Vici syndrome is a rare hereditary disease with a diagnosis that depends on the constellation of five main cardinal features: agenesis of the corpus callosum, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency, which are found in almost all reported cases of Vici syndrome [6]. In addition, more recently recognized but equally consistent features include profound developmental delay, progressive microcephaly, and failure to thrive [9]. Furthermore, a wide range of additional findings has been reported in isolated cases including features such as hearing loss, lung hypoplasia, renal tubular necrosis, idiopathic thrombocytopenic purpura, and myopathy [10,11,12,13].
The initial presentation of our case included four out of the five classical features: oculocutaneous hypopigmentation, immunodeficiency, and agenesis of the corpus callosum. Cardiomyopathy developed a few months later following his initial presentation and is consistent with other reported cases in which initial echocardiography was normal. Thus, regular follow-up with ECHO for any suspected case of Vici syndrome is of crucial importance [14].
Moreover, our patient had profound developmental delay and failure to thrive, representing six out of the eight key features that were found to have a specificity of 97% and a sensitivity of 89% for cases with a positive EPG5 genetic test [9]. Other less common manifestations in our case included facial dysmorphism in the form of receding mandible and low-set ears, reported by Said et.al [15]. and Vojcek et al. [4]. Other dysmorphic features reported in some children with Vici syndrome include cleft lip and palate, hypertelorism, high-arched palate, micrognathia [1, 13, 16, 17], coarse facial features [5, 9], small anterior fontanelle with overlapping sutures, and broad nose [10], and Epicanthal folds were being reported less frequently [3].
Our index case had a hearing defect, which has been reported in a very few cases, specifically the sensory neural hearing loss subtype (SNHL) [4, 10, 17, 18]. However, we believe that it might be frequently unrecognized because of the overwhelming multisystem effects of Vici syndrome that may present very early in life and cause early death. Therefore, although ABR was not included as a baseline investigation for the diagnosis of a patient with suspected Vici syndrome, it should be investigated [6]. Moreover, the index case showed a tuft of hair on his lower back over the sacral region and talipes equinovarus of the left foot, which are reported here for the first time in Vici syndrome.
Other neurological manifestations of Vici syndrome, besides developmental delay, hearing deficits, and hypotonia documented in our case, include seizures, myopathy, progressive microcephaly, and neuropathy which have been reported in more than half of the children [6]. CNS affection is not fully explained by the associated structural brain lesion such as ACC, pontine hypoplasia, and others, as recent studies have suggested that Vici syndrome has a neurodegenerative pattern with progressive loss of skills and profound acquired microcephaly. Furthermore, the EPG5 genes were linked to early-onset epileptic encephalopathies, respiratory chain enzyme abnormalities, and secondary mitochondrial dysfunction as a possible downstream effect of defective autophagy [9].
The genetic testing of our patient revealed a homozygous likely pathogenic variant in the EPG5 gene confirming the clinical diagnosis of Vici syndrome. The c.1252+1G>T substitution that we discovered affects the first nucleotide of intron 3 and, to date, has not been reported in Vici syndrome patients. It is predicted to disrupt the highly conserved donor splice site [19, 20] and cause skipping of exon 3 and the complete loss of functional EPG5 protein either through protein truncation or, more likely, through nonsense-mediated decay. In line with this finding, the majority of the previously reported EPG5 pathogenic variants are nonsense, frameshift, and splice site changes indicating a loss of function mechanism in Vici syndrome patients. Unfortunately, no RNA or cell sample was available from the parents of the index patient or any other family member potentially carrying the c.1252+1G>T change. Thus, we were unable to experimentally validate the occurrence of altered splicing and nonsense-mediated RNA decay.
As for clinicians, suspicion of Vici syndrome is based on the characteristic clinical manifestations. Differential diagnosis based on other syndromes showing phenotypical overlap with Vici syndrome [6], or other neurometabolic etiologies of agenesis of the corpus callosum [21], has been suggested. One approach is to be aware of other differential diagnoses particularly other inherited hypopigmentation disorders, and especially those associated with neurological manifestations and structural brain lesions. This approach is a real challenge due to overlapping features. These rare disorders could include gray hair syndromes like Griscelli syndrome (GS), Chediak-Higashi syndrome (CHS), and oculocerebral hypopigmentation syndrome, cross-type (OHS). However, they all share the presence of silvery gray hair and the characteristic hair trichogram which is not commonly found in cases of Vici syndrome. Besides, CHS is characterized by giant azurophilic granules within neutrophils and regular small melanin granules visible in a trichogram while the neurological manifestations are either primary (developmental and degenerative) or secondary to an accelerated phase of hemophagocytic lymphohistiocytosis (CNS-HLH) [22]. Unlike CHS, the trichogram of GS shows small and large unevenly distributed melanin clumps. Neurological manifestations are found in all types except for GS type 3 [23]. Neurological presentations of GS1 are mostly primary due to myosin-Va deficiency [24], while those of GS2 are either due to CNS infections, due to a consequence of the associated immune deficiency, or due to CNS-HLH [25]. Although hypopigmentation may not be a consistent major finding in both Prader-Willi and Angelman syndromes, it should be included in the differential diagnosis and can be recognized by their characteristic somatic and behavioral problems [26, 27]. Laboratory investigations might narrow the list such as in cases of suspected phenylketonuria, which can be excluded by phenylalanine level in the blood and urine, and Menkes syndrome by measuring serum copper and ceruloplasmin in a child with short friable sparse hair (Table 1).
Counseling for the parents involved discussing their concerns about themselves, their healthy older child, and their future pregnancy probabilities. They were told that they were both carriers which means that both only have a genetic change that does not cause any health problems for them. For their older healthy child, they were advised to perform molecular testing to determine if he was a carrier or not affected. But the most important concerns for them were about the next pregnancies; genetic counseling was provided, and they were advised to perform prenatal diagnosis if they are intending to have other children.
Regarding patient prognosis, Vici syndrome is a devastating neurodegenerative disease with progressive multisystem pathology. The prognosis is variable with reported attenuated Vici syndrome phenotype [28]. However, most of the cases had a poor prognosis and a median survival time of 24 months. Cardiomyopathy and recurrent infections, the causes of death of the current case, are the most common causes of death [9].
