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provided by Elsevier - Publisher Connector Pediatrics and Neonatology (2013) 54, 198e201

Available online at www.sciencedirect.com

journal homepage: http://www.pediatr-neonatol.com

CASE REPORT Restrictive Dermopathy: Report of Two Siblings

Chih-Sheng Lu a, Shu-Chuan Wu a,*, Jia-Woei Hou b, Chih-Ping Chu c, Lo-Lin Tseng a, Hung-Chi Lue a,d

a Department of Pediatrics, Saint Mary’s Hospital Luodong, Luodong, Yilan County, Taiwan b Division of Medical Genetics, Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan c Department of Pathology, Saint Mary’s Hospital Luodong, Luodong, Yilan County, Taiwan d Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan

Received Dec 4, 2009; received in revised form Sep 6, 2011; accepted Oct 18, 2011

Key Words Restrictive dermopathy (RD) is a rare and lethal autosomal recessive syndrome characterized congenital anomaly; by very tight, thin, and easily eroded skin and contracture of joints. We present two siblings in genetic analysis; a family. Case 1, a female neonate, showed mild characteristic presentations of RD and restrictive survived for 16 days, and Case 2, a male neonate, was stillborn with typical severe features dermopathy; of RD. His skin biopsy showed typical histological findings, and genetic study revealed a homo- ZMPSTE24 gene zygous nonsense mutation on theexon6ofzincmetalloproteinase STE24 (ZMPSTE24). The exact pathogenic mechanism of RD remains poorly understood. The most recent studies on mutations in lamin A and/or ZMPSTE24 have shed some light on the pathophysiology of RD and may help direct the development of future therapeutic approaches. Copyright ª 2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.

1. Introduction of known , involving mutations in lamin A/C (LMNA/C) and/or zinc metalloproteinase STE24 (ZMPSTE24), both associated in the same processing Restrictive dermopathy (RD) is a form of lethal geno- 1 dermatosis, which represents one extreme of the spectrum pathway. Newborns with this condition are usually born prematurely and bear the appearance of having been wrapped in a cellophane plastic sheet because of very tight shiny skin, resulting in limited joint movement and * Corresponding author. Department of Pediatrics, Saint Mary’s restricted growth of the underlying tissues, and often Hospital Luodong, Number 160, Jhongjheng South Road, Luodong, Yilan County 265, Taiwan. rupturing and lacerating over the joints during delivery. E-mail address: [email protected] (S.-C. Wu). Early mortality is common in affected babies because of

1875-9572/$36 Copyright ª 2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.pedneo.2012.11.012 Two siblings with restrictive dermopathy 199 multiple anomalies and unavailability of any specific (Figure 1). There was a skin laceration of approximately treatment. Here, we report a case of a family with two of 3 cm in depth over the anterior neck because of rupture of the three children being RD patients. The first child was the tight skin during delivery. The family consented to our normal. The second child, a female neonate (Case 1), suggestions of postmortem examinations. An X-ray showed presented with mild physical characteristic features of RD clavicular hypoplasia. Blood specimens from the parents as and survived for more than 2 weeks; however, the third well as from the infant were sent for genetic analysis. child, a boy (Case 2), was stillborn with severe clinical Chromosome study of the infant showed a 46,XY karyotype. features of RD. Postmortem examinations and genetic Autopsy findings included pulmonary atelectasis, marked analyses were performed to confirm RD. congestion of the lungs, and hemorrhage in the subgaleal area and subarachnoid space, and also in the esophagus and 2. Case Reports testes. Cardiac findings included patent ductus arteriosus and patent foramen ovale. Microscopic examination of the skin showed a smooth epidermis with flattened rete ridges, The parents of the infants we studied were of indigenous a thin dermis with horizontal collagen fibers, sparse elastic Taiwanese descent and lived in a remote area. They denied fibers, and a straight dermohypodermal border (Figure 2). any consanguinity, congenital anomaly, or infant deaths The results of the genetic analysis, which involved among their relatives. No prenatal examination was per- screening of all 10 exons of the ZMPSTE24 gene, showed formed during any pregnancies. At the time of this study, a homozygous stop codon TAA in exon 6 c.715 G>T [GAA the first-born boy was 5 years old and healthy. (glutamic acid) TAA (stop), E239X] (Figure 3). The parents were heterozygous carriers (Figure 3). On the basis of the 2.1. Case 1 above findings, RD was confirmed.

