{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:21:29Z","timestamp":1787653289289,"version":"build-2736575974"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"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>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Familial short stature (FSS) has traditionally been considered a benign growth pattern characterized by short stature clustering within families and has often been regarded as a normal variant of growth. However, recent advances in genomic technologies have demonstrated that a subset of children presenting with an FSS phenotype harbor identifiable monogenic variants, particularly in genes involved in growth plate development and skeletal growth. These findings challenge the traditional phenotype-based understanding of FSS and support an etiology-oriented diagnostic framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To summarize current knowledge regarding the genetic architecture of FSS, review existing clinical risk stratification frameworks for genetic evaluation, and evaluate available evidence regarding treatment outcomes across different genetic etiologies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A literature search was performed in PubMed, Embase, and Web of Science from inception to May 2026, using keywords including \u201cfamilial short stature,\u201d \u201cfamilial idiopathic short stature,\u201d \u201cgenetic testing,\u201d \u201c\n                      <jats:italic>ACAN<\/jats:italic>\n                      ,\u201d \u201c\n                      <jats:italic>SHOX<\/jats:italic>\n                      ,\u201d and \u201c\n                      <jats:italic>NPR2<\/jats:italic>\n                      \u201d. Relevant original studies and review articles addressing genotype\u2013phenotype correlations, diagnostic yield of genetic testing, or responses to recombinant human growth hormone (rhGH) therapy were considered.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Emerging evidence indicates that monogenic variants can be identified in a subset of children with an FSS phenotype, especially among those with more severe short stature and autosomal dominant inheritance patterns. Variants affecting growth plate biology represent some of the most frequently reported genetic causes of FSS, with\n                      <jats:italic>ACAN, SHOX<\/jats:italic>\n                      , and\n                      <jats:italic>NPR2<\/jats:italic>\n                      being the most frequently implicated genes. Existing clinical frameworks based on parental height patterns and inheritance characteristics may help stratify patients with FSS according to the likelihood of monogenic etiology and guide selection of individuals who may benefit from genetic testing. Available evidence suggests that rhGH therapy may improve growth outcomes in several monogenic forms of FSS, although treatment responses vary according to genetic etiology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>FSS should be regarded as a heterogeneous clinical phenotype rather than a single diagnostic entity. Integration of existing clinical risk stratification approaches with molecular diagnosis may enable more precise identification of underlying genetic causes and facilitate individualized therapeutic decision-making. Future advances in FSS management will likely depend on precision medicine approaches linking phenotype, genotype, and treatment response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1890896","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:44:29Z","timestamp":1787651069000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Familial short stature: genetic architecture, risk stratification, and precision management"],"prefix":"10.3389","volume":"17","author":[{"given":"Chang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingzhe","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","volume-title":"Human Growth","author":"Tanner","year":"1960"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.49.6.417","article-title":"The normal short child. 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