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

Li, ChuanChen, RongyuFan, XinLuo, JingsiQian, JialeWang, JinXie, BoboShen, YipingChen, Shaoke2015-06-022015Li, Chuan, Rongyu Chen, Xin Fan, Jingsi Luo, Jiale Qian, Jin Wang, Bobo Xie, Yiping Shen, and Shaoke Chen. 2015. “EPHA4 haploinsufficiency is responsible for the short stature of a patient with 2q35-q36.2 deletion and Waardenburg syndrome.” BMC Medical Genetics 16 (1): 23. doi:10.1186/s12881-015-0165-2. http://dx.doi.org/10.1186/s12881-015-0165-2.1471-2350http://nrs.harvard.edu/urn-3:HUL.InstRepos:16121000Background: Waardenburg 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 presentation: We 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). Conclusions: PAX3 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.en-USChromosomal microarray2q35-q36.2Waardenburg syndromeShort statureEPHA4 haploinsufficiency is responsible for the short stature of a patient with 2q35-q36.2 deletion and Waardenburg syndromeJournal Article2015-06-0210.1186/s12881-015-0165-2