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].

• Short Finger

  fingers or toes 0001156 Cataract Clouding of the lens of the eye Cloudy lens [ more ] 0000518 Cellular immunodeficiency 0005374 Endometrial carcinoma 0012114 Enlarged polycystic ovaries Enlarged ovaries with cysts 0008675 Failure to thrive Faltering [rarediseases.info.nih.gov]

• 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]

• 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]

  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]

• Subcutaneous Nodule

  nodule Firm lump under the skin Growth of abnormal tissue under the skin [ more ] 0001482 5%-29% of people have these symptoms Abnormal cerebellum morphology Abnormality of the cerebellum Cerebellar abnormalities Cerebellar abnormality Cerebellar anomaly [rarediseases.info.nih.gov]

• 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

  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]

  A brother-sister kindred and two unrelated patients had multiple colonic polyps 0.1-0.4 cm in diameter. [insights.ovid.com]

• Cardiomegaly on Chest X-ray

  M mitrale (in lead aVF) was seen in electrocardiogram (ECG) and cardiomegaly in chest X-ray. Ultrasonography of thyroid and fine needle aspiration cytology (FNAC) revealed multinodular goiter. [clinicaldermatology.eu]

• 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]

Multiple biopsies of the skin and lower intestine, and possibly the tumor in patients with cancer, before starting treatment, at 2 weeks of treatment and at 8 weeks of treatment. [clinicaltrials.gov]

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]

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]

Treatment of the cutaneous features includes: Oral retinoids, usually acitretin, which may temporarily control some of the cutaneous lesions. Lesions often reappear when treatment is stopped. [dermnetnz.org]

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]

SDHB-D, AKT1, PIK3CA and KLLN ) have not been formally studied in BRRS, it is not clear if they are also etiologic for non-PTEN-related BRRS. [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]

Epidemiology [ edit ] Lhermitte–Duclos disease is a rare entity; approximately 222 cases of LDD have been reported in medical literature. [3] Symptoms of the disease most commonly manifest in the third and fourth decades of life, although it may onset [en.wikipedia.org]

Summary Epidemiology CS has been described in many ancestral groups. The prevalence is unknown but is estimated at 1/200,000. [orpha.net]

[…] 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]

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]

Contenuti: Molecular Tools in Cancer Research -- Intracellular Signaling -- The Cellular Microenvironment and Metastases -- Control of the Cell Cycle -- Pathophysiology of Cancer Cell Death -- Cancer Immunology -- Stem Cells, Cell Differentiation, and [worldcat.org]

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]

Preventive surgery: Women with CS: The preventive removal of the breasts before cancer develops through a surgery called a prophylactic mastectomy may be considered. [cancer.net]

Hematopoietic Stem Cell Transplantation -- Gene Therapy in Oncology -- Therapeutic Antibodies and Immunologic Conjugates -- Complementary and Alternative Medicine -- Disorders of Blood Cell Production in Clinical Oncology -- Diagnosis, Treatment, and Prevention [worldcat.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.