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The Journal of Clinical Endocrinology... Jun 202417α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare subtype of congenital adrenal hyperplasia (CAH) caused by homozygous or compound heterozygous pathogenic...
BACKGROUND
17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare subtype of congenital adrenal hyperplasia (CAH) caused by homozygous or compound heterozygous pathogenic variants in the CYP17A1 gene.
PURPOSE
This study aimed to identify and characterize pathogenic variants in individuals with 17-OHD, and to classify and validate the pathogenicity of novel variants.
METHODS
Variants were identified via targeted long-read sequencing (TLRS) of the entire CYP17A1 gene in enrolled 17-OHD patients. The American College of Medical Genetics and Genomics guidelines were employed to assess the pathogenicity of novel variants. A minigene splicing assay was utilized to determine the impact of variants on RNA splicing.
RESULTS
This study encompassed 26 patients with 17-OHD, detecting two trans pathogenic variants per patient using the TLRS method. A total of 20 pathogenic variants in the CYP17A1 were identified, with variant c.985_987delinsAA being the most frequent (28/52 alleles), followed by variant c.1459_1467del (4/52 alleles). Five novel variants including c.280T>C, c.470T>A, c.636_637del, c.866A>G, and c.1095del, were classified as pathogenic/likely pathogenic ones according to ACMG criteria. The minigene assay revealed c.866A>G in exon 5 causes a frameshift due to a 104 base pair deletion, while c.470T>A generates two transcripts, with vast majority spliced like the wild-type, and a small fraction lack 35 base pairs in the 5' flank of exon 3.
CONCLUSION
The TLRS can determine the cis/trans orientation of two distant variants. Five novel pathogenic variants were reported, broadening the spectrum of CYP17A1 pathogenic variant. The variant c.866A>G, located deep in exon, affects gene function through mechanisms of aberrant splicing.
PubMed: 38934795
DOI: 10.1210/clinem/dgae414 -
Endocrine Connections Jun 2024Prednisolone and prednisone are recommended treatment options for adults with Congenital Adrenal Hyperplasia (CAH); however, there is no randomised comparison of...
BACKGROUND
Prednisolone and prednisone are recommended treatment options for adults with Congenital Adrenal Hyperplasia (CAH); however, there is no randomised comparison of prednis(ol)one with hydrocortisone.
OBJECTIVE
To assess 17-hydroxyprogesterone (17OHP) levels and glucocorticoid dose in CAH comparing prednis(ol)one versus modified-release hydrocortisone (MRHC).
DESIGN
Six-month open-label randomised phase 3 study and interim analysis of a single-arm extension study.
METHODS
Hydrocortisone dose equivalent and 09:00h 17OHP from 48 patients taking prednis(ol)one at baseline.
RESULTS
At baseline, the median hydrocortisone dose equivalent was 30 mg /day and 17OHP was <36nmol/l (3X upper limit of normal) in 56% of patients. Patients were randomised to continue prednis(ol)one or switch to MRHC at the same hydrocortisone equivalent dose. At 4 weeks, 94% on MRHC and 71% on prednis(ol)one had 17OHP <36nmol/l. At 18 months in the extension study of MRHC, the median MRHC dose was 20 mg /day and 82% had 17OHP <36nmol/l. The percent of patients with 17OHP <36nmol/l on a hydrocortisone dose equivalent ≤25mg /day was greater at 18 months in the extension study on MRHC than while on prednis(ol)one at baseline: 57% vs 27%, P=0.04. In the randomised study, no patients had an adrenal crisis on MRHC and one on prednisolone. In the extension study (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years).
CONCLUSIONS
MRHC reduces 17OHP at 09:00h compared to prednis(ol)one and the dose of MRHC can be down-titrated over time in the majority of patients.
PubMed: 38934378
DOI: 10.1530/EC-24-0150 -
JCEM Case Reports Jun 2024Isolated 17,20-lyase deficiency (ILD) is a partial form of 17α-hydroxylase/17,20-lyase deficiency that typically presents with infertility and lack of pubertal...
