Hereditary Benign Intraepithelial Dyskeratosis (HBID)

Key points at a glance

Key Points at a Glance

• An autosomal dominant genetic disease that causes benign plaque formation on the conjunctiva, cornea, and oral mucosa.
• Characterized by prominent bilateral conjunctival injection, also known as “red eye disease.”
• Onset in early childhood, with lifelong exacerbations and remissions. Seasonal worsening in spring to summer.
• Causes identified include duplication of the long arm of chromosome 4 (4q35) or mutation of the NLRP1 gene on the short arm of chromosome 17.
• No effective curative treatment exists, and recurrence is high after surgical excision.

1. What is Hereditary Benign Intraepithelial Dyskeratosis (HBID)?

Hereditary benign intraepithelial dyskeratosis (HBID) is a rare genetic disease that causes benign plaque formation on the conjunctiva, cornea, and oral mucosa. It follows an autosomal dominant inheritance pattern with high penetrance.

Prominent bilateral conjunctival injection is the most striking clinical feature, and this disease is also called “red eye disease.”

History

In 1959, it was first reported by Von Sallmann, Paton, and Witkop during a survey of the Haliwa-Saponi tribe in eastern North Carolina, USA. They examined over 300 individuals from the Haliwa family and found clinical signs of ocular surface or oral mucosa in 74 people.

In 1981, two cases were reported in Waco, Texas, without known Haliwa-Saponi ancestry. Subsequently, sporadic cases have been found across North America, South America, Europe, and Asia.

Epidemiology

• Inheritance pattern: Autosomal dominant (high penetrance)
• Age of onset: Early childhood. Not present at birth.
• Affected populations: Originally common among the Hariwa-Saponi tribe, but now reported worldwide
• Malignant transformation: No reports in the literature. Follows a benign course

2. Main symptoms and clinical findings

Subjective symptoms

Bilateral prominent conjunctival injection (red eye) is the most common complaint.

• Redness: Marked injection of the bulbar conjunctiva. May be mistaken for drug or alcohol abuse, leading to social stigma
• Discomfort and foreign body sensation: Foreign body sensation or burning sensation due to corneal plaques
• Tearing: Associated with ocular surface irritation
• Photophobia: Complaints of light sensitivity
• Decreased vision: Occurs when corneal plaques involve the visual axis
• Seasonal variation: Symptoms worsen in spring to summer and tend to improve in cooler periods

Clinical findings (findings confirmed by physician examination)

Affected patients may have ocular symptoms, oral symptoms, or both.

Ocular findings

• Conjunctival injection: Bilateral prominent redness. This is the most characteristic finding of HBID
• Corneal plaque: Forms a white-gray, raised, gelatinous plaque around the limbus (especially nasally and temporally). Can be bilateral or unilateral.
• Corneal neovascularization: Superficial new blood vessels are observed around the plaque. In some cases, it extends to the middle to deep stroma.
• Progression to the visual axis: When the corneal plaque extends to the central area, it can induce astigmatism and cause visual impairment.

Oral findings

• White spongy plaque: White plaques appear on the buccal mucosa, tongue, and lips.

Symptoms begin in early childhood and recur with exacerbations and remissions throughout life. Although there are reports of spontaneous shedding of plaques, no photographic documentation exists.

Q Do HBID symptoms vary by season?

A

HBID symptoms have a clear seasonal pattern. Symptoms tend to worsen from spring to summer and improve during cooler periods. Because exacerbation occurs in warm weather, affected patients often experience greater discomfort in the summer.

3. Causes and Risk Factors

Genetic Causes

Two different genetic loci have been identified for HBID.

| Locus | Chromosomal Location | Type of Mutation | Year Reported | Features | |---|---|---|---| | 4q35 duplication | Long arm of chromosome 4 | Genomic duplication | 2001 | Identified in the Halwa-Saponi tribe | | NLRP1 mutation | Short arm of chromosome 17 (17p13.2) | Missense mutation (M77T) | 2013 | Identified in a French Caucasian family |

4q35 duplication: In 2001, Allingham et al. investigated two large families in North Carolina and discovered a genomic duplication on the long arm of chromosome 4 (4q35) (lod score 8.97)¹⁾. The human homolog of the FAT gene (a tumor suppressor gene) in this region has been proposed as a candidate gene. Subsequent studies have examined the correspondence between histopathological diagnosis and 4q35 duplication²⁾.