The second child of the family, a girl, was born at 31 weeks of gestation by cesarean delivery because of breech 3. Discussion presentation and weighed 1425 g. At the time of delivery, the mother and father were 29 and 30 years old, respec- Having a malformed or deformed newborn may be tively. Since the infant presented with respiratory distress, a shocking experience for parents and families. In 1983, she was sent to the neonatal intensive care unit. She was Toriello et al2 presented the first clinical description of found to have dysmorphic features with shiny tight skin and typical manifestations about two affected siblings, whereas contracture of multiple joints. Large deep bilateral inguinal the term ‘‘restrictive dermopathy’’ was first used by Witt lacerations were caused due to flexion of the hip joints et al.3 They described RD as a syndrome characterized by during delivery. Clavicular hypoplasia was revealed by X-ray rigid or tight skin involving the entire body, dysmorphic examination. During hospitalization, the baby suffered face, arthrogryposis multiplex congenita, and pulmonary from metabolic acidosis, respiratory distress syndrome hypoplasia.3 (grade II), disseminated intravascular coagulopathy, Because of similarities in the clinical features between anemia, and hyperbilirubinemia, all of which were subse- RD and , recently, Navarro et al4 checked RD quently corrected and treated. The inguinal laceration patients for mutations in the LMNA gene and found that the wounds were repaired surgically, and secondary repair was loss of ZMPSTE24 (FACE-1) caused autosomal recessive RD done on right side due to dehiscence. Hydrocortisone and accumulation of LMNA precursors. They studied genetic acetate cream and Vaseline cream were used for skin care, and the condition of the skin gradually normalized. Chro- mosome study showed a 46,XX karyotype. On the 16th day, after weaning from oxygen supplementation for 2 days, she developed sudden onset of bradycardia and cyanosis and expired despite vigorous efforts at resuscitation. The family refused autopsy.

2.2. Case 2

The third child, a boy, was born 1 year after the baby in Case 1. The mother visited the obstetrician in labor at 33 weeks of gestation. Emergency cesarean delivery was performed because of fetal distress. The baby was stillborn with a weight of 1220 g and found to have multiple congenital anomalies, including hyperkeratosisdrigid, tight, and translucent skin with prominent vessels that restricted underlying tissue movement; absence of Figure 1 The patient in Case 2 presenting tight and shiny skin eyebrows and eyelashes with severe conjunctival ectro- and multiple immovable joints. (A) Prominent deep lacerations pion; micrognathia with an “O”-shaped mouth, resulting in on the neck; (B) absence of eyebrows and eyelashes with severe difficulty closing or opening the mouth; low pinched nose conjunctival ectropion; (C) micrognathia with a very prominent and low-set ears; and contracture and immovability in “O”-shaped mouth and multiple contractures and immovable multiple joints and anus with eventration of inner mucosa joints; (D) eventration of anal mucosa. 200 C.-S. Lu et al

analysis in our Case 2 (see Figure 3), which involved screening of all 10 exons of the ZMPSTE24 gene, showed that a homozygous stop codon TAA was detected in exon 6 c.715 G>T [(GAA (glutamic acid) TAA (stop), E239X]. Both parents were found to be heterozygous carriers. In RD patients, there are several clinical features at birth that resemble premature aging disorders, including hypoplastic clavicles, bone density reduction, sparse eyebrows and eyelashes, micrognathism, and joint contractures, which are similar to the features of Hutch- insoneGilford progeria syndrome (HGPS).1 However, RD is easily differentiated from other forms of congenital fetal akinesia deformation sequence such as PenaeShokeir syndrome, cerebrooculofacioskeletal syndrome, Parana´ Figure 2 Histologic examination of the skin. (A) Smooth hard-skin syndrome, and some lethal congenital syndromes epidermis; (B) flattened rete ridges; (C) thin dermis; (D) hori- involving the skin and bone, such as Neu-Laxova, aplasia zontal collagen fibers and sparse elastic fibers; (E) a straight cutis congenita, and lethal multiple pterygium syndrome.6,7 dermohypodermal border. The diagnosis of RD was based on the clinical and histopathologic findings, including a fixed facial expression (“porcelain face”) with palpebral fissures inclined laterally relations and found that several enzymes were involved in downward, microstomia with the mouth in an “O” position, the processing of prelamin A (the precursor) to mature micrognathia and low-set rear-inclined ears, prominent LMNA. The gene, ZMPSTE24, encodes an endoprotease that blood vessels in the skin, and contracture of all the joints.8 is essential for the post-translational cleavage of LMNA Histopathologic examinations of the skin in RD patients precursor and the production of mature LMNA. Research show a smooth epidermis and a relatively thin dermis with also noted that a functional knockout of ZMPSTE24 may an abnormal dermal connective tissue structure in which cause severe RD, resulting in early neonatal death.5 The the collagen fibers were arranged more or less horizontally autosomal recessive inheritance of RD suggested a further and parallel to the epidermis; further, in these patients, molecular defect either in the second ZMPSTE24 allele or in the number of elastin fibers showed a sharp decrease. another gene involved in LMNA processing.4 The genetic Various adnexal structures were present, but the hair

