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Cowden's disease; multiple hamartoma syndrome including Lhermitte-Duclos disease (cerebelloparenchymal disorder)

Rare hereditary neoplastic syndrome Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma & related symptoms) is seen in a subset of Cowden's disease. Epidemiology: 1) fewer than 100 cases reported 2) age of onset 4-75 years, median age 40 years 3) males > females 4) mostly in whites Pathology: 1) multiple harmatomatous neoplasms of ectodermal, mesodermal & endodermal origin in many organ systems including the breast (70-85%), thyroid (40-60%), skin, CNS (40%), kidney (34%), endometreium (28%) gastrointestinal tract 2) trichilemmomas (tan facial papules) & mucocutaneous papillomatosis (cobblestoning) & acral ketatoses are hallmarks of Cowden's disease (99%) 3) trichilemmomas show differentiation towards the outer root sheath cells of the hair follicles 4) multiple biopsies may be required to obtain characteristic histopathology 5) oral lesions are fibromas 6) dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease variant) 7) macrocephaly & intellectual disability [7] Genetics: - autosomal dominant - associated with defects in PTEN & BMPR1A Clinical manifestations: 1) skin lesions* a) trichilemmomas 1] portend the onset of breast & thyroid cancers 2] skin-colored pink or brown papules with the appearance of flat warts 3] distribution: central areas of the face, perioral areas, lips near the angles of the mouth & ears 4] lesions may be extensive & disfiguring b) translucent punctate keratosis of palms & soles c) hyperkeratotic, flat-topped papules on the dorsal aspect of the hands & forearms d) lipomas & angiomas (rare) 2) mucous membranes* a) papules of the gingival, labial & palatal surfaces - whiter than surrounding mucosa giving a "cobblestone" appearance b) papillomas of the buccal mucosa & tongue c) oral fibromas d) squamous cell carcinoma of the tongue may occur e) basal cell carcinoma may occur in the anal area 3) breasts a) fibrocystic disease b) fibroadenoma c) adenocarcinoma (20%) d) gynecomastia in males 4) thyroid a) goiter b) adenomas c) thyroglossal duct cysts d) follicular adenocarcinoma (8%) 5) GI tract a) harmatomatous polyps throughout the intestine, but especially in the colon b) adenocarcinoma (rare) 6) female genital tract a) ovarian cysts b) menstrual irregularities c) uterine carcinoma (rare) 7) male genital tract - carcinoma of the prostate (rare) 8) musculoskeletal system a) craniomegaly b) kyphoscoliosis c) high-arched palate 9) CNS involvement a) mental retardation b) seizures c) neuromas d) ganglioneuromas e) meningiomas of the ear canal f) cerebellar signs * images [5,6] Laboratory: 1) thyroid scan 2) skin biopsy 3) PTEN gene mutation Radiology: - annual thyroid ultrasonography beginning at age 18 years [7] - colonoscopy beginning at age 35 years - kidney ultrasonography beginning at age 40 years - annual mammogram beginning at ages 30-35 years - annual endometrial cancer ultrasonography beginning at ages 30-35 years [7] Differential diagnosis: 1) multiple syringomas 2) multiple angiofibromas 3) tuberous sclerosis 4) multiple trichilemmomas 5) verruca plana (flat warts) 6) Muir-Torre syndrome 7) lipoid proteinosis 8) multiple endocrine neoplasia (MEN) IIb Complications: 1) adenocarcinoma of the breast (20%) 2) follicular adenocarcinoma, follicular thyroid carcinoma (8%) 3) gastrointestinal polyps [4] Management: 1) follow closely for evidence of breast or thyroid cancer 2) annual skin checks 3) genetic counseling 4) prognosis - tumors continue to develop throughout life

Related

chromosome 10q23 deletion syndrome mutated in multiple advanced cancers 1; protein tyrosine phosphatase PTEN; phosphatase & tensin homolog deleted on chromosome ten; phosphatase & tensin homolog; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase & dual-specificity protein phosphatase PTEN (PTEN, MMAC1, TEP1)

General

hamartomatous polyposis syndrome; familial hamartomatous polyposis skin disease (dermatologic disorder, dermatopathy, dermatosis)

Properties

ASSOCIATED-NEOPLASM[S]: hamartoma polyp :SITE intestine trichilemmoma dysplastic cerebellar gangliocytoma meningioma breast cancer Merkel cell carcinoma renal cell carcinoma

Database Correlations

OMIM 158350

References

  1. Liaw D et al, Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May;16(1):64-7. PMID: 9140396
  2. Color Atlas and Synopsis of Clinical Dermatology, Common and Serious Diseases, 3rd ed, Fitzpatrick et al, McGraw Hill, NY, 1997, pg 508-511
  3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 171
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 17, 18. American College of Physicians, Philadelphia 1998, 2015, 2018.
  5. Fiala KH, James WD (images) Medscape: Cowden Disease (Multiple Hamartoma Syndrome) http://emedicine.medscape.com/article/1093383-overview
  6. DermNet NZ. Cowden disease (images) http://www.dermnetnz.org/systemic/cowden.html
  7. Bhanot A, Harrell K, Levin J. Treatment of Trichilemmomas With Topical Sirolimus. JAMA Dermatol. Published online January 4, 2023 PMID: 36598777 https://jamanetwork.com/journals/jamadermatology/fullarticle/2800121