Frame shift mutations of the ZMPSTE24 gene in two siblings with restrictive dermopathy Aušra Matulevičienė a , Raimonda Meškienė a , Aušra Morkūnienė a , Laima Ambrozaitytė a , Raimundas Meškauskas c , Rasa Garunkštienė d , Nijolė Drazdienė b , Algirdas Utkus a and Vaidutis Kučinskas a Restrictive dermopathy (RD) is a rare lethal autosomal recessive genodermatosis, characterized by abnormally rigid skin with prominent superficial vasculature, erosions and epidermal hyperkeratosis, dysplastic clavicles, joint contractures, mouth fixed in the ‘O’ position, small pinched nose, and neonatal death. Mutations of ZMPSTE24 and LMNA genes are reported as the causes of RD, with those of ZMPSTE24 being more prevalent. Here, we report on a familial c.50delA (p.Lys17Serfs*21) mutation of the ZMPSTE24 gene, causing RD in two siblings. Clin Dysmorphol 25:7–11 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Clinical Dysmorphology 2016, 25:7–11 Keywords: lethal genodermatosis, restrictive dermopathy, ZMPSTE24 gene a Department of Human and Medical Genetics, b Centre of Neonatology, Clinics of Children’s Diseases, Faculty of Medicine, Vilnius University, c National Centre of Pathology and d Centre of Neonatology, Children’s Hospital, Affiliate of Vilnius University Hospital Santariškių Klinikos, Vilnius, Lithuania Correspondence to Aušra Matulevičienė, MD, PhD, Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania, Santariškių g. 2, Vilnius LT-08661, Lithuania Tel: +370 6 112 7287; fax: +370 5 239 8705; e-mail: ausra.matuleviciene@mf.vu.lt Received 24 June 2015 Accepted 19 August 2015 Introduction Restrictive dermopathy (RD; OMIM 275210) is a rare, lethal, autosomal recessive genodermatosis (the tight skin contracture syndrome), characterized by prematurity, intrauterine growth retardation, abnormally tight and rigid skin with prominent superficial vasculature, ero- sions and epidermal hyperkeratosis, bone mineralization defects, dysplastic clavicles, flexion contractures of the joints, micrognathia, a mouth fixed in the ‘O’ position, low-set ears, small pinched nose, antimongoloid eye slant, and early neonatal death (Graham and Esterly, 1999; Nijsten et al., 2002). The syndrome is usually caused by autosomal recessive mutations of ZMPSTE24, or, less frequently, by autosomal dominant mutations of the LMNA gene (Smigiel et al., 2010). RD was first described as a separate clinical syn- drome in 1986 by Witt et al. (1986) and Smigiel et al. (2010), and there have been around 60 known cases of RD to date (Thill et al., 2008), with no children of Lithuanian origin reported previously. Nearly all 25 previously reported neonates with RD had homozygous or compound hetero- zygous null mutations in the ZMPSTE24 gene (Ahmad et al., 2012). We report a case of two siblings from con- secutive pregnancies affected by RD. Case report The proband was the second child of healthy non- consanguineous parents, delivered by Cesarean section at 28 weeks’ gestation because of severe preeclampsia of the mother. The family history showed that the first child, also born preterm, had died because of respiratory insufficiency on his 16th day, having been diagnosed with ‘congenital ichthyosis’. Although we had no possi- bility to evaluate the clinical features of the latter infant, his phenotypic description appeared to be almost iden- tical to that of the proband. This second pregnancy was complicated by poly- hydramnios and threatened preterm delivery at 23 weeks’ gestation and preterm premature rupture of membranes at 24 weeks. Corticosteroids were adminis- tered for fetal lung maturation at 28 weeks’ gestation. The proband weighed 980 g (10th centile), with a body length of 34 cm (10th centile) and head circumference of 28 cm (90th centile). His Apgar scores were 7/8 at 1 and 5 min, respectively. Postnatally, he developed pro- gressive respiratory distress. This improved after the patient was intubated and received a surfactant at the 10th minute. Physical examination showed extensive areas of tight, shiny, translucent skin with multiple fissures on the neck and shoulders, and prominent cutaneous vessels with scurf observed on the neck area. Characteristic dys- morphic features were hypertelorism, antimongoloid slant, sparse eyelashes, small pinched nose, micrognathia, and an ‘O-shaped’ mouth. Multiple joint contractures of the hips, knees, ankles, elbows, and wrists with severely restricted active movements of the extremities were Original article 7 0962-8827 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MCD.0000000000000100 Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.