Rare Frequency of Mutations in Pituitary Transcription Factor Genes in Combined Pituitary Hormone or Isolated Growth Hormone Deficiencies in Korea

Abstract

PurposeCongenital hypopituitarism is caused by mutations in pituitary transcription factors involved in the development of the hypothalamic-pituitary axis. Mutation frequencies of genes involved in congenital hypopituitarism are extremely low and vary substantially between ethnicities. This study was undertaken to compare the clinical, endocrinological, and radiological features of patients with an isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD).Materials and MethodsThis study included 27 patients with sporadic IGHD and CPHD. A mutation analysis of the POU1F1, PROP1, LHX3, LHX4, and HESX1 genes was performed using genomic DNA from peripheral blood leukocytes.ResultsIGHD and CPHD were observed in 4 and 23 patients, respectively. Mean age at diagnosis was 8.28±7.25 years for IGHD and 13.48±10.46 years for CPHD (p=0.37). Serum insulin-like growth factor-1 and peak growth hormone (GH) levels following GH stimulation tests were significantly lower in patients with CPHD than in those with IGHD (p<0.05). Sellar MRI findings revealed structural abnormalities in 3 patients with IGHD (75%) and 21 patients with CPHD (91.3%) (p=0.62). A mutation analysis identified homozygous p.R109Q mutations in HESX1 in a patient with CPHD. Patients with CPHD had more severe GHD than those with IGHD.ConclusionThe frequency of defects in the genes encoding pituitary transcription factors was extremely low in Korean patients with congenital hypopituitarism. Environmental factors and the impact of other causative genes may contribute to this clinical phenotype.

LHX3 deficiency presenting in the United States with severe developmental delay in a child of Syrian refugee parents

“…Poorly developed sella turcica is associated with LHX4 mutations ( 9 ). Additionally, LHX3 and LHX4 mutations are associated with Chiari I malformation, corpus callosum agenesis or hypoplasia and skeletal abnormalities ( 10 ). Specific genetic mutations in CPHD patients are not frequently identified.…”

Congenital hypopituitarism: how to select the patients for genetic analyses

“…Lithuania for PROP1 gene) or in cases with a specific hormonal, neuroradiological or extra-pituitary phenotype. By contrast, the genetic screening of pituitary transcription factors should not be part of routine work-up for Western-European sporadic patients with MPHD, as also suggested by other authors [ 15 – 17 ].…”

“…However, the endocrine phenotypes of all these mutations may be characterized by variable degrees of anterior pituitary hormone deficiency, ranging from isolated GHD to the complete failure of all anterior pituitary cell lineages and this complex hormonal picture may be furtherly complicated by a possible evolution of the endocrinological status over the life-span of the same patient [ 15 ].…”

“…Finally, another essential aspect which needs to be evaluated is whether MPHD syndrome is either sporadic or familial. In fact, all familial cases should undergo genetic analyses, since the probability of finding a causative mutation within any of the transcriptional factor genes is 63%, whilst such probability is very low in sporadic cases [ 15 – 17 ]. Therefore, in sporadic patients with MPHD, genetic analyses should be performed only in individuals coming from a country with high prevalence of specific mutations (e.g.…”

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients

“…The causes of GHD include pituitary dysplasia and pathogenic mutations in GH-insulin like growth factor 1 (IGF1) axis-related genes, such as GH1 , GHRHR ( 3 , 4 ). However, recent cohort studies of the genetic causes of GHD patients in South and East Asian populations reported that the proportion of patients with molecular diagnosis ranges from 4% to 43% ( 5 , 6 ). The undiagnosed rate indicates that there are still a lot of unknowns about the genetic predispositions of GHD.…”