Oral clues to a rare keratin disorder: review maps mouth signs to gene mutations

Pachyonychia congenita is a rare inherited disorder of keratinization in which mutations in one of five keratin genes—KRT6A, KRT6B, KRT6C, KRT16, or KRT17—disrupt the structural proteins of the epithelial cytoskeleton. A new narrative review published in Discover Medicine turns its attention to a part of the body that is often overshadowed by the condition’s better-known skin and nail features: the mouth. The review, led by Edmond Kubi Appiah with Joseph Nimako-Boateng and Jennifer Ekua Duker, synthesizes findings from twenty peer-reviewed studies spanning 1958 to 2025, drawn from PubMed, Scopus, Web of Science, and Google Scholar, and argues that oral findings deserve far more attention from clinicians than they currently receive.

The condition itself is an autosomal dominant genodermatosis whose classic features include pachyonychia, or thickened dystrophic nails; palmoplantar keratoderma, the painful focal or diffuse thickening of skin on the palms and soles; follicular keratosis, hyperkeratotic papules on the extremities, buttocks, and trunk; and oral leukokeratosis. Historically the disorder has been divided into two major clinical subtypes, Jadassohn–Lewandowsky syndrome, known as PC-1, and Murray–Jackson–Lawler syndrome, known as PC-2, with additional forms such as Schafer–Brunauer syndrome and PC tarda described later. PC-1 is typically associated with prominent oral leukokeratosis, whereas PC-2 more frequently presents with cyst formation and natal or neonatal teeth. Prevalence is unknown, though an estimated two thousand to ten thousand individuals are affected worldwide.

The review’s central finding is that oral leukokeratosis is the most frequently reported oral manifestation of pachyonychia congenita, documented in fifteen of the twenty included studies. These lesions typically present as white-to-yellowish hyperkeratotic plaques on the lateral tongue, buccal mucosa, and palate, and they are most commonly associated with mutations in KRT6A. Histologically, the lesions show acanthosis, parakeratosis, and intracellular vacuolization—a so-called ballooning or washed-out appearance of epithelial cells—along with absence of the stratum granulosum and, crucially, no dysplastic changes. Gingival surfaces are uncommonly involved, and examination of the palate has revealed subepithelial clefts accompanied by areas of deep chronic inflammation in the surrounding connective tissue.

Natal and neonatal teeth—teeth present at birth or erupting within the first thirty days of life—were the second most common finding, reported in seven studies and widely associated with KRT17 mutations. These teeth are often malformed, small, or hypoplastic, generally erupt in the anterior region, tend to be soft and fragile, and are frequently lost within the first few months after eruption. They can lacerate an infant’s tongue, cause feeding difficulties in neonates, increase aspiration risk, or traumatize the oral mucosa, often necessitating extraction under local anesthesia or sedation. Angular cheilitis, the fissuring and inflammation at the corners of the mouth, was documented in five studies, while laryngeal involvement, including posterior commissure masses and hoarseness, appeared in four. Oral candidiasis represented an atypical presentation in three studies, and unusual dental findings including multiple idiopathic osteosclerosis, talon cusps, and mesiodens were reported for the first time, expanding the recognized dental phenotype of the condition.

Genotype–phenotype correlations emerged as a key theme of the synthesis. KRT6A mutations were consistently associated with oral leukokeratosis, feeding difficulties, and familial autosomal dominant inheritance, often involving missense or in-frame deletion variants, and several studies described more extensive oral involvement and reports of hoarseness among individuals carrying these mutations. KRT17 mutations showed a distinct phenotype that included natal teeth, gingival lesions, and cysts, with one study reporting a novel de novo missense variant, c.307C > T, p.Arg103Cys. Mixed phenotypes were observed in patients carrying both KRT6A and KRT17 mutations, presenting with overlapping features of both traditional subtypes. The review notes that this pattern aligns with broader registry data, in which KRT6A variants correlated with earlier onset and higher oral symptom burden compared with KRT16 or KRT6B, supporting a shift from traditional PC-1 and PC-2 labels toward gene-based nomenclature.

Some of the review’s quantitative anchors come from larger cohort data it cites. Samuelov and colleagues analyzed 815 genetically confirmed pachyonychia congenita patients and found oral leukokeratosis in 58 percent overall, while the review itself reports a prevalence range of 50 to 75 percent across subtypes drawn from registry data. Among patients enrolled in the International Pachyonychia Congenita Research Registry, 16 percent reported hoarseness, occurring in both PC-1 and PC-2 subtypes. Laryngeal lesions typically present as whitish keratotic plaques or nodular growths on the laryngeal mucosa and may be entirely silent or progress to significant upper airway compromise; leukokeratosis extending to the larynx can cause hoarseness or, rarely, life-threatening respiratory obstruction in young children, often triggered by upper respiratory infections.

