Genetic Evaluation of Idiopathic Short Stature

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KARAMAN B., BAŞ F., Najaflı A., Avcı Ş., Kardelen A. D., Toksoy G., ...More

European Society for Paediatric Endocrinology (ESPE)58th Annual Meeting, 6 - 08 September 2019

  • Publication Type: Conference Paper / Summary Text
  • Istanbul University Affiliated: Yes


Introduction: Short stature is a multifactorial condition caused
by both genetic and environmental factors. Genetic causes include
chromosomal disorders and diseases inherited by monogenic and
multifactorial inheritance. The purpose of genetic evaluation in
short stature is not only for diagnosis, but also to provide additional
information to the patients and their families about prognosis of
the disease, treatment approaches and genetic counseling.

Aim: This study aims to investigate genetic etiology by using
cytogenetic, molecular cytogenetic and next generation sequencing
methods in patients with idiopathic short stature.
Patients and Method: In this study, 189 patients, in
whom chronic diseases, hormonal disorders and skeletal dysplasia
were excluded, and diagnosed as idiopathic short stature were
included in the study. We did an algorithmic approach for genetic
screening.In the first phase cytogenetic investigations were done
and chromosomal anomalies were excluded. Then SHOX gene deletions
were investigated by fluorescent in situ hybridization and
possible submicroscopic deletions and duplications by a-CGH
technique. After these evaluation 41patients, found to have normal
chromosomal segments, underwent to next generation sequencing
of the Ion Torrent platform with 25 gene-containing panelgene
tests. Gene panel consisted of 10 genes associated with short
HOX,STAT5B) and 15 genes (POU1F1,PROP1,HESX1,LHX3,LH
X3,HHIP)associated with isolated or multiple pituitary hormone
Results: Of the 189 patients with short stature, 16(8.5%) had
chromosomal anomaly,1 had microdeletion in the SHOX gene
with FISH examination, and 1 patient had a deletion of 2.7MB
in the 5q32 region with a-CGH assay. In five patients, 5 different
variations were detected (BMP4,GHR, IGSF1, LHX4 and-
PROKR2) (one in short stature genes, 4 in MPHD genes). One of
this mutations was novel, one of them was previously defined and
3 of them were found in databases. The changes that were thought
to be of clinical importance were confirmed by Sanger sequencing
method. It was shown that 4 heterozygous changes found in the
segregation analysis were also found in the healthy individuals in
the family and in one patient with homozygous change, the parents
were shown to be heterozygous carriers.
Conclusion: Short stature for gene panel test was first evaluated
in Turkey. We recommend cytogenetic examination before
molecular analysis to exclude chromosomal anomalies and microdeletions.
Because short stature has a wide genetic spectrum, we
think that the targeted panels are not sufficient. We propose whole
exom or whole genome sequencing analysis with a healthy control
group and the index patients and parents.