Tenascin-X Haploinsufficiency Associated with Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia

Merke, Deborah P.; Chen, Wuyan; Morissette, Rachel; Zhi, Xu; Ryzin, Carol Van; Sachdev, Vandana; Hannoush, Hwaida; Shanbhag, Sujata M.; Acevedo, Ana T.; Nishitani, Miki; Arai, Andrew E.; McDonnell, Nazli B.

doi:10.1210/jc.2012-3148

Cited by 61 publications

(99 citation statements)

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“…This 8.5kb CYP779f/Tena32F amplicon is able to reveal TNXA/TNXB chimeras and has been utilized to study CAH-X patients. 41,43,44 Hannah-Shmouni et al Page 7…”

Section: Molecular Analysis Of Cyp21a2 Mutationsmentioning

confidence: 99%

Section: Cah-x Syndromementioning

confidence: 99%

“…43 The deletions associated with CAH-X are TNXA/TNXB chimeras ( Figure 4) and 3 types of chimeric genes have been identified to date, designated CAH-X CH-1, CAH-X CH-2, and CAH-X CH-3. 41,43,44 CAH-X CH-1 involves the 120bp deletion in the exon 35 region of TNXB and leads to haploinsufficiency with reduced tenascin-X; CAH-X CH-2 involves the c.12174C>G (p.Cys4058Trp) variant in exon 40 of TNXB, which does not alter tenascin-X expression but rather causes a dominant-negative effect due to the loss of a critical disulfide bond in the tenascin-X fibrinogen-like domain; and CAH-X CH-3 involves a cluster of three variants and also causes a dominant-negative effect.…”

Section: Cah-x Syndromementioning

confidence: 99%

“…41 Other clinical features include midline defects and major cardiac structural abnormalities. 42 Thus, clinicians involved in the care of patients with CAH, particularly those harboring a CYP21A2 deletion, should provide a comprehensive evaluation for a connective tissue dysplasia.…”

Section: Cah-x Syndromementioning

confidence: 99%

“…This contiguous gene deletion syndrome, involving both the CYP21A2 and TNXB genes, is termed CAH-X syndrome. 41,42 The first study of the genetic spectrum of CAH-X in a mixed population of CAH patients showed a contiguous CYP21A2 deletion that extended into TNXB in 13% of patients (n=12/91) carrying a CYP21A2 deletion, and a TNXB premature stop codon in a The deletions associated with CAH-X are TNXA/TNXB chimeras ( Figure 4) and 3 types of chimeric genes have been identified to date, designated CAH-X CH-1, CAH-X CH-2, and CAH-X CH-3. 41,43,44 CAH-X CH-1 involves the 120bp deletion in the exon 35 region of TNXB and leads to haploinsufficiency with reduced tenascin-X; CAH-X CH-2 involves the c.12174C>G (p.Cys4058Trp) variant in exon 40 of TNXB, which does not alter tenascin-X expression but rather causes a dominant-negative effect due to the loss of a critical disulfide bond in the tenascin-X fibrinogen-like domain; and CAH-X CH-3 involves a cluster of three variants and also causes a dominant-negative effect.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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“…This 8.5kb CYP779f/Tena32F amplicon is able to reveal TNXA/TNXB chimeras and has been utilized to study CAH-X patients. 41,43,44 Hannah-Shmouni et al Page 7…”

Section: Molecular Analysis Of Cyp21a2 Mutationsmentioning

confidence: 99%

Section: Cah-x Syndromementioning

confidence: 99%

Section: Cah-x Syndromementioning

confidence: 99%

Section: Cah-x Syndromementioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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Molecular Genetics of 21‐Hydroxylase Deficiency