NLRP1 mutation: In 2013, a French group investigated a family of seven French Caucasians and discovered a missense mutation (M77T) in the NLRP1 gene. This mutation is presumed to cause destabilization of the protein structure. No 4q35 duplication was found in this family²⁾. Clinically, it presented a more severe phenotype, with total corneal opacity, extension of oral lesions to the larynx, and palmoplantar keratoderma. Bui et al. (2016) re-examined locus heterogeneity in the NLRP1 region and pointed out differences in genotype based on geographic and ethnic background²⁾. In a case series of 17 patients by Seely et al. (2022), 52.9% had Native American ancestry, medical treatment showed poor lesion reduction, and recurrence was frequent after surgical excision³⁾.

Risk factors

• Genetic predisposition: Carrying 4q35 duplication or NLRP1 mutation
• Halwa-Saponi tribe lineage: Originally a high-risk population, but now reported worldwide
• Warm climate: Known as an exacerbating factor for symptoms

About genetic counseling

HBID is an autosomal dominant disorder, with a 50% chance of passing from an affected parent to a child. If you have a family member with HBID, we recommend considering genetic counseling. Since this disease follows a benign course, excessive worry is unnecessary.

4. Diagnosis and Testing Methods

Key points for diagnosis

Because HBID presents a distinctive clinical picture, a clinical diagnosis can be made with slit-lamp examination alone. Histopathological and genetic testing are useful for confirming the diagnosis but are not essential.

Examination points

• Slit-lamp examination: Check for conjunctival injection and corneal plaques (white-gray, gelatinous, around the limbus). Regular examination and photographic documentation are recommended.
• Oral examination: Check for white spongy plaques on the buccal mucosa, tongue, and lips.
• Family history taking: Since it is autosomal dominant, check for affected individuals within the family.

Histopathological examination

A definitive diagnosis can be made by plaque biopsy. Characteristic findings are as follows.

• Acanthosis: Thickening of the stratified squamous epithelium
• Dyskeratosis: Characteristic dyskeratotic cells with condensed cytoplasm and pyknotic nuclei
• Parakeratosis: Incomplete keratinization with retained nuclei in the stratum corneum
• Stromal inflammation: Mild to moderate chronic lymphocytic inflammation in the subepithelial stroma

In a 1977 electron microscopy study by Sadeghi and Witkop, cells of HBID patients showed a shift toward keratinocytic differentiation, densely packed tonofilaments, and loss of intercellular desmosomes and interdigitations.

Genetic testing

Genetic testing is useful for confirmation but not essential for diagnosis. Duplications in the 4q35 region can be detected by PCR or fluorescent allele-specific static scanning (FASST). NLRP1 mutations are identified by whole genome analysis.

Differential diagnosis

Darier disease

Acantholysis: Found in the suprabasal layer of the epidermis

Dyskeratotic cells: Show pyknotic nuclei surrounded by a clear halo

Conjunctival lesions: None. An important distinguishing feature from HBID

White sponge nevus

Surface parakeratosis: Accompanied by hydropic swelling of epithelial cells

Inclusions: Characterized by dense perinuclear eosinophilic cytoplasmic inclusions

Conjunctival lesions: None. Affects external genitalia and rectum

Hereditary benign intraepithelial dyskeratosis

Adhesion defect: Abnormal epithelial adhesion due to desmosomal defects

Multiorgan mucosal lesions: Painless erythema of the conjunctiva, oral cavity, nose, cervix, and urethra

Alopecia: Not seen in HBID

Vitamin A deficiency

Bitot’s spots: Keratinizing changes of the conjunctiva

Nutritional status: Nutritional analysis was performed in the original study by Von Sallmann et al. to rule out deficiency

Q Is genetic testing necessary for the diagnosis of HBID?

A

Genetic testing is useful for confirming HBID but is not essential for diagnosis. HBID presents with a distinctive clinical picture (bilateral conjunctival hyperemia, corneal plaques, oral mucosal plaques), allowing clinical diagnosis based on slit-lamp examination and family history. Histopathological examination (acanthosis, abnormal keratinization, parakeratosis) can also confirm the diagnosis.

5. Standard treatment

Treatment of HBID is very challenging, and no curative therapy has been established to date.

Medical treatment

• Artificial tears: Used to protect the ocular surface and relieve symptoms
• Topical steroid eye drops: Used to suppress inflammation, but efficacy is limited
• Systemic immunosuppressive therapy: Considered when local treatment fails, but symptom improvement is minimal

Local management alone has not been shown to reduce plaque size.

Surgical treatment

Various surgical approaches have been attempted, but plaque recurrence after excision remains a problem.

