Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene.
BACKGROUND
Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations occur in 15% of familial isolated pituitary adenoma (FIPA) cases. To date, studies have focused on the identification of such mutations in large international cohorts. Detailed genetic and clinical studies within AIP mutation-positive families have been limited.


OBJECTIVE
To undertake a comprehensive study of a large Brazilian FIPA kindred with an E174 frameshift (E174fs) AIP mutation to assess clinical, hormonal, and radiological features in mutation carriers.


METHODS
The kindred included 122 subjects across six generations; all underwent clinical examination. Genetic studies were performed to identify E174fs mutation carriers. E174fs-positive subjects underwent magnetic resonance imaging (MRI) and hormonal assessments.


RESULTS
Of the ten germline AIP mutation carriers, three had pituitary tumors, while seven were asymptomatic carriers. Three patients with pituitary tumors showed variability in terms of tumor phenotype (two with acromegaly, one with prolactinoma, or mixed prolactin/GH-secreting tumor) and age at diagnosis; both patients with acromegaly had poor responses to octreotide. Tumor AIP immunohistochemistry from the operated patient showed decreased expression when compared with normal tissue. Two adult subjects with normal MRI had elevated IGF-I in the absence of other causes. A 2-year-old child with the E174fs mutation and a normal MRI had premature thelarche, ovarian development, and advanced bone age in the absence of other underlying causes.


CONCLUSIONS
The penetrance of pituitary tumors in AIP mutation-positive adult subjects was 33.3%, while clinical/hormonal features were variable. The features noted in AIP-mutation carriers in this kindred suggest that clinical characteristics of such carriers may extend beyond pituitary tumors.
Naves
Luciana A
LA
Department of Endocrinology, Internal Medicine, University of Brasília, Brasília DF, Brazil. lunaves@unb.br
Daly
Adrian F
AF
Vanbellinghen
Jean-François
JF
Casulari
Luiz A
LA
Spilioti
Cristina
C
Magalhães
Albino V
AV
Azevedo
Monalisa F
MF
Giacomini
Leonardo A
LA
Nascimento
Paula P
PP
Nunes
Rousielysson O
RO
Rosa
Joao W C
JW
Jaffrain-Rea
Marie-Lise
ML
Bours
Vincent
V
Beckers
Albert
A
D000236:Adenoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D001938:Brazil; D002675:Child, Preschool; D005190:Family; D005260:Female; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010911:Pituitary Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D011506:Proteins / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C103265:aryl hydrocarbon receptor-interacting protein