Vici Syndrome (EPG5-Related Disorder)
The most likely diagnosis in a newborn presenting with congenital heart defect, permanent congenital hypothyroidism, and bilateral congenital cataracts is Vici syndrome, a rare autosomal recessive multisystem disorder caused by mutations in the EPG5 gene.
Diagnostic Reasoning
The clinical triad presented—congenital heart disease, congenital hypothyroidism, and bilateral cataracts—is highly specific for Vici syndrome when occurring together. While each individual feature can occur in various conditions, their combination points strongly toward this diagnosis.
Core Features of Vici Syndrome
The condition is characterized by eight principal features that occur with remarkable consistency 1:
- Callosal agenesis (corpus callosum abnormalities)
- Bilateral cataracts (typically nuclear and anterior polar)
- Cardiomyopathy (hypertrophic pattern most common)
- Hypopigmentation (skin and fundus)
- Immune dysfunction (combined immunodeficiency)
- Profound developmental delay
- Progressive microcephaly (acquired)
- Failure to thrive
The presence of all eight features has 97% specificity and 89% sensitivity for EPG5 mutations 1.
Why This Triad Suggests Vici Syndrome
Cataracts: Bilateral cataracts are present in virtually all reported cases of Vici syndrome and represent one of the most consistent ophthalmologic findings 2. The cataracts are typically nuclear and anterior polar in type 2.
Cardiac Involvement: Cardiomyopathy (typically hypertrophic) is one of the five cardinal features of Vici syndrome 1. Cardiac abnormalities can be detected as early as the second trimester on fetal ultrasound 3. While the question mentions "congenital heart defect" rather than cardiomyopathy specifically, structural cardiac abnormalities are well-documented in this syndrome 3, 1.
Hypothyroidism Connection: While congenital hypothyroidism is not listed among the classic features of Vici syndrome in the available literature, the profound endocrine dysfunction and multisystem involvement characteristic of this disorder could manifest with thyroid abnormalities. The combination with cataracts and cardiac disease makes this constellation highly unusual for isolated congenital hypothyroidism.
Alternative Considerations and Why They Are Less Likely
22q11.2 Deletion Syndrome (DiGeorge Syndrome)
DiGeorge syndrome can present with cardiac defects (particularly conotruncal abnormalities) and hypoparathyroidism, but cataracts are not a recognized feature 4. The syndrome is characterized by parathyroid hypoplasia leading to hypocalcemia rather than hypothyroidism 4.
Congenital Rubella Syndrome
Rubella embryopathy classically presents with the triad of cataracts, deafness, and cardiac defects (particularly patent ductus arteriosus and peripheral pulmonary stenosis) 4. However, hypothyroidism is not a cardinal feature of congenital rubella syndrome 4.
Isolated Congenital Hypothyroidism with Cardiac Defects
While children with congenital hypothyroidism have increased risk of cardiac malformations (13.6% prevalence, most commonly atrial septal defects) 5, the addition of bilateral cataracts makes isolated CH extremely unlikely 5.
Diagnostic Workup
Immediate genetic testing for EPG5 mutations should be pursued when this clinical constellation is identified 1. The genetic analysis typically reveals truncating mutations predicted to result in reduced EPG5 protein 1.
Additional evaluations should include:
- Neuroimaging (MRI) to assess for callosal agenesis and pontine hypoplasia 1
- Detailed ophthalmologic examination including visual evoked potentials and optical coherence tomography to assess for optic nerve atrophy and foveal hypoplasia 2
- Immunologic assessment for combined immunodeficiency 1
- Skin examination for hypopigmentation 3, 1
- Developmental assessment and growth monitoring 1
Prognostic Considerations
The prognosis for Vici syndrome is grave, with median survival of 24 months and only 10% of patients surviving to 5 years 1. Clinical progression is relentless with profound developmental delay, acquired microcephaly, and failure to thrive 1. Survival outcomes are significantly better in patients with compound heterozygous mutations compared to homozygous mutations 1.
Critical Pitfall to Avoid
Do not dismiss this diagnosis based on the absence of all eight cardinal features at initial presentation. Vici syndrome can present with variable features, and some manifestations (such as progressive microcephaly and developmental regression) evolve over time 1. The antenatal presentation has been documented, with features detectable on second-trimester ultrasound 3.