Cobblestone appearance of oral mucosa: A diagnostic conundrum

Introduction

Oral mucosal cobblestone appearance is described in conditions such as Darier disease, Cowden’s syndrome, lipoid proteinosis, granulomatous cheilitis, mucosal neuroma, Crohn’s disease, and mucous membrane plasmacytosis.^1,2 Diffuse oral mucosal melanosis and lentigenosis are described due to Peutz–Jeghers syndrome, Laugier–Hunziker–Baran syndrome, Cowden syndrome, Addison’s disease, smoking, and hemochromatosis. ³ The estimated incidence is about 1 in 200,000 individuals in the general population, making the disease a rare entity. ⁴ We hereby, report this rare genodermatosis which presents as oral papillomatosis, thereby aid in early recognition and screening for thyroid malignancy and gastrointestinal polyposis in Cowden syndrome.

Case

A 15-year-old boy presented with pink to red proliferative plaque over both upper and lower lips. The child was born to a nonconsanguineous couple, at full term, with birth weight of 2.5 kg, and uneventful antenatal and perinatal history. Initially, parents started to note these tiny discrete lesions in the lower lip at birth, which gradually progressed in number and size to their current size over the next 15 years. The rest of the family members were unaffected. Examination revealed a cobblestone appearance of gingiva, buccal and palatal mucosa, and the pebbly surface of tongue with papilliferous projections in both upper and lower labial mucosa in a background of slate grey to grey-black pigmentation. The child also had multiple lipomatosis over bilateral forearms and thyroid swelling appreciated on deglutination. Father had thyroid swelling with multiple epidermoid cysts (Supplemental Figures 1(a)–(d) and 2(a)–(d)). Genetic analysis could not be performed due to financial constraints. Histopathology revealed papillomatosis, acanthosis, and elongation of rete ridges with lamina propria showing congested vessels, and minor salivary glands (Supplemental Figure 3(a) and (b)). A final diagnosis of Cowden syndrome was considered with phenotypic correlation and histopathology correlation.

Discussion

Cowden syndrome (OMIM 158350) is a rare autosomal dominant hamarto-neoplastic syndrome of endodermal, mesodermal, and ectodermal origin. It is due to germline mutations involving phosphatase and tensin homolog tumor suppressor gene, with slight female preponderance. ¹ It is clinically characterized by mucocutaneous papillomatosis, fibromatosis, trichilemmoma, and acral keratosis (pathognomonic criteria for diagnosis). Major criteria for diagnosis include breast cancer, thyroid cancer (follicular thyroid carcinoma), macrocephaly, and hamartomatous outgrowths of the cerebellum (Lhermitte–Duclos disease). Minor features include thyroid lesions (such as adenoma or goiter), mental retardation (IQ <75), hamartomatous intestinal polyps, fibrocystic disease of the breast, lipomas, fibromas, and genitourinary tumors or malformations. ⁴

Most of the characteristic skin features are seen in the second and fourth decades. But in our case, features are seen since birth, thereby appearance of lesions depends on inheritance and expressivity. The dermatological features described in the literature are periorificial facial papules (86%), mucosal papillomatosis (80%), acral verrucous hyperkeratosis (26%), and palmoplantar keratosis (20%). Other less frequent findings described are hemangioma, café au lait macule, vitiligo, xanthomas, neuroma, lentigines, and lipomatosis (as in our case). ³ Nearly all internal malignancies have been linked with Cowden syndrome. Gastrointestinal polyposis (40%–60%), fibrocystic disease of breast (53%), and breast carcinoma (20%) are more frequent, and thyroid disorders such as multinodular goiter, thyroiditis, thyroid dysfunction, and thyroid cancer (7%) are also associated.^3,4 Once the diagnosis of Cowden syndrome is suspected, patient should undergo neurodevelopmental evaluation, breast examination (above 30 years), colonoscopy (above 30–35 years), and renal magnetic resonance imaging (above 40 years). ⁵

The cobblestoning of the oral mucosa seen in Cowden syndrome warrants careful differentiation from several other conditions with overlapping features. Darier disease may present with oral cobblestoning along with keratotic papules, nail changes, and seborrheic distribution papules. Lipoid proteinosis is characterized by beaded eyelid papules, hoarseness, a thickened tongue, and similar mucosal changes. Granulomatous cheilitis in the spectrum of Melkersson Rosenthal syndrome can show lip swelling, cobblestoning, and a fissured tongue. Mucosal neuromas in MEN2B syndrome manifest as mucosal nodules in association with marfanoid habitus and a high risk of medullary thyroid carcinoma. Likewise, Crohn’s disease can mimic the presentation with oral cobblestoning and linear ulcers alongside gastrointestinal involvement. Mucous membrane plasmacytosis may also resemble Cowden syndrome, presenting with diffuse red plaques and cobblestone mucosal changes in a chronic course. Careful clinicopathological correlation and recognition of associated systemic features are therefore essential in establishing the correct diagnosis.^1,2

Conclusion

In conclusion, the clinical presentation of Cowden syndrome can be variable, and the distinctive mucosal cobblestone pattern enabled us to approach this case effectively. A limitation of this report is the absence of confirmatory genetic testing due to financial constraints, which restricted molecular correlation. Future research should focus on expanding genotype–phenotype correlations, especially in diverse populations, and refining surveillance protocols tailored to early-onset cases. Physicians should be aware of the diverse presentations of this rare genetic syndrome. Early recognition not only facilitates timely screening for associated malignancies but also highlights the role of genetic counseling in identifying at-risk family members, guiding surveillance protocols, and providing reproductive advice. In addition, a multidisciplinary follow-up involving dermatologists, endocrinologists, gastroenterologists, oncologists, and geneticists is crucial to ensure comprehensive monitoring, early detection of internal malignancies, and holistic long-term care.

Supplemental Material

Supplemental Material