Figure 3 Molecular study of the ZMPSTE24 gene and the family tree. A homozygous stop codon TAA was detected on exon 6 c.715 G>T [GAA (glutamic acid) TAA (stop), E239X] in the patient after screening all 10 exons of the ZMPSTE24 gene. The parents were heterozygous carriers. Two siblings with restrictive dermopathy 201 follicles had an abortive appearance.8 In our Case 1, we References observed only mild physical characteristics with shiny tight skin and contracture of joints. However, typical clinical 1. Navarro C, De Sandre-Giovannoli A, Bernadr R, Boccaccio I, characteristics were noted in Case 2; furthermore, micro- Boyer A, Genevie`ve D, et al. Lamin A and ZMPSTE 24 (FACE-1) scopic examination of the skin showed a smooth epidermis defects cause nuclear disorganization and identify restrictive with flattened rete ridges, a thin dermis with horizontal dermopathy as a lethal neonatal . Hum Mol Genet collagen fibers, sparse elastin fibers, and a straight der- 2004;13:2493e503. mohypodermal border. 2. Toriello VH, Higgins VJ, Waterman DF. Letter to the editor: d Consistent with prior findings, including skin tear at the autosomal recessive aplasia cutis congenita report of two e inguinal and frontal neck region that developed during affected sibs. Am J Med Genet 1983;15:153 6. 3. Witt DR, Hayden MR, Holbrook KA, Dale BA, Baldwin VJ, delivery due to the tight skin and contracture of joints,9 our Taylor GP. Restrictive dermopathy: a newly recognized auto- Case 1 showed prominent and deep bilateral inguinal somal recessive skin dysplasia. Am J Med Genet 1986;24: lacerations due to breech presentation and Case 2 showed 631e48. a deep laceration on the anterior neck region. These 4. Navarro C, Cadinanos J, De Sandre-Giovannoli A, Bernard R, complications may necessitate further surgical interven- Courrier S, Boccaccio I, et al. Loss of ZMPSTE 24 (FACE-1) causes tions, as seen in case 1. autosomal recessive restrictive dermopathy and accumulation Live-born infants have usually died within the 1st week of Lamin A precursors. Hum Mol Genet 2005;14:1503e13. of their lives. In our Case 1, the patient survived up to the 5. Denecke J, Brune T, Feldhaus T, Robenek H, Kranz C, 16th postnatal day under intensive skin care, including Auchus RJ, et al. A homogenous ZMPSTE24 null mutation in repair of the open skin lacerations, avoidance of radiant combination with a heterozygous mutation in the LMNA gene causes HutchinsoneGilford progeria syndrome (HGPS): insights heat, high humidity isolate, and placement of the patient in into the pathophysiology of HGPS. Hum Mutat 2006;6:524e31. a comfortable position. Unfortunately, the baby died due to 6. Mau U, Kendziorra H, Kaiser P, Enders H. Restrictive dermop- sudden onset of bradycardia and cyanosis. athy: report and review. Am J Med Genet 1997;71:179e85. Researchers have provided evidence that fetal biopsy 7. Hou JW, Mai CF. Restrictive dermopathy in two sisters. Chang specimens obtained during the 20th week of gestation were Gung Med J 2003;26:510e4. nondiagnostic,10 since the abnormalities usually appear 8. Straver B, Koopmans AK, van Hagen JM, Fetter WP. Restrictive after 22e24 weeks of gestation. High-resolution or three- dermopathy: a rare, lethal genodermatosis. Ned Tijdschr dimensional ultrasonography might be helpful for subse- Geneeskd 2005;149:2062e6. quent pregnancy.7 Molecular diagnosis using chorionic 9. Sillevis Smitt JH, van Asperen CJ, Niessen CM, Beemer FA, van villous sample has also been reported to facilitate prenatal Essen AJ, Hulsmans RF, et al. Restrictive dermopathy report of 12 cases. Arch Dermatol 1998;134:577e9. diagnosis as well.11 Removal of unprocessed prelamin 10. Happle R, Stekhoven JH, Hamel BC, Kollee LA, Nijhuis JG, A (progerin) or defective DNA repair could be potential Anton-Lamprecht I, et al. Restrictive dermopathy in two 4 therapeutic strategies for the treatment of HGPS in future. brothers. Arch Dermatol 1992;128:232e5. Any future implications might require more emphasis on 11. Jagadeesh S, Bhat L, Suresh I, Muralidhar SL. Prenatal diagnosis genetic counseling and prenatal diagnosis. of restrictive dermopathy. Indian Pediatr 2009;46:349e51.