Restrictive Dermopathy due to ZMPSTE24 Deficiency

Summary

Restrictive dermopathy (RD) (OMIM 275210) is a rare, lethal genodermatosis belonging to the group of laminopathies. It is caused by biallelic variants in ZMPSTE24, which is involved in lamin A post-translational processing or, less frequently, by monoallelic variants in LMNA, leading to accumulation of truncated prelamin A protein (Navarro et al., 2004; Navarro et al., 2005). The main characteristics of RD include intrauterine growth retardation (IUGR), reduced fetal movement, premature rupture of membranes, translucent rigid skin, dysmorphic features and joint contractures. The prognosis is poor with all reported cases resulting in stillbirth or neonatal death (Navarro et al., 2014).

Herein we report a neonate born to healthy, non-consanguineous parents from Greece. The pregnancy was uneventful until the 32^nd week, when a routine scan showed severe fetal growth restriction with normal Doppler flows. The female proband was born at 33 weeks of gestation by caesarean section, due to premature rupture of membranes, as well as anhydramnios, IUGR, fetal hypokinesia and distress. Her birth weight was 1.36 kg (5^th centile, −1.6SD), length was 41 cm (14^th centile) and head circumference was 29 cm (14^th centile). Apgar score was 4 and 8 at the 1^st and 5^th minutes, respectively. She required immediate intubation and admission to the neonatal intensive care unit. She had a large fontanelle, short palpebral fissures, a small pinched nose, low-set dysplastic ears and an open, O-shaped mouth (Fig. 1). She had multiple joint contractures. Her skin was rigid and translucent and progressively developed erosions and scaling. She did not have eyebrows or eyelashes. She had severe lung hypoplasia and died of respiratory insufficiency on the 22^nd day of life.

Investigations

Based on her phenotype, the proband was diagnosed clinically with RD, confirmed by targeted genetic testing (Sanger sequencing) of the ZMPSTE24 gene (OMIM 606480). She was found to carry in-trans two variants in the ZMPSTE24: one splice site c.1204–1G>A (rs61751009, pathogenic with minor allele frequency of 0.00006 in Europeans) (Phan et al., 2020), and one frameshift c.1085dupT p.(Leu362Phefs*19) (rs137854889, pathogenic with minor allele frequency of 0.00061 in Europeans) (Phan et al., 2020), with each parent carrying a heterozygous variant (Fig. 2). The splice variant had been previously reported in two siblings from Turkey with mandibuloacral dysplasia (MAD) in compound heterozygosity with a missense variant (Navarro et al., 2014). The p.(Leu362Phefs*19) variant is a recurrent RD disease-causing variant, which accounts for almost 75% of RD variants in the literature (Loucks et al., 2012). It is found in individuals from various ethnic backgrounds and may represent a mutational hotspot, resulting from a slippage effect of the DNA polymerase due to the presence of a repeated thymine (T) at this position in the normal sequence (Moir et al., 2000).

Fig. 2a.

Pedigree showing segregation of the ZMPSTE24 variants c.1204–1G>A and c.1085dupT.

Fig. 2b. Sequencing electropherograms of the proband RD 1100.4 showing the heterozygous c.1204–1G>A ZMPSTE24 variant (Top). The variant is predicted to create a newly generated splice site. The wild type (WT) sequence is shown below for reference (Bottom). The arrow indicates the start of exon.

Fig. 2c. Sequencing electropherograms of the proband RD 1100.4 showing the heterozygous c.1085dupT ZMPSTE24 variant (Top). The variant is predicted to cause a frameshift leading to a premature termination codon. The wild type (WT) sequence is shown below for reference (Bottom).

Discussion

ZMPSTE24 deficiency causes MAD when one of the variants is missense and the other is a null variant, and RD when both the variants are null. Null variants have no ZMPSTE24 enzymatic activity whereas knownmissense variants have partial loss or slightly reduced activity (Agarwal et al., 2003). Thus, the severe and lethal phenotype of RD compared to MAD could be due to increased cellular accumulation of prelamin A.

To the best of our knowledge, this is the first case report of RD in a patient from Greece. The neonate was carrying the recurrent p.(Leu362Phefs*19), adding to the existing evidence that the variant occurs in individuals of various ethnic backgrounds. Her second variant has been reported in one more family, from Turkey. Given the geographical proximity and frequent migration between the two counties, further, haplotype analysis may prove a shared genetic background of the families.

Currently, there is no therapeutic option for infants with RD and they typically die within the first few weeks of life. Lonafarnib was recently approved by the Food and Drug Administration of the United States for patients with ZMPSTE24 deficiency older than 12 months of age. Additionally, fibroblasts of a patient with ZMPSTE24 deficiency have been recently reported to exhibit improved nuclear morphology and cell proliferation after treatment with rapamycin and dimethylsulfoxide. This observation may open a novel therapeutic avenue for RD in the future (Akinci et al., 2017).

Fig. 1.

Proband with characteristic facial features of restrictive dermopathy, including absent eyebrows, short palpebral fissures, small pinched nose, O-shaped mouth and prominent superficial vasculature.