A case of restrictive dermopathy in a Hutterite newborn: Diagnosis and creative skin-directed management.

Restrictive dermopathy is a lethal autosomal recessive disease characterized by tightly adherent skin, distinctive facial dysmorphisms, arthrogryposis, and pulmonary hypoplasia. While clinical findings are unique, histopathology and genetic analysis are critical for early diagnostic confirmation and to initiate appropriate management for this lethal disease. We report on a preterm Hutterite male neonate with biallelic ZMPSTE24 mutations to highlight the clinical and histopathological features of restrictive dermopathy and share our skin-directed management strategies.

Analysis of a non-lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons.

Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss-of-function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. Remarkably, we identified a homozygous, presumably loss-of-function mutation in ZMPSTE24 [c.28_29insA, p.(Leu10Tyrfs*37)] in two consanguineous Pakistani families segregating MADB. To clarify how lethal consequences are prevented in affected individuals, functional analysis was performed. Expression experiments supported utilization of two alternative translation initiation sites, preventing complete loss of protein function consistent with the relatively mild phenotypic outcome in affected patients. One of these alternative start codons is newly formed at the insertion site. Our findings indicate that the creation of new potential start codons through N-terminal mutations in other disease-associated genes should generally be taken into consideration in the variant interpretation process.

Lethal Restrictive Dermopathy with ZMPSTE24 Mutation.

Lethal restrictive dermopathy is genodermatoses associated with lamin protein defects resulting in connective tissue abnormalities of skin, musculoskeletal, and adipose tissue. We report one such case with a mutation in the ZMPSTE24 gene which is involved in lamin protein synthesis, resulting in fetal akinesia or hypokinesia deformation sequence. Early recognition in the perinatal period of distinctive clinical and skin histological features followed by molecular diagnosis enabled genetic counseling for the affected family.

Restrictive dermopathy: Three new patients with ZMPSTE24 mutations and a review of the literature.

Restrictive dermopathy (RD) is a rare and lethal laminopathy caused by mutations in LMNA or ZMPSTE24. This series reports 3 patients with RD and reviews the literature of the 113 previously reported cases, including highlights of the unique constellation of clinical findings in RD, as well as histologic, radiographic, and genetic features. Early recognition of these characteristic features is vital to establish a prompt diagnosis and provide adequate family counseling for this terminal condition.

Phenotypic heterogeneity of ZMPSTE24 deficiency.

A 4-year-old girl was referred to the Undiagnosed Diseases Network with a history of short stature, thin and translucent skin, macrocephaly, small hands, and camptodactyly. She had been diagnosed with possible Hallerman-Streiff syndrome. Her evaluation showed that she was mosaic for uniparental isodisomy of chromosome 1, which harbored a pathogenic c.1077dupT variant in ZMPSTE24 which predicts p.(Leu362fsX18). ZMPSTE24 is a zinc metalloproteinase that is involved in processing farnesylated proteins and pathogenic ZMPSTE24 variants cause accumulation of abnormal farnesylated forms of prelamin A. This, in turn, causes a spectrum of disease severity which is based on enzyme activity. The current patient has an intermediate form, which is a genocopy of severe Progeria.

Prelamin A and ZMPSTE24 in premature and physiological aging.

As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders. Premature aging disorders or progeroid syndromes can provide critical insights into aspects of physiological aging. A major cause of progeroid syndromes which result from mutations in the genes LMNA and ZMPSTE24 is disruption of the final posttranslational processing step in the production of the nuclear scaffold protein lamin A. LMNA encodes the lamin A precursor, prelamin A and ZMPSTE24 encodes the prelamin A processing enzyme, the zinc metalloprotease ZMPSTE24. Progeroid syndromes resulting from mutations in these genes include the clinically related disorders Hutchinson-Gilford progeria syndrome (HGPS), mandibuloacral dysplasia-type B, and restrictive dermopathy. These diseases have features that overlap with one another and with some aspects of physiological aging, including bone defects resembling osteoporosis and atherosclerosis (the latter primarily in HGPS). The progeroid syndromes have ignited keen interest in the relationship between defective prelamin A processing and its accumulation in normal physiological aging. In this review, we examine the hypothesis that diminished processing of prelamin A by ZMPSTE24 is a driver of physiological aging. We review features a new mouse (LmnaL648R/L648R) that produces solely unprocessed prelamin A and provides an ideal model for examining the effects of its accumulation during aging. We also discuss existing data on the accumulation of prelamin A or its variants in human physiological aging, which call out for further validation and more rigorous experimental approaches to determine if prelamin A contributes to normal aging.

An exceptional biallelic N-terminal frame shift mutation in ZMPSTE24 leads to non-lethal progeria due to possible utilization of a downstream alternative start codon.