Isolated 17,20-lyase deficiency (ILD) is a partial form of 17α-hydroxylase/17,20-lyase deficiency that typically presents with infertility and lack of pubertal development. Successful live births have been achieved using assisted reproductive techniques. We present a case of spontaneous pregnancy in an 18-year-old female with ILD without reproduction treatments or glucocorticoid use. She presented to our clinic with absence of pubarche and oligomenorrhea and had typical external genitalia and complete breast development. Follicular phase progesterone and estradiol were within reference values, and androgen levels were undetectable. Corticosterone was increased, and cortisol responded partially to the ACTH-stimulation test. This profile raised a suspicion for ILD, which was confirmed by the finding of the homozygous p.R347H variant in the gene. Sex steroid replacement and glucocorticoid use during stress were prescribed. She returned 2 years later 20 weeks pregnant. Her gestation was uneventful, and a full-term healthy male was born. This phenomenon could be partially explained by sufficient estrogen synthesis via residual 17,20-lyase enzymatic activity. Intermittent estradiol use may have favored uterine development and fine-tuned the pituitary-gonadal axis rhythm. Normal progesterone levels may have permitted an adequate endometrial "implantation window" without glucocorticoid use. Finally, elevated corticosterone may have compensated for the partial cortisol deficiency.
PubMed: 38933733
DOI: 10.1210/jcemcr/luae100 -
Acta Endocrinologica (Bucharest,... 2023Children having gonadal tumors and disorder of sex differentiation (DSD) are rare.
CONTEXT
Children having gonadal tumors and disorder of sex differentiation (DSD) are rare.
OBJECTIVE
To investigate the presentation of DSD children with malignant gonadal tumors.
METHODS
A retrospective study from 2010-2020, that evaluated 17 children with DSD, including 13 females, eight months to 16 years, with congenital adrenal hyperplasia, 5-alpha reductase deficiency, androgen insensitivity syndrome, Turner, Sywer, and Klinefelter syndromes.
RESULTS
Ten children had malignant gonadal tumor; nine had germ cell tumors and one person granulosa cell tumors, while seven children with non-malignant tumor had gonadoblastoma, cystadenoma (five children), and cysts. Systemic malformations, obesity, elevated tumor markers, and psychosocial issues were observed in 90%, 90%, 70%, and 50% of children with malignancy unlike 28.6%, 42.9%, 14.35%, and 57.1% children without malignancy respectively. Most (9/10) children >12 years, had psychosocial issues, unlike 0/7 children ≤12 years. From 8/17 children presenting with symptoms suggestive of tumor, 75% had malignancy, while from 9/17 children with DSD presentation, 44% had malignant tumors. Malignancy was observed in 3/10 children between eight months to age six, while 7/10 children had stage 1-2 tumors. We reported a child, identified as female, aged 13 years, with partial androgen insensivity syndrome (PAIS) 46,XY, and testicular papillary serous cystadenoma with genomic variant AR NM_000044.4:c.2750del. p.(F917Sfs*27) chromosome Xq12, never published in people with PAIS nor population databases (GnomAD).
CONCLUSION
DSD diagnosis raises numerous challenges. People with DSD have increased risk of malignancy, especially when obesity and, systemic malformations are present; also, psychosocial issues in these children are associated with postpubertal age.
PubMed: 38933245
DOI: 10.4183/aeb.2023.487 -
The Journal of Molecular Diagnostics :... Jun 2024Genetic analysis of congenital adrenal hyperplasia (CAH) has been challenging due to high homology between CYP21A2 and its pseudogene CYP21A1P. This study aimed to...
Improved genetic characterization of congenital adrenal hyperplasia by long-read sequencing compared with multiplex ligation-dependent probe amplification plus Sanger sequencing.
