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A congenital genodermatosis with skin/mucosae involvement, characterized by very tight and thin skin with erosions and scaling, associated to a typical facial dysmorphism, arthrogryposis multiplex, fetal akinesia or hypokinesia deformation sequence (FADS) and pulmonary hypoplasia without neurological abnormalities.
ORPHA:1662Classification level: Disorder
- Lethal hyperkeratosis-contracture syndrome
- Lethal restrictive dermopathy
- Lethal tight skin-contracture syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant or Autosomal recessive
- Age of onset: Antenatal, Neonatal
- ICD-10: Q82.8
- OMIM: 275210
- UMLS: C0406585
- MeSH: -
- GARD: 1516
- MedDRA: -
To date, approximately 80 children with restrictive dermopathy (RD) have been described in the world literature.
RD is a congenital disorder and newborns are usually born prematurely (due to premature rupture of membranes with delivery at about 30-32 weeks of gestation). They present at birth with a very typical and recognizable clinical phenotype including tight, thin, rigid and translucent skin with epidermal hyperkeratosis and shedding, erosions and scaling at flexure sites, protruding nipples. Skeletal defects include: bone mineralization defects, large fontanelles, thin dysplastic clavicles, narrow chest, overtubulated long bones, generalized arthrogryposis with rocker-bottom feet. Facial dysmorphism is also characteristic and includes telecanthus, short, down-slanting palpebral fissures, sparse/absent eyelashes and eyebrows, a small and pinched nose, posteriorly rotated low-set ears, retromicrognathism and a small mouth fixed in the ''O'' position with expressionless facies. Additional features may include congenital anonychia, neonatal teeth, ectropion, choanal atresia, patent ductus arteriosus, interatrial septal defects, kyphoscoliosis, camptodactyly, hypospadias (males), ureteral duplication, adrenal hypoplasia. Intrauterine growth retardation (IUGR) with polyhydramnios, and decreased fetal movements are almost always reported. Pulmonary hypoplasia most often leads to respiratory insufficiency and death. Neither structural central nervous system nor visceral defects occur in RD.
RD can be caused by heterozygous, de novo mutations of the LMNA gene (primary Laminopathy) or, much more frequently, by homozygous or compound heterozygous null mutations of the ZMPSTE24 gene (secondary Laminopathy). Defects in ZMPSTE24 impair the processing of Prelamin A into mature Lamin A, causing the massive intranuclear accumulation of wild type Prelamin A which exerts sytemic toxic effects and leads to the development of RD.
The diagnosis is based upon physical examination at birth and skin histology (flat dermis with paucity/hypoplasia of appendages, abnormally dense collagen bundles parallel to the dermo-epidermic basal lamina and almost total depletion of elastic fibers), cerebral imagery, blood analysis. Molecular genetic testing for mutations confirms the diagnosis and allows genetic counselling.
Yunis-varon syndrome, Neu-laxova syndrome, Pena-Shokeir syndrome, cerebrooculofacioskeletal syndrome, Paraná hard-skin syndrome, aplasia cutis congenita, lethal multiple pterygium syndrome.
Earliest manifestations are only apparent in the late second trimester/early third trimester and include intrauterine growth retardation, decreased fetal movements, eventual joint contractures, and mouth fixed in an 'O' position. However, these signs are too nonspecific to suggest the diagnosis prenatally in cases with no family history.
The ZMPSTE24 mutations are inherited recessively, leading to the possibility of genetic counseling and prenatal diagnosis for further pregnancies if the molecular bases of the disease are identified (25% risk of having an affected child for two mutation carriers). The rare dominant mutations in the LMNA gene are de novo and the risk of recurrence of the disorder is very low (eventual germinal mosaicism).
Management and treatment
Corticosteroids are administered for fetal lung maturation. Gavage feeding may be necessary. Supportive treatment consists of mechanical ventilation, broad-spectrum antibiotics, parenteral nutrition, and intravenous analgesia.
The affected babies who are liveborn often die within the first week of life.