Combined pituitary hormone deficiency in Australian children: clinical and genetic correlates.
OBJECTIVE
Mutations in the gene for the POU domain transcription factor POU1F1 (human Pit-1) have been reported in patients with GH, TSH and PRL deficiencies. PROP1 (Prophet of Pit-1) gene mutations also cause gonadotrophin deficiencies and in some cases partial ACTH deficiency. This study analyses the POU1F1 and PROP1 genes in a cohort of Australian children with combined pituitary hormone deficiency (CPHD) and correlates results with patient phenotype.


METHODS
Genomic analysis was carried out on 33 patients with CPHD referred from centres around Australia. Clinical data were collected from medical records and referring physicans.


RESULTS
POU1F1 mutations were identified in two of four patients with a suggestive phenotype. In a female patient, novel compound heterozygous POU1F1 mutations were identified: Arg143Leu in exon 3 and Leu194Gln in exon 4. This patient presented with failure to thrive at 6 weeks of age and has deficiencies of TSH and GH. A previously described heterozygous Arg271Trp mutation in exon 6 of the POU1F1 gene was identified in a female infant who presented with growth failure and was diagnosed with TSH then GH deficiencies. No PROP1 mutations were identified; however, we describe a number of previously unreported PROP1 polymorphisms. No patients presenting with deficiencies of all anterior pituitary hormones early in life had POU1F1 or PROP1 gene mutations.


CONCLUSIONS
In 33 Australian children with CPHD we have identified POU1F1 mutations in two patients and no PROP1 mutations. We speculate that in the majority of children other genes must be responsible for the CPHD phenotype.
McLennan
Kim
K
Department of Paediatric Endocrinology, Mater Children's Hospital and University of Queensland, South Brisbane, Australia.
Jeske
Yvette
Y
Cotterill
Andrew
A
Cowley
David
D
Penfold
James
J
Jones
Tim
T
Howard
Neville
N
Thomsett
Michael
M
Choong
Catherine
C
D000293:Adolescent; D000328:Adult; D001315:Australia; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006130:Growth Disorders / Q000235:genetics*; D013006:Growth Hormone / Q000172:deficiency; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D010907:Pituitary Hormones / Q000172:deficiency*; D013972:Thyrotropin / Q000172:deficiency; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C494187:POU1F1 protein, human; D010907:Pituitary Hormones; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D013972:Thyrotropin; D013006:Growth Hormone