Diagnosis remains one of the most difficult aspects of caring for these patients. Oral leukokeratosis in pachyonychia congenita closely resembles leukoplakia, a potentially premalignant condition, and the review recounts a case in which leukokeratosis in a five-year-old patient was initially mistaken for leukoplakia, delaying diagnosis until nail changes appeared. The striated or reticular appearance of the lesions can mimic oral lichen planus, particularly on the buccal mucosa or tongue, and misdiagnosis as lichen planus in infants has contributed to diagnostic delays. White sponge nevus, which is typically painless and lacks the systemic features of the disorder such as nail dystrophy or plantar keratoderma, is another common source of confusion, as is candidiasis; in infants, oral lesions may be mistaken for a Candida albicans infection and can interfere with sucking during feeding.

Two diagnostic tools help resolve this uncertainty. Biopsy of oral lesions is a key instrument for differentiating the condition from its mimics, and while the histological features may distinguish it from other oral lesions, they are not pathognomonic; a biopsy alone cannot confirm the diagnosis and must be correlated with clinical features. Genetic testing via multigene panels or targeted sequencing of the five keratin genes is described as the gold standard for confirmation, though variants of uncertain significance can complicate interpretation and require clinical correlation, and comprehensive genomic testing such as exome or genome sequencing may be considered in those cases. In the included studies, diagnosis was achieved primarily through genetic testing in five studies and clinical assessment in six, and oral findings were instrumental in prompting a correct diagnosis in several reports even as they led to delays when misattributed.

Treatment remains supportive and symptom-focused, as no curative therapies are currently available. For oral leukokeratosis, symptomatic relief includes gentle oral hygiene with a soft toothbrush to reduce plaque thickness while avoiding vigorous scrubbing that could traumatize the mucosa, and topical corticosteroids such as 0.01 percent dexamethasone mouthwash three times daily have been reported to alleviate pain and achieve regression. Oral antibiotics may reduce leukokeratosis in some individuals, likely through anti-inflammatory rather than antibacterial effects, and systemic retinoids such as acitretin may control hyperkeratosis but may also increase discomfort. In severe cases, surgical excision using high-power lasers removes lesions, and biannual monitoring with annual biopsies is recommended for smokers due to malignancy risk, though no malignant transformations have been reported in the condition. For laryngeal involvement, conservative measures include steroids and antibiotics for acute exacerbations, surgical debulking with KTP or CO2 laser removes keratin plaques with serial laryngoscopies, and tracheostomy is needed to secure the airway in severe cases.

The review’s authors are candid about its limitations. Sixty percent of the included studies were case reports, sample sizes ranged from single cases to 254 patients, and the predominance of small studies precluded meta-analysis while potentially biasing the synthesis toward severe phenotypes. Heterogeneity in study design, outcome reporting, and genetic characterization limited quantitative synthesis, publication bias may have overrepresented severe or atypical presentations, and restriction to English-language publications may have excluded relevant data. As a narrative review, the work aims to synthesize descriptive patterns rather than establish prevalence estimates, causal relationships, or treatment efficacy. Even so, the authors argue that the oral findings highlight the significance of awareness in dentistry, where early recognition can change outcomes, and they call for future research on oral-specific care and quality of life to be prospective and multicenter, using patient registries to foster precision medicine. Emerging therapies, including mutation-specific small interfering RNA, topical sirolimus, and anti-TNF biologics, show promise in reducing hyperkeratosis and pain and may eventually enable genotype-guided treatment, but for now the message to clinicians is that the mouth may hold the first and most telling clues to this rare disorder.

Subject of Research: Oral manifestations, genotype–phenotype correlations, and management of pachyonychia congenita

Article Title: A narrative review of oral manifestations, genotype–phenotype links, and management in pachyonychia congenita

Article References: Appiah, E. K., Nimako-Boateng, J., & Duker, J. E. (2026). A narrative review of oral manifestations, genotype–phenotype links, and management in pachyonychia congenita. Discover Medicine, 3(1), Article 149. https://doi.org/10.1007/s44337-026-00651-3

Image Credits: AI Generated

DOI: 10.1007/s44337-026-00651-3

Keywords: pachyonychia congenita, oral leukokeratosis, KRT6A, KRT17, natal teeth, genodermatosis, keratin mutations, diagnostic delay, laryngeal involvement, genotype–phenotype correlation, narrative review, multidisciplinary care