RESUMO
OBJECTIVE: It is recognised that 5% - 10 % of children with macrocephaly and autism spectrum disorder (ASD) and/or intellectual disability (ID) have a heterozygous pathogenic mutation in the PTEN tumour suppressor gene that is associated with PTEN hamartoma tumour syndrome. However, the clinical features and course in children with a pathogenic PTEN mutation are unclear and have not been well documented. STUDY OBJECTIVES: We undertook a retrospective chart review of children (< 18 years) with pathogenic PTEN mutations to ascertain clinical findings, clinical course and possible outcomes. RESULTS: Clinical and molecular data were collected and analysed for 47 patients with PTEN mutation from 38 eligible families. Macrocephaly (average head circumference of + 5.7 SD) with developmental delay, ID and/or ASD were the most common presenting signs/symptoms (66 %). Clinical features included dermatological findings (66 %), gastrointestinal (GI) symptoms (34 %), ASD diagnosis (50 %), abnormal brain imaging (53 % of those examined) and abnormal thyroid imaging (26 %). CONCLUSIONS: This is the largest survey of clinical features in children with PTEN pathogenic mutations to date. It confirms earlier reports of increased rates of neurodevelopmental disorders. Dermatological, GI and thyroid abnormalities are age dependent and may not be present at the time of diagnosis, requiring regular monitoring and medical surveillance. Early paediatric diagnosis is important for institution of medical and developmental surveillance as well as for testing other at- risk family members.
Assuntos
Síndrome do Hamartoma Múltiplo/enzimologia , Síndrome do Hamartoma Múltiplo/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Endoscopia , Feminino , Substância Cinzenta/patologia , Síndrome do Hamartoma Múltiplo/psicologia , Humanos , Lactente , Masculino , Fenótipo , Estudos Retrospectivos , Adulto JovemRESUMO
In unselected populations, less than 10% of breast cancers are associated with germline mutations in predisposing genes. Breast cancer type 1 and 2 (BRCA1 and BRCA2) susceptibility genes are the most common involved genes and confer a 10-30 times higher risk of developing the disease compared to the general population. A personal or family history suggestive of inherited breast cancer syndrome may be further evaluated to assess the risk of genetic predisposition and the presence of a genetic mutation. Breast cancer genetic counseling should include a careful risk assessment with associated psychosocial evaluation and support, possible molecular testing, personalized discussion of results. Knowledge of BRCA status can influence individualized cancer risk-reduction strategies. i.e. active surveillance, prophylactic surgery and/or pharmacoprevention.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético/métodos , Testes Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Quinases Proteína-Quinases Ativadas por AMP , Antígenos CD , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/psicologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/prevenção & controle , Neoplasias da Mama Masculina/psicologia , Caderinas/genética , Feminino , Genes p53 , Predisposição Genética para Doença/psicologia , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/psicologia , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/psicologia , Masculino , Mastectomia , Mutação , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/psicologia , PTEN Fosfo-Hidrolase/genética , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/psicologia , Proteínas Serina-Treonina Quinases/genéticaRESUMO
PURPOSE: We sought to characterize cognition in individuals with germline PTEN mutations (n = 23) as well as in PTEN mutation-negative individuals with classic Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (n = 2). METHODS: Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. χ(2) analyses compared these classifications to expected proportions in normal control samples. RESULTS: The mean intelligence quotient was in the average range, and the range of intellectual functioning was very wide (from extremely low to very superior). However, in a large subset of patients, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants. CONCLUSION: This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous reports suggesting an association with intellectual disability, the mean intelligence quotient was average, and there was a broad range of intellectual abilities. Specific evidence of disruption of frontal circuits may have implications for treatment compliance and cancer surveillance, and further investigation is warranted.
