Compound heterozygosity for a whole gene deletion and p.R124C mutation in CYP21A2 causing nonclassic congenital adrenal hyperplasia

Abstract The contiguous gene deletion syndrome of congenital adrenal hyperplasia and Ehlers-Danlos syndrome, named CAH-X, is a rare entity that occurs because of a deletion of a chromosomal area containing 2 neighboring genes, TNXB and CYP21A. Here, we describe a patient from a consanguineous family in which coincidentally MEN-1 syndrome is associated with CAH-X, causing particular challenges explaining the phenotypic features of the patient. A 33-year-old man with salt-wasting congenital adrenal hyperplasia and classic-like Ehlers-Danlos syndrome presented with an adrenal crisis with a history of recurrent hypoglycemia, abdominal pain, and vomiting. He was found to have primary hyperparathyroidism, hyperprolactinemia, and pancreatic neuroendocrine tumors, as well as primary hypogonadism, large adrenal myelolipomas, and low bone mineral density. A bladder diverticulum was incidentally found. Genetic analysis revealed a heterozygous previously well-described MEN1 mutation (c.784-9G > A), a homozygous complete deletion of CYP21A2 (c.1-?_1488+? del), as well as a large deletion of the neighboring TNXB gene (c.11381-?_11524+?). The deletion includes the complete CYP21A2 gene and exons 35 through 44 of the TNXB gene. CGH array found 12% homozygosity over the whole genome. This rare case illustrates a complex clinical scenario with some initial diagnostic challenges.

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Ehlers-Danlos syndrome: molecular and clinical characterization of TNXA/TNXB chimeras in congenital adrenal hyperplasia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab033 ◽

2021 ◽

Author(s):

Roxana Marino ◽

Natalia Perez Garrido ◽

Pablo Ramirez ◽

Guillermo Notaristéfano ◽

Angélica Moresco ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Gene Deletion ◽

Joint Hypermobility ◽

Sequencing Analysis ◽

Adrenal Hyperplasia ◽

Ehlers Danlos Syndrome ◽

Cyp21a2 Gene ◽

Number Of Patients ◽

Contiguous Gene ◽

Danlos Syndrome

Abstract Context The syndrome CAH-X is due to a contiguous gene deletion of CYP21A2 and TNXB resulting in TNXA/TNXB chimeras. Objective To analyze TNXB gene status and to clinically evaluate the Ehlers-Danlos syndrome phenotype in a large cohort of Argentine congenital adrenal hyperplasia (CAH) patients to assess the prevalence of this condition in our population. Design, settings, participants, intervention TNXB-gene analysis was performed in 66 non-related CAH patients that were carriers of the CYP21A2 gene deletion. A molecular strategy based on Multiplex ligation-dependent probe amplification and Sanger sequencing analysis was developed allowing for the detection of different, previously described TNXA/TNXB chimeras, named CH1, CH2, and CH3. Main outcome measures TNXB status of CAH patients that were carriers of the CYP21A2 deletion in the homozygous or heterozygous state. Results TNXA/TNXB CH1 was found in 41%, CH2 in 29% and CH3 in 1.5% of non-related alleles carrying the CYP21A2 deletion. Thus, overall 71% of alleles were found to carry a contiguous gene deletion. 67% of patients analyzed had a monoallelic and 6% a biallelic form. All patients with the biallelic form had severe skin hyperextensibility and generalized joint hypermobility. Conclusions Based on the high frequency of TNXB alterations in CYP21A2-deletion carrier alleles found, we recommend to evaluate TNXB status in these patients, and to assess connective tissue dysplasia including cardiologic alterations in positive cases. The number of patients undergoing cardiological evaluation should be expanded to determine the incidence of structural and functional abnormalities in this cohort.

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Measurement of serum tenascin-X in patients with congenital adrenal hyperplasia at risk for Ehlers–Danlos contiguous gene deletion syndrome CAH-X

BMC Research Notes ◽

10.1186/s13104-019-4753-7 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Vipula Kolli ◽

Hannah Kim ◽

Hamsini Rao ◽

Qizong Lao ◽

Alison Gaynor ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Gene Deletion ◽

Deletion Syndrome ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Ehlers Danlos Syndrome ◽

