{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:17:16Z","timestamp":1760149036333,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T00:00:00Z","timestamp":1688428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Genetic tests have led to the discovery of many novel genetic variants related to growth failure, but the clinical significance of some results is not always easy to establish. The aim of this report is to describe both clinical phenotype and genetic characteristics in an adult patient with short stature associated with a homozygous variant in disintegrin and metalloproteinase with thrombospondin motifs type 17 gene (ADAMTS17) combined with a homozygous variant in the GH secretagogue receptor (GHS-R). The index case had severe short stature (SS) (\u22123.0 SD), small hands and feet, associated with eye disturbances. Genetic tests revealed homozygous compounds for ADAMTS17 responsible for Weill\u2013Marchesani-like syndrome but a homozygous variant in GHS-R was also detected. Dynamic stimulation with an insulin tolerance test showed a normal elevation of GH, while the GH response to macimorelin stimulus was totally flattened. We show the implication of the GHS-R variant and review the molecular mechanisms of both entities. These results allowed us to better interpret the phenotypic spectrum, associated co-morbidities, its implications in dynamic tests, genetic counselling and treatment options not only to the index case but also for her relatives.<\/jats:p>","DOI":"10.3390\/diagnostics13132259","type":"journal-article","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T01:38:32Z","timestamp":1688434712000},"page":"2259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Contribution of Dynamic and Genetic Tests for Short Stature Diagnosing: A Case Report"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8837-4343","authenticated-orcid":false,"given":"Betina","family":"Biagetti","sequence":"first","affiliation":[{"name":"Endocrinology Department, Diabetes and Metabolism Research Unit, Vall d\u2019Hebron University Hospital and Vall d\u2019Hebron Research Institute (VHIR), Universidad Aut\u00f3noma de Barcelona, Reference Networks (ERN), 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2350-6058","authenticated-orcid":false,"given":"Irene","family":"Valenzuela","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics and Rare Disease Unit and Medicine Genetics Group, Vall Hebron Research Institute, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariadna","family":"Campos-Martorell","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Section, Vall d\u2019Hebron University Hospital and Vall d\u2019Hebron Research Institute (VHIR), Universidad Aut\u00f3noma de Barcelona, 08193 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4343-8331","authenticated-orcid":false,"given":"Berta","family":"Campos","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics and Rare Disease Unit and Medicine Genetics Group, Vall Hebron Research Institute, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Section, Vall d\u2019Hebron University Hospital and Vall d\u2019Hebron Research Institute (VHIR), Universidad Aut\u00f3noma de Barcelona, 08193 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Giralt","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9392-0142","authenticated-orcid":false,"given":"Noelia","family":"D\u00edaz-Troyano","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4950-5627","authenticated-orcid":false,"given":"Emilio","family":"Iniesta-Serrano","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6620-6525","authenticated-orcid":false,"given":"Diego","family":"Yeste","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Section, Vall d\u2019Hebron University Hospital and Vall d\u2019Hebron Research Institute (VHIR), Universidad Aut\u00f3noma de Barcelona, 08193 Barcelona, Spain"},{"name":"CIBER Enfermedades Raras, Instituto Carlos III, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0475-3096","authenticated-orcid":false,"given":"Rafael","family":"Sim\u00f3","sequence":"additional","affiliation":[{"name":"Endocrinology Department, Diabetes and Metabolism Research Unit, Vall d\u2019Hebron University Hospital and Vall d\u2019Hebron Research Institute (VHIR), Universidad Aut\u00f3noma de Barcelona, Reference Networks (ERN), 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4210","DOI":"10.1210\/jc.2008-0509","article-title":"Consensus Statement on the Diagnosis and Treatment of Children with Idiopathic Short Stature: A Summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop","volume":"93","author":"Cohen","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.jpeds.2013.04.002","article-title":"Low Incidence of Pathology Detection and High Cost of Screening in the Evaluation of Asymptomatic Short Children","volume":"163","author":"Sisley","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/nrendo.2015.165","article-title":"Short and Tall Stature: A New Paradigm Emerges","volume":"11","author":"Baron","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1210\/jc.2011-0179","article-title":"Endocrine Society Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline","volume":"96","author":"Molitch","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.4158\/GL-2019-0405","article-title":"American association of clinical endocrinologists and american college of endocrinology guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care","volume":"25","author":"Yuen","year":"2019","journal-title":"Endocr. Prac."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1080\/17446651.2019.1689119","article-title":"Adult Growth Hormone Deficiency: Clinical Advances and Approaches to Improve Adherence","volume":"14","author":"Yuen","year":"2019","journal-title":"Expert. Rev. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1210\/jc.2013-1157","article-title":"Macimorelin (AEZS-130)-Stimulated Growth Hormone (GH) Test: Validation of a Novel Oral Stimulation Test for the Diagnosis of Adult GH Deficiency","volume":"98","author":"Garcia","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1210\/jc.2018-00665","article-title":"Macimorelin as a Diagnostic Test for Adult GH Deficiency","volume":"103","author":"Garcia","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1159\/000519232","article-title":"Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Macimorelin in Children with Suspected Growth Hormone Deficiency: An Open-Label, Group Comparison, Dose-Escalation Trial","volume":"94","author":"Ammer","year":"2021","journal-title":"Horm. Res. Paediatr."