Hereditary benign intraepithelial dyskeratosis (HBID) is a rare inherited disease characterized by elevated plaques on the ocular and oral mucous membranes. Hereditary benign intraepithelial dyskeratosis is a rare autosomal dominant disease of the conjunctiva and the oral mucosa caused by a duplication of. Context.—Hereditary benign intraepithelial dyskeratosis (HBID) is a rare autosomal dominant disorder characterized by elevated epibulbar and oral plaques.
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Hereditary benign intraepithelial dyskeratosis HBID is a rare autosomal-dominant disorder of the conjunctiva and oral mucosa first described in and predominantly affecting descendents of Haliwa-Saponi Native Americans. We report a spontaneous case of histopathologically-confirmed HBID affecting an individual not of Native American ancestry. Report of a case with histopathologic examination of an excised conjunctival specimen as ryskeratosis as molecular and cytogenetic analysis.
A Caucasian boy with a history of oral lesions and conjunctival injection from birth developed bilateral corneal opacities at age 5 and underwent penetrating keratoplasty, with recurrence of the corneal opacification shortly after surgery.
Examination of a conjuctival biopsy specimen revealed features consistent with HBID. Copy number variant CNV analysis revealed a de novo 4q35 duplication that overlapped the duplication previously associated with HBID, although no genes were identified in the common interval.
NLRP1 gene sequencing failed to reveal a presumed pathogenic variant. The absence of coding regions in a duplicated region of 4q35 common to both the individual that we report and previously associated with HBID raises questions regarding the significance of this CNV in the pathogenesis of HBID.
Hereditary benign intraepithelial dyskeratosis HBID is a disorder of the bulbar conjunctiva and oral mucosa associated with epithelial hyperplasia and hyperkeratosis. Clinical features include white plaques on the bulbar conjunctiva and oral mucosa that may present at birth and progress over time. In cases in which the conjunctival epithelial abnormalities extend onto the cornea, vision may be affected and corneal transplantation may be required. Although the investigators commented on candidate genes in the duplicated region, no further studies investigating the genetic dyskertaosis of HBID in these pedigrees have been published.
The dyskeratoiss of HBID with both 4q35 in Native Americans and 17p13 heredittary a Caucasian French family raises the possibility that the bdnign similar entities described in the different populations are in fact genetically distinct. As a second dyskeratisis for locus heterogeneity in HBID, we performed both copy number variant analysis and whole exome sequencing in a previously unreported Caucasian American individual with histopathologically-confirmed HBID.
The authors followed the tenets of the Declaration of Helsinki in the treatment of the intraepthelial reported herein. Previously reported duplications in the region of 4q35 intraepithellial identified using the Database of Genomic Variants dgvbeta.
A Caucasian boy, the youngest of seven children, was evaluated independently by two of the authors TCM and AJA for chronic conjunctival injection and photophobia since infancy Figure 1. The patient was diagnosed at birth with patches of oral leukoplakia that extended into dyyskeratosis esophagus and were diagnosed as consistent with HBID. The patient also had a history of congenital bilateral sensorineural hearing loss, for which he began wearing hearing aids at 1 year of age.
As corneal opacificaiton recurred only several months after surgery, no further corneal procedures were performed for management of the corneal opacification in each eye Figure 1. No other immediate family members, including his 6 siblings, had a history of ocular, oral or auditory disorders. Pedigree of a family with HBID. Filled symbols indicates affected individual; open symbols indicate unaffected individuals; arrowhead indicates proband.
Hereditary Benign Intraepithelial Dyskeratosis
External photographs of 6-year old boy with clinical and histopathologic changes consistent with HBID. Iintraepithelial conjunctival injection, an elevated lesion overlying the limbus and diffuse superficial corneal vascularization and opacification are noted OD B. Significant inferior conjunctival injection, and corneal vascularization and opacification of the previous penetrating keratoplasty are noted OS C. Diffuse bulbar conjunctival injection was noted, intrsepithelial with elevated foci of epithelial thickening and keratinization overlying the limbus Figure 1.
Ocular ultrasonography revealed a normal axial length and unremarkable posterior segment of each eye. A biopsy of the elevated limbal lesion in the right eye revealed marked thickening dyskeeatosis the epithelium associated with dyskeratosis, hyperkeratosis and apparent apoptosis Figure 2.
Conjunctival biopsy specimen from an individual with HBID. A moderate chronic inflammatory infiltrate resides in the superficial substantia propria, above which the conjunctival squamous epithelium is hyperplastic and acanthotic.
Brightly eosinophilic cytoplasmic material is present in the superficial epithelial cells arrowspresumably representing keratin, and anucleate squamous cells are evident on the epithelial surface arrowheads.
Individual epithelial cells show margination and fragmentation of nuclear material with eosinophilic cytoplasm and apoptotic changes hematoxylin and eosin stain. Sequencing of NLRP1 in the proband revealed only a single synonymous coding variant c. Ser38Sera known SNP rspresent in the heterozygous state.
Segregation analysis from SNP data shows that at least one unaffected sibling inherited the same alleles from both parents in the intraepthelial that flanks the NLRP1 locus, excluding the possibility of an inherited autosomal recessive deleterious change even outside the Sanger sequenced areas of this locus. Copy number dyskerattosis analysis in the proband revealed seven regions of CNV across the genome, heredutary of which involved chromosome 17 but 3 of which involved chromosome 4: While the Kbp duplication overlaps the previously reported duplication associated with HBID 8no open reading frames are found in the common interval and the nearest functional gene FRG1 is located Kbp from the dyskeratosiss border of the common interval Figure 3.
