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Multiple Hamartoma Syndrome

LDD

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.


Presentation

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].

Hunting
  • Hunt, Rebecca S. Nagy, Wendy C. McKinnon, Nancie M. Petrucelli, Robin L. Bennett and Angela M.[doi.org]
Pediatric Disorder
  • disorder characterized by macrocephaly, developmental retardation and penile pigmented macules Among the many abnormalities, the following are of most relevance to surgical pathologists: Subcutaneous lipomas and angiolipomas Lymphangiomyomas and hemangiomas[surgpathcriteria.stanford.edu]
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]
Palpitations
  • There was history of difficulty in swallowing, easy fatigability, exertional dypnea, palpitations, tremors and occasional giddiness on walking.[clinicaldermatology.eu]
  • She did not report any shortness of breath, palpitations or significant weight loss. A left cheek swelling was palpated, which was pulsatile in nature. Our patient also had a thoracolumbar scoliosis and complained of symptoms of sciatica.[doi.org]
Long Arm
  • 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.[symptoma.com]
  • Eighty percent of patients have a mutation in the tumor suppressor gene phosphatase and tensin homolog, which is located on long arm of chromosome 10q22-23.[2] MHS has not been discussed in Indian literature till date.[ncbi.nlm.nih.gov]
Cutaneous Manifestation
  • . european journal of dermatology. 2013; 23(5): 581-591 [Pubmed] 6 Cutaneous manifestations of gastrointestinal disease: Part i Shah, K.R. and Boland, C.R. and Patel, M. and Thrash, B. and Menter, A.[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]
Breast Mass
  • There was an isolated case of bladder carcinoma, and the one woman studied had breast masses.[ncbi.nlm.nih.gov]
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]
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]
  • Patients have macrocephaly, slowly progressive cerebellar ataxia (which usually appears in adulthood), and signs of increased intracranial pressure.[dermaamin.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]
Sciatica
  • Our patient also had a thoracolumbar scoliosis and complained of symptoms of sciatica. Unfortunately, as she was estranged from her family, her family medical history and genetic testing of family members could not be obtained.[doi.org]

Workup

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
  • 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]
  • […] 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]
  • EGD revealed esophageal multiple glycogenic acanthosis and duodenal polyps, but no significant lesions were found in the stomach, unlike her mother. A colonoscopy revealed small hamartomatous polyps in the rectum.[hindawi.com]
Hepatocellular Carcinoma
  • Chemistry panels: These should include a calcium level to screen for parathyroid disease and liver function tests to detect possible hepatocellular carcinoma.[dermaamin.com]
  • These cancers included three cases of lung adenocarcinoma and solitary cases of carcinoid, testicular seminoma, testicular cancer, trichilemmomal carcinoma, prostate adenocarcinoma, hepatocellular carcinoma, melanoma, transitional cell carcinoma of the[ncbi.nlm.nih.gov]
  • Further reading Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway Xiao Fu, Mengjie Liu, Shengyang Qu, Jiequn Ma, Yamin Zhang, Tingting Shi, Hongqing Wen, Yujuan Yang, Shuhong Wang, Jing Wang, Kejun[nature.com]

Treatment

  • 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]
  • The clinical manifestations, surgical treatment and postoperative results of three patients with gangliocytomas of the cerebellum (Lhermitte-Duclos disease) are presented.[ncbi.nlm.nih.gov]
  • 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 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]

Prognosis

  • 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]
  • […] includes a brief description of each individual lesion or pathologic condition and the kind of pathologic process that it represents, followed by a discussion of its clinical and/or radiographic presentation, histopathologic features, and its treatment and prognosis[books.google.com]
  • […] spectroscopy elevated lactate 1,2 slightly reduced NAA (by about 10%) 1,2 reduced myo-inositol (by 30-80%) reduced choline (by 20-50%) reduced Cho/Cr ratio 2 PET/SPECT FDG-PET: shows increased uptake Tl- 201 SPECT: shows increased uptake Treatment and prognosis[radiopaedia.org]

Etiology

  • They are organised into groups, and further divided into clinical, etiological or histopathological sub-types.[orpha.net]
  • Additionally, this condition has also been described in association with other multisystemic disorders of known genetic etiologies [ 4 ].[academic.oup.com]

Epidemiology

  • 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]
Sex distribution
Age distribution

Pathophysiology

  • […] 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]
  • Kelly Passarello, Shiney Kurian and Valerie Villanueva, Endometrial Cancer: An Overview of Pathophysiology, Management, and Care, Seminars in Oncology Nursing, 10.1016/j.soncn.2019.02.002, (2019). Ruchi Tiwari, Achint K. Singh, Alexander S.[doi.org]
  • 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]
  • 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]
  • Pathophysiology Traditionally, Cowden disease (multiple hamartoma syndrome) is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1 ) on band 10q23.3.[emedicine.com]

Prevention

  • 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]
  • Furthermore, early and continuous screening is essential in the management of this disorder to prevent malignancies.[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]
  • Yurgelun, Genetic predisposition to colorectal cancer: Implications for treatment and prevention, Seminars in Oncology, 43, 5, (536), (2016). Nicholas R.[doi.org]

References

Article

  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.

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Last updated: 2019-07-11 20:22