Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers

Laura C Hernández-Ramírez; Plamena Gabrovska; Judit Dénes; Karen Stals; Giampaolo Trivellin; Daniel Tilley; Francesco Ferrau; Jane Evanson; Sian Ellard; Ashley B Grossman; Niki Karavitaki

doi:10.1210/jc.2015-1869

Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers

Laura C Hernández-Ramírez, Plamena Gabrovska, Judit Dénes, Karen Stals, Giampaolo Trivellin, Daniel Tilley, Francesco Ferrau, Jane Evanson, Sian Ellard, Ashley B Grossman, Niki Karavitaki

Metabolism and Systems Research

Research output: Contribution to journal › Article › peer-review

92 Citations (Scopus)

111 Downloads (Pure)

Abstract

CONTEXT: Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.

OBJECTIVE: To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.

DESIGN: This was an observational, longitudinal study conducted over 7 years.

SETTING: International collaborative study conducted at referral centers for pituitary diseases.

PARTICIPANTS: FIPA families (n 216) and sporadic young-onset (30 y) pituitary adenoma patients (n 404) participated in the study.

INTERVENTIONS: We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.

MAIN OUTCOME MEASURE(S): We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.

RESULTS: Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.

CONCLUSIONS: A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

Original language	English
Pages (from-to)	E1242-E1254
Journal	The Journal of clinical endocrinology and metabolism
Volume	100
Issue number	9
DOIs	https://doi.org/10.1210/jc.2015-1869
Publication status	Published - 1 Sept 2015

Keywords

Adenoma
Adolescent
Adult
Aged
Aged, 80 and over
Child
Child, Preschool
Female
Genetic Testing
Germ-Line Mutation
Growth Hormone-Secreting Pituitary Adenoma
Humans
Intracellular Signaling Peptides and Proteins
Longitudinal Studies
Male
Middle Aged
Mutation
Pituitary Neoplasms
Prospective Studies
Young Adult

Access to Document

10.1210/jc.2015-1869Licence: Creative Commons: Attribution (CC BY)

Hernandez-Ramirez_et_al_Landscape_of_familial_isolated_JCEM_2015
The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 9, 1 September 2015, Pages E1242–E1254, https://doi.org/10.1210/jc.2015-1869
Final published version, 522 KBLicence: Creative Commons: Attribution (CC BY)

Steroid Profiling as a Biomarker Tool in the Diagnosis and Monitoring of Adrenal Tumours
Arlt, W. & Stewart, P.
Medical Research Council
2/03/09 → 29/02/12
Project: Research Councils

Cite this

Hernández-Ramírez, L. C., Gabrovska, P., Dénes, J., Stals, K., Trivellin, G., Tilley, D., Ferrau, F., Evanson, J., Ellard, S., Grossman, A. B., & Karavitaki, N. (2015). Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers. The Journal of clinical endocrinology and metabolism, 100(9), E1242-E1254. https://doi.org/10.1210/jc.2015-1869

@article{d24121a62b9a4dc9aa10c1886414fac1,

title = "Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers",

abstract = "CONTEXT: Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.OBJECTIVE: To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.DESIGN: This was an observational, longitudinal study conducted over 7 years.SETTING: International collaborative study conducted at referral centers for pituitary diseases.PARTICIPANTS: FIPA families (n 216) and sporadic young-onset (30 y) pituitary adenoma patients (n 404) participated in the study.INTERVENTIONS: We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.MAIN OUTCOME MEASURE(S): We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.RESULTS: Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.CONCLUSIONS: A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.",

keywords = "Adenoma, Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Genetic Testing, Germ-Line Mutation, Growth Hormone-Secreting Pituitary Adenoma, Humans, Intracellular Signaling Peptides and Proteins, Longitudinal Studies, Male, Middle Aged, Mutation, Pituitary Neoplasms, Prospective Studies, Young Adult",

author = "Hern{\'a}ndez-Ram{\'i}rez, {Laura C} and Plamena Gabrovska and Judit D{\'e}nes and Karen Stals and Giampaolo Trivellin and Daniel Tilley and Francesco Ferrau and Jane Evanson and Sian Ellard and Grossman, {Ashley B} and Niki Karavitaki",

year = "2015",

month = sep,

day = "1",

doi = "10.1210/jc.2015-1869",

language = "English",

volume = "100",

pages = "E1242--E1254",

journal = "The Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "9",

}

Hernández-Ramírez, LC, Gabrovska, P, Dénes, J, Stals, K, Trivellin, G, Tilley, D, Ferrau, F, Evanson, J, Ellard, S, Grossman, AB & Karavitaki, N 2015, 'Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers', The Journal of clinical endocrinology and metabolism, vol. 100, no. 9, pp. E1242-E1254. https://doi.org/10.1210/jc.2015-1869

TY - JOUR

T1 - Landscape of Familial Isolated and Young-Onset Pituitary Adenomas

T2 - Prospective Diagnosis in AIP Mutation Carriers

AU - Hernández-Ramírez, Laura C

AU - Gabrovska, Plamena

AU - Dénes, Judit

AU - Stals, Karen

AU - Trivellin, Giampaolo

AU - Tilley, Daniel

AU - Ferrau, Francesco

AU - Evanson, Jane

AU - Ellard, Sian

AU - Grossman, Ashley B

AU - Karavitaki, Niki

PY - 2015/9/1

Y1 - 2015/9/1

N2 - CONTEXT: Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.OBJECTIVE: To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.DESIGN: This was an observational, longitudinal study conducted over 7 years.SETTING: International collaborative study conducted at referral centers for pituitary diseases.PARTICIPANTS: FIPA families (n 216) and sporadic young-onset (30 y) pituitary adenoma patients (n 404) participated in the study.INTERVENTIONS: We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.MAIN OUTCOME MEASURE(S): We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.RESULTS: Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.CONCLUSIONS: A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

AB - CONTEXT: Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.OBJECTIVE: To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.DESIGN: This was an observational, longitudinal study conducted over 7 years.SETTING: International collaborative study conducted at referral centers for pituitary diseases.PARTICIPANTS: FIPA families (n 216) and sporadic young-onset (30 y) pituitary adenoma patients (n 404) participated in the study.INTERVENTIONS: We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.MAIN OUTCOME MEASURE(S): We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.RESULTS: Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.CONCLUSIONS: A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

KW - Adenoma

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Child

KW - Child, Preschool

KW - Female

KW - Genetic Testing

KW - Germ-Line Mutation

KW - Growth Hormone-Secreting Pituitary Adenoma

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - Longitudinal Studies

KW - Male

KW - Middle Aged

KW - Mutation

KW - Pituitary Neoplasms

KW - Prospective Studies

KW - Young Adult

U2 - 10.1210/jc.2015-1869

DO - 10.1210/jc.2015-1869

M3 - Article

C2 - 26186299

SN - 0021-972X

VL - 100

SP - E1242-E1254

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 9

ER -

Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers

Abstract

Keywords

Access to Document

Fingerprint

Projects

Steroid Profiling as a Biomarker Tool in the Diagnosis and Monitoring of Adrenal Tumours

Cite this