EPHA4 haploinsufficiency is responsible for the short stature of a patient with 2q35-q36.2 deletion and Waardenburg syndrome

BMC Medical Genetics

Case Report

Bobo Xie¹  Chuan Li¹  Rongyu Chen¹  Shaoke Chen¹  Jingsi Luo¹  Jiale Qian¹  Jin Wang¹  Xin Fan¹  Yiping Shen² 

[1] Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China;Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China;Department of Laboratory Medicine, Department of Pathology, Boston Children’s Hospital, Harvard Medical School, 02115, Boston, MA, USA;Claritas Genomics, 02139, Boston, MA, USA;

关键词: Chromosomal microarray;    2q35-q36.2;    PAX3;    Waardenburg syndrome;    EPHA4;    Short stature;   

DOI  :  10.1186/s12881-015-0165-2

 received in 2014-11-13, accepted in 2015-03-20,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundWaardenburg syndrome type I (WS1), an auditory-pigmentary genetic disorder, is caused by heterozygous loss-of-function mutations in PAX3. Abnormal physical signs such as dystopia canthorum, patchy hypopigmentation and sensorineural hearing loss are common, but short stature is not associated with WS1.Case presentationWe reported a 4-year and 6 month-old boy with a rare combination of WS1 and severe short stature (83.5 cm (−5.8SD)). His facial features include dystopia canthorum, mild synophrys, slightly up-slanted palpebral fissure, posteriorly rotated ears, alae nasi hypoplasia and micrognathia. No heterochromia was noticed. He had a normal intelligence quotient and hearing. Insulin-like growth factor-1 (IGF-1) was 52.7 ng/ml, lower than the normal range (55 ~ 452 ng/ml) and the peak growth hormone level was 7.57 ng/ml at 90 minutes after taking moderate levodopa and pyridostigmine bromide. The patient exhibited a good response to human growth hormone (rhGH) replacement therapy, showing a 9.2 cm/year growth rate and an improvement of 1 standard deviation (SD) of height after one year treatment. CMA test of patient’s DNA revealed a 4.46 Mb de novo deletion at 2q35-q36.2 (hg19; chr2:221,234,146-225,697,363).ConclusionsPAX3 haploinsufficiency is known to cause Waardenburg syndrome. Examining overlapping deletions in patients led to the conclusion that EPHA4 is a novel short stature gene. The finding is supported by the splotch-retarded and epha4 knockout mouse models which both showed growth retardation. We believe this rare condition is caused by the haploinsufficiency of both PAX3 and EPH4 genes. We further reported a growth response to recombinant human growth hormone treatment in this patient.

【 授权许可】

Unknown   
© Li et al.; licensee BioMed Central Ltd. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.