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


METHODS
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.
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. veo12398@126.com.
Chuan
C
Li
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. robbinchen2009@foxmail.com.
Rongyu
R
Chen
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. fanxin602@163.com.
Xin
X
Fan
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. ljs0815freedom@163.com.
Jingsi
J
Luo
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. qjl220@163.com.
Jiale
J
Qian
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. jinwj521@126.com.
Jin
J
Wang
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. hnxiebobo@126.com.
Bobo
B
Xie
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. yiping.shen@childrens.harvard.edu.|Department of Laboratory Medicine, Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. yiping.shen@childrens.harvard.edu.|Claritas Genomics, Boston, MA, 02139, USA. yiping.shen@childrens.harvard.edu.
Yiping
Y
Shen
Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China. chenshaoke123@163.com.
Shaoke
S
Chen
D000818:Animals; D001827:Body Height / Q000187:drug effects / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D057895:Haploinsufficiency; D019382:Human Growth Hormone / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D036122:Receptor, EphA4 / Q000235:genetics*; D014849:Waardenburg Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*
D019382:Human Growth Hormone; D036122:Receptor, EphA4