PTEN germline mutations in patients initially tested for other hereditary cancer syndromes: would use of risk assessment tools reduce genetic testing?

[cowden syndrome]

PTEN Hamartoma Tumor syndrome (PHTS ) includes patients with Cowden syndrome or other syndromes with germline mutation of the PTEN tumor suppressor gene . The risk for breast , colorectal , and endometrial cancer and polyposis is increased , creating clinical overlap with hereditary breast and ovarian cancer (HBOC ), Lynch syndrome (LS ), and adenomatous polyposis syndromes (APS ). We reviewed our series of patients with PHTS to determine how often testing criteria for these syndromes were met and how often other-gene testing was ordered before testing PTEN .Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation . Mutations were identified by mutation scanning /multiplex ligation-dependent probe amplification analysis and confirmed by sequencing /quantitative polymerase chain reaction . Patients were excluded if they were adopted , were <18 years of age , or if they were diagnosed with Cowden syndrome before 1998 . Standard risk-assessment models were applied to determine whether patients met HBOC testing criteria , LS-relevant Amsterdam II /Bethesda 2004 criteria , or had adenomatous polyps . Prior probability of PTEN mutation was estimated with the Cleveland Clinic PTEN risk calculator .Of 137 PTEN mutation -positive adult probands , 59 (43 .1 %) met testing criteria for HBOC or LS . Of these , 45 (32 .8 %) were first offered HBOC , LS , or APS testing . Of those who underwent APS testing , none of the six patients met criteria . Initial risk assessment by a genetics specialist was significantly associated with immediate PTEN testing in patients also meeting HBOC testing criteria . Using this PTEN risk assessment tool could have spared gene testing for 22 unlikely syndromes , at a total cost of $66 ,080 .PHTS is an important differential diagnosis for patients referred for HBOC , LS , or APS . Risk assessment tools may help focus genetic analysis and aid in the interpretation of multiplex testing .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated