Multiple hamartoma syndrome (MHS) is a hereditary disorder with autosomal dominant mode of inheritance. Mutations in the PTEN gene on the long arm of chromosome 10 are the sole culprit for this disorder [1]. MHS was first described in 1963 by Lloyd and Dennis, who termed the disorder "Cowden disease" after the family of its first reported occurrence [2].

Together with Proteus syndrome, Proteus-like syndrome, and Bannayan-Riley-Ruvulcaba syndrome, MHS can be categorized into a set of syndromes which are all associated with pathological modifications of the PTEN gene [3]. PTEN encodes a phosphatase which dephosphorylates the 3 position of phosphoinositide, thus affecting a cell signaling pathway and eventually disrupting the unwanted cell proliferation. Hence, PTEN mutations inhibiting this suppression favour tumor growth [4].

Cutaneous neoplasms are most often found in the form of facial trichilemmomas and periorificial flesh-colored lichenoid or verrucoid papules with a size of up to 5 mm. Moreover, smooth oral whitish papules on palate, gingiva, and lips affect up to 80% of MHS patients. 60% of patients also present with acral keratoses on the dorsal hands and feet. Sclerotic fibromas are another key finding in MHS patients [5]. PTEN mutations are associated with an approximate 6% lifetime risk of developing melanoma [6].

MHS is associated with a notably increased risk of malignant thyroid and breast neoplasms. Additionally, malignancies in the colon, uterus, bladder, lung, and cervix have been found in MHS patients [6] [7]. MHS can also manifest with macrocephaly, autistic features, mental retardation, and vascular anomalies [8].

• Pseudotumor

  […] important unreported findings that include multiple cutaneous trichilemmomas, cafe-au-lait spots, cutaneous squamous cell carcinoma, pathologic fracture, craniomegaly, probable malignant lung tumor, retinal glioma, drusens of the optic disk and retina, pseudotumor [ncbi.nlm.nih.gov]

  […] of the soft palate and uvula, scrotal tongue, periodontitis and extensive dental cavities.9,13 Regarding eye alterations, lenticular opacity, hypertelorism, congenital vascular abnormality of the bottom of the eye, glaucoma, angioid streaks, cerebral pseudotumor [scielo.br]

  The fifth chapter presents the so-called infiltrative dermatoses: pseudotumor reactions resulting from the process of endocytosis following lipoprotein extravasation, deposition of acid mucopolysaccharides in dermopathy, in endocrine and internal organ [healthdocbox.com]

• Euthyroid

  She developed a goitre at the age of 16 years, but was euthyroid and ultrasonography showed a multinodular goitre. Hypertrichosis was noted when she was 17 years old. [hkmj.org]

• Plethora

  Diagnostic criteria for CS were initially proposed by Salem and Steck in 1983. [3] International Cowden Consortium (1995) recommended a revised classification to ascertain CS families, to which were added endometrial and renal cell carcinoma in 2000. [8] The plethora [e-ijd.org]

• Tracheal Deviation

  Left thyroidectomy noted with multinodular enlargement of the right thyroid lobe with marked tracheal deviation to the left Fig. 4 Axial contrast enhanced CT of the Chest. [doi.org]

• Cutaneous Manifestation

  european journal of dermatology. 2013; 23(5): 581-591 8 Cutaneous manifestations of gastrointestinal disease Kejal R. [ijdr.in]

  manifestations of the histiocytoses -- Vascular neoplasms and malformations -- Diabetes and the skin -- Thyroid and the skin -- Cutaneous manifestations of lipid disorders -- Adrenal, androgen-related, and pituitary disorders -- Porphyrias -- Cutaneous [worldcat.org]

  Most patients present to the physician because of cutaneous manifestations. [dermaamin.com]

• Neck Swelling

  A visible right neck swelling was also noted and further questioning revealed symptoms of dysphagia as well as a history of prior left thyroidectomy for a multinodular goiter. [doi.org]

• Neck Mass

  Young, PTEN hamartoma tumor syndrome presenting as a neck mass in a pediatric patient, International Journal of Pediatric Otorhinolaryngology Extra, 19, (1), (2018). Paul J. Newey and Rajesh V. [doi.org]

• Secondary Amenorrhea

  Case presentation A 29-year-old woman presented with secondary amenorrhea and focal seizure. Examination revealed a well-developed adult woman with macrocephaly. Visual field as well as other neurologic exams was unremarkable. [academic.oup.com]