Amino Terminal ◽

Contiguous Gene ◽

21 Hydroxylase Deficiency ◽

Contiguous Gene Deletion Syndrome

Abstract Objective Approximately 10% of patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency carry a mutation that disrupts CYP21A2 and the flanking TNXB gene resulting in CAH-X, a contiguous gene deletion syndrome. TNXB encodes tenascin-X (TNX), an extracellular matrix glycoprotein that plays an important role in collagen organization. TNXB impairment is associated with Ehlers–Danlos syndrome. Symptoms include joint hypermobility, hernias and cardiac defects. We measured serum TNX using an antibody targeting the amino-terminal of the TNX protein in 161 subjects, including extensively genotyped and phenotyped CAH patients, their relatives, and healthy controls. Results We evaluated the potential of serum TNX as a screening tool for CAH-X. CAH-X patients, especially haploinsufficient patients carrying the TNXA-TNXB chimeric gene CAH-X-CH-1 showed reduced TNX levels compared to controls (P < 0.05). TNX levels were similar in all subjects carrying a TNXB mutation. However, CAH patients who did not harbor a TNXB mutation also had reduced TNX compared to controls (P < 0.001). Thus, measuring serum TNX is not an effective screen for CAH-X amongst patients with CAH. TNXB genotyping is recommended for CAH patients who have symptoms of a connective tissue disorder. Epigenetic factors that influence TNX expression require further study.

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Compound heterozygosity of a novel Q73X mutation and a known R141X mutation in CYP11B1 resulting in 11β-hydroxylase deficiency in a Chinese boy with congenital adrenal hyperplasia

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2021.105882 ◽

2021 ◽

pp. 105882

Author(s):

Chenmin Wei ◽

Zichen Zhang ◽

Miaomiao Sang ◽

Hao Dai ◽

Tao Yang ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Compound Heterozygosity ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency

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Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia

Acta Endocrinologica ◽

10.1530/eje.1.01944 ◽

2005 ◽

Vol 153 (1) ◽

pp. 99-106 ◽

Cited By ~ 63

Author(s):

V Dolž;an ◽

J Sólyom ◽

G Fekete ◽

J Kovács ◽

V Rakosnikova ◽

...

Keyword(s):

High Resolution ◽

Congenital Adrenal Hyperplasia ◽

Gene Deletion ◽

Point Mutations ◽

Common Point ◽

Adrenal Hyperplasia ◽

Low Resolution ◽

Phenotype Correlation ◽

Mutational Spectrum ◽

Cyp21 Gene

Objective: To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype– phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations. Design and methods: Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversions, point mutations or other sequence changes. Results: CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype–phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutations could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH. Conclusions: By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94–99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.

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Monozygotic twins discordant for congenital adrenal hyperplasia due to mosaicism

Acta Endocrinologica ◽

10.1530/eje-19-0249 ◽

2020 ◽

Vol 182 (2) ◽

pp. K7-K13 ◽

Cited By ~ 1

Author(s):

Michelle L Kluge ◽

Evan Graber ◽

Kathryn Foley ◽

Lynnette V Hansen ◽

Heidi L Sellers ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Cell Line ◽

Gene Deletion ◽

Molecular Genetic ◽

Monozygotic Twins ◽

Adrenal Hyperplasia ◽

Differential Distribution ◽

Salt Wasting ◽

Show Evidence ◽

17 Hydroxyprogesterone

Introduction Genotype-phenotype discordance occurs occasionally in congenital adrenal hyperplasia (CAH). Its causes are largely unknown. We describe a case of monochorionic, diamniotic twins with discordant clinical presentations of CAH, and show evidence for this being due to mosaicism resulting from a postzygotic full gene deletion of CYP21A2 prior to twinning. Case description A 7-day-old 36-week gestation female infant (Twin A) presented to the emergency department with elevated 17-hydroxyprogesterone (17-OHP). Her identical twin (Twin B) had normal 17-OHP on newborn screening. Both twins showed signs of virilization, more pronounced in Twin B. Molecular genetic testing of both twins and their parents showed a WT paternally-inherited CYP21A2 and a maternally-inherited copy containing the c.293-13C>G mutation. Both twins were also found to have a 5′-CYP21A1P/CYP21A2-3′ hybrid (product of the common 30-kb deletion), derived from the deletion of the paternally-inherited CYP21A2. Neither mother nor father carried the deletion. Conclusions The genetic findings are consistent with mosaicism for two CYP21A2 cell lines in both twins. The first cell line is expected, based on parental results, while the second line is due to a postzygotic full gene deletion of the paternally-inherited WT CYP21A2. The resultant genotype, compound heterozygosity for c.293-13C>G and a CYP21A2 full gene deletion, is consistent with a salt-wasting CAH phenotype. Differential distribution of the second cell line between the twins is most likely the cause for their discrepant phenotypes. We believe this is the first report of somatic CYP21A2 mosaicism, and represents a novel cause for discrepant CAH phenotypes in monozygotic twins.

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