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].

• Cutaneous Manifestation

  […] lymphomas and cutaneous signs of systemic lymphomas -- Dysproteinemias, plasma cell disorders, and amyloidosis -- Cutaneous manifestations of the histiocytoses -- Vascular neoplasms and malformations -- Diabetes and the skin -- Thyroid and the skin - [worldcat.org]

  Clinical, imaging, and pathologic features of conditions with combined esophageal and cutaneous manifestations. RadioGraphics 2019;39(5):1411–1434. Link, Google Scholar 2. Katabathina VS, Menias CO, Khanna L, et al. [pubs.rsna.org]

  Journal of the American Academy of Dermatology. 2013; 68(2): 189.e1-189.e21 [Pubmed] 7 Cutaneous manifestations of gastrointestinal disease Kejal R. Shah,C. [ijdr.in]

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

• Skin Rash

  Abstract We report here, we believe for the first time, the primary antiphospholipid syndrome, presenting with fever, meningismus and skin rash. Serology was positive for antiphospholipid antibodies but negative for antinuclear factor. [pmj.bmj.com]

  No skin rash was noted. [academic.oup.com]

  In spite of the therapy, the skin rash was spreading, therefore hospitalization was recommended. [healthdocbox.com]

• Suggestibility

  Interestingly, suggestions arise that mast cells may lead to better prognosis though some would disagree(8,9). [abs.amegroups.com]

  Fine mapping suggested that one deletion encompassed the whole gene and the other two included exon 1 and encompassed exons 1-5 of PTEN, respectively. [ncbi.nlm.nih.gov]

  Further, it suggests that the presence of endometrial cancer may increase the likelihood of finding germline PTEN mutation, even in CS-like families. [doi.org]

• 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]

• 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].

• Polyps

  Polyps can occur in the esophagus, stomach, small or large intestine, or anus and are most common in the colon. [emedicine.medscape.com]

  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]

  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]

  Gastrointestinal polyps are very common in adults with PHTS. Among patients who had undergone endoscopy, 93% were found to have polyps. [snpedia.com]

  Advertisement Stomach Polyps Cowden syndrome Topic Completed: 1 August 2012 Revised: 26 April 2019 Copyright : 2003-2019, PathologyOutlines.com, Inc. [pathologyoutlines.com]

In addition, rapamycin is effective against treatment different biomarkers of the targeted tissues, which includes fast revert the mucocutaneous papillomatous lesions present in the face and limbs, acral keratosis, and abnormalities of nipples, attendant [syndromespedia.com]

Treatment with systemic retinoids has shown to control the skin lesions associated with Cowden syndrome. Topical treatment has shown to be of minimal benefit. [aocd.org]

Management and treatment Management and treatment are multidisciplinary and based on genotype. Once a PTEN germline mutation is identified, surveillance guidelines should be followed. [orpha.net]

Patient's satisfied smile confirmed the success of our treatment [Figure 9]. She was not interested in the treatment of the thyroid and breast cyst. [jhrr.org]

Antithyroid drugs (ATDs) are generally considered the first-line treatment. [hindawi.com]

Prognosis The pinpointing of the diagnosis (especially by gene) and instituting organ-specific surveillance at the right time results in a good prognosis. When advanced cancers occur before diagnosis is made, a poor outcome is common. [orpha.net]

Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer. [lecturio.com]

Etiology It is now believed that 25% of CS and CS-like cases are caused by germline mutations in PTEN (10q23), which encodes a dual-specificity phosphatase. [orpha.net]

Summary Epidemiology The prevalence of Cowden syndrome is unknown but is estimated at 1/200,000. Clinical description Disease manifestations usually occur between the second and third decades of life but can appear at any age. [orpha.net]

E Epidemiology of Cowden syndrome‎ (2 F) Media in category "Cowden syndrome" The following 4 files are in this category, out of 4 total. [commons.wikimedia.org]

Taken together, these molecular based observations, together with previous clinical epidemiological studies, 2 were felt sufficient to revise the Consortium criteria for the diagnosis of CS to include endometrial carcinoma (table 2 ). [doi.org]

The discussion covers the phenotype spectrum, epidemiology, mode of inheritance, pathogenesis, and clinical profile of each condition, all of which is accompanied by a wealth of illustrations. [books.google.com]

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test Germline mutations in the PTEN gene are associated with a rare collection of clinical syndromes referred to as PTEN hamartoma [mayomedicallaboratories.com]

This may raise the possibility of new pathophysiology and clinical syndrome as target of PTEN pathway. Conflict of interest: None declared. Reference 1 Epidemiology and etiopathogenesis of pituitary adenomas. [academic.oup.com]

Breast: 8 cases of hamartoma per 20,000 mammograms Kidney: renal hamartoma (angiomyolipoma) found in 40–80% of patients with tuberous sclerosis Etiology and Pathophysiology Functional disorder will depend on tissue of origin. [unboundmedicine.com]

Lhermitte-Duclos disease, so named for French neurologists Jacques Lhermitte and P Duclos after their initial description of the entity in 1920, has undergone a spectrum of growth in pathophysiologic understanding recently and is now considered to be [appliedradiology.com]

[…] lhermitte-duclos disease) 1>Enlarged circumscribed cerebellar folia 2>internal granular layer is focally indistinct and is occupied by large ganglion cells 3>myelinated tracks in outer molecular layer 4>underlying white matter is atrophic and gliotic Pathophysiology [en.wikipedia.org]

Starting at age 40: All adults with CS: a colonoscopy every 2 years, and a kidney ultrasound scan or MRI every 2 years Preventive surgery: Women with CS: The preventive removal of the breasts before cancer develops through a surgery called a prophylactic [cancer.net]

Mutations in the PTEN gene prevent the protein from regulating cell proliferation effectively, leading to uncontrolled cell division and the formation of hamartomas and cancerous tumors. [encyclopedia.pub]

Timely diagnosis of affected patients is key, as early recognition allows for high-risk screening and other preventative measures prior to a patient enduring multiple cancer diagnoses. [ncbi.nlm.nih.gov]

Some women at increased risk for breast cancer consider prophylactic mastectomy (removal of the breasts to prevent cancer). Thyroid cancer screening. [my.clevelandclinic.org]

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.