Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation

Gómez-Garre, Pilar; Seijo, Mariana; Gutierrez-Delicado, Eva; Rio, M.; Torre, Carolina De La; Gómez-Abad, C.; Morales-Corraliza, Jose; Puig, M.; Serratosa, Joan

doi:10.1136/jmg.2004.029173

Cited by 33 publications

(34 citation statements)

References 23 publications

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“…3 Over the past few years, several new forms have been clinically and molecularly delineated, including dermatan 4-O-sulfotransferase 1 deficient-EDS, spondylocheiro dysplastic EDS (caused by mutation of the SLC39A13 gene) and the X-linked periventricular heterotopia variant (PH-EDS), caused by mutations in Filamin A. [4][5][6][7] In fact, the existence of EDS type VIII, as a specific EDS form associated with periodontal disease and having a distinct underlying genetic basis, is still debated in the literature. This is based in part on the reported association of gingivitis (and sometimes subsequent periodontitis) with other subtypes of EDS (eg, the classic, hypermobile and vascular forms), 3,8 arguing that gingival involvement may be considered a nonspecific consequence of various heritable connective tissue disorders.…”

Section: Discussionmentioning

confidence: 99%

Ehlers–Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features

Reinstein

Delozier²,

Simon

et al. 2012

Eur J Hum Genet

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We would like to dedicate this article to the memory of David Rimoin, MD, PhD, who passed away on May 27, 2012. He was an outstanding geneticist, mentor, and human being.Ehlers-Danlos syndrome (EDS) type VIII (periodontitis type) is a distinct form of EDS characterized by periodontal disease leading to precocious dental loss and a spectrum of joint and skin manifestations. EDS type VIII is transmitted in an autosomal dominant pattern; however, the mutated gene has not been identified. There are insufficient data on the spectrum of clinical manifestations and natural history of the disorder, and only a limited number of patients and pedigrees with this condition have been reported. We present a four-generation EDS type VIII kindred and show that EDS VIII is clinically variable and although some cases lack the associated skin and joint manifestations, microscopic evidence of collagen disorganization is detectable. We further propose that the diagnosis of EDS type VIII should be considered in familial forms of periodontitis, even when the associated skin and joint manifestations are unconvincing for the diagnosis of a connective tissue disorder. This novel observation highlights the uncertainty of using connective tissue signs in clinical practice to diagnose EDS type VIII.

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Section: Discussionmentioning

confidence: 99%

Ehlers–Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features

Reinstein

Delozier²,

Simon

et al. 2012

Eur J Hum Genet

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“…19 The recognition of progressive vascular defects associated with XL-PH raises the potential for rupture and sudden death in this condition. Descriptions of cohorts of patients with XL-PH do not report such clinical incidents suggesting that this is not a common complication of the disorder, 4,5,7,8,11,12,15,16 although data have not been prospectively sought to answer this specific question. The precise incidence of XL-PH and aortic dilatation is unknown, complicating this uncertainty.…”

Section: Discussionmentioning

confidence: 99%

“…3 Two previous reports linked XL-PH to a connective tissue disorder characterized by joint hypermobility, cutaneous anomalies and aortic aneurysms (Ehlers-Danlos syndrome (EDS)-PH; OMIM #300537), and reported three sporadic and one familial case of the association. 4,5 The clinical manifestations of this syndrome are poorly defined since the detailed descriptions of some reported cases are not available. It is also unclear if the four FLNA mutations that underlie EDS-PH are functionally different from those that cause generic XL-PH.…”

Section: Introductionmentioning

confidence: 99%

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

et al. 2012

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Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.

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“…Two genes were identified that can cause PNH. Mutations in the Xlinked gene filamin-A (FLNA) result in PNH, but also can give rise to aortic aneurysms, blood abnormalities, and the heritable connective tissue disorder called Ehlers-Danlos syndrome [Sheen et al, 2001[Sheen et al, , 2005Gomez-Garre et al, 2006]. In addition, mutations in FLNA also can give rise to OPD/Frontometaphyseal spectrum of conditions [Robertson et al, 2003;Zenker et al, 2004;Hehr et al, 2005].…”

Section: Introductionmentioning

confidence: 97%

Periventricular nodular heterotopia and Williams syndrome

Ferland

Gaitanis

Apse

et al. 2006

American J of Med Genetics Pt A

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We report here on the first case of a child with bilateral periventricular nodular heterotopia (PNH) and Williams syndrome. Fluorescent in situ hybridization (FISH) analyses demonstrated a deletion of the elastin gene in the Williams syndrome critical region (WSCR). Further mapping by loss of heterozygosity analysis both by microsatellite marker and SNP profiling demonstrated a 1.5 Mb deletion beyond the telomeric end of the typical WSCR. No mutations were identified in the X-linked filamin-A gene (the most common cause of PNH). These findings suggest another dominant PNH disorder along chromosome 7q11.23.

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Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation

Cited by 33 publications

References 23 publications

Ehlers–Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features

Ehlers–Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

Periventricular nodular heterotopia and Williams syndrome

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