{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T01:34:50Z","timestamp":1776562490681,"version":"3.51.2"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T00:00:00Z","timestamp":1728259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Isolated growth hormone deficiency type II (IGHD II) is an autosomal dominant disorder characterized by a <jats:italic>GH1<\/jats:italic> gene variant resulting in a significant reduction in growth hormone (GH) secretion and a subsequent decrease of plasma insulin-like growth factor 1 (IGF-1) levels and eventual growth impairment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aimed to identify causative variants in six Chinese families with IGHD II, exploring both clinical and genetic characteristics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Detailed clinical data, including clinical presentations, physical charateristics, medical and family histories, as well as genetic test results, were systematically examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Six children, comprising four males and two females, with a mean age of 4.64 \u00b1 1.15 years, exhibited short stature with a mean height of -3.95 \u00b1 1.41 SDS. Four of them had a family history of short stature, while one patient presented with pulmonary hypertension. All children demonstrated GH deficiency in growth hormone stimulation tests (mean peak GH value: 2.83 \u00b1 2.46 ng\/mL). Exome sequencing for the six patients and targeted gene sequencing for their family members revealed heterozygous variants in the <jats:italic>GH1<\/jats:italic> gene, including Exon2-5del, c.334T&amp;gt;C, c.291 + 1G&amp;gt;A, c.291 + 2T&amp;gt;A, 1.5 kb deletion, and 1.7 kb deletion, with four variants being novel. Four patients underwent human recombinant growth hormone (rhGH) replacement therapy, initiating treatment at a mean age of 4.6 \u00b1 0.7 years. The mean height increase in patients was 1.21 \u00b1 0.3 SDS in the first six months of treatment and 1.79 \u00b1 0.15 SDS in the first year.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings contribute to expanding the genotypic and phenotypic spectra of individuals with IGHD II.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2024.1363050","type":"journal-article","created":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T04:36:05Z","timestamp":1728275765000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The clinical and genetic aspects of six individuals with GH1 variants and isolated growth hormone deficiency type II"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiaozhen","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huakun","family":"Shangguan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuanzhuan","family":"Ai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhifeng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruimin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD010736.pub2","article-title":"Oxandrolone for growth hormone-treated girls aged up to 18 years with Turner syndrome","volume":"2019","author":"Mohamed","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1141039","article-title":"Short stature related to Growth Hormone Insensitivity (GHI) in childhood","volume":"14","author":"Mastromauro","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-022-00649-8","article-title":"Skeletal disorders associated with the growth hormone-insulin-like growth factor 1 axis","volume":"18","author":"Mazziotti","year":"2022","journal-title":"Nat Rev Endocrinol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac217","article-title":"Safety and efficacy of lonapegsomatropin in children with growth hormone deficiency: enliGHten trial 2-year results","volume":"107","author":"Maniatis","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bcp.2016.07.016","article-title":"Targeting GH-1 splicing as a novel pharmacological strategy for growth hormone deficiency type II","volume":"124","author":"Miletta","year":"2017","journal-title":"Biochem Pharmacol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.galenos.2020.2020.0005","article-title":"Different growth responses to recombinant human growth hormone in three siblings with isolated growth hormone deficiency type 1A due to a 6.7Kb deletion in the GH1 gene","volume":"13","author":"Ghosh","year":"2021","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac517","article-title":"Safety and efficacy of pediatric growth hormone therapy: results from the full KIGS cohort","volume":"107","author":"Maghnie","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"B8","doi-asserted-by":"publisher","first-page":"106805","DOI":"10.1016\/j.phrs.2023.106805","article-title":"Efficacy, safety, quality of life, adherence and cost-effectiveness of long-acting growth hormone replacement therapy compared to daily growth hormone in children with growth hormone deficiency: A systematic review and meta-analysis","volume":"193","author":"Mameli","year":"2023","journal-title":"Pharmacol Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa443","article-title":"A genome-wide pharmacogenetic study of growth hormone responsiveness","volume":"105","author":"Dauber","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab088","article-title":"A high proportion of novel ACAN mutations and their prevalence in a large cohort of chinese short stature children","volume":"106","author":"Lin","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B11","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.eprac.2022.04.004","article-title":"Pediatric continuous reference intervals of serum insulin-like growth factor 1 levels in a healthy chinese children population - based on PRINCE study","volume":"28","author":"Cao","year":"2022","journal-title":"Endocr Pract"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22981","article-title":"HGVS recommendations for the description of sequence variants: 2016 update","volume":"37","author":"den Dunnen","year":"2016","journal-title":"Hum Mutat"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.736988","article-title":"MAP3K1 variant causes hyperactivation of wnt4\/\u03b2-catenin\/FOXL2 signaling contributing to 46,XY disorders\/differences of sex development","volume":"13","author":"Chen","year":"2022","journal-title":"Front Genet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003440","article-title":"PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations","volume":"10","author":"Bendl","year":"2014","journal-title":"PloS Comput Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-022-00728-0","article-title":"I-TASSER-MTD: a deep-learning-based platform for multi-domain protein structure and function prediction","volume":"17","author":"Zhou","year":"2022","journal-title":"Nat Protoc"},{"key":"B17","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1186\/1471-2105-11-548","article-title":"Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces","volume":"11","author":"Venselaar","year":"2010","journal-title":"BMC Bioinf"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnad002","article-title":"International consensus guideline on small for gestational age: etiology and management from infancy to early adulthood","volume":"44","author":"Hokken-Koelega","year":"2023","journal-title":"Endocr Rev"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnac014","article-title":"Management of growth disorders in puberty: GH, gnRHa, and aromatase inhibitors: A clinical review","volume":"44","author":"Mauras","year":"2023","journal-title":"Endocr Rev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-3265","article-title":"IGHD II: A novel GH-1 gene mutation (GH-L76P) severely affects GH folding, stability, and secretion","volume":"100","author":"Miletta","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1159\/000341766","article-title":"Isolated growth hormone deficiency type 2: from gene to therapy","volume":"23","author":"Miletta","year":"2012","journal-title":"Endocr Dev"},{"key":"B22","doi-asserted-by":"publisher","first-page":"101423","DOI":"10.1016\/j.ghir.2021.101423","article-title":"Mutations in GH1 gene and isolated growth hormone deficiency (IGHD): A familial case of IGHD type I and systematic review","author":"Li","year":"2021","journal-title":"Growth Horm IGF Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1159\/000091607","article-title":"Impact of del32-71-GH (exon 3 skipped GH) on intracellular GH distribution, secretion and cell viability: a quantitative confocal microscopy analysis","volume":"65","author":"Salemi","year":"2006","journal-title":"Horm Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1210\/en.2009-1280","article-title":"Growth hormone (GH)-releasing hormone increases the expression of the dominant-negative GH isoform in cases of isolated GH deficiency due to GH splice-site mutations","volume":"151","author":"Petkovic","year":"2010","journal-title":"Endocrinology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-0746","article-title":"A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II","volume":"94","author":"Hamid","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-0684","article-title":"Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene","volume":"92","author":"Hess","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"B27","doi-asserted-by":"publisher","first-page":"100881","DOI":"10.1016\/j.gim.2023.100881","article-title":"Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders","volume":"25","author":"Gregory","year":"2023","journal-title":"Genet Med"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1363050\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T04:36:07Z","timestamp":1728275767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1363050\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,7]]},"references-count":27,"alternative-id":["10.3389\/fendo.2024.1363050"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2024.1363050","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,7]]},"article-number":"1363050"}}