Abstract
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.
Highlights
Waardenburg syndrome type I (WS1), an auditory-pigmentary genetic disorder, is caused by heterozygous loss-of-function mutations in Paired box 3 (PAX3)
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
In addition to Ephrin Receptor A type 4 (EPHA4) and PAX3, there are about 10 more OMIM genes involved at the deletion interval of our patient, three are associated with human diseases (AP1S3 is associated with the susceptibility to pustular psoriasis-15; MRPL44 is likely associated with Combined oxidative phosphorylation deficiency 16; CUL3 is associated with Pseudohypoaldosteronism, type IIE)
Summary
The rare combination of Waardenburg syndrome phenotype and short stature observed in our patient can be explained by the haploinsufficiency of both PAX3 and EPHA4 genes involved within the deletion. Recombinant human growth hormone treatment improved the height of the patient; suggesting that diagnosis may help in determining utility of growth hormone in other individuals with EPHA4 associated short stature. Genetic analysis of PAX3 for diagnosis of Waardenburg syndrome type I. Molecular characterization of a deletion encompassing the splotch mutation on mouse chromosome 1. The splotch-delayed (Spd) mouse mutant carries a point mutation within the paired box of the Pax-3 gene. Waardenburg syndrome type I in a child with deletion (2) (q35q36.2). 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.
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