbidity. This paper provides an overview of novel insights into human adrenal steroid biosynthesis. Inborn errors of steroidogenesis associated with congenital adrenal hyperplasia are discussed, with a particular focus on the pathophysiology and clinical features of 21-hydroxylase deficiency. The final section of the review presents more recent findings and clinical implications of adrenal-specific androgen biosynthesis.
Topics: Adrenal Hyperplasia, Congenital; Glucocorticoids; Hormone Replacement Therapy; Humans; Infant, Newborn; Practice Guidelines as Topic; Steroid 21-Hydroxylase; Steroids
PubMed: 31175123
DOI: 10.1136/archdischild-2017-313873 -
Frontiers in Endocrinology 2022Many patients with congenital adrenal hyperplasia (CAH) refrain from seeking pregnancy, suffer from infertility or worry about pregnancy complications, mainly due to... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Many patients with congenital adrenal hyperplasia (CAH) refrain from seeking pregnancy, suffer from infertility or worry about pregnancy complications, mainly due to genitalia abnormalities, anovulation, unreceptive endometrium and metabolic disturbances. Despite those challenges, many live births have been reported. In this systematic review, we focused on the key to successful assisted reproduction strategies and the potential pregnancy complications. We did a systematic literature search of Pubmed, Medline and Scopus for articles reporting successful pregnancies in CAH other than 21-hydroxylase deficiency, and found 25 studies reporting 39 pregnancies covering deficiency in steroidogenic acute regulatory protein, 17α-hydroxylase/17,20-lyase, 11β-hydroxylase, P450 oxidoreductase, cytochrome b5 and 3β-hydroxysteroid dehydrogenase. We summarized various clinical manifestations and tailored reproduction strategy for each subtype. Furthermore, a meta-analysis was performed to evaluate the pregnancy complications of CAH patients. A total of 19 cross-sectional or cohort studies involving 1311 pregnancies of classic and non-classic CAH patients were included. Surprisingly, as high as 5.5% (95% CI 2.3%-9.7%) of pregnancies were electively aborted, and the risk was significantly higher in those studies with a larger proportion of classic CAH than those with only non-classical patients (8.43% (4.1%-13.81%) VS 3.75%(1.2%-7.49%)), which called for better family planning. Pooled incidence of miscarriage was 18.2% (13.4%-23.4%) with a relative risk (RR) of 1.86 (1.27-2.72) compared to control. Glucocorticoid treatment in non-classical CAH patients significantly lowered the miscarriage rate when compared to the untreated group (RR 0.25 (0.13-0.47)). CAH patients were also more susceptible to gestational diabetes mellitus, with a prevalence of 7.3% (2.4%-14.1%) and a RR 2.57 (1.29-5.12). However, risks of preeclampsia, preterm birth and small for gestational age were not significantly different. 67.8% (50.8%-86.9%) CAH patients underwent Cesarean delivery, 3.86 (1.66-8.97) times the risk of the control group. These results showed that fertility is possible for CAH patients but special care was necessary when planning, seeking and during pregnancy.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=342642, CRD42022342642.
Topics: Abortion, Spontaneous; Adrenal Hyperplasia, Congenital; Cross-Sectional Studies; Cytochromes b5; Female; Glucocorticoids; Humans; Hydroxysteroid Dehydrogenases; Infant, Newborn; Pregnancy; Pregnancy Complications; Premature Birth; Reproduction; Steroid 17-alpha-Hydroxylase
PubMed: 36120452
DOI: 10.3389/fendo.2022.982953 -
Pediatric Endocrinology, Diabetes, and... 2023In view of the modifications in the endocrine society guidelines on evaluation and management of children with congenital adrenal hyperplasia (CAH), we performed... (Review)
Review
INTRODUCTION
In view of the modifications in the endocrine society guidelines on evaluation and management of children with congenital adrenal hyperplasia (CAH), we performed a review of children and adolescents with CAH.
MATERIAL AND METHODS
An audit of 35 children with CAH presenting to the pediatric endocrinology clinic between January 2014 to November 2021 was conducted by formulating ten audit questions. The areas of focus included: genital reconstructive surgery, neonatal screening for CAH, stress dosing, need for adrenocorticotrophic hormone (ACTH) stimulation test, growth promoting therapy, bone age assessment, adrenal imaging, bone mineral density assessment, adequacy of hormone replacement and appropriate management of non-classical CAH.
RESULTS
Conservative approach to genitoplasty in female children increased from 42.9% to 88.9%. Newborn screening identified 4 babies including two asymptomatic males averting saltwasting crisis. Stress dosing of steroids were advised in all and emergency usage of injectable glucocorticoids was warranted in two children. Gonadotropin-releasing hormone (GnRH) analogue therapy improved the final median predicted height by 7 cm in 5 children. Twenty-three (65.7%) had bone age assessment with 14 (40%) having advanced bone age. ACTH stimulation test, Adrenal imaging, dual energy X-ray absorptiometry (DEXA) scan were done in accordance with the guideline. One child with nonclassical CAH was initiated on hydrocortisone replacement for advanced bone age.
CONCLUSIONS
A shift to conservative surgical management of females, utility of neonatal screening for CAH, judicious use of growth promoting therapy is highlighted. Need for bone age testing, emergency hydrocortisone provision is warranted in our series.
Topics: Male; Infant; Infant, Newborn; Child; Humans; Female; Adolescent; Adrenal Hyperplasia, Congenital; Hydrocortisone; Glucocorticoids; Bone Density; Adrenocorticotropic Hormone
PubMed: 36734395
DOI: 10.5114/pedm.2022.122547