Dyskeratosis, Hereditary Benign Intraepithelial

Description

Hereditary benign intraepithelial dyskeratosis (HBID) is a rare inherited disease characterized by elevated plaques on the ocular and oral mucous membranes. The bulbar conjunctiva is involved, especially in the nasal and temporal perilimbal region. Dilated superficial vessels in association with the conjunctival plaques give the eye an overall red appearance, which accounts for the disease's nickname of 'red eye.' Morphologically, the lesions consist of a dyskeratotic hyperplastic epithelium. The oral lesions, which are typically asymptomatic and may go unrecognized, usually appear as thick, soft, white papules and plaques of various sizes, involving any part of the oral cavity. The ocular manifestations in this condition vary in severity from asymptomatic plaques on the bulbar conjunctiva to complete involvement of the cornea with severe vision loss. Patients commonly complain of symptoms of irritation, such as erythema, itching, excessive lacrimation, and photophobia. Periods of acute intensification of symptoms are common, especially in the spring. The lesions may become apparent in early infancy and may date from birth. The plaques persist throughout life and sometimes progress, but may wax and wane (summary by Witkop et al., 1960; Reed et al., 1979; and Baroni et al., 2009).

Clinical Features

Von Sallmann and Paton (1959, 1960) studied members of a large, triracial, consanguineous North Carolinian isolate population, so-called 'Halowar Indians,' who had dyskeratosis of the conjunctival epithelium. Of approximately 309 individuals who were examined, 74 were affected and 4 were equivocal. Patients displayed bilateral gelatinous plaques of the perilimbal bulbar conjunctiva of variable severity that were present at birth or shortly thereafter and persisted throughout life. A few patients had a corneal membrane or vascularized corneal opacity. Biopsies of the involved perilimbal conjunctiva from 5 patients all showed dyskeratosis and acanthosis of the conjunctival epithelium. The eye lesions were invariably associated with a comparable epithelial lesion of the oral mucosa.

Witkop et al. (1960) also studied the triracial isolate in North Carolina, and identified 83 affected individuals. Characteristic histologic changes in the prickle cell layer of the mucosa include numerous round, waxy-looking, eosinophilic cells that appear to be engulfed by normal cells, giving a cell-within-cell appearance; these changes are seen in both oral and eye specimens. The oral lesion, which grossly resembles leukoplakia, is not precancerous. The eye lesions resemble pterygia (see 178000). The only symptoms are produced by involvement of the cornea, resulting in impairment of vision. Histologically, characteristic findings are obtained in oral and eye scraping. Penetrance is about 97% and there is little effect on reproductive fitness.

Yanoff (1968) described the condition in mother and daughter. This was the only report of the condition in persons apparently unrelated to the North Carolinian triracial isolate, the 'Haliwa Indians,' studied by Witkop and Gorlin (1961). However, Gorlin (1971) stated that Yanoff's patients were in fact related to Witkop's. (Members of the triracial isolate are called Haliwa Indians because they live in Halifax and Warren Counties, North Carolina.) Shields et al. (1987) described an affected 37-year-old woman of Haliwa ancestry who was born in Philadelphia.

Sadeghi and Witkop (1977) used transmission electron microscopy to examine biopsy specimens from the molar region of the buccal mucosa of a 16-year-old boy and a 22-year-old woman with hereditary benign intraepithelial dyskeratosis. Ultrastructural findings revealed a striking change in cellular differentiation toward keratinization in some but not all epithelial cells. HBID is differentiated from other dyskeratotic conditions of the mucous membranes by the presence of numerous vesicular bodies in immature dyskeratotic cells; a marked increase in the production of tonofilaments in dyskeratotic cells, densely filling the entire cytoplasm; disappearance of cellular interdigitation and desmosomes in mature dyskeratotic cells; and prominent nuclear degeneration.

Reed et al. (1979) studied 13 patients with HBID, all of whom had the thickened opaque plaques on the bulbar conjunctiva adjacent to the limbus that are the hallmark of the disorder; in addition, 10 of the 13 had similar lesions on the cornea. The corneal abnormalities had 2 distinct features: deep, stromal vessels and thickened, opaque, gelatinous-appearing unilateral or bilateral epithelial plaques. The corneal epithelium was slightly abnormal in some cases and almost totally involved in other instances, covering the visual axis of 1 eye in 4 patients. Examination by light microscopy of surgically excised tissue from 5 of the patients showed similar features in all specimens, with markedly thickened mucosal epithelium that exhibited hyperkeratosis and acanthosis. Adjacent to the abnormal epithelium were portions of normal thickness and morphology. A mild to moderate infiltrate of lymphocytes and plasma cells was usually present beneath the hyperplastic and dyskeratotic epithelium. Reed et al. (1979) noted that although surgical procedures are commonly only of temporary benefit, excision is nonetheless recommended when chronic epithelial plaques significantly reduce vision; in addition, the tendency to regrowth may lead the clinician to conclude that the lesion is malignant and requires radical surgery, but the histopathologic attributes are diagnostic and unlike those of any premalignant or malignant neoplasm.