Genetic analysis of congenital adrenal hyperplasia (CAH) has been challenging due to high homology between CYP21A2 and its pseudogene CYP21A1P. This study aimed to evaluate the clinical utility of long-read sequencing (LRS) in diagnosis of CAH due to 21-hydroxylase deficiency by comparing with multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing. In this retrospective study, 69 samples including 49 probands from 47 families with high-risk of CAH were enrolled and blindly subjected to detection of CAH by LRS. The genotype results were compared with control methods, and discordant samples were validated by additional Sanger sequencing. LRS successfully identified biallelic variants of CYP21A2 in the 39 probands diagnosed as CAH. The remaining 10 probands were not CAH patients. Additionally, LRS directly identified two pathogenic SNVs (c.293-13C/A>G and c.955C>T) in the presence of interference caused by nearby indels. The cis-trans configuration of two or more single-nucleotide variants and indels (SNVs/indels) identified in 18 samples was directly determined by LRS without family analysis. Eight CYP21A1P/A2 or TNXA/B deletion chimeras comprised of five subtypes were identified and the junction sites were precisely determined. Moreover, LRS determined the exact genotype in two probands that had three heterozygous SNVs/indels and duplication, which could not be clarified by control methods. These findings highlight that LRS could assist in more accurate genotype imputation and more precise CAH diagnosis.
PubMed: 38925455
DOI: 10.1016/j.jmoldx.2024.05.009 -
The Journal of Clinical Endocrinology... Jun 2024
PubMed: 38922819
DOI: 10.1210/clinem/dgae402 -
The Journal of Clinical Endocrinology... Jun 2024
PubMed: 38922807
DOI: 10.1210/clinem/dgae401 -
The Journal of Endocrinology Jun 2024Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a... (Review)
Review
Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid Congenital Adrenal Hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype-phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two hit model: The first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis. The second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.
PubMed: 38913505
DOI: 10.1530/JOE-24-0078 -
Gynecological Endocrinology : the... Dec 2024To investigate the association between female sexual function and metabolic features among women with polycystic ovary syndrome (PCOS) during reproductive age.
OBJECTIVE
To investigate the association between female sexual function and metabolic features among women with polycystic ovary syndrome (PCOS) during reproductive age.
METHOD
This was a cross-sectional study in which 288 women with PCOS and 180 women without PCOS between the ages of 20 and 40 years were evaluated. All women had serum total testosterone, androstenedione, DHEA-S, fasting glucose, total cholesterol, HDL-C, LDL-C, and triglyceride levels analyzed. The McCoy Female Sexual Questionnaire (MFSQ) was applied to all studied women. Exploratory factor analysis and reliability analysis were done after data collection. The factor loadings of MFSQ domains were compared between women with PCOS and controls.
RESULTS
Average factor loadings of the MFSQ sexuality domain and MFSQ sexual partner domain were significantly lower in the PCOS group when compared to controls. There was no correlation between the two sexual function domains of the MFSQ and the PCOS features either in the PCOS group or the controls.
CONCLUSION
PCOS is a heterogeneous disease with different metabolic components, such as insulin resistance, obesity, and hyperandrogenism. Although sexual function among women with PCOS was lower than controls, no differences were found in metabolic features of the PCOS and non-PCOS groups with relation to sexual function determined by the MFSQ.
Topics: Humans; Female; Polycystic Ovary Syndrome; Adult; Cross-Sectional Studies; Turkey; Young Adult; Insulin Resistance; Sexual Dysfunction, Physiological; Testosterone; Surveys and Questionnaires; Case-Control Studies; Hyperandrogenism; Sexual Behavior; Androstenedione; Dehydroepiandrosterone Sulfate; Obesity
PubMed: 38913084
DOI: 10.1080/09513590.2024.2362249 -
Journal of Clinical Research in... Jun 202417α‑hydroxylase/17,20‑lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia that causes decreased cortisol and sex steroid levels and leads to...
17α‑hydroxylase/17,20‑lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia that causes decreased cortisol and sex steroid levels and leads to high production of adrenocorticotropic hormone (ACTH). Although affected patients have absolute cortisol deficiency, they do not show clinical signs of cortisol deficiency or hyperpigmentation. These patients most commonly present with delayed puberty and amenorrhea at late pubertal age. Impaired production of sex steroids leads to ambiguous or female external genitalia in affected 46, XY individuals. In this report, we describe a patient with 17OHD who presented with hyperpigmentation and hypergonodotropic hypogonadism while receiving chemotherapy.
PubMed: 38912718
DOI: 10.4274/jcrpe.galenos.2024.2024-3-13