PTEN Hamartoma Tumor Syndrome

Lamis Yehia, Charis Eng, Margaret P Adam, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Anne Amemiya, Lamis Yehia, Charis Eng, Margaret P Adam, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Anne Amemiya

Excerpt

Clinical characteristics: The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome.

  1. CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, kidney, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 35%. The lifetime risk for renal cell cancer (predominantly of papillary histology) is 34%. The risk for endometrial cancer may approach 28%.

  2. BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis.

  3. PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses.

  4. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

Diagnosis/testing: The diagnosis of PHTS is established in a proband by identification of a heterozygous germline PTEN pathogenic variant on molecular genetic testing.

Management: Treatment of manifestations: Treatment for the benign and malignant manifestations of PHTS is the same as for their sporadic counterparts. Topical agents (e.g., 5-fluorouracil), curettage, cryosurgery, or laser ablation may alleviate the mucocutaneous manifestations of CS but are rarely utilized; cutaneous lesions should be excised only if malignancy is suspected or symptoms (e.g., pain, deformity, increased scarring) are significant.

Surveillance: To detect tumors at the earliest, most treatable stages:

  1. Children (age <18 years). Yearly thyroid ultrasound from the time of diagnosis (earliest reported at age 7 years) and skin check with physical examination

  2. Adults. Yearly thyroid ultrasound and dermatologic evaluation

  3. Women beginning at age 30 years. Monthly breast self-examination; annual breast screening (at minimum mammogram; MRI may also be incorporated). Starting by age 35 years, consider transvaginal ultrasound or endometrial biopsy.

  4. Men and women. Colonoscopy beginning at age 35 years with frequency dependent on degree of polyposis identified or family history of early-onset colon cancer (before age 40); biennial (every 2 years) renal imaging (CT or MRI preferred) beginning at age 40 years

  5. Those with a family history of a particular cancer type at an early age. Consider initiating screening 5 to 10 years prior to the youngest age of diagnosis in the family.

Evaluation of relatives at risk: When a PTEN pathogenic variant has been identified in a proband, molecular genetic testing of asymptomatic at-risk relatives can identify those who have the family-specific pathogenic variant and warrant ongoing surveillance.

Genetic counseling: PHTS is inherited in an autosomal dominant manner. Because CS is likely underdiagnosed, the actual proportion of simplex cases (defined as individuals with no obvious family history) and familial cases (defined as ≥2 related affected individuals) cannot be determined. The majority of CS cases are simplex. Perhaps 10%-50% of individuals with CS have an affected parent. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing PHTS. Once a PTEN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible.