• Plaque excision: The most basic surgical approach, but with a high recurrence rate. Recurrent plaques may become more extensive and symptoms may worsen.
• Excision with beta irradiation: Attempted by Reed et al., but plaque recurred within 5 weeks and visual function worsened further.
• Penetrating keratoplasty (PKP): The central graft remained clear for 10 months postoperatively, but recurrence of peripheral plaques with neovascularization at the graft edge has been reported.
• Limbal allograft transplantation: Performed in cases with concurrent limbal stem cell deficiency, with reports of no recurrence after 1.5 years.
• Superficial keratectomy + ProKera: Superficial keratectomy combined with an amniotic membrane contact lens (ProKera) improved best corrected visual acuity from counting fingers to 0.1 in a reported case.

Precautions for surgical treatment

Corneal plaques in HBID recur at a high rate after surgical excision. Recurrent plaques may become more extensive and vision loss may worsen. The indication for surgery should be carefully considered, and please consult your ophthalmologist thoroughly.

Q Do corneal plaques recur after excision?

A

Corneal plaques in HBID recur at a high rate after excision. Moreover, recurrent plaques may become more extensive than the original plaque, leading to worsening of symptoms. Even with beta irradiation, recurrence within 5 weeks has been reported. However, there are cases with good results reported with limbal allograft transplantation or superficial keratectomy combined with ProKera, so the choice of surgical technique is important.

6. Pathophysiology and detailed pathogenesis

Abnormal keratinization of the epithelium

The exact pathophysiology of HBID is not understood. The disease process involves the following changes in the stratified squamous epithelium of the cornea and oral mucosa:

• Acanthosis: Abnormal thickening of the epithelium
• Dyskeratosis: Abnormal keratinization process
• Parakeratosis: retention of nuclei in the stratum corneum

Ultrastructural Changes

An electron microscopy study by Sadeghi and Witkop in 1977 reported the following findings.

• Shift toward keratinization: Epithelial cells in HBID patients show an abnormal differentiation direction
• Accumulation of tonofilaments: Densely packed tonofilaments are observed in the cytoplasm
• Numerous vesicular structures: Abnormal vesicles appear in the cytoplasm
• Loss of desmosomes and interdigitations: Disruption of intercellular adhesion structures

Genetic Basis

Two distinct genetic mechanisms have been identified: 4q35 duplication and NLRP1 mutation. However, the detailed molecular mechanisms by which these cause abnormal epithelial keratinization remain unknown. The FAT gene homolog in the 4q35 region is known as a tumor suppressor gene, and its dysfunction may promote abnormal epithelial cell proliferation. NLRP1 mutation is presumed to cause destabilization of protein structure.

7. Recent Research and Future Perspectives

Advances in Genetic Research

Since the identification of 4q35 duplication by Allingham et al. in 2001, the genetic understanding of HBID has steadily progressed ¹⁾.

• 2008: The correlation between histopathological diagnosis and 4q35 duplication was examined
• 2013: A French group identified the NLRP1 gene mutation (M77T), revealing genetic heterogeneity in HBID

Families with NLRP1 mutations show more severe phenotypes (total corneal opacity, laryngeal involvement, palmoplantar keratosis), and elucidating the genotype-phenotype correlation remains a future challenge.

Development of Treatments

Conventional surgical excision had the problem of plaque recurrence, but good results have been reported with limbal allograft transplantation and superficial keratectomy combined with ProKera. Elucidation of the molecular mechanism may lead to the development of targeted therapies.

For Patients: Please Read Carefully

The treatments and examination methods introduced in this article include information intended for medical professionals. Please be sure to discuss treatment plans with your ophthalmologist. HBID is a very rare disease and may require referral to a specialized facility.

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References

1. Allingham RR, Seo B, Rampersaud E, et al. A duplication in chromosome 4q35 is associated with hereditary benign intraepithelial dyskeratosis. Am J Hum Genet. 2001;68(2):491-494.
2. Bui T, Young JW, Frausto RF, Markello TC, Glasgow BJ, Aldave AJ. Hereditary benign intraepithelial dyskeratosis: report of a case and re-examination of the evidence for locus heterogeneity. Ophthalmic Genet. 2016;37(1):76-80.
3. Seely M, Jackson K, Meeker A, Daluvoy M. Case Series of Patients With Hereditary Benign Intraepithelial Dyskeratosis. Cornea. 2022;41(11):1451-1454. doi:10.1097/ICO.0000000000003085. PMID:36219214.