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

BMC Medical Genetics

Shaoke Chen²  Yiping Shen¹  Bobo Xie²  Jin Wang²  Jiale Qian²  Jingsi Luo²  Xin Fan²  Rongyu Chen²  Chuan Li² 

[1] Claritas Genomics, Boston 02139, MA, USA;Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China

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

Others  :  1177680
DOI  :  10.1186/s12881-015-0165-2

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

【 摘 要 】

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.

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.

【 授权许可】

   
2015 Li et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Arias S, Mota M: Apparent non-penetrance for dystopia in Waardenburg syndrome type I, with some hints on the diagnosis of dystopia canthorum. J Genet Hum 1978, 26(2):103-131.
• [2]Farrer LA, Grundfast KM, Amos J, Arnos KS, Asher JH Jr, Beighton P, Diehl SR, Fex J, Foy C, Friedman TB, Greenberg J, Hoth C, Marazita M, Milunsky A, Morell R, Nance W, Newton V, Ramesar R, San Agustin TB, Skare J, Stevens CA, Wagner RG, Wilcox ER, Winship I, Andrew P: Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium. Am J Hum Genet 1992, 50(5):902-913.
• [3]Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N: Review and update of mutations causing Waardenburg syndrome. Hum Mutat 2010, 31(4):391-406.
• [4]Tassabehji M, Newton VE, Leverton K, Turnbull K, Seemanova E, Kunze J, Sperling K, Strachan T, Read AP: PAX3 gene structure and mutations: close analogies between Waardenburg syndrome and the Splotch mouse. Hum Mol Genet 1994, 3(7):1069-1074.
• [5]Pasteris NG, Trask BJ, Sheldon S, Gorski JL: Discordant phenotype of two overlapping deletions involving the PAX3 gene in chromosome 2q35. Hum Mol Genet 1993, 2(7):953-9.
• [6]Wu BL, Milunsky A, Wyandt H, Hoth C, Baldwin C, Skare J: In situ hybridization applied to Waardenburg syndrome. Cytogenet Cell Genet 1993, 63(1):29-32.
• [7]Lu-Kuo J, Ward DC, Spritz RA: Fluorescence in situ hybridization mapping of 25 markers on distal human chromosome 2q surrounding the human Waardenburg syndrome, type I (WS1) locus (PAX3 gene). Genomics 1993, 16(1):173-179.
• [8]Milunsky JM, Maher TA, Ito M, Milunsky A: The value of MLPA in Waardenburg syndrome. Genet Test 2007, 11(2):179-182.
• [9]Matsunaga T, Mutai H, Namba K, Morita N, Masuda S: Genetic analysis of PAX3 for diagnosis of Waardenburg syndrome type I. Acta Otolaryngol 2013, 133(4):345-351.
• [10]Epstein DJ, Malo D, Vekemans M, Gros P: Molecular characterization of a deletion encompassing the splotch mutation on mouse chromosome 1. Genomics 1991, 10(1):89-93.
• [11]Vogan KJ, Epstein DJ, Trasler DG, Gros P: The splotch-delayed (Spd) mouse mutant carries a point mutation within the paired box of the Pax-3 gene. Genomics 1993, 7(2):364-369.
• [12]Epstein DJ, Vogan KJ, Trasler DG, Gros P: A mutation within intron 3 of the Pax-3 gene produces aberrantly spliced mRNA transcripts in the splotch (Sp) mouse mutant. Proc Natl Acad Sci U S A 1993, 90(2):532-536.
• [13]Jing X, Miyajima M, Sawada T, Chen Q, Iida K, Furushima K, Arai D, Chihara K, Sakaguchi K: Crosstalk of humoral and cell-cell contact-mediated signals in postnatal body growth. Cell Rep 2012, 2(3):652-665.
• [14]Warter S, Lausecker C, Pennerath A: A girl with a deletion (2) (q34q36): cytogenetic and clinical observations. Hum Genet 1976, 32(2):225-227.
• [15]Kirkpatrick SJ, Kent CM, Laxova R, Sekhon GS: Waardenburg syndrome type I in a child with deletion (2) (q35q36.2). Am J Med Genet 1992, 44(5):699-700.
• [16]Nye JS, Balkin N, Lucas H, Knepper PA, McLone DG, Charrow J: Myelomeningocele and Waardenburg syndrome (type 3) in patients with interstitial deletions of 2q35 and the PAX3 gene: possible digenic inheritance of a neural tube defect. Am J Med Genet 1998, 75(4):401-408.
• [17]Melnyk AR, Muraskas J: Interstitial deletion of chromosome 2 region in a malformed infant. Am J Med Genet 1993, 45(1):49-51.