Clinical and genetic features of childhood-onset congenital combined pituitary hormone deficiency: a retrospective, single-center cohort study
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Purpose: To investigate the clinical characteristics and genetic features of childhood-onset congenital combined pituitary hormone deficiency (cCPHD) in Korean patients.Methods: We retrospectively analyzed 444 patients diagnosed with childhood-onset CPHD at a tertiary center between 1994 and 2021. After excluding acquired case, 43 patients with cCPHD were enrolled. Anthropometric measurements, hormone evaluations, brain magnetic resonance imaging (MRI), extrapituitary phenotypes, and adult outcomes were analyzed. Genetic analyses were performed on 26 patients using a targeted gene panel or whole exome sequencing.Results: Mean age at diagnosis was 3.2 years, and 41.9% were diagnosed at less than 1 year old. Short stature was the most frequent (37.2%) initial presentation, and mean height z-score was -2.4. More than half (n=23, 53.5%) of patients had neonatal features suggestive of hypopituitarism; however, only 15 (65.2%) were diagnosed in infancy. Growth hormone deficiency (GHD) was prevalent in 42 (97.7%), and 33 (76.7%) had 3 or more hormone deficiencies. Extrapituitary phenotypes were identified in 31 (72.1%). Brain MRI abnormalities correlated with a higher number of hormone deficiencies (P for trend 0.049) and were present in 33 patients (80.5%). Adult GHD was diagnosed in all 17 investigated patients, and metabolic disturbances were noted in 10 (58.9%). Pathogenic variants in POU1F1, GLI2, HESX1, TBC1D32, and ROBO1 were found in 5 (19.2%).Conclusion: Considering the high proportion of neonatal presentations, identification of the early neonatal features of hypopituitarism to manage pituitary and extrapituitary phenotypes is critical. The genetic etiology of cCPHD warrants further exploration.
Abstract
Purpose: To investigate the clinical characteristics and genetic features of childhood-onset congenital combined pituitary hormone deficiency (cCPHD) in Korean patients.Methods: We retrospectively analyzed 444 patients diagnosed with childhood-onset CPHD at a tertiary center between 1994 and 2021. After excluding acquired case, 43 patients with cCPHD were enrolled. Anthropometric measurements, hormone evaluations, brain magnetic resonance imaging (MRI), extrapituitary phenotypes, and adult outcomes were analyzed. Genetic analyses were performed on 26 patients using a targeted gene panel or whole exome sequencing.Results: Mean age at diagnosis was 3.2 years, and 41.9% were diagnosed at less than 1 year old. Short stature was the most frequent (37.2%) initial presentation, and mean height z-score was -2.4. More than half (n=23, 53.5%) of patients had neonatal features suggestive of hypopituitarism; however, only 15 (65.2%) were diagnosed in infancy. Growth hormone deficiency (GHD) was prevalent in 42 (97.7%), and 33 (76.7%) had 3 or more hormone deficiencies. Extrapituitary phenotypes were identified in 31 (72.1%). Brain MRI abnormalities correlated with a higher number of hormone deficiencies (P for trend 0.049) and were present in 33 patients (80.5%). Adult GHD was diagnosed in all 17 investigated patients, and metabolic disturbances were noted in 10 (58.9%). Pathogenic variants in POU1F1, GLI2, HESX1, TBC1D32, and ROBO1 were found in 5 (19.2%).Conclusion: Considering the high proportion of neonatal presentations, identification of the early neonatal features of hypopituitarism to manage pituitary and extrapituitary phenotypes is critical. The genetic etiology of cCPHD warrants further exploration.
