Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: evidence of genetic heterogeneity
Article first published online: 25 NOV 2010
© 2010 John Wiley & Sons A/S
Volume 81, Issue 2, pages 158–164, February 2012
How to Cite
Ahmad, Z., Phadke, S., Arch, E., Glass, J., Agarwal, A. and Garg, A. (2012), Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: evidence of genetic heterogeneity. Clinical Genetics, 81: 158–164. doi: 10.1111/j.1399-0004.2010.01580.x
- Issue published online: 12 JAN 2012
- Article first published online: 25 NOV 2010
- Accepted manuscript online: 23 OCT 2010 09:33AM EST
- Received 5 October 2010, revised and accepted for publication 18 October 2010
- Lamin A/C;
- mandibuloacral dysplasia;
- Restrictive dermopathy;
Ahmad Z, Phadke SR, Arch E, Glass J, Agarwal AK, Garg A. Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: evidence of genetic heterogeneity.
Restrictive dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the ‘o’ position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report three new cases of RD; all died within 3 weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, the second case had a novel homozygous c.1020G>A (p.Trp340X) null mutation in ZMPSTE24, but the third case, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease-causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly-shaped thoracic 5 vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020G>A ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified.