Restrictive Dermopathy, Lethal

A number sign (#) is used with this entry because of evidence that lethal restrictive dermopathy can be caused by heterozygous mutation in the LMNA gene (150330) on chromosome 1q22 or by homozygous or compound heterozygous mutation in the ZMPSTE24 gene (606480) on chromosome 1p34.

Description

Restrictive dermopathy is a rare, lethal genodermatosis with characteristic manifestations that are easily recognizable at birth: thin, tightly adherent translucent skin with erosions at flexure sites, superficial vessels, typical facial dysmorphism, and generalized joint ankylosis. Prenatal signs can include intrauterine growth retardation, reduced fetal movements, polyhydramnios, and premature rupture of the membranes. Most infants die within the first week of life (summary by Smigiel et al., 2010).

Clinical Features

In 2 Hutterite sibships from different endogamous subdivisions ('leut,' or deme) and in a Mennonite kindred, Lowry et al. (1985) described a unique fatal disorder. The major manifestations were severe intrauterine growth retardation, congenital contractures, and tense skin that was easily eroded. The skin was drawn tightly over the face causing a narrow, pinched nose, small mouth, limited jaw mobility, and ectropion (in 1). No organ malformations were found. Histologically, the skin showed hyperkeratosis. Lowry et al. (1985) postulated that the primary defect represents a skin dysplasia and presented a 'pedigree of causes' (term of Hans Gruneberg) or 'pathogenesis chart' (term of Lowry et al.) relating all features of the disorder back to a mutant gene through that basic defect.

Witt et al. (1986) reported a similar condition in brother and sister born from consecutive pregnancies. Both had rigid and tightly adherent skin in association with generalized contractures, unusual facies, pulmonary hypoplasia, abnormal placenta, and short umbilical cord. Both died soon after birth.

Holbrook et al. (1987) were apparently of the opinion that this is the same disorder as that described in entry 226730: aplasia cutis congenita with pyloric stenosis. Although gastrointestinal atresia was not present in these cases, this feature is not always present; it was found in 1 patient reported by Carmi et al. (1982) and was absent in the sib. Holbrook et al. (1987) indicated that a third affected baby had been born in the family originally reported by Witt et al. (1986).

Mok et al. (1990) reported 3 cases; 1 was in a child of consanguineous Pakistani parents. Van Hoestenberghe et al. (1990) described an affected infant with neonatal teeth and survival to the age of 4 months. Verloes et al. (1992) described 3 unrelated affected stillborn infants, each with consanguineous parents. Two of them were of Algerian ancestry and one Turkish. Clinical findings included a tight, thin, translucent skin which tore spontaneously in flexion creases, arthrogryposis multiplex congenita (which included the temporomandibular joint), enlarged fontanels, typical face, and dysplasia of clavicles and long bones. Lenz and Meschede (1993) found in the German literature 2 cases with typical manifestations of this disorder. Antoine (1929) called this condition 'generalized congenital skin atrophy,' and Wepler (1938) described it as a 'generalized skin hypoplasia.'

Happle et al. (1992) observed restrictive dermopathy in 2 brothers. The first-born brother died 4 days after birth. He showed generalized desquamation, marked joint contractures, and facial hypoplasia. Prominent light microscopic findings were hyperorthokeratosis intermingled with parakeratosis and absence of elastic fibers in a thinned dermis. Electron microscopic examination of the epidermis showed lack of keratin filaments and an abnormal globular shape of the keratohyalin granules. The following pregnancy resulted in the birth of a preterm boy who died within 2 hours. At the twentieth week of gestational age, fetal biopsy specimens failed to reveal any abnormalities by light or electron microscopy. Thus, feasibility of prenatal diagnosis must be regarded with great caution.

Hoffmann et al. (1993) reported 2 unrelated cases. One died at 5 days of age, the second at 2 months of age. Hamel et al. (1992) reported 2 successively born male infants with this disorder. After the birth of the first affected child, who died after 4 days, a prenatal diagnosis was performed in the second pregnancy; at 19.5 weeks, 5 fetal skin biopsies from various parts of the body were obtained and investigated by light and electron microscopy. No morphologic abnormalities could be detected. The pregnancy was monitored by ultrasound and continued uneventfully until, at 29 weeks, polyhydramnios developed and the fetal movements disappeared abruptly. The infant was born in breech position at 29.5 weeks and had typical restrictive dermopathy. He died after 1 hour. Thus, skin biopsy is not a reliable means of prenatal diagnosis.

Paige et al. (1992) found many dead and degenerating fibroblasts in the dermis on ultrastructural examination, and 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. Paige et al. (1992) suggested that the findings indicate a primary disorder of fibroblasts.

Dean et al. (1993) reported the clinical features and histologic findings in 2 sibs who died from restrictive dermopathy in the neonatal period. Fibroblasts displayed increased expression of the alpha-1 (192968) and alpha-2 (192974) subunits of integrin, which are responsible for collagen binding. Since integrins may play an important role in tissue differentiation, the findings were thought to support the hypothesis that restrictive dermopathy is a disorder of skin differentiation.

