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Clinical Case Reports Jul 2024In previous reports, hypothyroidism, hypopituitrism, and hypogonadism were common endocrine causes of SCFE, but this is the first time that congenital adrenal...
In previous reports, hypothyroidism, hypopituitrism, and hypogonadism were common endocrine causes of SCFE, but this is the first time that congenital adrenal hyperplasia has been observed. As such, patients who have undergone long-term endocrine treatment for congenital adrenal hyperplasia could potentially be subjected to a higher risk for SCFE.
PubMed: 38947535
DOI: 10.1002/ccr3.9131 -
Advances in Pediatrics Aug 2024Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic condition caused by various enzyme deficiencies that result in disruptions of pathways of adrenal... (Review)
Review
Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic condition caused by various enzyme deficiencies that result in disruptions of pathways of adrenal steroidogenesis. 21-hydroxylase deficiency is the most common form of CAH and has a variable phenotype which ranges a spectrum, from the most severe salt-wasting type to the simple-virilizing type and the least severe nonclassical form. Patients with CAH are at risk for various comorbidities due to the underlying adrenal hormone production imbalance as well as the treatment of the condition, which typically includes supraphysiologic glucocorticoid dosing. Children and adults require frequent monitoring and careful medication dosing adjustment. However, there are multiple novel therapies on the horizon that offer promise to patients with CAH in optimizing their treatment regimens and reducing the risk of comorbidities.
Topics: Humans; Adrenal Hyperplasia, Congenital; Glucocorticoids; Child
PubMed: 38944479
DOI: 10.1016/j.yapd.2024.02.006 -
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 -
Endocrine Journal Jun 2024Lipid metabolism includes lipogenesis, lipolysis, and cholesterol metabolism and it exerts a wide range of biological effects. We previously found novel roles of...
Lipid metabolism includes lipogenesis, lipolysis, and cholesterol metabolism and it exerts a wide range of biological effects. We previously found novel roles of adipocyte oxidative stress in diet-induced obesity, adipocyte glucocorticoid receptor in Cushing syndrome, and ARMC5 in adrenocortical cells. Using genetically modified mice in which oxidative stress was eliminated or augmented specifically in adipose tissues, we have been able to elucidate that obesity-induced oxidative stress inhibited healthy adipose expansion and ameliorated insulin sensitivity. Using adipocyte-specific glucocorticoid receptor knockout mice, we found that glucocorticoids also inhibited healthy adipose expansion and decreased insulin sensitivity. This was partly due to the transcriptional upregulation of ATGL. We identified ARMC5 as a novel ubiquitin E3 ligase of full-length SREBF, a master regulator of lipid metabolism. In adrenocortical cells, ARMC5 suppresses SREBF2 activity, and loss of ARMC5 may lead to cholesterol accumulation and the development of primary bilateral macronodular adrenal hyperplasia.
PubMed: 38925988
DOI: 10.1507/endocrj.EJ24-0177 -
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 -
Endocrinology Jun 2024The neuroendocrine marker genes Ptprn and Ptprn2 encode protein tyrosine phosphatase receptors N and N2, two members of protein tyrosine phosphatase receptors void of...
The neuroendocrine marker genes Ptprn and Ptprn2 encode protein tyrosine phosphatase receptors N and N2, two members of protein tyrosine phosphatase receptors void of enzymatic activity, and whose function and mechanism of action have not been elucidated. To explore the role(s) of Ptprn and Ptprn2 on the hypothalamic-pituitary-adrenal axis, we used mice in which both genes were knocked out (DKO). The focus in study was on corticotrophs and melanotrophs from the anterior and intermediate lobes of the pituitary gland, respectively. In both sexes, DKO caused an increase in the expression of the corticotroph/melanotroph genes Pomc and Tbx19 and the melanotroph-specific gene Pax7. We also found in vivo and in vitro increased synthesis and release of beta-endorphin, alpha-MSH, and ACTH in DKO mice, which was associated with increased serum corticosterone levels and adrenal mass. DKO also increased the expression of other melanotroph-specific genes, but not corticotroph-specific genes. The dopaminergic pathway in the hypothalamus and dopaminergic receptors in melanotrophs were not affected in DKO mice. However, hyperplasia of the intermediate lobe was observed in DKO females and males, accompanied by increased POMC immunoreactivity per cell. These results indicate that PTPRNs contribute to hypothalamic-pituitary-adrenal function by being involved in processes governing postnatal melanotroph development and Pomc expression.
PubMed: 38923438
DOI: 10.1210/endocr/bqae076 -
The Journal of Clinical Endocrinology... Jun 2024
PubMed: 38922819
DOI: 10.1210/clinem/dgae402