Genetic screening of combined pituitary hormone deficiency: experience in 195 patients.
BACKGROUND
Mutations in transcription factors result in combined pituitary hormone deficiency (CPHD).


OBJECTIVE
A genetic screening strategy, based on endocrine and neuroradiological phenotype according to published knowledge, was applied to establish the prevalence of gene defects in each category of patients and provide a useful framework for clinicians to determine the genetic etiology and recurrence risks for individuals and families.


METHODS
One hundred ninety-five CPHD patients from the international GENHYPOPIT network were studied, according to their phenotype, for POU1F1, PROP1, LHX3, LHX4, and HESX1.


METHODS
Patients selected had two pituitary hormone deficiencies or at least one deficiency with intracerebral malformations.


RESULTS
Total prevalence of mutations was 13.3 and 52.4% in 20 patients with familial CPHD history. No mutation of HESX1 was observed in 16 patients harboring septooptic dysplasia. A mutation of LHX4 gene, previously reported, was found in one familial case from 39 patients bearing pituitary stalk interruption syndrome. In 109 patients without extrapituitary abnormalities, 20 had PROP1 mutations, including eight patients with a family history of CPHD. Among 20 patients without pituitary stalk interruption syndrome, no LHX3 gene defect was found, even with a neck rotation deficit. One POU1F1 gene defect was found in one patient presenting the rare postpubertal association of thyrotroph (TSH deficiency) and somatotroph (GH deficiency) deficits.


CONCLUSIONS
Mutation of PROP1 gene remains the first to be looked for, and POU1F1 mutations should be sought in GH deficiency and TSH deficiency postpubertal population without extrapituitary malformations. Identification of gene defects allows early treatment of any deficit and prevention of their potentially fatal consequences. Genotyping appears highly beneficial at an individual and familial level.
Reynaud
Rachel
R
Laboratoire de Biochimie et Biologie Moléculaire, Hôpital de la Conception, 13385 Marseille Cedex 5, France.
Gueydan
Magali
M
Saveanu
Alexandru
A
Vallette-Kasic
Sophie
S
Enjalbert
Alain
A
Brue
Thierry
T
Barlier
Anne
A
D000324:Adrenocorticotropic Hormone / Q000097:blood; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D019382:Human Growth Hormone / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D060850:LIM-Homeodomain Proteins; D008297:Male; D010907:Pituitary Hormones / Q000172:deficiency* / Q000235:genetics; D017422:Sequence Analysis, DNA; D013972:Thyrotropin / Q000097:blood; D050817:Transcription Factor Pit-1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection
C489736:HESX1 protein, human; D018398:Homeodomain Proteins; C486362:LHX4 protein, human; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; C494187:POU1F1 protein, human; D010907:Pituitary Hormones; C102134:Prophet of Pit-1 protein; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D019382:Human Growth Hormone; D000324:Adrenocorticotropic Hormone; D013972:Thyrotropin; D004247:DNA; D006854:Hydrocortisone