Multiple hamartoma syndrome (MHS) also known as Cowden syndrome is a hereditary autosomal dominant genetic disorder caused by mutations in the PTEN gene on chromosome 10q23.3. MHS typically manifests with hamartomatous cutaneous and mucosal changes. Furthermore, MHS-associated carcinomas often develop in the thyroid gland as well as in female breasts.
MHS patients must undergo long-term clinical and radiological monitoring and consult medical professionals to screen for neoplasm growth, particularly in breasts, testes, and thyroid annually or biannually.
Genetic counseling in families with MHS occurrence is advisable due to the autosomal dominant mode of inheritance. Prevalence is estimated to be 1/200,000 with a penetrance of 90% by the age of 20 years.
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 . MHS was first described in 1963 by Lloyd and Dennis, who termed the disorder "Cowden disease" after the family of its first reported occurrence .
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 . 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 .
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 . PTEN mutations are associated with an approximate 6% lifetime risk of developing melanoma .
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  . MHS can also manifest with macrocephaly, autistic features, mental retardation, and vascular anomalies .
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 . 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 .
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 .