Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: evidence of genetic heterogeneity

Abstract

Restrictive dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the 'o' position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report three new cases of RD; all died within 3 weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, the second case had a novel homozygous c.1020G>A (p.Trp340X) null mutation in ZMPSTE24, but the third case, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease-causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly-shaped thoracic 5 vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020G>A ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified.

Figure 1. Pedigrees and chromatograms of patients with restrictive dermopathy

A. RD 200 Pedigree. No disease-causing mutations were found in either ZMPSTE24 or LMNA B. RD 500 Pedigree. Affected individual with homozygous c.1020G>A (p.W340X) mutation of ZMPSTE24 is shown as filled black symbol, whereas heterozygous subjects are shown as half filled symbols. The parents of the affected subject were second cousins. WT indicates wild type allele. C,D: Chromatograms from direct sequencing of exon 8 of ZMPSTE24 gene showing normal sequence from a control individual (C), and from the proband RD 500.3 showing homozygous c.1020G>A mutation (D) E. RD 600 Pedigree. Affected individual with homozygous c.1085dupT mutation of ZMPSTE24 is shown as filled black symbol, whereas heterozygous subjects are shown as half filled symbols. A previous male fetus stillborn at 33 weeks gestation was described as having features consistent with RD. Five spontaneous abortions occurred between 11–12 wks gestation. F,G: Chromatograms from direct sequencing of exon 9 of ZMPSTE24 gene showing normal sequence from a control individual (F) and from the proband RD 600.3 showing homozygous c.1085dupT mutation (G).

Figure 2. Radiographs and histopathology of skin biopsy of RD 500.3

A. Anterior-posterior chest radiograph of patient RD 500.3 shows a butterfly vertebra at the thoracic 5 level (white arrow). Clavicles were dysmorphic with a pseudoarthrosis at the juncture of the middle and distal one-thirds with the distal portions bulbous in appearance (black arrow). B. Lateral radiograph of the skull of patient RD 500.3 reveals prominent sutures (gray arrow), micrognathia (white arrow), and hypoplastic cervical vertebral bodies (black arrow). C. Hematoxylin and eosin stain of skin biopsy shows the epidermis and dermis to be slightly attenuated, and the dermis shows marked fibrosis and parallel collagen bundles. D. An elastic tissue stain, Verhoeff van Gieson, shows complete absence of elastic fibers throughout the dermis.

Figure 3. Clinical features of RD 200.3

A. The infant had tight skin with skin breakdown in the neck, contractures in the elbows and digits in hands, and mouth in fixed “o” position. A large circumferential neck laceration can be appreciated. B. Prominent superficial vessels are seen in the posterior and lateral truncal region. There is normal number of digits on hands and feet, but fingers appear tapered. Scalp hair in the temporal and occipital regions appears normal.