{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T05:33:19Z","timestamp":1766467999627},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,4,13]],"date-time":"2013-04-13T00:00:00Z","timestamp":1365811200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The acid\u2010labile subunit (<jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>) protein is crucial for maintaining the circulating <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">IGFBP<\/jats:styled-content> system. Inactivating mutations of <jats:italic><jats:styled-content style=\"fixed-case\">IGFALS<\/jats:styled-content><\/jats:italic> result in <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1 deficiency associated with growth retardation. Although the first <jats:italic><jats:styled-content style=\"fixed-case\">IGFALS<\/jats:styled-content><\/jats:italic> mutation in humans was described in 2004, only 16 mutations have been reported since. Moreover, the phenotype of affected patients as a consequence of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> deficiency is still highly variable. We assessed whether children with idiopathic short stature (<jats:styled-content style=\"fixed-case\">ISS<\/jats:styled-content>) harbour mutations in <jats:italic><jats:styled-content style=\"fixed-case\">IGFALS<\/jats:styled-content><\/jats:italic> and characterized affected patients' phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Sixty\u2010five children with <jats:styled-content style=\"fixed-case\">ISS<\/jats:styled-content> were enrolled in the study. Serum <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> levels were measured by <jats:styled-content style=\"fixed-case\">ELISA<\/jats:styled-content>, and <jats:italic><jats:styled-content style=\"fixed-case\">IGFALS<\/jats:styled-content><\/jats:italic> was sequenced.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel homozygous mutation in <jats:italic><jats:styled-content style=\"fixed-case\">IGFALS<\/jats:styled-content><\/jats:italic>, c.380<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>&gt;<jats:styled-content style=\"fixed-case\">C<\/jats:styled-content> (p.L127<jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>), was identified in two siblings of a consanguineous family. The proband, a 17\u00b775\u2010year\u2010old male, was \u22121\u00b79\u00a0SDS in height and \u22124\u00b75\u00a0SDS in weight. Exaggerated stimulated GH (38\u00a0ng\/ml) and extremely low <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1 and <jats:styled-content style=\"fixed-case\">IGFBP<\/jats:styled-content>3 (&lt;25 and &lt;500\u00a0ng\/ml, respectively) indicated <jats:styled-content style=\"fixed-case\">GH<\/jats:styled-content> insensitivity. Both affected siblings had low or no <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> (43 and 0\u00a0<jats:styled-content style=\"fixed-case\">mU<\/jats:styled-content>\/ml, respectively). They were also mildly small for gestational age, severely underweight and showed osteopenia, insulin insensitivity and delayed and slow puberty progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Acid\u2010labile subunit deficiency due to <jats:italic><jats:styled-content style=\"fixed-case\">IGFALS<\/jats:styled-content><\/jats:italic> mutations is a rare cause of growth retardation in children. The unique combination of features presented by the two affected siblings emphasizes the important role of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1 in bone formation, insulin regulation and the pubertal process, in addition to its crucial effect on growth. Long\u2010term follow\u2010up is indicated since the clinical outcome with respect to osteoporosis, <jats:italic>diabetes mellitus<\/jats:italic> and fertility has not been recognized.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.12200","type":"journal-article","created":{"date-parts":[[2013,3,15]],"date-time":"2013-03-15T17:59:39Z","timestamp":1363370379000},"page":"838-844","source":"Crossref","is-referenced-by-count":21,"title":["A novel mutation in <i><scp>IGFALS<\/scp><\/i>, c.380<scp>T<\/scp>&gt;<scp>C<\/scp> (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinaemia in two siblings: insights into the roles of insulin growth factor\u20101 (<scp>IGF<\/scp>1)"],"prefix":"10.1111","volume":"79","author":[{"given":"Ora","family":"Hess","sequence":"first","affiliation":[{"name":"Pediatric Endocrine Institute Ha'Emek Medical Center Afula Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morad","family":"Khayat","sequence":"additional","affiliation":[{"name":"Genetic Institute Ha'Emek Medical Center Afula Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian","family":"Hwa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Oregon Health and Science University Portland OR USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen E.","family":"Heath","sequence":"additional","affiliation":[{"name":"Institute of Medical &amp; Molecular Genetics (INGEMM) Hospital Universitario La Paz Universidad Aut\u00f3noma de Madrid, IdiPAZ, and CIBERER, ISCIII Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amnon","family":"Teitler","sequence":"additional","affiliation":[{"name":"Immunology Laboratory Ha'Emek Medical Center Afula Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifat","family":"Hritan","sequence":"additional","affiliation":[{"name":"Immunology Laboratory Ha'Emek Medical Center Afula Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stavit","family":"Allon\u2010Shalev","sequence":"additional","affiliation":[{"name":"Genetic Institute Ha'Emek Medical Center Afula Israel"},{"name":"The Ruth &amp; Rappoport School of Medicine Technion Haifa Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yardena","family":"Tenenbaum\u2010Rakover","sequence":"additional","affiliation":[{"name":"Pediatric Endocrine Institute Ha'Emek Medical Center Afula Israel"},{"name":"The Ruth &amp; 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