A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency.
BACKGROUND
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.


METHODS
The index patient was evaluated at an academic medical center, and DNA was obtained from the proband and both parents.


METHODS
Genome-wide copy number analysis was performed in the proband with confirmatory quantitative PCR in the proband and his parents.


METHODS
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.
Division of Endocrinology (L.B., J.E.M., J.N.H., A.D.), Boston Children's Hospital, Boston, Massachusetts 02115; Shanghai Children's Medical Center (Y.Y.), Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; Pediatrics Institute (B.W.), Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai 201102, PR China; Program in Medical and Population Genetics (J.N.H.), Broad Institute, Cambridge, Massachusetts 02142; Department of Genetics (J.N.H.), Harvard Medical School, Boston, Massachusetts 02115; Department of Pathology (Y.S.), Harvard Medical School, and Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts 02115; and Shanghai Children's Medical Center (Y.S.), Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
Lara
L
Batey
Jennifer E
JE
Moon
Yongguo
Y
Yu
Bingbing
B
Wu
Joel N
JN
Hirschhorn
Yiping
Y
Shen
Andrew
A
Dauber
D002648:Child; D056915:DNA Copy Number Variations; D004392:Dwarfism / Q000235:genetics*; D017353:Gene Deletion; D057238:Growth Charts; D057895:Haploinsufficiency / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male
D007334:Insulin-Like Growth Factor I