Biallelic mutations in ZMPSTE24 are known to be associated with autosomal recessive mandibuloacral dysplasia with type B lipodystrophy (MADB) and lethal restrictive dermopathy (RD), respectively. Disease manifestation is depending on the remaining enzyme activity of the mutated ZMPSTE24 protein. To date, complete loss of function has exclusively been reported in RD cases. In this study, we identified a novel N-terminal homozygous frameshift mutation (c.28_29insA) in a consanguineous family segregating with MADB. An in-depth analysis of the mutated sequence revealed, that the one base pair insertion creates a novel downstream in-frame start codon, which supposedly serves as an alternative translation initiation site (TIS). This possible rescue mechanism would explain the relatively mild clinical outcome in the studied individuals. Our findings demonstrate the necessity for careful interpretation of N-terminal variants potentially effecting translation initiation.

Prenatal Diagnosis of Neu-Laxova Syndrome.

Neu-Laxova syndrome is a rare and lethal genetic disease with autosomal recessive inheritance involving abnormalities of multiple systems. It was first reported in 1971. Since then, just eighty-eight cases have been reported. The syndrome is characterized by early and severe growth restriction, and craniofacial anomalies, such as microcephaly, hypertelorism and other malformations, resulting in quite characteristic features. Additionally, it might appear as generalized edema, flexion contractures and other malformations of the extremities, abnormalities in the CNS (central nervous system), skin (severe ichthyosis), and genitourinary and cardiac abnormalities. We present the case of a patient who had her first pregnancy with a fetus with Neu-Laxova syndrome diagnosed in our center during the second-trimester ultrasound. The ultrasound findings suggested the diagnosis, which was confirmed with a genetic study of the amniotic fluid: the variant of the PSAT1 gene, associated with NLS (Neu-Laxova syndrome) 2 in homozygosis. Moreover, there was a second pregnancy with a fetus carrying the same mutation in heterozygosis. In addition, we have carried out a review of published literature about this disease up to the present time.

Mutations Involved in Premature-Ageing Syndromes.

Premature-ageing syndromes are a heterogeneous group of rare genetic disorders resembling features of accelerated ageing and resulting from mutations in genes coding for proteins required for nuclear lamina architecture, DNA repair and maintenance of genome stability, mitochondrial function and other cellular processes. Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best-characterized progeroid syndromes referred to as childhood- and adulthood-progeria, respectively. This article provides an updated overview of the mutations leading to HGPS, WS, and to the spectrum of premature-ageing laminopathies ranging in severity from congenital restrictive dermopathy (RD) to adult-onset atypical WS, including RD-like laminopathies, typical and atypical HGPS, more and less severe forms of mandibuloacral dysplasia (MAD), Néstor-Guillermo progeria syndrome (NGPS), atypical WS, and atypical progeroid syndromes resembling features of HGPS and/or MAD but resulting from impaired DNA repair or mitochondrial functions, including mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and mandibuloacral dysplasia associated to MTX2 (MADaM). The overlapping signs and symptoms among different premature-ageing syndromes, resulting from both a large genetic heterogeneity and shared pathological pathways underlying these conditions, require an expert clinical evaluation in specialized centers paralleled by next-generation sequencing of panels of genes involved in these disorders in order to establish as early as possible an accurate clinical and molecular diagnosis for a proper patient management.

Neonatal presentation of COG6-CDG with prominent skin phenotype.

Many of the genetic childhood disorders leading to death in the perinatal period follow autosomal recessive inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Often, affected children die before a genetic diagnosis can be established, thereby precluding targeted carrier testing in parents and prenatal or preimplantation genetic diagnosis in further pregnancies. The clinical phenotype of congenital disorders of glycosylation (CDG) is very heterogeneous and ranges from relatively mild symptoms to severe multisystem dysfunction and even a fatal course. A very rare subtype, COG6-CDG, is caused by deficiency of subunit 6 of the conserved oligomeric Golgi complex and is usually characterized by growth retardation, developmental delay, microcephaly, liver and gastrointestinal disease, joint contractures and episodic fever. It has been proposed that a distinctive feature of COG6-CDG can be ectodermal signs such as hypohidrosis/hyperthermia, hyperkeratosis and tooth anomalies. In a Greek family, who had lost two children in the neonatal period, with prominent skin features initially resembling restrictive dermopathy, severe arthrogryposis, respiratory insufficiency and a rapid fatal course trio whole-exome sequencing revealed the homozygous nonsense mutation c.511C>T, p.(Arg171*) in the COG6 gene. Skin manifestations such as dry skin and hyperkeratosis have been reported in only five out of the 21 reported COG6-CDG cases so far, including two patients with the c.511C>T variant in COG6 but with milder ectodermal symptoms. Our case adds to the phenotypic spectrum of COG6-CDG with prominent ectodermal manifestations at birth and underlines the importance of considering CDG among the possible causes for congenital syndromic genodermatoses.

Restrictive Dermopathy - A Rare Congenital Skin Disorder.

Restrictive dermopathy is a rare, autosomal recessive, lethal congenital skin disorder. This congenital genodermatosis could be mistaken for various other similar skin disorders. Diagnosis is a must in the context of genetic counseling for the subsequent pregnancy. We herein report a preterm male neonate with restrictive dermopathy, with additional feature of multiple bone fractures.

Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates.