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Karoulias, S.Z., Taye, N., Stanley, S., and Hubmacher, D. (2020). The ADAMTS\/Fibrillin Connection: Insights into the Biological Functions of ADAMTS10 and ADAMTS17 and Their Respective Sister Proteases. Biomolecules, 10.","DOI":"10.3390\/biom10040596"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3109\/13816810.2012.666708","article-title":"Familial Spherophakia with Short Stature Caused by a Novel Homozygous ADAMTS17 Mutation","volume":"33","author":"Khan","year":"2012","journal-title":"Ophthalmic Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4679","DOI":"10.1073\/pnas.0305930101","article-title":"Ghrelin Stimulation of Growth Hormone Release and Appetite Is Mediated through the Growth Hormone Secretagogue Receptor","volume":"101","author":"Sun","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7974","DOI":"10.1038\/s41598-020-64883-8","article-title":"Genetic and Environmental Influences on Human Height from Infancy through Adulthood at Different Levels of Parental Education","volume":"10","author":"Jelenkovic","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1210\/clinem\/dgac510","article-title":"Growth Patterns of Children with Short Stature in Adulthood According to Auxological Status and Maturity at Birth","volume":"107","author":"Vogel","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"157","DOI":"10.4274\/jcrpe.v1i4.39","article-title":"Nutrition and Growth","volume":"1","author":"Lifshitz","year":"2009","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/s41586-022-05275-y","article-title":"A Saturated Map of Common Genetic Variants Associated with Human Height","volume":"610","author":"Yengo","year":"2022","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nrendo.2012.251","article-title":"Height Matters\u2014From Monogenic Disorders to Normal Variation","volume":"9","author":"Durand","year":"2013","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13059-015-0676-3","article-title":"The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) Family","volume":"16","author":"Kelwick","year":"2015","journal-title":"Genome Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"114","DOI":"10.4103\/abr.abr_138_22","article-title":"A Novel Missense Mutation in the TGF-\u03b2-Binding Protein-Like Domain 3 of FBN1 Causes Weill-Marchesani Syndrome with Intellectual Disability","volume":"12","author":"Hassani","year":"2023","journal-title":"Adv. Biomed. Res."},{"key":"ref_20","first-page":"790","article-title":"Whole Exome Sequencing Identifies a Novel Splice-Site Mutation in ADAMTS17 in an Indian Family with Weill-Marchesani Syndrome","volume":"20","author":"Shah","year":"2014","journal-title":"Mol. Vis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.ajhg.2009.09.011","article-title":"Homozygous Mutations in ADAMTS10 and ADAMTS17 Cause Lenticular Myopia, Ectopia Lentis, Glaucoma, Spherophakia, and Short Stature","volume":"85","author":"Morales","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1677\/joe.0.1800247","article-title":"Evidence Supporting Dual, IGF-I-Independent and IGF-I-Dependent, Roles for GH in Promoting Longitudinal Bone Growth","volume":"180","author":"Wang","year":"2004","journal-title":"J. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1159\/000125166","article-title":"Activation of Cholinergic Neurotransmission by Pyridostigmine Reverses the Inhibitory Effect of Hyperglycemia on Growth Hormone (GH) Releasing Hormone-Induced GH Secretion in Man: Does Acute Hyperglycemia Act through Hypothalamic Release of Somatostatin?","volume":"49","author":"Burguera","year":"1989","journal-title":"Neuroendocrinology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1507\/endocrj1954.17.369","article-title":"Effect of Changes in Plasma Free Fatty Acids Level on Secretion of Human Growth Hormone","volume":"17","author":"Tsushima","year":"1970","journal-title":"Endocrinol. Jpn."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1210\/endo-118-1-176","article-title":"Insulin-like Growth Factor I Action on Rat Anterior Pituitary Cells: Suppression of Growth Hormone Secretion and Messenger Ribonucleic Acid Levels","volume":"118","author":"Yamashita","year":"1986","journal-title":"Endocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/45230","article-title":"Ghrelin Is a Growth-Hormone-Releasing Acylated Peptide from Stomach","volume":"402","author":"Kojima","year":"1999","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1126\/science.140.3570.987","article-title":"Bersonsa, null Hypoglycemia: A Potent Stimulus to Secretion of Growth Hormone","volume":"140","author":"Roth","year":"1963","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/S0140-6736(67)90291-7","article-title":"Changes in Plasma Levels of Insulin and Growth-Hormone Levels after a Protein Meal","volume":"2","author":"Sukkar","year":"1967","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1749-6632.2010.05516.x","article-title":"Ghrelin: More than Endogenous Growth Hormone Secretagogue","volume":"1200","author":"Kojima","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1097\/MCO.0b013e328365b9be","article-title":"Ghrelin: Much More than a Hunger Hormone","volume":"16","author":"Pradhan","year":"2013","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1210\/jc.2008-0620","article-title":"Twenty-Four Hour Continuous Ghrelin Infusion Augments Physiologically Pulsatile, Nycthemeral, and Entropic (Feedback-Regulated) Modes of Growth Hormone Secretion","volume":"93","author":"Veldhuis","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1172\/JCI25303","article-title":"Loss of Constitutive Activity of the Growth Hormone Secretagogue Receptor in Familial Short Stature","volume":"116","author":"Pantel","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4334","DOI":"10.1210\/jc.2009-1327","article-title":"Recessive Isolated Growth Hormone Deficiency and Mutations in the Ghrelin Receptor","volume":"94","author":"Pantel","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3836","DOI":"10.1210\/en.2005-0212","article-title":"Endogenous Ghrelin Regulates Episodic Growth Hormone (GH) Secretion by Amplifying GH Pulse Amplitude: Evidence from Antagonism of the GH Secretagogue-R1a Receptor","volume":"146","author":"Zizzari","year":"2005","journal-title":"Endocrinology"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/13\/2259\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:05:36Z","timestamp":1760126736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/13\/2259"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,4]]},"references-count":34,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["diagnostics13132259"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics13132259","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2023,7,4]]}}}