Mau et al. (1997) described an affected boy of consanguineous parents and reviewed 30 previous cases. Sillevis Smitt et al. (1998) reported on 12 cases of restrictive dermopathy seen during a period of 8 years by the Dutch Task Force on Genodermatology. In most of these children the features were prematurity, fixed facial expression, micrognathia, mouth in the 'O' position, rigid and tense skin with erosions and denudations, and multiple joint contractures. A wide ascending aorta and dextrocardia were present in single patients.

Molecular Genetics

In 2 of 9 fetuses with restrictive dermopathy, Navarro et al. (2004) identified heterozygous splicing mutations in the LMNA gene, resulting in the complete or partial loss of exon 11 (150330.0036 and 150330.0022, respectively). In the other 7 patients, they identified a heterozygous 1-bp insertion resulting in a premature stop codon in the ZMPSTE24 gene (606480.0001). This metalloproteinase is specifically involved in the posttranslational processing of lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of lamin-associated proteins was seen. Navarro et al. (2004) concluded that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in restrictive dermopathy.

Navarro et al. (2005) described 7 previously reported patients and 3 new patients with restrictive dermopathy who were homozygous or compound heterozygous for ZMPSTE24 mutations. In all cases there was complete absence of both ZMPSTE24 and mature lamin A, associated with prelamin A accumulation. The authors concluded that restrictive dermopathy is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations. The accumulation of truncated or normal length prelamin A is, therefore, a shared pathophysiologic feature in recessive and dominant restrictive dermopathy.

Moulson et al. (2003) suggested that the gene encoding fatty acid transport protein-4 (SLC27A4; 604194) is a candidate gene for restrictive dermopathy because of the findings in a phenotypically identical mutation in the mouse called 'wrinkle-free' (wrfr). Moulson et al. (2005) ruled out SLC27A4 as a candidate, and subsequently, they identified homozygous or compound heterozygous mutations in the ZMPSTE24 gene (606480.0001; 606480.0007; 606480.0008) in patients with lethal restrictive dermopathy. All the mutations resulted in premature termination and lack of a functional protein. Cultured cells and tissue from affected individuals showed accumulation of unprocessed toxic lamin A and aggregates of lamin A in nuclei, suggesting that the disorder results from defective processing of lamin A.

In a female infant with lethal restrictive dermopathy, born to aboriginal Taiwanese parents from the same tribe but not known to be consanguineous, Chen et al. (2009) identified homozygosity for a nonsense mutation in the ZMPSTE24 gene (606480.0006). The infant, who died at 3 hours of life due to respiratory insufficiency, had no mutation in the LMNA gene. The unaffected parents and both grandmothers were heterozygous for the ZMPSTE24 mutation; an unaffected older sister did not inherit the mutation. An uncommon prenatal finding observed in the affected infant was spontaneous complete chorioamniotic membrane separation at 31 weeks' gestation.

Smigiel et al. (2010) reported 2 Polish brothers with restrictive dermopathy who died at 7 days and 12 days of age. In the second brother, they identified compound heterozygosity for 2 inactivating mutations in the ZMPSTE24 gene (606480.0010 and 606480.0011). No DNA was available from the first brother; the unaffected parents were each heterozygous for one of the mutations.

Population Genetics

Li (2010) identified a homozygous mutation in the ZMPSTE24 gene (1085dupT; 606480.0001) in an infant girl with restrictive dermopathy. She was born of Mexican Mennonite parents who had immigrated to Canada. The mother reported several neonatal deaths in her family. Li (2010) postulated that since this family was of Mennonite descent, it may represent a founder mutation in this group. However, Miner (2010) noted that Moulson et al. (2005) had previously identified a different truncating mutation in the ZMPSTE24 gene (54dupT; 606480.0007) as causing restrictive dermopathy in 2 related Mennonite families from Pennsylvania, suggesting allelic heterogeneity even within this isolated population.

In 2 unrelated Old Colony Mennonite infants, 1 from Alberta and 1 from Ontario, who died shortly after birth from restrictive dermopathy, Loucks et al. (2012) identified homozygosity for the common 1085dupT mutation in the ZMPSTE24 gene. In addition, the mutation was found in heterozygosity in the obligate-carrier parents of 2 unrelated deceased Schmiedeleut Hutterite infants with restrictive dermopathy, 1 from South Dakota and 1 from Manitoba (the latter patient was originally reported by Reed et al., 1993). Haplotype analysis suggested a small 1.36-Mb shared haplotype distal to the mutation. In a cohort of approximately 1,200 Schmiedeleut Hutterites from South Dakota, Loucks et al. (2012) determined a high carrier frequency of the 1085dupT mutation (approximately 1/21), making it likely that the mutation predates the 1874 separation of the Hutterites into the 3 current essentially endogamous leuts and lending support to the hypothesis (Lowry et al., 1985) that the mutation was introduced into the Hutterites in 1783 when some Mennonites joined the Hutterite brethren. Noting that the 1085dupT mutation accounts for nearly 75% of the reported causative ZMPSTE24 mutations in restrictive dermopathy, Loucks et al. (2012) suggested that 1085dupT may represent a recurrent mutation due to a mutational hotspot.

In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified the restrictive dermopathy mutation 1085dupT (rs137854889, 606480.0007) in heterozygous state in 87 individuals among 1,361 screened and in homozygous state in none, for a carrier frequency of 0.064 (1 in 15.5). The carrier frequency in other populations was unknown, and Chong et al. (2012) noted that less than 60 cases had been reported worldwide.