Gombos et al. (1986) reported a 4-generation Italian family with HBID. The proband was a 65-year-old man, whose 3 sons and 1 daughter all exhibited similar symptoms in infancy; 2 of 8 grandchildren were also affected. The ocular lesions involved significant conjunctival hyperemia and gelatinous plaques, similar to pingueculae, located on the nasal and temporal bulbar conjunctiva. The oral manifestations consisted of soft and spongy white patches, round or linear, that were present on the corners and floor of the mouth, gingival mucosa, and ventral surface of the tongue. Gombos et al. (1986) noted that the daughter had primarily oral involvement, and the 2 grandchildren, a 12-year-old girl and a 7-year-old boy, had mild lesions of the oral mucosa as well as conjunctival hyperemia, with tearing and photophobia, particularly in the summer months. Histologic examination of a fragment of gingival mucosa showed a dyskeratotic, thickened epithelium, with loss of cell-cell adhesion towards the upper layers. Some cells in the upper-middle region of the Malpighian layer exhibited marked eosinophilia and early keratinization with a waxy appearance, and some of those cells also displayed a cell-within-cell appearance.

Jham et al. (2007) described a 32-year-old Brazilian man who was referred for evaluation of multiple asymptomatic intraoral white, rough, diffuse, folded plaques bilaterally in the posterior buccal mucosa. He also had asymptomatic reddened gelatinous plaques and dilated vessels on the conjunctiva of both eyes. Intraoral incisional biopsy revealed increased epithelial thickness, hyperplasia, and acanthosis, with numerous large vacuolated cells throughout the epithelium. Dyskeratotic cells were observed in the suprabasal and superficial epithelium, with some cells appearing to be engulfed by the surrounding cells in a cell-within-cell pattern, findings that were compatible with HBID. The patient's brother had eye changes consistent with HBID, but had no oral lesions. Their mother and a sister were unaffected; their father was deceased.

Baroni et al. (2009) reported a 12-year-old girl who presented with a 4-year history of asymptomatic soft, white spotty lesions, aggregated in roundish and linear spongy plaques on the buccal mucosa and lower lip. No ocular or associated skin or nail lesions were observed. A mucosal biopsy showed thickening of the epithelium, prominent dyskeratosis with decreased cell-cell adhesion in the superficial layers, and a cell-within-cell pattern of epithelial cells engulfed by other normal cells. Tzanck smear of the affected mucosa revealed epithelial cells with cytoplasm discolored in a yellow-orange-brown tobacco-like hue (so-called 'tobacco cells'). Examination of her mother revealed dilated vessels and a superficial gelatinous plaque on the bulbar conjunctiva; a maternal uncle and the maternal grandmother also had dilated vessels and superficial gelatinous plaque on the bulbar conjunctiva, as well as white papules on the buccal mucosa. All affected family members were asymptomatic. Baroni et al. (2009) noted that HBID oral lesions are remarkably similar to those of white sponge nevus (see 193900), but that in the latter disorder no eye lesions are observed, and the disorder also involves the external genitalia and rectum.

Mapping

By linkage analysis in 2 North Carolina families, one of which was originally described by Witkop et al. (1960) and later studied by Reed et al. (1979), Allingham et al. (2001) localized the benign intraepithelial dyskeratosis locus to chromosome 4q35 with a peak lod score of 8.97. Molecular analysis revealed that all affected individuals in the 2 large families studied had 3 alleles for 2 tightly linked markers, D4S1652 and D4S2390, which map to the telomeric region of 4q35. They suggested that a duplication is involved in the causation of the disorder.

Molecular Genetics

Exclusion Studies

In 4 Native Americans with HBID, Soler et al. (2013) analyzed the NLRP1 gene (606636), mutation in which had been found to cause corneal intraepithelial dyskeratosis and ectodermal dysplasia (CIDED; 615225), but detected no pathogenic mutations.