PROP1, HESX1, POU1F1, LHX3 and LHX4 mutation and deletion screening and GH1 P89L and IVS3+1/+2 mutation screening in a Dutch nationwide cohort of patients with combined pituitary hormone deficiency.
OBJECTIVE
Mutation frequencies of genes involved in combined pituitary hormone deficiency (CPHD) vary substantially between populations. The HYPOPIT study aims to obtain an overall picture of known and new genetic defects and variations in a nationwide cohort of Dutch (mostly) sporadic CPHD patients.


METHODS
We screened 79 CPHD patients from 78 families (regardless of MRI and hormonal phenotype) for mutations and deletions in PROP1, HESX1, POU1F1, LHX3 and LHX4, as well as the P89L and IVS3+1/+2 mutations in GH1, recently described to cause pituitary hormone impairment in addition to GH deficiency.


RESULTS
We did not find any mutation or deletion in PROP1, HESX1, LHX3 or LHX4, nor GH1 P89L and GH1 IVS3+1/+2 mutations. Among 12 patients with a typical 'POU1F1 phenotype', 1 patient was formerly known to have a POU1F1 mutation. This results in a POU1F1 mutation frequency in these patients of 8.3%.


CONCLUSIONS
Thorough screening for mutations and deletions in PROP1, HESX1, POU1F1, LHX3, LHX4, as well as screening for GH1 P89L or GH1 IVS3+1/+2 mutations, did not reveal any genetic defect in our cohort of CPHD patients except for one formerly known POU1F1 mutation in 1 patient. Future research should focus on alternative explanations for CPHD, like other genes or environmental factors.
de Graaff
Laura C G
LC
Department of Pediatrics, Division of Endocrinology, Sophia Children's Hospital, Rotterdam, The Netherlands. l.degraaff@erasmusmc.nl
Argente
Jesús
J
Veenma
Danielle C M
DC
Drent
Madeleine L
ML
Uitterlinden
André G
AG
Hokken-Koelega
Anita C S
AC
D000293:Adolescent; D002675:Child, Preschool; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D019382:Human Growth Hormone / Q000235:genetics; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics*; D060850:LIM-Homeodomain Proteins; D008297:Male; D009154:Mutation; D010907:Pituitary Hormones / Q000172:deficiency*; D017384:Sequence Deletion; D050817:Transcription Factor Pit-1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
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