Clinical characteristics and molecular analysis of PIT1, PROP1,LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging.
OBJECTIVE
Many genes encoding pituitary transcription factors involved in the formation of the pituitary gland are identified. Different mutations in these genes have been reported in patients with familial combined pituitary hormone deficiency (CPHD). This study was undertaken to analyze PIT1, PROP1, LHX3, and HESX1 in 12 CPHD patients with abnormal pituitary magnetic resonance imaging (MRI). Since embryonic development of the pituitary requires the coordinated expression of specific transcription factors, we postulated the presence of mutations in PIT1, PROP1, LHX3, and HESX1 genes.


METHODS
Anterior pituitary function was evaluated. Each gene was PCR amplified exon by exon, and subsequently sequenced.


RESULTS
In all cases, MRI examination showed abnormal pituitary gland development featuring ectopic neurohypophysis, hypoplastic anterior lobe, empty sella, and septo-optic dysplasia. Endocrinologically, all patients revealed multiple pituitary hormone deficiency including growth hormone, thyroid stimulating hormone, luteinizing hormone, follicular stimulating hormone and adrenocorticotropin. They were all sporadic cases without a positive family history. None of disease-causing specific mutations were identified in PIT1, PROP1, LHX3, and HESX1 genes of 12 sporadic CPHD patients with abnormal pituitary imaging. However, 2 novel polymorphisms were found in PROP1 gene: IVS1+3 A-->G and 27 T-->C (Ala9Ala) in exon 1. Their allele frequencies in patients and normal controls were not statistically different. Overall, allele frequencies of these polymorphisms were as follows: for the IVS1+3 A-->G polymorphism, the allele frequency of A was 54%, and 46% for G, with 58% of an A/G heterozygosity. For the 27 T-->C (Ala9Ala) polymorphism, the allele frequency of T was 46%, and 54% for G, with 42% of a T/C heterozygosity.


CONCLUSIONS
Mutations of PIT1, PROP1, LHX3, and HESX1 genes are very rare in sporadic CPHD patients with abnormal pituitary MRI.
Kim
Sung-Su
SS
Department of Pediatrics, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Kim
Youngho
Y
Shin
Young-Lim
YL
Kim
Gu-Hwan
GH
Kim
Tae-Ue
TU
Yoo
Han-Wook
HW
D000293:Adolescent; D001827:Body Height / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D010903:Pituitary Gland, Anterior / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure*; D010904:Pituitary Gland, Posterior / Q000002:abnormalities / Q000473:pathology / Q000648:ultrastructure*; D010907:Pituitary Hormones / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods
D010907:Pituitary Hormones