Fatal Neonatal DOLK-CDG as a Rare Form of Syndromic Ichthyosis.

Katalin Komlosi,Andreas D Zimmer,Nathalie Jonca,Sophie Collardeau-Frachon,Juliette Mazereeuw-Hautier,Julia Kopp,Damien Sanlaville,Ingrid Hausser,Olivier Claris,Judith Fischer

doi:10.3389/fgene.2021.719624

Abstract

Neonatal collodion baby or ichthyosis can pose a diagnostic challenge, and in many cases, only additional organ involvement or the course of the disease will help differentiate between non-syndromic and syndromic forms. Skin abnormalities are described in about 20% of the congenital disorders of glycosylation (CDG). Among those, some rare CDG forms constitute a special group among the syndromic ichthyoses and can initially misdirect the diagnosis towards non-syndromic genodermatosis. DOLK-CDG is such a rare subtype, resulting from a defect in dolichol kinase, in which the congenital skin phenotype (often ichthyosis) is later associated with variable extracutaneous features such as dilatative cardiomyopathy, epilepsy, microcephaly, visual impairment, and hypoglycemia and may lead to a fatal course. We report two neonatal cases of lethal ichthyosis from the same family, with distal digital constrictions and a progressive course leading to multi-organ failure and death. Postmortem trio whole-exome sequencing revealed the compound heterozygous variants NM_014908.3: c.1342G>A, p.(Gly448Arg) and NM_014908.3: c.1558A>G, p.(Thr520Ala) in the DOLK gene in the first affected child, which were confirmed in the affected sibling. Reduced staining with anti-α-Dystroglycan antibody was observed in frozen heart tissue of the second child as an expression of reduced O-mannosylation due to the dolichol kinase deficiency. In addition to the detailed dermatopathological changes, both cases presented hepatic and extrahepatic hemosiderosis on histological examination. Our patients represent an early and fatal form of DOLK-CDG with a striking presentation at birth resembling severe collodion baby. Both cases emphasize the phenotypic variability of glycosylation disorders and the importance to broaden the differential diagnosis of ichthyosis and to actively search for organ involvement in neonates with ichthyosis.

Highlights

Pediatric disorders leading to perinatal death still present a challenge for genetic counseling when rapid whole exome/ whole genome sequencing (WES/WGS) in the neonatal setting is not available
We present two children of a non-consanguineous French couple with compound heterozygous variants in the DOLK gene presenting with severe ichthyosis, distal digital constrictions, cardiomegaly, thrombocytopenia, diffuse coagulation defect, and progressive multi-organ failure, which resulted in death in the neonatal period
In addition to the clinical anomalies previously described in Patient 1, autopsy revealed a hypotrophic liver with diffuse steatosis (Figure 2, arrow) and hemosiderosis (Figure 3)

Summary

Introduction

Pediatric disorders leading to perinatal death still present a challenge for genetic counseling when rapid whole exome/ whole genome sequencing (WES/WGS) in the neonatal setting is not available. Complete and rigorous autopsy with multiple tissue sampling of affected fetuses or children is of great importance for detecting all anomalies that can indicate a potential diagnosis, and providing frozen tissue for genetic and functional analysis. A definitive diagnosis always requires a multidisciplinary approach including clinical data, autopsy findings, and genetic results, especially for correct interpretation of the pathogenicity of the identified DNA variants. Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are further defined on the basis of clinical and genetic features and can be divided into nonsyndromic and syndromic forms. The syndromic ichthyoses are generally very rare and are classified based on the mode of inheritance, and can be further subdivided according to the predominant symptoms (Oji et al, 2010; Fischer and Bourrat, 2020)

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