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Background
This is a rare inherited disorder characterized by abnormally tight noncompliant skin. Patients have flexion contractures of the extremities, low set malformed ears, micrognathia, hypertelorism, and a small fixed open mouth. Abnormalities of the hair and nails, linear skin splits, and ectropion are variably present.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION EPIDEMIOLOGIC ASSOCIATIONS OBSTETRICAL HISTORY Polyhydramnios, intrauterine growth retardation, decreased fetal movement, and premature rupture of membranes with birth at 29 to 37 weeks gestation.
PATHOGENESIS CHARACTERIZATION GENERAL Autosomal dominant inheritance
Restrictive dermopathy: a case report and a critical review of all hypotheses of its origin.Nijsten TE, De Moor A, Colpaert CG, Robert K, Mahieu LM, Lambert J.
Department of Dermatology, University Hospital Antwerp, Antwerp, Belgium.
Pediatr Dermatol. 2002 Jan-Feb;19(1):67-72. Abstract quote Restrictive dermopathy (RD) is a rare, fatal, autosomal recessive genodermatosis in which tautness of a translucent thin skin is the major clinical observation. This causes an intrauterine fetal akinesia deformation sequence (FADS) resulting in polyhydramnios, reduced fetal movements at around 31 weeks gestation, dysmorphic facies, arthrogryposis, and early neonatal death because of respiratory insufficiency.
The characteristic histologic abnormalities of the skin are located in a thin dermis, consisting of compactly arranged collagen fibers, scant elastic fibers, and poorly developed skin appendages. The epidermal rete ridges are flattened and the dermal-hypodermal border is remarkably straight. The etiology of these changes remains unclear. We tested several existing hypotheses and could not confirm them. These included fibroblast dysfunction, abnormal keratin composition, desmosomal changes, and increased proinflammatory cytokines [tumor necrosis factor (TNF)-alpha and interleukin (IL)-6].
We conclude that RD is a relatively easy clinical and pathologic diagnosis, but that the pathogenesis of the disease is not clarified.
FIBROBLASTS
Restrictive dermopathy: a disorder of fibroblasts.Paige DG, Lake BD, Bailey AJ, Ramani P, Harper JI.
Department of Dermatology, Hospital for Sick Children, London, U.K.
Br J Dermatol. 1992 Dec;127(6):630-4 Abstract quote Restrictive dermopathy is a rare, lethal genodermatosis, characterized by a thin, tightly adherent skin which causes a dysmorphic facies, arthrogryposis and respiratory insufficiency.
The recorded cases to date show a remarkable phenotypic similarity. Thinning of the dermis and the arrangement of collagen in parallel bundles appear to be constant findings.
We have found many dead and degenerating fibroblasts in the dermis on ultrastructural examination, and have demonstrated their poor growth in vitro. Studies of collagen from a skin sample showed a marked increase in mature cross-links, indicating a decrease in skin collagen turnover.
These findings suggest a primary disorder of fibroblasts, and may explain the apparent arrest in growth and differentiation of the skin which appears to be important in the pathogenesis of this rare condition.
INTEGRINS
Restrictive dermopathy: a disorder of skin differentiation with abnormal integrin expression.Dean JC, Gray ES, Stewart KN, Brown T, Lloyd DJ, Smith NC, Pope FM.
Department of Medical Genetics, University of Aberdeen Medical School, UK.
Clin Genet. 1993 Dec;44(6):287-91. Abstract quote Clinical features and histological findings in two sibs who died from restrictive dermopathy in the neonatal period are described.
Fibroblasts cultured from a skin biopsy from the second sib and fibroblasts from normal neonatal skin were studied using monoclonal antibodies to visualise integrin subunits by immunocytochemistry. Restrictive dermopathy fibroblasts displayed increased expression of the alpha-1 and alpha-2 subunits of integrin, those responsible for collagen binding.
The increase was not matrix dependent. Integrins may play an important role in tissue differentiation, and our findings support the hypothesis that restrictive dermopathy is a disorder of skin differentiation.
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOGRAPHS Skeletal abnormalities especially involving the clavicles and long bones
Restrictive dermopathy.Reed MH, Chudley AE, Kroeker M, Wilmot DM.