The cell nucleus is structurally and functionally organized by lamins, intermediate filament proteins that form the nuclear lamina. Point mutations in genes that encode a specific subset of lamins, the A-type lamins, cause a spectrum of diseases termed laminopathies. Recent evidence points to a role for A-type lamins in intracellular redox homeostasis. To determine whether lamin A/C depletion and prelamin A accumulation differentially induce oxidative stress, we have performed a quantitative microscopy-based analysis of reactive oxygen species (ROS) levels and mitochondrial membrane potential (Δψm) in human fibroblasts subjected to sustained siRNA-mediated knockdown of LMNA and ZMPSTE24, respectively. We measured a highly significant increase in basal ROS levels and an even more prominent rise of induced ROS levels in lamin A/C depleted cells, eventually resulting in Δψm hyperpolarization and apoptosis. Depletion of ZMPSTE24 on the other hand, triggered a senescence pathway that was associated with moderately increased ROS levels and a transient Δψm depolarization. Both knockdowns were accompanied by an upregulation of several ROS detoxifying enzymes. Taken together, our data suggest that both persistent prelamin A accumulation and lamin A/C depletion elevate ROS levels, but to a different extent and with different effects on cell fate. This may contribute to the variety of disease phenotypes witnessed in laminopathies.

Embryonic expression of the common progeroid lamin A splice mutation arrests postnatal skin development.

Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) are two laminopathies caused by mutations leading to cellular accumulation of prelamin A or one of its truncated forms, progerin. One proposed mechanism for the more severe symptoms in patients with RD compared with HGPS is that higher levels of farnesylated lamin A are produced in RD. Here, we show evidence in support of that hypothesis. Overexpression of the most common progeroid lamin A mutation (LMNA c.1824C>T, p.G608G) during skin development results in a severe phenotype, characterized by dry scaly skin. At postnatal day 5 (PD5), progeroid animals showed a hyperplastic epidermis, disorganized sebaceous glands and an acute inflammatory dermal response, also involving the hypodermal fat layer. PD5 animals also showed an upregulation of multiple inflammatory response genes and an activated NF-kB target pathway. Careful analysis of the interfollicular epidermis showed aberrant expression of the lamin B receptor (LBR) in the suprabasal layer. Prolonged expression of LBR, in 14.06% of the cells, likely contributes to the observed arrest of skin development, clearly evident at PD4 when the skin had developed into single-layer epithelium in the wild-type animals while progeroid animals still had the multilayered appearance typical for skin at PD3. Suprabasal cells expressing LBR showed altered DNA distribution, suggesting the induction of gene expression changes. Despite the formation of a functional epidermal barrier and proven functionality of the gap junctions, progeroid animals displayed a greater rate of water loss as compared with wild-type littermates and died within the first two postnatal weeks.

Investigating the purpose of prelamin A processing.

Lmna yields two major protein products in somatic cells, lamin C and prelamin A. Mature lamin A is produced from prelamin A by four posttranslational processing steps-farnesylation of a carboxyl-terminal cysteine, release of the last three amino acids of the protein, methylation of the farnesylcysteine, and the endoproteolytic release of the carboxyl-terminal 15 amino acids of the protein (including the farnesylcysteine methyl ester). Although the posttranslational processing of prelamin A has been conserved in vertebrate evolution, its physiologic significance remains unclear. Here we review recent studies in which we investigated prelamin A processing with Lmna knock-in mice that produce exclusively prelamin A (Lmna(PLAO)), mature lamin A (Lmna(LAO)) or nonfarnesylated prelamin A (Lmna(nPLAO)). We found that the synthesis of lamin C is dispensable in laboratory mice, that the direct production of mature lamin A (completely bypassing all prelamin A processing) causes no discernable pathology in mice, and that exclusive production of nonfarnesylated prelamin A leads to cardiomyopathy.

A Case of Restrictive Dermopathy

Restrictive dermopathy is a lethal, autosomal recessive disorder characterized by tautness of skin, multiple joint contractures, and respiratory insufficiency resulting in fetal akinesia and death during the neonatal period. Histologic findings show a flat dermoepidermal junction, overall thinned dermis with hypoplastic appendages, a dense fibrotic reticular dermis with collagen parallel to the epidermis, and a thick layer of subcutaneous adipose tissue. It is a rare disorder that has not yet been reported in the Korean literature. Herein, we present a case of restrictive dermopathy in a neonate.

A case of restrictive dermopathy / 소아과

Restrictive dermopathy is a rare autosomal recessive disorder in which rigidity or tautness of the skin from the second trimester causes a fetal akinesia deformation sequence (FADS) and early death. Characteristic features include taut skin with prominent subcutaneous vessels, widely open fontanelles and cranial sutures, distinctive facies, flexion contractures, pulmonary hypoplasia, sparse eyelashes and and eyebrows, thin dysplastic clavicles. The histologic abnormalities of the skin are located in a thin dermis, consisting of compactly arranged collagen fibers, scanty elastic fiber. The dermoepidermal junction is flat, and epidermal appendages are absent, miniaturized or immature. The presence of adipose tissue may be increased. We report on the first Korean case of restrictive dermopathy with typical clinical features and histological findings.