{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:54:07Z","timestamp":1781650447870,"version":"3.54.5"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"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. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Axenfeld-Rieger syndrome (ARS) is a multisystem disorder primarily caused by\n                      <jats:italic>PITX2<\/jats:italic>\n                      mutations. While eye and dental anomalies are classic, the role of\n                      <jats:italic>PITX2<\/jats:italic>\n                      as a dosage-sensitive regulator of the human growth axis remains clinically under-recognized. We aim to elucidate the link between large-scale 4q25 microdeletions and severe growth hormone deficiency (GHD).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A 5.4-year-old boy with ocular segment dysgenesis and short stature underwent family-based whole-exome sequencing (WES). Standardized growth hormone (GH) stimulation tests and longitudinal growth dynamics analysis based on 44 precise clinical data points collected from birth to age 7.45 years were performed. A systematic literature review of 10 ARS cases with growth failure was conducted to propose a pathogenic model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      WES identified a novel\n                      <jats:italic>de novo<\/jats:italic>\n                      3.824Mb heterozygous deletion at 4q25 (arr[GRCh38] 4q25(108,929,697\u2013112,753,289)\u00d71), encompassing critical genes including\n                      <jats:italic>CFI<\/jats:italic>\n                      ,\n                      <jats:italic>EGF<\/jats:italic>\n                      ,\n                      <jats:italic>PITX2<\/jats:italic>\n                      ,\n                      <jats:italic>PANCR<\/jats:italic>\n                      , and\n                      <jats:italic>LARP7<\/jats:italic>\n                      . Our systematic review revealed a dosage-sensitive correlation between the microdeletion scale at the 4q25 region and the severity of growth axis impairment. The patient exhibited complete GHD (peak GH: 4.22\u00a0ng\/mL) and a 1.5-year bone age delay. Following 20 months of PEG-rhGH therapy, the patient achieved a significant catch-up growth with a cumulative height gain of 16.5 cm, with his height standard deviation score (Ht-SDS) improving from \u22122.0 SD to within the normal range. Our mechanistic model suggests that\n                      <jats:italic>PITX2<\/jats:italic>\n                      haploinsufficiency disrupts the\n                      <jats:italic>POU1F1<\/jats:italic>\n                      (Pit-1) transcriptional cascade, leading to pituitary hypoplasia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study reports the one of the most extensive longitudinal follow-up of successful PEG-rhGH therapy in ARS to date. We propose that large 4q25 deletions represent a high-risk genotype for GHD. Mandatory growth monitoring and early endocrine screening are recommended for ARS patients with chromosomal deletions in this region to optimize developmental outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1856235","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:10:28Z","timestamp":1781647828000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy of long-acting growth hormone in Axenfeld-Rieger syndrome with a novel 3.824\u00a0Mb 4q25 deletion: a Case Report and systematic literature review"],"prefix":"10.3389","volume":"17","author":[{"given":"Shihui","family":"Guan","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]},{"name":"Diagnosis and Treatment Center for Children, The Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyu","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]},{"name":"Diagnosis and Treatment Center for Children, The Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxian","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]},{"name":"Diagnosis and Treatment Center for Children, The Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangfan","family":"Qi","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]},{"name":"Diagnosis and Treatment Center for Children, The Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangzhu","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]},{"name":"Diagnosis and Treatment Center for Children, The Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/j.earlhumdev.2009.08.057","article-title":"Genetic forms of hypopituitarism and their manifestation in the neonatal period","volume":"85","author":"Alatzoglou","year":"2009","journal-title":"Early Hum. 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