Department of Radiology, Children's Hospital, Winnipeg, Manitoba, Canada.
Pediatr Radiol. 1993;23(8):617-9 Abstract quote Restrictive dermopathy is an inherited syndrome characterized clinically by severe growth retardation, abnormal skin, characteristic facies, and multiple congenital contractures.
Distinctive radiologic features include deficient mineralization of the clavicles and the skull, overtubulation and frequent modeling defects of the long bones, and occasional abnormalities of the ribs and scapulae.ULTRASOUND
Restrictive dermopathy and associated prenatal ultrasound findings: case report.van der Stege JG, van Straaten HL, van der Wal AC, van Eyck J.
Department of Perinatal Medicine, Sophia Hospital, Zwolle, The Netherlands.
Ultrasound Obstet Gynecol. 1997 Aug;10(2):140-1 Abstract quote Restrictive dermopathy is a lethal autosomal recessive skin disease. Prenatal diagnosis has not yet been reported.
We present a case of restrictive demography and describe the associated prenatal sonographic findings.
A continuously open mouth was the most striking feature and this sonographic finding may be a marker of a skin disease.
CLINICAL VARIANTS CHARACTERIZATION
Restrictive dermopathy and fetal behaviour.Mulder EJ, Beemer FA, Stoutenbeek P.
Department of Obstetrics, Neonatology, and Gynaecology, University Medical Centre, Wilhelmina Children's Hospital, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
Prenat Diagn. 2001 Jul;21(7):581-5 Abstract quote We report three siblings from consecutive pregnancies affected with restrictive dermopathy (RD). During the second pregnancy, fetal behavioural development and growth were studied extensively using ultrasound at 1-4 week intervals.
Dramatic and sudden changes occurred in fetal body movements and growth but not until the end of the second trimester of pregnancy. Prominent at that time were prolonged periods of fetal quiescence and very low heart rate variability, together with abnormally executed body movements of short duration. Retarded femoral development and jerky abrupt fetal body movements (abnormal movement quality) were already present in the early second trimester of pregnancy. Facial anomalies emerged despite the presence of fetal mouth movements.
The clinical features of RD were only partly explained by present knowledge of skin development and the fetal akinesia deformation sequence hypothesis.
Quantitative assessment of fetal movements proved to be a poor early marker for antenatal diagnosis of this disorder.
Restrictive dermopathy. Report of 12 cases. Dutch Task Force on Genodermatology.Smitt JH, van Asperen CJ, Niessen CM, Beemer FA, van Essen AJ, Hulsmans RF, Oranje AP, Steijlen PM, Wesby-van Swaay E, Tamminga P, Breslau-Siderius EJ.
Department of Dermatovenereology, University of Amsterdam, the Netherlands.
Arch Dermatol. 1998 May;134(5):577-9. Abstract quote BACKGROUND: This study describes 12 cases of restrictive dermopathy seen during a period of 8 years by the Dutch Task Force on Genodermatology. We present these unique consecutive cases to provide more insight into the clinical picture and pathogenesis of the disease.
OBSERVATIONS: Clinical features in more than 85% of these children were prematurity, fixed facial expression, micrognathia, mouth in O position, rigid and tense skin with erosions and denudations, and multiple joint contractures. Ten patients underwent histopathologic skin biopsy. The biopsy results showed flattening of rete ridges in all 10 patients, a thin dermis with collagen aligned parallel to the epidermis in 9 patients, and poorly developed dermal appendages in 9 patients. Additional findings in individual patients included blepharophimosis, inguinal skin tear, skin tear in the frontal neck area that developed during delivery, absent eyelashes, a wide ascendent aorta, and dextrocardia. Fibroblast cultures taken from 5 patients did not show abnormal alpha 2 beta 1 and alpha 1 beta 1 integrin expressions.
CONCLUSIONS: The alleged rarity of restrictive dermopathy may be partially caused by medical unfamiliarity with this entity, despite its characteristic clinical and histopathologic picture. The pathogenesis of the disease still needs to be elucidated.
Restrictive dermopathy: report and review.Mau U, Kendziorra H, Kaiser P, Enders H.
Department of Clinical Genetics, University of Tuebingen, Germany.
