PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome

Debbie J. Marsh, Jennifer B. Kum, Kathryn L. Lunetta, Michael J. Bennett, Robert J. Gorlin, S. Faisal Ahmed, Joann N Bodurtha, Carol Crowe, Mary A. Curtis, Majed Dasouki, Teresa Dunn, Howard Feit, Michael T. Geraghty, John M. Graham, Shirley V. Hodgson, Alasdair Hunter, Bruce R. Korf, David Manchester, Susan Miesfeldt, Victoria A. Murday & 12 others Katherine L. Nathanson, Melissa Parisi, Barbara Pober, Corrado Romano, John L. Tolmie, Richard Trembath, Robin M. Winter, Elaine H. Zackai, Roberto T. Zori, Liang Ping Weng, Patricia L M Dahia, Charis Eng

Research output: Contribution to journalArticle

Abstract

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients (P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR (P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone (P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Original languageEnglish (US)
Pages (from-to)1461-1472
Number of pages12
JournalHuman Molecular Genetics
Volume8
Issue number8
DOIs
StatePublished - 1999
Externally publishedYes

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Multiple Hamartoma Syndrome
Genetic Association Studies
Mutation
Fibroadenoma
Hamartoma

ASJC Scopus subject areas

  • Genetics

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PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. / Marsh, Debbie J.; Kum, Jennifer B.; Lunetta, Kathryn L.; Bennett, Michael J.; Gorlin, Robert J.; Ahmed, S. Faisal; Bodurtha, Joann N; Crowe, Carol; Curtis, Mary A.; Dasouki, Majed; Dunn, Teresa; Feit, Howard; Geraghty, Michael T.; Graham, John M.; Hodgson, Shirley V.; Hunter, Alasdair; Korf, Bruce R.; Manchester, David; Miesfeldt, Susan; Murday, Victoria A.; Nathanson, Katherine L.; Parisi, Melissa; Pober, Barbara; Romano, Corrado; Tolmie, John L.; Trembath, Richard; Winter, Robin M.; Zackai, Elaine H.; Zori, Roberto T.; Weng, Liang Ping; Dahia, Patricia L M; Eng, Charis.

In: Human Molecular Genetics, Vol. 8, No. 8, 1999, p. 1461-1472.

Research output: Contribution to journalArticle

Marsh, DJ, Kum, JB, Lunetta, KL, Bennett, MJ, Gorlin, RJ, Ahmed, SF, Bodurtha, JN, Crowe, C, Curtis, MA, Dasouki, M, Dunn, T, Feit, H, Geraghty, MT, Graham, JM, Hodgson, SV, Hunter, A, Korf, BR, Manchester, D, Miesfeldt, S, Murday, VA, Nathanson, KL, Parisi, M, Pober, B, Romano, C, Tolmie, JL, Trembath, R, Winter, RM, Zackai, EH, Zori, RT, Weng, LP, Dahia, PLM & Eng, C 1999, 'PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome', Human Molecular Genetics, vol. 8, no. 8, pp. 1461-1472. https://doi.org/10.1093/hmg/8.8.1461
Marsh, Debbie J. ; Kum, Jennifer B. ; Lunetta, Kathryn L. ; Bennett, Michael J. ; Gorlin, Robert J. ; Ahmed, S. Faisal ; Bodurtha, Joann N ; Crowe, Carol ; Curtis, Mary A. ; Dasouki, Majed ; Dunn, Teresa ; Feit, Howard ; Geraghty, Michael T. ; Graham, John M. ; Hodgson, Shirley V. ; Hunter, Alasdair ; Korf, Bruce R. ; Manchester, David ; Miesfeldt, Susan ; Murday, Victoria A. ; Nathanson, Katherine L. ; Parisi, Melissa ; Pober, Barbara ; Romano, Corrado ; Tolmie, John L. ; Trembath, Richard ; Winter, Robin M. ; Zackai, Elaine H. ; Zori, Roberto T. ; Weng, Liang Ping ; Dahia, Patricia L M ; Eng, Charis. / PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. In: Human Molecular Genetics. 1999 ; Vol. 8, No. 8. pp. 1461-1472.
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title = "PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome",
abstract = "Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60{\%}) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients (P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR (P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone (P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.",
author = "Marsh, {Debbie J.} and Kum, {Jennifer B.} and Lunetta, {Kathryn L.} and Bennett, {Michael J.} and Gorlin, {Robert J.} and Ahmed, {S. Faisal} and Bodurtha, {Joann N} and Carol Crowe and Curtis, {Mary A.} and Majed Dasouki and Teresa Dunn and Howard Feit and Geraghty, {Michael T.} and Graham, {John M.} and Hodgson, {Shirley V.} and Alasdair Hunter and Korf, {Bruce R.} and David Manchester and Susan Miesfeldt and Murday, {Victoria A.} and Nathanson, {Katherine L.} and Melissa Parisi and Barbara Pober and Corrado Romano and Tolmie, {John L.} and Richard Trembath and Winter, {Robin M.} and Zackai, {Elaine H.} and Zori, {Roberto T.} and Weng, {Liang Ping} and Dahia, {Patricia L M} and Charis Eng",
year = "1999",
doi = "10.1093/hmg/8.8.1461",
language = "English (US)",
volume = "8",
pages = "1461--1472",
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TY - JOUR

T1 - PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome

AU - Marsh, Debbie J.

AU - Kum, Jennifer B.

AU - Lunetta, Kathryn L.

AU - Bennett, Michael J.

AU - Gorlin, Robert J.

AU - Ahmed, S. Faisal

AU - Bodurtha, Joann N

AU - Crowe, Carol

AU - Curtis, Mary A.

AU - Dasouki, Majed

AU - Dunn, Teresa

AU - Feit, Howard

AU - Geraghty, Michael T.

AU - Graham, John M.

AU - Hodgson, Shirley V.

AU - Hunter, Alasdair

AU - Korf, Bruce R.

AU - Manchester, David

AU - Miesfeldt, Susan

AU - Murday, Victoria A.

AU - Nathanson, Katherine L.

AU - Parisi, Melissa

AU - Pober, Barbara

AU - Romano, Corrado

AU - Tolmie, John L.

AU - Trembath, Richard

AU - Winter, Robin M.

AU - Zackai, Elaine H.

AU - Zori, Roberto T.

AU - Weng, Liang Ping

AU - Dahia, Patricia L M

AU - Eng, Charis

PY - 1999

Y1 - 1999

N2 - Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients (P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR (P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone (P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

AB - Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients (P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR (P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone (P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

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