참고문헌 (35)
- Bosch IAL, "Congenital hypopituitarism during the neonatal period : epidemiology, pathogenesis, therapeutic options, and outcome", Front Pediatr, 8, pp.600962~ (2020)
- Prodam F, "Insights into non-classic and emerging causes of hypopituitarism", Nat Rev Endocrinol, 17, pp.114~129 (2021)
- Higham CE, "Hypopituitarism", Lancet, 388, pp.2403~2415 (2016)
- Gregory LC, "The molecular basis of congenital hypopituitarism and related disorders", J Clin Endocrinol Metab, 105, pp.dgz184~ (2020)
- Alatzoglou KS, "Development of the pituitary gland", Compr Physiol, 10, pp.389~413 (2020)
- Choi JH, "Rare frequency of mutations in pituitary transcription factor genes in combined pituitary hormone or isolated growth hormone deficiencies in Korea", Yonsei Med J, 58, pp.527~532 (2017)
- De Rienzo F, "Frequency of genetic defects in combined pituitary hormone deficiency : a systematic review and analysis of a multicentre Italian cohort", Clin Endocrinol(Oxf), 83, pp.849~860 (2015)
- de Graaff LC, "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, 2010, pp.73, 363~371
- Takagi M, "Gradual loss of ACTH due to a novel mutation in LHX4 : comprehensive mutation screening in Japanese patients with congenital hypopituitarism", PLoS One, 7, pp.e46008~ (2012)
- Elizabeth M, "Genetic screening of regulatory regions of pituitary transcription factors in patients with idiopathic pituitary hormone deficiencies", Pituitary, 21, pp.76~83 (2018)
- Hietamaki J, "Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency : a single center experience from over 30 years", EClinicalMedicine, 51, pp.101556~ (2022)
- Jakobsen LK, "Diagnosis and incidence of congenital combined pituitary hormone deficiency in Denmark-a national observational study", J Clin Endocrinol Metab, 108, pp.2475~2485 (2023)
- Gregory LC, "Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders", Genet Med, 25, pp.100881~ (2023)
- Blum WF, "Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency", Eur J Endocrinol, 170, pp.13~21 (2014)
- Sperling M, "Sperling pediatric endocrinology", pp.336~681 (2021), Elsevier
- Persani L, "Clinical review : central hypothyroidism : pathogenic, diagnostic, and therapeutic challenges", J Clin Endocrinol Metab, 97, pp.3068~3078 (2012)
- Kim JH, "The 2017 Korean National Growth Charts for children and adolescents : development, improvement, and prospects", Korean J Pediatr, 61, pp.135~149 (2018)
- Ahn JY, "A case of TBC1D32-related ciliopathy with novel compound heterozygous variants", J Gen Med, 18, pp.64~69 (2021)
- Jullien N, "Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort", Clin Endocrinol(Oxf), 94, pp.277~289 (2021)
- Wadams HD, "Onset of pituitary hormone deficiencies in optic nerve hypoplasia : a temporal trend analysis of 32 children at Mayo Clinic", J Pediatr Endocrinol Metab, 33, pp.139~145 (2020)
- Hassan SS, "Aetiologies and clinical patterns of hypopituitarism in Sudanese children", Sudan J Paediatr, 21, pp.53~60 (2021)
- Lee YJ, "Metabolic impacts of discontinuation and resumption of recombinant human growth hormone treatment during the transition period in patients with childhood-onset growth hormone deficiency", Endocrinol Metab(Seoul), 37, pp.359~368 (2022)
- Moller N, "Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects", Endocr Rev, 30, pp.152~177 (2009)
- Hepprich M, "Dyslipidaemia and growth hormone deficiency-a comprehensive review", Best Pract Res Clin Endocrinol Metab, 37, pp.101821~ (2023)
- Diez JJ, "Treatment with growth hormone for adults with growth hormone deficiency syndrome : benefits and risks", Int J Mol Sci, 19, pp.893~ (2018)
- Courtillot C, "Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition", Eur J Endocrinol, 169, pp.587~596 (2013)
- Ratku B, "Effects of adult growth hormone deficiency and replacement therapy on the cardiometabolic risk profile", Pituitary, 25, pp.211~228 (2022)
- Hietamäki J, "Loss-of-function variants in TBC1D32 underlie syndromic hypopituitarism", J Clin Endocrinol Metab, 105, pp.1748~1758 (2020)
- Kim SS, "Clinical characteristics and molecular analysis of PIT1, PROP1, LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging", Horm Res, 60, pp.277~283 (2003)
- Fang Q, "Genetics of combined pituitary hormone deficiency : roadmap into the genome era", Endocr Rev, 37, pp.636~675 (2016)
- Xatzipsalti M, "Congenital hypopituitarism : various genes, various phenotypes", Horm Metab Res, 51, pp.81~90 (2019)
- Hietamaki J, "Loss-of-function variants in TBC1D32 underlie syndromic hypopituitarism", J Clin Endocrinol Metab, 105, pp.1748~1758 (2020)
- Brauner R, "Pituitary stalk interruption syndrome is characterized by genetic heterogeneity", PLoS One, 15, pp.e0242358~ (2020)
- Bashamboo A, "Mutations in the human ROBO1 gene in pituitary stalk interruption syndrome", J Clin Endocrinol Metab, 102, pp.2401~2406 (2017)
- Bando H, "Novel genes and variants associated with congenital pituitary hormone deficiency in the era of nextgeneration sequencing", Front Endocrinol(Lausanne), 13, pp.1008306~ (2022)