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References

Published Guidelines / Consensus Statements

    1. American Society of Clinical Oncology. Policy statement update: genetic and genomic testing for cancer susceptibility. Available . 2015. Accessed 2-24-22.
    1. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. Available . 2000. Accessed 2-24-22.
Literature Cited
    1. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM, Jr, Viljoen DL, Cohen MM., Jr Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999;84:389–95.
    1. Busch RM, Srivastava S, Hogue O, Frazier TW, Klaas P, Hardan A, Martinez-Agosto JA, Sahin M, Eng C, et al. Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Transl Psychiatry. 2019;9:253.
    1. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet. 2005;42:318–21.
    1. Caux F, Plauchu H, Chibon F, Faivre L, Fain O, Vabres P, Bonnet F, Selma ZB, Laroche L, Gérard M, Longy M. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLEMAN) syndrome is related to mosaic PTEN nulligosity. Eur J Hum Genet. 2007;15:767–73.
    1. Dahia PLM, FitzGerald MG, Zhang X, Marsh DJ, Zheng Z, Pietsch T, von Deimling A, Haluska FG, Haber DA, Eng C. A highly conserved processed PTEN pseudogene is located on chromosome band 9p21. Oncogene. 1998;16:2403–6.
    1. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37:828–30.
    1. Fackenthal JD, Marsh DJ, Richardson AL, Cummings SA, Eng C, Robinson BG, Olopade OI. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet. 2001;38:159–64.
    1. Frazier TW, Embacher R, Tilot AK, Koenig K, Mester JL, Eng C. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism spectrum disorder. Mol Psychiatry. 2015;20:1132–8.
    1. Goffin A, Hoefsloot LH, Bosgoed E, Swillen A, Fryns JP. PTEN mutation in a family with Cowden syndrome and autism. Am J Med Genet. 2001;105:521–4.
    1. Gorlin RJ, Cohen MM, Jr, Condon LM, Burke BA. Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet. 1992;44:307–14.
    1. Hansen-Kiss E, Beinkampen S, Adler B, Frazier T, Prior T, Erdman S, Eng C, Herman G. A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children. J Med Genet. 2017;54:471–8.
    1. Harach HR, Soubeyran I, Brown A, Bonneau D, Longy M. Thyroid pathologic findings in patients with Cowden disease. Ann Diagn Pathol. 1999;3:331–40.
    1. Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, Frost MH, Jenkins RB. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340:77–84.
    1. Heald B, Mester J, Rybicki L, Orloff MS, Burke CA, Eng C. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology. 2010;139:1927–33.
    1. Hildenbrand C, Burgdorf WH, Lautenschlager S. Cowden syndrome-diagnostic skin signs. Dermatology. 2001;202:362–6.
    1. Kim RH, Wang X, Evans AJ, Campbell SC, Nguyen JK, Farncombe KM, Eng C. Early-onset renal cell carcinoma in PTEN harmatoma tumour syndrome. NPJ Genom Med. 2020;5:40.
    1. Komiya T, Blumenthal GM, DeChowdhury R, Fioravanti S, Ballas MS, Morris J, Hornyak TJ, Wank S, Hewitt SM, Morrow B, Memmott RM, Rajan A, Dennis PA. A pilot study of sirolimus in subjects with Cowden syndrome or other syndromes characterized by germline mutations in PTEN. Oncologist. 2019;24:1510–e1265.
    1. Lee YR, Yehia L, Kishikawa T, Ni Y, Leach B, Zhang J, Panch N, Liu J, Wei W, Eng C, Pandolfi PP. WWP1 gain-of-function inactivation of PTEN in cancer predisposition. N Engl J Med. 2020;382:2103–16.
    1. Lindhurst MJ, Sapp JC, Teer JL, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG. A mosaic activating mutation in AKT1 associated with Proteus syndrome. N Engl J Med. 2011;365:611–9.
    1. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, Liaw D, Caron S, Duboué B, Lin AY, Richardson AL, Bonnetblanc JM, Bressieux JM, Cabarrot-Moreau A, Chompret A, Demange L, Eeles RA, Yahanda AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV, Huson S, Lacombe D, Eng C, LePrat F, Odent S, Toulouse C, Olopade OI, Sobol H, Tishler S, Woods CG, Robinson BG, Weber HC, Parsons R, Peacocke M, Longy M, Eng C. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507–15.
    1. McGarrity TJ, Wagner Baker MJ, Ruggiero FM, Thiboutot DM, Hampel H, Zhou XP, Eng C. GI polyposis and glycogenic acanthosis of the esophagus associated with PTEN mutation positive Cowden syndrome in the absence of cutaneous manifestations. Am J Gastroenterol. 2003;98:1429–34.
    1. Mester J, Eng C. Estimate of de novo mutation frequency in probands with PTEN hamartoma tumor syndrome. Genet Med. 2012;14:819–22.
    1. Mester JL, Tilot AK, Rybicki LA, Frazier TW, Eng C. Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model. Eur J Hum Genet. 2011;19:763–8.
    1. Mester JL, Zhou M, Prescott N, Eng C. Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology. 2012;79:1187.e1–7.
    1. Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, Weng LP, Eng C. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92:924–30.
    1. Nelen MR, Kremer H, Konings IB, Schoute F, van Essen AJ, Koch R, Woods CG, Fryns JP, Hamel B, Hoefsloot LH, Peeters EA, Padberg GW. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet. 1999;7:267–73.
    1. Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet. 1996;13:114–6.
    1. Ngeow J, Eng C. Germline PTEN mutation analysis for PTEN hamartoma tumor syndrome. Methods Mol Biol. 2016;1388:63–73.
    1. Ngeow J, Mester J, Rybicki LA, Ni Y, Milas M, Eng C. Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations. J Clin Endocrinol Metab. 2011;96:E2063–71.
    1. Ngeow J, Stanuch K, Mester JL, Barnholtz-Sloan J, Eng C. Second malignant neoplasms in Cowden syndrome patients with underlying germline PTEN mutations. J Clin Oncol. 2014;32:1818–24.
    1. Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008;83:261–8.
    1. Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL, Eng C. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. 2013;92:76–80.
    1. Papa A, Wan L, Bonora M, Salmena L, Song MS, Hobbs RM, Lunardi A, Webster K, Ng C, Newton RH, Knoblauch N, Guarnerio J, Ito K, Turka LA, Beck AH, Pinton P, Bronson RT, Wei W, Pandolfi PP. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell. 2014;157:595–610.
    1. Pritchard CC, Smith C, Marushchak T, Koehler K, Holmes H, Raskind W, Walsh T, Bennett RL. A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing. Genet Med. 2013;15:1004–7.
    1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
    1. Tan MH, Mester J, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18:400–7.
    1. Tan MH, Mester J, Peterson C, Yang Y, Chen JL, Rybicki LA, Milas K, Pederson H, Remzi B, Orloff MS, Eng C. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011;88:42–56.
    1. Yehia L, Eng C. 65 Years of the double helix: One gene, many endocrine and metabolic syndromes: PTEN-opathies and precision medicine. Endocr Relat Cancer. 2018;25:T121–T140.
    1. Yehia L, Eng C. PTEN hamartoma tumour syndrome: what happens when there is no PTEN germline mutation? Hum Mol Genet. 2020;29:R150–R157.
    1. Yehia L, Keel E, Eng C. Clinical spectrum of PTEN mutations. Annu Rev Med. 2020;71:103–16.
    1. Yehia L, Ngeow J, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019;129:452–64.
    1. Yehia L, Niazi F, Ni Y, Ngeow J, Sankunny M, Liu Z, Wei W, Mester JL, Keri RA, Zhang B, Eng C. Germline heterozygous variants in SEC23B are associated with Cowden syndrome and enriched in apparently sporadic thyroid cancer. Am J Hum Genet. 2015;97:661–76.
    1. Zhou XP, Marsh DJ, Hampel H, Mulliken JB, Gimm O, Eng C. Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet. 2000;9:765–8.
    1. Zhou XP, Marsh DJ, Morrison CD, Chaudhury AR, Maxwell M, Reifenberger G, Eng C. Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet. 2003a;73:1191–8.
    1. Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, Dasouki M, Feldman GL, Greenberg LA, Ivanovich J, Matloff E, Patterson A, Pierpont ME, Russo D, Nassif NT, Eng C. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet. 2003b;73:404–11.

Source: PubMed

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