Am J Med Genet. 1997 Aug 8;71(2):179-85. Abstract quote Restrictive dermopathy (RD) is a lethal autosomal recessive genodermatosis (MIM No. 275210) in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence (FADS). Polyhydramnios with reduced fetal movements is followed by premature delivery at around 31 weeks gestation.
Manifestations include a tightly adherent, thin, translucent skin with prominent vessels, typical facial changes, generalized joint contractures, enlarged fontanelles, dysplasia of clavicles, respiratory insufficiency, and an enlarged placenta with short umbilical cord. Histologic abnormalities of the skin include thin dermis with paucity and hypoplasia of the appendages and abnormally arranged collagen bundles. Elastic fibers are nearly missing. The subcutaneous fat is slightly increased. These skin findings usually appear after 22 or 24 weeks of gestation, which is why prenatal diagnosis with skin biopsy may fail.
This disease is easily differentiated from other congenital FADS, such as Pena-Shokeir syndrome, COFS syndrome, Parana hard-skin syndrome, etc. We report on an affected boy of consanguineous parents and 30 previous cases are reviewed.
Restrictive dermopathy: a lethal congenital skin disorder.Hoffmann R, Lohner M, Bohm N, Leititis J, Helwig H.
Institute of Pathology, Paediatric Pathology Section, Freiburg, Federal Republic of Germany.
Eur J Pediatr. 1993 Feb;152(2):95-8. Abstract quote Restrictive dermopathy is a recently described lethal congenital disorder of the skin with an autosomal recessive mode of inheritance.
The rigidity of the skin impairs fetal movements in utero and causes arthrogryposis, as well as highly characteristic facial features and pulmonary hypoplasia.
We report two cases of restrictive dermopathy in prematurely born infants, describe the typical pathological findings and discuss this disorder in the context of the fetal akinesia/hypokinesia deformation sequence.
Restrictive dermopathy. Report of two affected siblings and a review of the literature.Welsh KM, Smoller BR, Holbrook KA, Johnston K.
Department of Dermatology, Stanford University, Calif.
Arch Dermatol. 1992 Feb;128(2):228-31. Abstract quote BACKGROUND--Restrictive dermopathy is a lethal genetic disorder consisting of abnormally tight skin, generalized joint contractures, distinctive facies, and pulmonary hypoplasia. Autosomal recessive inheritance has been suggested based on multiply affected siblings and some reports of parental consanguinity. This article describes two siblings with the restrictive dermopathy syndrome and reviews previously reported cases.
OBSERVATIONS--Eight other cases have been reported in the literature as restrictive dermopathy. These cases have shared striking similarities in their clinical histories and phenotypes. The skin in these infants has been described as rigid and tense, with skin biopsy specimens showing a thick epidermis, thin dermis, abnormally arranged collagen bundles, and poorly developed appendages. Other prominent features are flexion contractures and craniofacial and pulmonary abnormalities. The genetic and/or developmental defects leading to the restrictive dermopathy syndrome are presently not known.
CONCLUSIONS--The restrictive dermopathy syndrome is distinct and is easily differentiated from other congenital diseases such as the icthyoses and also from the clinical conditions of sclerema neonatorum and subcutaneous fat necrosis of the newborn. Recognition of this syndrome is important for determining the prognosis of affected infants and for recommending genetic counseling to affected families.Restrictive dermopathy with distinct morphological abnormalities.
Van Hoestenberghe M, Legius E, Vandevoorde W, Eykens A, Jaeken J, Eggermont E, Devos R, De Wolf-Peeters C, Fryns JP.
Department of Pediatrics, University of Leuven, Belgium.
Am J Med Genet. 1990 Jul;36(3):297-300. Abstract quote A newborn child is described with the fetal hypokinesia sequence as a consequence of a restrictive dermopathy.
Remarkable findings in this infant were neonatal teeth and survival till age 4 months.
Ultrastructural examination of the skin showed thin epidermis and absence of elastic fibres.Restrictive dermopathy: a report of three cases.
Mok Q, Curley R, Tolmie JL, Marsden RA, Patton MA, Davies EG.
Department of Child Health, St. George's Hospital Medical School, London.
J Med Genet. 1990 May;27(5):315-9. Abstract quote We report three infants with a rare syndrome of restrictive dermopathy, in which rigidity of the skin at birth is associated with characteristic facial anomalies, generalised arthrogryposis, bony abnormalities, and lung hypoplasia.
