Autopsy findings in EPG5-related Vici syndrome with antenatal onset.

Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome-lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal agenesis and other developmental brain abnormalities were detected on fetal ultrasound scan (US) and subsequent MRI scan in the second trimester. Postmortem examination performed after medically indicated termination of pregnancy confirmed CNS abnormalities and provided additional evidence for skin hypopigmentation, nascent cataracts, and hypertrophic cardiomyopathy. Genetic testing prompted by a suggestive combination of features revealed a homozygous EPG5 mutation (c.5870-1G>A) predicted to cause aberrant splicing of the EPG5 transcript. Our findings expand the phenotypical spectrum of EPG5-related Vici syndrome and suggest that this severe condition may already present in utero. While callosal agenesis is not an uncommon finding in fetal medicine, additional presence of hypopigmentation, cataracts and cardiomyopathy is rare and should prompt EPG5 testing.

Clinical Presentation and Molecular Characterization of 3 Patients with Vici Syndrome: Two Novel Variants in the EPG5 Gene.

Introduction: Vici syndrome is an ultra-rare, congenital disorder of autophagy characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Patients usually present in the neonatal period or infancy with profound hypotonia, based on information available from the nearly 100 cases reported to date. Case Presentation: We present 3 new cases of Vici syndrome confirmed by genetic analysis of EPG5 gene. The 3 male patients had neonatal hypotonia, progressive microcephaly, psychomotor retardation, recurrent respiratory tract infections, optic atrophy, and failure to thrive, but no cataracts or hepatomegaly. Three disease-causing variants in homozygous state were detected in the EPG5 gene: two novel c.1652C>T and c.7557+2T>C forms; and one previously reported c.7447C>T. The patient, who was homozygous for the c.1652C>T mutation, presented with neonatal onset seizures that had not been reported previously. Discussion/Conclusion: The present study provides data for the evaluation of the natural history and genotype-phenotype correlations for treatment options that are expected to be available in the future.

A Saudi Infant with Vici Syndrome: Case Report and Literature Review.

INTRODUCTION: Vici syndrome, a rare autosomal recessive disorder, was first described in 1988 by Vici et al. Only 78 cases have been reported to date. The syndrome is characterised by agenesis of the corpus callosum, hypopigmentation, cardiomyopathy, progressive failure to thrive, dysmorphic features, immunodeficiency and cataracts. Mutations in the gene epg5 have been identified as the cause of Vici syndrome. CASE DESCRIPTION: The parents are a consanguineous Saudi couple with two other children diagnosed with Gaucher disease. The patient was born at term and in the first 5 months had many hospital admissions for a recurrent chest infection. Physical examination, investigations and imaging studies revealed that the patient had agenesis of the corpus callosum, cataracts, psychomotor delay, immunodeficiency and hypopigmentation. The initial echocardiogram was normal. At 7 months, genetic testing confirmed the diagnosis of Vici syndrome with a c.3693G>Ap (Gln1231Gln) mutation in the gene EPG5. The patient developed a chest infection and was admitted to the pediatric intensive care unit. An echocardiogram was repeated and showed significant left ventricular dilation with a Z-score of 3.1, moderate mitral and tricuspid regurgitation, and depressed ventricular function with a fractional shortening of 17% and ejection fraction 37%. The patient's condition deteriorated, and he died aged 8 months. CONCLUSION: The symptoms of extensive system involvement in Vici syndrome have been present in the majority of reported cases and should prompt careful evaluation of this syndrome when such symptoms are present in an infant. In confirmed cases, close monitoring of the immune status and cardiac function, the two main causes of death among Vici syndrome patients, is vital to prevent rapid deterioration and improve life expectancy.