In addition to FRG1two other genes TUBB4Q and FRG2 are located in the Kb duplication, although dysregulation of these genes is known to be associated with muscular dystrophy, and has not been associated with epithelial pathology. Schematic of chromosome 4q35 indicating location of duplications previously identified in Haliwa-Saponi Native American tribe hatched rectangle and 6-year hersditary boy with HBID shaded rectangles.
The location and names of genes in the duplicated regions are shown. Genomic base position is depicted ryskeratosis the schematic. The location of previously reported duplications and incidence of each in control populations Database of Genomic Variants are depicted underneath the schematic. No open reading frames or identified genes were found in the Kb duplicated region of 4q. Additionally, an exonic sequence variant that inyraepithelial in a change in the encoded protein sequence was not identified in the NLRP1 coding region when aligned to hg18 all exonic seqments had adequate depth of coverage.
Realignment of the original data to hg19 showed dyskeratossis difference for mapped reads in these exons and no new variants were discovered. Of the six reported affected probands that do not have Native American ancestry, four demonstrated conjunctival and corneal changes that were diagnosed by an ophthalmologist as consistent with HBID, with the diagnosis confirmed by histopathologic examination of conjunctival and corneal biopsy specimens.
These conjunctival lesions, photographs of which appear in the reports, appear to have been misinterpreted by the dermatologists, oral surgeons and pathologists who reported intraepithflial cases as ocular manifestations of HBID.
Hereditary benign intraepithelial dyskeratosis – Wikipedia
However, the absence of any genes present in the overlapping duplicated regions of 4q35 in both the proband we report and in the Native American families effectively excludes altered gene dosage as a dyskerratosis cause of HBID, assuming that gene annotation is complete in this region. Even in the Caucasian French family in which the NLRP1 missense mutation was identified, questions remain about the pathogenicity of the identified variant, which was identified in just two affected individuals and absent in five unaffected individuals that were screened.
In addition, the 4q35 locus was not definitively excluded in this family as qPCR amplification of only a single polymorphic marker in 4q35 to dyekeratosis a normal copy number was performed.
While whole exome sequencing was performed, the extensive filtering of identified variants that was required given that DNA from only two affected and one unaffected individuals from this single family were used increases the chances of the pathogenic mutation being filtered out. Given these considerations, and in the absence of functional studies, the identified NLRP1 variant can only be considered as potentially pathogenic.
The absence of a NLRP1 coding region mutation and even a predicted gene in the region of 4q35 duplicated in both the Caucasian American individual we report and in two Haliwa-Saponi Native American families is evidence of a distinct genetic locus for HBID.
It is possible that locus heterogeneity exists for HBID, as is the case for many genetic phenotypes given a single medical diagnostic label, such as Meesmann corneal dystrophy. Subsequently, screening of non-Native American affected individuals, such as the individual that we report, will reveal whether locus heterogeneity does in fact exist for HBID.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. National Center for Biotechnology InformationU. Author manuscript; available in PMC Mar 1. Tina BuiB. Author information Copyright and License information Disclaimer. Correspondence and reprint requests: The publisher’s final edited version of this article is available at Ophthalmic Genet.
Abstract Background Hereditary benign intraepithelial dyskeratosis HBID is a rare autosomal-dominant disorder of the conjunctiva and oral mucosa first described in and predominantly affecting descendents of Haliwa-Saponi Native Americans. Materials and Methods Report of a case with histopathologic examination of an excised conjunctival specimen as well as molecular and cytogenetic analysis.
Results A Caucasian boy with a history of oral lesions and conjunctival injection from birth developed bilateral corneal opacities at age 5 and underwent penetrating keratoplasty, with recurrence of the corneal opacification shortly after surgery.
Hereditary benign intraepithelial dyskeratosis, NLRP1segment duplication. Open in a separate window. Copy number variant analysis Copy number variation analysis in the proband revealed seven regions of CNV across the genome, none of which involved chromosome 17 but 3 of which involved chromosome 4: Whole exome sequencing No open reading frames or identified genes were found in the Kb duplicated region of 4q.
Footnotes Declaration of interest: Clinicopathological features of a suspected case of hereditary benign intraepithelial dyskeratosis with bilateral corneas involved: Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis.
Hereditary Dyskeratosis of the Perilimbal Conjunctiva. Trans Am Ophthalmol Soc. Hereditary benign intraepithelial dyskeratosis. Corneal manifestations of hereditary benign intraepithelial dyskeratosis. Hereditary benign intraepithelial dyskeratosis: Report of two cases with prominent oral lesions. J Am Acad Dermatol. Arch Pathol Lab Med.
A duplication in chromosome 4q35 is associated with hereditary benign intraepithelial dyskeratosis. Am J Hum Genet. Oral manifestations and hereditary transmission. Hereditary Bneign Intraepithelial Dyskeratosis: J Oral Pathol Med.
A report of two cases from Texas. Analysis of DNA sequence variants detected by high-throughput sequencing. The FSHD region on human chromosome 4q35 contains potential coding regions among pseudogenes and a high density of repeat elements. Four hereditary mucosal syndromes: Isolation and chromosomal localization of a cornea-specific human keratin 12 gene and detection of four mutations in Meesmann corneal epithelial dystrophy. Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann’s corneal dystrophy.
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