Restrictive Dermopathy: Report of 12 Cases

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 12 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 α₂β₁ and α₁β₁ 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 (RD) is a rare (approximately 24 cases reported^1-3), lethal, autosomal recessively inherited disease. In a study that encompassed 8 years, a Dutch task force on genodermatology¹ demonstrated 12 cases of RD in a series of 130 patients (3 of them have already been presented).^4,5 Herein we summarize the clinical and histological characteristics of these patients to increase the clinical knowledge of this syndrome and to help trace associated anomalies not yet delineated. Since an abnormal integrin expression on fibroblasts in RD has been reported,⁶ integrin expression was determined in the fibroblasts of the cultures available.

We used the extremely taut skin resulting in joint contractures and a peculiar facial appearance exclusive of a primary central nervous system defect as diagnostic characteristics of RD. Clinical features of the patients are shown in Table 1. Figure 1 illustrates one of the patients diagnosed as having RD. In 4 instances, RD recurred in a sib. For the integrin determinations, fibroblast cultures from 5 patients were used. One fibroblast culture of a fetus of comparable age was available as a control. Cultured fibroblasts were stained with monoclonal antibodies directed against β₁, α₁, α₂, or, as a control, a₅ integrin. No consistent abnormal integrin expression on fibroblasts was found using fluorescence-activated cell sorter analysis in the patients tested.

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Clinical and Histopathologic Characteristics of the Patients*

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A representative patient with restrictive dermopathy showing ectropion, small pinched nose, low-set ears, micrognathia, microstomia, mouth in an o position, joint contractures, rocker-bottom feet, tense skin with tears in the neck and lower abdomen, erosions, and scaling.

The first clinical description of what was later called RD⁷ was published in 1929⁸ as a case of generalized skin atrophy. Twelve cases were seen in our genodermatology group. In one patient, the sib of another well-described patient, the diagnosis was based on information given by parents and the gynecologist; therefore, only limited details of the case were available. Since RD is reportedly rare, we were surprised by the relatively frequent observations of the disease by our task force. The recurrence of RD in sibs in 4 instances may be the main reason for the frequent reporting by our group. Whether the carrier frequency is higher in the Dutch population may be determined after gene identification by looking for a founder effect in haplotype studies. The alleged rarity may be partially caused by medical unfamiliarity with this entity, in which case the actual incidence might be substantially higher. The clinical features are so highly characteristic that after having observed an affected patient once, subsequent cases will be instantly recognized. A listing of characteristics of RD from the literature⁹ reflected the features of our patients. Analyzing the symptoms, we concluded that virtually all the cases had certain features in common: prematurity, fixed facial expression, micrognathia, mouth in the o position, rigid and tense skin with erosions and denudations, and multiple joint contractures. In at least 8 patients, wide cranial sutures, small pinched nose, low-set ears, microstomia, rocker-bottom feet, scaly skin, and respiratory insufficiency were observed. Natal teeth were noted twice, and ectropion or chemosis was noted 3 times. Bone deformities resulted in a wide range of abnormalities, such as diaphyseal undertubulation, a tendency for overcurvature of long bones, a large metaphysis in relation to the diaphysis, and abnormal configurations of individual bones. Additional findings included blepharophimosis in 2 of our patients, skin tear in the frontal neck area during delivery in 3 patients, inguinal skin tear in 1 patient, and absent eyelashes, a wide ascendent aorta, and dextrocardia in 1 patient. The histopathological characteristics of the skin biopsy specimens were highly informative. Flattening of rete ridges was found in all 10 of the patients undergoing biopsy, and a thin dermis with collagen aligned parallel to the epidermis and poorly developed dermal appendages were found in at least 9 patients. The pathogenesis of RD remains unknown. A reported overexpression of α₁β₁ and α₂β₁ integrins on fibroblasts taken from patients diagnosed as having RD⁶ could not be confirmed by fluorescence-activated cell sorter analysis of integrin expression in 5 patients. Based on a lack of differentiation-specific keratins and the arrested development of skin adnexa, it has been suggested that dermal-epidermal interactions are abnormal, leading to a skin differentiation defect. Recently degenerative changes in elastic fibers and fibroblasts were observed, which might explain many of the predominant features of this disease.¹

Accepted for publication October 10, 1997.

The determination of integrins was sponsored by the Dutch Cancer Society, Amsterdam, the Netherlands (No. 91-260).

Presented in part at the Symposium of Pediatric Dermatology in Honor of Professor J. Maleville, Bordeaux, France, April 22, 1995.

We thank B. C. van Pelt, MD, St Clara Hospital, for patient referral, and V. D. Vuzevski, MD, Rotterdam, the Netherlands, for histopathologic analysis and electron microscopic study in one case. The photograph was provided by D. Zoetekouw, St Clara Hospital.

C. J. van Asperen, MD, Academic Hospital Leiden, Leiden; F. A. Beemer, MD, PhD, Clinical Genetics Center and Wilhelmina Children's Hospital, Utrecht; J. N. Bouwes Bavinck, MD, PhD, Academisch Ziekenhuis Leiden, Leiden; E. J. Breslau-Siderius, MD, Clinical Genetics Center, Utrecht; C. A. F. M. Bruynzeel-Koomen, MD, PhD, Academisch Ziekenhuis Utrecht, Utrecht; I. van de Burgt, MD, Academisch Ziekenhuis Nijmegen, Nijmegen; A. J. van Essen, MD, University of Groningen, Groningen; P. Fleury, MD, PhD;† M. Goeteyn, MD, St Jan Ziekenhuis, Bruges, Belgium; W. P. de Groot, MD, PhD, Amsterdam; D. R. E. Van Gysel, MD, Onze Lieve Vrouwe Ziekenhuis, Aalst, Belgium; L. Habbema, MD, Medisch Centrum't Gooi, Bussum; R. Happle, MD, PhD, Medisch Zentrum für Hautkrankheiten, Marburg, Germany; R. Hausman, MD, PhD;† F. Heule, MD, PhD, Sophia/Dijkzigt University Hospital, Rotterdam; R. F. H. J. Hulsmans, MD, Huisartscentrum Annadal, Maastricht; R. J. J. Koopman, MD, Medisch Spectrum Twente, Enschede; A. P. Oranje, MD, PhD, Sophia/Dijkzigt University Hospital, Rotterdam; J. W. E. Oorthuys, MD;† J. G. van der Schroeff, MD, PhD, Bronovo Ziekenhuis, Den Haag; J. H. Sillevis Smitt, MD, PhD, Academic Medical Center, Amsterdam; Th. M. Starink, MD, PhD, Academic Hospital of the Free University, Amsterdam; P. M. Steijlen, MD, PhD, Academisch Ziekenhuis, Nijmegen; W. A. van Vloten, MD, PhD, Academisch Ziekenhuis, Utrecht; P. C. M. van Voorst Vader, MD, PhD, University Hospital Gronigen, Gronigen.

†Deceased.

Reprints: J. H. Sillevis Smitt, MD, PhD, Department of Dermatovenereology, Academic Medical Center, University of Amsterdam, Postbox 22700, 1100 DE Amsterdam, the Netherlands.