The skin has a distinctive pathology with compaction of the dermal collagen and fibrosis of the subcutaneous tissue. The inheritance is likely to be autosomal recessive and the condition appears to be fatal in the early neonatal period.
Restrictive dermopathy: a newly recognized autosomal recessive skin dysplasia.Witt DR, Hayden MR, Holbrook KA, Dale BA, Baldwin VJ, Taylor GP
Am J Med Genet. 1986 Aug;24(4):631-48. Abstract quote A brother and sister from consecutive pregnancies had rigid and tightly adherent skin in association with generalized contractures, unusual facies, pulmonary hypoplasia, an abnormal placenta, and a short umbilical cord. Both died shortly after birth.
Pathologic examination of the skin by light and electron microscopy showed structural abnormalities of the epidermis, dermis, and subcutaneous fat. An abnormal pattern of keratin proteins was determined biochemically using extracted epidermal proteins.
Autopsy showed a normal spinal cord and muscle histology. It is postulated that the defective skin severely restricted movement and secondarily led to the other abnormalities. Familial occurrence is most consistent with autosomal recessive transmission.
These patients and the primary skin defect are discussed within the framework of the Fetal Akinesia or Hypokinesia Deformation Sequence.
HISTOLOGICAL TYPES CHARACTERIZATION General Restrictive dermopathy: report of a case and review of the literature
W. A. Wesche, etal.
J Cutan Pathol 2001;28 (4):211-218 Abstract quote
Background: Restrictive dermopathy is a rare autosomal recessive skin disorder that is fatal in the neonatal period. Clinical and pathologic findings are distinctive and allow for a specific diagnosis in most cases.
Methods: We present a case of an affected infant and a review of the previously reported cases in the literature.
Results: The infant had thick shiny skin with reduced compliance and multiple spontaneous linear splits. Additional findings included an abnormal facies with a distinctive small, round and open mouth, low set ears, small nose, widely spaced sutures, flexion contractures of the extremities, and poorly expanded lungs. The infant expired 65 h after birth. Histologic findings of the skin at autopsy included a relatively unremarkable epidermis, a flat dermal-epidermal junction (absent rete ridges), an overall thinned dermis with hypoplastic appendage structures, a dense fibrotic reticular dermis with collagen parallel to the epidermis, a sharp subcutaneous margin, and an abnormally thick layer of subcutaneous adipose tissue. Electron microscopic findings included dense dermal patches of collagen and fibroblasts with abundant endoplasmic reticulum and unusually small tonofilaments. Review of previously reported cases reveals strikingly consistent findings.
Conclusions: This rare condition illustrates that abnormal cutaneous development may produce fetal hypokinesia, leading to profound effects on intrauterine growth and development. The autosomal recessive pattern of inheritance and morphologic changes of the skin and skeletal system in this disorder suggest that a structural protein or enzyme defect, perhaps of collagen metabolism, may underlie the pathogenesis.
Dermatopathological aspects of restrictive dermopathy.Pierard-Franchimont C, Pierard GE, Hermanns-Le T, Estrada JA, Verloes A, Mulliez N.
Department of Dermatopathology, University of Liege, Belgium.
J Pathol. 1992 Jun;167(2):223-8. Abstract quote We present an immunopathological and electronmicroscopic study of the skin of two newborns affected by restrictive dermopathy. Evidence of abnormal maturation was found in the epidermis, cutaneous appendages, dermis, and hypodermis.
Our observations confirm two previous descriptions. We emphasize some unreported data concerning the L1 antigen and Factor XIIIa in the skin. The L1 antigen is expressed in the interadnexal epidermis, but not in hair follicles. This is the reverse pattern compared with normal skin. Factor XIIIa is poorly expressed in dermal dendrocytes, which appear rare compared with controls.
The multiple defects in maturation found in all cutaneous tissues suggest a qualitative or quantitative aberration in control mechanisms of tissue interactions.
PROGNOSIS AND TREATMENT CHARACTERIZATION Prognostic Factors Survival Patients usually die immediately following birth, or may struggle to survive for several weeks, but the affliction is uniformly fatal
Death is often attributed to mechanical ventilatory compromise
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