• Cerebellar Ataxia

  Patients have macrocephaly, slowly progressive cerebellar ataxia (which usually appears in adulthood), and signs of increased intracranial pressure. [23] Cases of Lhermitte-Duclos disease occurring without any other evidence of Cowden disease (multiple [emedicine.medscape.com]

  Lhermitte-Duclos disease: part of Cowden syndrome; hamartoma of cerebellum, macrocephaly, progressive cerebellar ataxia, signs of increased ICP Joseph Merrick “The Elephant Man” once thought to have neurofibromatosis-1 (NF1), reclassified as having Proteus [unboundmedicine.com]

  Patients have macrocephaly, slowly progressive cerebellar ataxia (which usually appears in adulthood), and signs of increased intracranial pressure. [dermaamin.com]

The diagnosis of MHS requires a detailed analysis of the family history to corroborate a suspicion for this inherited disorder. Clinical signs of MHS are characteristic benign cutaneous changes in the periorificial region and oral tumors.

Key laboratory tests include a complete blood count (CBC) which, if anemia is present, may hint towards gastrointestinal hemorrhage as a consequence of colonic neoplasms, which will then have to be verified in an endoscopic procedure. Furthermore, thyroid function should be checked upon the first presentation and monitored annually in the case of an MHS diagnosis. Thyroid ultrasonography is recommended with the same interval [9]. Urinalysis may yield proteinuria or hematuria, which can be a consequence of renal neoplasms. A skin biopsy will be necessary to assess the nature of cutaneous changes. Regular ultrasonography of the testes, as well as mammography for both genders, are imperative [10].

Irrefutable evidence for an MHS diagnosis is provided by a positive test for PTEN mutations. Multiple ligation-dependent probe amplification (MLPA) is the method of choice [3].

• Multiple Colonic Polyps

  A brother-sister kindred and two unrelated patients had multiple colonic polyps 0.1-0.4 cm in diameter. [ncbi.nlm.nih.gov]

• Mediastinal Mass

  mass, and multiple small papillomatous lesions of the esophagus, stomach, and duodenum. [ncbi.nlm.nih.gov]

• Polyps

  Colorectal polyps are described in five patients with Cowden's disease. A brother-sister kindred and two unrelated patients had multiple colonic polyps 0.1-0.4 cm in diameter. [ncbi.nlm.nih.gov]

  The quality of bowel preparation and imaging could affect polyp detection by CE; nevertheless, we think that there were more jejunal polyps than ileal polyps in our patients. [hindawi.com]

  […] with thyroid carcinomas Frequent thyroid carcinomas PTEN mutations not seen PTEN mutations in 80% GI polyps exophytic, cystic, eroded GI polyps sessile, few cysts, not eroded Ganglion cells not seen in GI polyps Ganglion cells may be present in GI polyps [surgpathcriteria.stanford.edu]

  hyperplastic polyp, ganglioneuroma, adenoma and inflammatory polyp Possible association with gastric cancer (Am J Gastroenterol 2005;100:476) Colon: multiple polyps, usually hamartomas (resemble juvenile polyps); also ganglioneuroma, adenoma, inflammatory [pathologyoutlines.com]

1. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997; 16(1):64-67.
2. Lloyd KM II, Dennis M. Cowden's disease. A possible new symptoms complex with multiple system involvement. Ann Intern Med. 1963; 58:136-142.
3. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009; 11(10):687-694.
4. Bennett KL, Mester J, Eng C. Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA. 2010; 304(24):2724-2731.
5. Requena L, Gutierrez J, Sanchez Yus E. Multiple sclerotic fibromas of the skin. A cutaneous marker of Cowden's disease. J Cutan Pathol. 1992; 19(4):346-351.
6. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012; 18(2):400-407.
7. Diggelmann HR, Van Daele DJ, O'Dorisio TM, Hoffman HT. Insular thyroid carcinoma in a patient with Cowden syndrome. Laryngoscope. 2010; 120(3):454-457.
8. Eng C. PTEN Hamartoma Tumor Syndrome (PHTS). In: GeneReviews. Seattle, WA: University of Washington, Seattle; 2016. http://www.ncbi.nlm.nih.gov/books/NBK1488 Accessed October 28th, 2017.
9. Milas M, Mester J, Metzger R, Shin J, Mitchell J, Berber E. Should patients with Cowden syndrome undergo prophylactic thyroidectomy?. Surgery. 2012; 152(6):1201-1210.
10. Woodhouse J, Ferguson MM. Multiple hyperechoic testicular lesions are a common finding on ultrasound in Cowden disease and represent lipomatosis of the testis. Br J Radiol. 2006;79(946):801-803.