{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:44:46Z","timestamp":1786121086743,"version":"build-2736575974"},"reference-count":16,"publisher":"Walter de Gruyter GmbH","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n \n The melanocortin-4 receptor (MC4R) is a G protein\u2013coupled receptor that regulates energy homeostasis. Pathogenic\n MC4R<\/jats:italic>\n variants represent the most common cause of monogenic obesity and are frequently associated with increased linear growth. However, the mechanisms linking MC4R signaling to somatic growth remain incompletely understood. We report a child with severe growth hormone deficiency (GHD) carrying a heterozygous\n MC4R<\/jats:italic>\n variant (c.496G>A; p.V166I), in whom recombinant human growth hormone (rhGH) therapy triggered an unexpectedly exaggerated clinical and biochemical response, suggesting a potential pharmacogenetic interaction between MC4R signaling and the GH\/IGF-1\u00a0axis.\n <\/jats:p>\n <\/jats:sec>\n \n Case presentation<\/jats:title>\n The male patient was first evaluated at 1\u00a0month of age due to micropenis and diagnosed with multiple pituitary hormone deficiencies. At 57\u00a0months of age, his height was 97.3\u202fcm (\u22122.56 SDS) and annual growth velocity was 4.1\u202fcm\/year (<\u22122 SDS); rhGH (somatropin) therapy was initiated. Despite severe biochemically confirmed GHD, rhGH at 0.03\u202fmg\/kg\/day triggered an exaggerated response: IGF-1 levels increased from\u00a0\u22123.35 SDS to +8.00 SDS. Concurrently, his height velocity accelerated to 16\u202fcm\/year, and his bone age rapidly advanced by approximately 4\u00a0years over a 23-month period, culminating in mandibular prognathism.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n The coexistence of severe GHD and an\n MC4R<\/jats:italic>\n variant is rarely described, and such a pronounced response to rhGH has not previously been reported. These findings suggest that\n MC4R<\/jats:italic>\n p.V166I may modulate peripheral GH\/IGF-1 signaling and act as a pharmacogenetic modifier of GH responsiveness. Careful rhGH dose titration with close IGF-1 monitoring may be considered in patients carrying the\n MC4R<\/jats:italic>\n p.V166I variant.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1515\/jpem-2026-0165","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T02:55:55Z","timestamp":1786071355000},"source":"Crossref","is-referenced-by-count":0,"title":["Pharmacogenetic hypersensitivity to somatropin in a child with severe growth hormone deficiency and\n MC4R<\/i>\n p.V166I variant"],"prefix":"10.1515","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6313-639X","authenticated-orcid":false,"given":"Ertugrul","family":"Sancak","sequence":"first","affiliation":[{"name":"Department of Pediatric Endocrinology , Selcuk University Faculty of Medicine , Konya , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2937-823X","authenticated-orcid":false,"given":"Muammer","family":"B\u00fcy\u00fckinan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , Selcuk University Faculty of Medicine , Konya , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5719-7733","authenticated-orcid":false,"given":"Ahmet Fatih","family":"Y\u0131lmaz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , Selcuk University Faculty of Medicine , Konya , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-7883","authenticated-orcid":false,"given":"Berna","family":"Karsl\u0131","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , Selcuk University Faculty of Medicine , Konya , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2752-3480","authenticated-orcid":false,"given":"Fatma \u00d6zg\u00fc\u00e7","family":"\u00c7\u00f6mlek","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , Selcuk University Faculty of Medicine , Konya , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2276-4410","authenticated-orcid":false,"given":"Fuat","family":"Bu\u011frul","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , Selcuk University Faculty of Medicine , Konya , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"2026080702554497769_j_jpem-2026-0165_ref_001","doi-asserted-by":"crossref","unstructured":"Dayton, K, Miller, J. 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