ESPE Abstracts

Introduction: Variegated mosaic aneuploidy syndrome (MVA) is a rare autosomal recessive disease characterized by a variable percentage of chromosomal gains and losses, resulting in multiple mosaic aneuploidies, which explains a great phenotypic variety and may predispose to the development of cancer. Bi-allelic mutations in CEP57 are the cause of MVA2. CEP57 encodes a centrosome protein involved in microtubule stabilization and is crucial for maintaining proper chromosome separation during cell division. The main features of MVA2 include intra and extrauterine growth retardation, facial dimorphism (triangular face, prominent forehead, micrognathia, low-set ears...), skeletal deformities (rhizomelic limb shortening, clinodactyly...), congenital hypothyroidism, congenital cardiac and vascular anomalies and normal or mildly impaired psychomotor development.

Description of The Case and Evolution: We present two siblings of 8 and 4 years, from Tangier, children of non-consanguineous parents. The first sibling is an 8-year-old male, born at term, with severe intrauterine growth retardation and current harmonic short stature at -5.2DS, with low IGF1 and growth hormone (GH) insensitivity. Phenotypically he has microcephaly (-3.5DS), scaphocephaly, triangular face, prominent forehead, micrognathia and hypodontia. Clinodactyly of the 5th finger, bilateral cryptorchidism, non-compacted cardiomyopathy and corrected atrial septal defect. Functional humoral immunodeficiency requiring periodic treatment with immunoglobulins. Cervical-dorsal syringomyelia and intellectual disability with language delay. The second sibling is a 4-year-old male, born at term, with both severe intrauterine and postnatal growth retardation with current height at -7DS, normal IGF1 and IGFBP3 and GH insensitivity. Phenotypically same facial features as his brother. Bilateral cryptorchidism, hypospadias, bilateral hip dislocation. Normal cardiological study and mild developmental delay. Genetic study by clinical exome revealed that both siblings carried the pathogenic variant c.915_925dup(p.(Leu309Profs*9)) in CEP57. This pathogenic variant confirms the diagnosis of MVA2. Both were also heterozygous carriers of the pathogenic variant c.32465delA (P.(Asn10822Ilefs*5)) in TTN.

Conclusions: Few cases of bi-allelic mutations in CEP57 have been described in the literature. We present two cases of MVA2 that present most of the clinical features described in the literature, including severe short stature without response to GH treatment. This is a new case of variegated mosaic aneuploidy syndrome related to CEP57 without chromosomal alterations in peripheral blood. No association of this syndrome with cardiomyopathy has been described; in our patients this could be explained by the concurrence of a TTN mutation. The absence of aneuploidies in a single determination and tissue does not allow us to exclude the diagnosis of this syndrome.