A Novel Deletion of IGF1 in a Patient With Idiopathic Short Stature Provides Insight Into IGF1 Haploinsufficiency

Context: Short stature is a common reason for referral to pediatric endocrinology centers. Frequently, the underlying etiology of short stature is unknown, resulting in a diagnosis of idiopathic short stature. Rare genetic defects in the GH/IGF-1 axis have been found to cause short stature. Objectiv...

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Published inThe journal of clinical endocrinology and metabolism Vol. 99; no. 1; pp. E153 - E159
Main Authors Batey, Lara, Moon, Jennifer E, Yu, Yongguo, Wu, Bingbing, Hirschhorn, Joel N, Shen, Yiping, Dauber, Andrew
Format Journal Article
LanguageEnglish
Published United States Endocrine Society 01.01.2014
Copyright by The Endocrine Society
Subjects
Child
DNA Copy Number Variations
Dwarfism - genetics
Gene Deletion
Growth Charts
Haploinsufficiency - physiology
Humans
Insulin-Like Growth Factor I - genetics
JCEM Online: Advances in Genetics
Male
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Summary:Context: Short stature is a common reason for referral to pediatric endocrinology centers. Frequently, the underlying etiology of short stature is unknown, resulting in a diagnosis of idiopathic short stature. Rare genetic defects in the GH/IGF-1 axis have been found to cause short stature. Objective: The objective of this study was to identify the genetic etiology of short stature in a patient with Idiopathic Short Stature and to review the clinical presentation of patients with genetic defects in IGF1, and specifically IGF-1 haploinsufficiency. Design/Setting/Participants: The index patient was evaluated at an academic medical center, and DNA was obtained from the proband and both parents. Intervention: Genome-wide copy number analysis was performed in the proband with confirmatory quantitative PCR in the proband and his parents. Main Outcome Measure: We measured novel copy number variants (CNVs) thought to explain the patient's short stature. Results: CNV analysis revealed that the proband carried a paternally inherited heterozygous IGF1 gene deletion. His phenotypic features are consistent with those found in previous case reports of IGF-1 deficiency. Conclusions: This study, as the first case of a complete heterozygous 1GF1 deletion, provides insight into the effects of true IGF-1 haploinsufficiency. Given the similarities in phenotype between the present proband and those previously described, it is highly likely that his IGF1 deletion is the cause for his short stature. Broadly, this study emphasizes how CNV analysis and other genetic sequencing techniques are evolving as an important tool to identify genetic causes underlying human disease, allowing for improved diagnosis and targeted treatment.
Bibliography:National Institute of Child Health and Human Development of the National Institutes of Health, support from the Translational Research Program at Boston Children's Hospital, and a Clinical Scholar Award from the Pediatric Endocrine Society. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health.
This work was conducted with support from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Institutes of Health Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers) as well as award number K23HD073351 from the
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2013-3106