Parajes

Krone

2014

Encyclopedia of Life Sciences

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Steroid 21‐hydroxylase deficiency (21OHD) accounts for approximately 95% of cases of congenital adrenal hyperplasia, one of the most common inherited metabolic disorders. It can be clinically classified into classic and nonclassic 21OHD. Classic 21OHD is associated with glucocorticoid deficiency and, in 46,XX patients, with disorder of sex development. Mineralocorticoid synthesis may also be significantly impaired in two‐thirds of patients, leading to life‐threatening salt‐wasting (SW) crises. Nonclassic 21OHD is milder and presents mainly with hyperandrogenism. 21OHD is caused by mutations in the CYP21A2 gene. The vast majority of CYP21A2 mutations are a result of unequal crossing overs and gene conversions with its highly homologous pseudogene, CYP21A1P . Molecular genetic analysis is challenging and requires the combination of different methods to detect gene deletions, chimeric genes, gene duplications and point mutations. An overall good genotype–phenotype correlation exists for the SW phenotype. Therefore, molecular diagnosis of 21OHD complements clinical diagnosis and allows for clinical and genetic counselling. Key Concepts: Steroid 21‐hydroxylase deficiency (21OHD) is an autosomal recessive disorder caused by mutations in the CYP21A2 gene and represents the most common form of congenital adrenal hyperplasia. A good genotype–phenotype correlation exists for the mineralocorticoid deficiency phenotype. Although a trend exists, the severity of 46,XX disorder of sex development as well as of other hyperandrogenic signs and symptoms correlates less strongly with the CYP21A2 genotype. Common pseudogene‐derived mutations account for the majority of 21OHD disease‐causing alleles; these include gene deletions, chimeric genes, seven single point mutations, an 8 base‐pair deletion and a cluster of three point mutations. Molecular genetic analysis of the CYP21A2 gene is challenging due to the high‐sequence homology with its pseudogene ( CYP21A1P ), the high rate of large rearrangements with different break points, and the presence of complex alleles carrying various mutations. Some less common mutations are highly prevalent in specific populations due to founder effects. These should be considered in the genetic diagnosis of 21OHD when only screening for otherwise common CYP21A2 mutations. CYP21A2 gene duplications should be considered in carriers of the p.Gln318X mutation to provide the correct molecular genetic diagnosis. Molecular genetic diagnosis is essential to provide the correct diagnosis and allows for appropriate clinical and genetic counselling.

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Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers‐danlos syndrome hypermobility type compared to other heritable connective tissue disorders

Colombi¹,

Dordoni²,

Chiarelli³

et al. 2015

American J of Med Genetics Pt C

100

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Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT) is an evolving and protean disorder mostly recognized by generalized joint hypermobility and without a defined molecular basis. JHS/EDS-HT also presents with other connective tissue features affecting a variety of structures and organs, such as skin, eye, bone, and internal organs. However, most of these signs are present in variable combinations and severity in many other heritable connective tissue disorders. Accordingly, JHS/EDS-HT is an "exclusion" diagnosis which needs the absence of any consistent feature indicative of other partially overlapping connective tissue disorders. While both Villefranche and Brighton criteria include such an exclusion as a mandatory item, a systematic approach for reaching a stringent clinical diagnosis of JHS/EDS-HT is still lacking. The absence of a consensus on the diagnostic approach to JHS/EDS-HT concerning its clinical boundaries with similar conditions contribute to limit our actual understanding of the pathologic and molecular bases of this disorder. In this review, we revise the differential diagnosis of JHS/EDS-HT with those heritable connective tissue disorders which show a significant overlap with the former and mostly include EDS classic, vascular and kyphoscoliotic types, osteogenesis imperfecta, Marfan syndrome, Loeys-Dietz syndrome, arterial tortuosity syndrome, and lateral meningocele syndrome. A diagnostic flow chart is also offered with the attempt to support the less experienced clinician in stringently recognizing JHS/EDS-HT and stimulate the debate in the scientific community for both management and research purposes.

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Tenascin-X Haploinsufficiency Associated with Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia

Abstract: Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.

Cited by 61 publications

References 32 publications

Genetics of Congenital Adrenal Hyperplasia

Genetics of Congenital Adrenal Hyperplasia

Molecular Genetics of 21‐Hydroxylase Deficiency

Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers‐danlos syndrome hypermobility type compared to other heritable connective tissue disorders

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