Vici syndrome

Dionisi Vici et al. 1988

Vici syndrome is a rare congenital multisystem disorder characterized by agenesis of the corpus callosum (ACC), cataracts, pigmentary abnormalities, progressive cardiomyopathy, and variable immunodeficiency. Affected individuals also have profound psychomotor retardation and hypotonia due to myopathy. (Finocchi et al. 2012).

The identification of loss-of-function mutations in the EPG5 gene involved in autophagy suggests that Vici syndrome is due to impaired autophagy. Treatment of patient and control cells with autophagy inducers and inhibitors indicate that patient cells have a severe deficit in autophagosome clearance and impaired fusion to lysosomes.

These lead to storage of abnormal material, secondary mitochondrial abnormalities in skeletal muscle, multisystem defects in the heart, immune system, skin (hypopigmentation), and central nervous system.

Dionisi Vici et al (1988) described two brothers with a malformation syndrome consisting of agenesis of the corpus callosum, cutaneous hypopigmentation, bilateral cataract, cleft lip and palate, and combined immunodeficiency. The siblings suffered from severe psychomotor retardation, seizures, recurrent severe respiratory infections, and chronic mucocutaneous candidiasis. They died of bronchopneumonia at the ages of 2 and 3 years. One sibling examined was found to have skin allergy to recall antigens, severe depletion of T4-positive lymphocytes, and serum IgG2 deficiency. Autopsy revealed agenesis of the corpus callosum, hypoplasia of the cerebellar vermis, and profound hypoplasia of the thymus and peripheral lymphoid tissue. No exactly similar cases were found.

Del Campo et al (1999) reported 4 other cases (including 2 siblings, a male, and a female) with this disorder. Their patients had agenesis of the corpus callosum, oculocutaneous albinism, repeated infections suggestive of immunodeficiency, cardiomyopathy, postnatal growth retardation, microcephaly, and profound developmental delay. The authors felt that these cases confirmed the existence of this disorder, which they called Vici syndrome. The finding of affected siblings of both sexes born to unaffected parents argues for an autosomal recessive inheritance.

McClelland et al (2010) reported an infant with Vici syndrome who presented at birth with hypotonia, weak cry, and difficulty feeding. Examination revealed microcephaly, hypertrophic cardiomyopathy, hypopigmentation, and dysmorphic facial features, such as a broad nose, full lips, and a long philtrum. He also had nystagmus, cataracts, profound sensorineural hearing loss, decreased lymphocytes, and recurrent infections. The infant died of heart failure at 3 months of age.

Histology: Skeletal muscle biopsy showed wide variation in fiber size, centralized nuclei, and small fibers with high glycogen content. EM: Electron microscopy showed redundant basal lamina with small areas of debris between layers, suggestive of exocytosis. There were also multiple enlarged abnormal mitochondria with abnormal crystals. In this case, myopathy was added to the clinical features of Vici syndrome.

Al-Owain et al (2010) reported a male infant born to distantly related Saudi parents with Vici syndrome. At birth, he showed poor sucking and feeding behavior and low weight gain. Physical features included an inverted triangular face, hypotonia with an open mouth, mild ptosis, epicanthal folds, micrognathia, and a high arched palate. He also had axial hypotonia with mildly increased limb tone, bilateral cataracts, and optic neuropathy. MRI of the brain showed agenesis of the corpus callosum, hypoplasia of the cerebellum and pontus, and delayed myelination. He had severe global developmental delay. He developed frequent recurrent infections, especially with Pseudomonas and Klebsiella, which were accompanied by lymphopenia, although he showed normal immunologic responses to immunizations. The patient died of sepsis at 9 months of age. The parents had 3 other children who died of similar disease, suggesting autosomal recessive inheritance.

1. Al-Owain M et al. (2010) Vici syndrome associated with unilateral lung hypoplasia and myopathy. (Letter) Am J Med Genet 152A: 1849-1853.
2. Cullup T et al (2013) Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature Genet 45: 83-87.
3. del Campo M et al (1999) Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance. Am J Med Genet 85: 479-485.
4. Dionisi Vici C et al (1988) Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers. Am J Med Genet 29: 1-8.
5. Finocchi A et al (2012) Immunodeficiency in Vici syndrome: a heterogeneous phenotype. Am J Med Genet 158A: 434-439.
6. McClelland V et al (2010) Vici syndrome associated with sensorineural hearing loss and evidence of neuromuscular involvement on muscle biopsy. Am J Med Genet 152A: 741-747.