Figure 1: a-d Case 1- showing bilateral xanthomas in achielles tendons and around nose bridge with pes-cavus.

Figure 2: a-d Case 2 -showing xanthomas over Achilles tendons, hands and lower-eyelids.

Discussion

Earliest reports of CTX was made by Bogaert’s in 1937 followed by few hundred cases worldwide [4,5]. There are no consensus data on the prevalence of CTX, the estimated rate being <5/100000 worldwide. Most patients were traced to Israel, Netherlands, and USA. From India, Sodhi et al. documented the first case of CTX in 1973 [6]. Subsequently by Nair et al. from Trivandrum [7].

CTX can present to different specialists because of its multisysteminvolvement. It may manifest in neonates and in early childhood with chronic diarrhea, congenital or juvenile cataract, delayed developmental milestones, mental retardation and occasionally, neonatal cholestatic jaundice. The typical triad of neurological dysfunction, tendon xanthoma, and early onset cataract is the clinical hallmark. This is often not found on first contact with specialist. Bordia and Saifee from India reported oro-mandibular dyskinesia as the presenting feature of CTX which was seen at first by dentist [8]. CTX shares presence of xanthoma and premature atherosclerosis with other lipid storage disorders including familial hyper cholesterolemia and sitosterolemia. Progressive neurological dysfunction and early cataract are seen in CTX only.

The presented cases highlighted the classical manifestations ofCTX in the form of progressive dementia, pyramidal, cerebellar,peripheral neuropathy in association with bilateral cataracts, tendonand eyelid xanthomas on a background of chronic diarrohea. Case 2, also had hypothyroidism, osteoporosis induced pathological fractures. The clinical syndrome may include other neurological features like fronto-temporal dementia [9,10], extra pyramidal symptoms, including dystonia and oromandibular dyskinesia [8], early-onset Parkinson disease [11], seizures [12], muscular symptoms like myopathic facies [13] (Table 1).

Table 1: Differential diagnosis based on clinical features.

According to the clinical suspicion index of Mignarri et al. for CTX, where our both cases had all the four clinical features evolved in the same order as described like diarrohea, presenile cataracts, xanthomas and neurological abnormalities [14].

Soffer and colleagues [15] demonstrated that the parenchymal destruction in the brain starts in the white matter with cholestanol cumulation and progresses in a centrifugal manner with axonalspheroids being more marked in the brainstem with decreasing order of severity in the centrum semiovale. The presenile cataracts of CTX contain high cholestanol compared to the cholesterol of senile cataracts.

Earliest and most important abnormalities are noted in the cerebellum with high signal of deep gray nuclei namely dentate nuclei with occsaional hypointensity. Sometimes white matter lesions are surrounded by rim of hypointensity in T2 weighted images suggestive of macroscopic xanthomata, calcium or hemosiderin deposits. Neuro-imaging modalities demonstrate diffuse atrophy of the brain, as well as focal lesions (including demyelinating lesions and, rarely, xanthomata) in the cerebellum, basal ganglia, and cerebrum. CT scan is less sensitive but MRI abnormalities are obvious. Typical patterns on MRI brain include bilateral lesions consistent with a metabolic abnormality. Destefano et al. had reported T2 hyperintensity of the dentate nuclei as an earliest and characteristic finding of CTX in their 79% of patients [16]. T2 abnormalities are also found in the globus pallidus, substantia nigra, and inferior olives with extension into the surrounding white matter with sparing of the U fibers and the corpus callosum in later years of the disease. Hence CTX should be considered in the differential diagnosis of leukodystrophies [17].

Focal lesions in the brain involving the corona radiata, centrumsemiovale, globus palldum [18,19], and posterolateral columns of spinal cord [19] are described and on the other hand brainstem, corpus callosum [19] and atrophy of spinal cord [20], have been reported.

Choroid plexus xanthogranulomas are benign tumors composed of xanthoma cells (macrophages), cholesterol clefts, chronic inflammatory cellular reaction, and hemosiderin. At autopsy series they have been found incidentally in 1.6-7% of cases [21]. These lesionsare most commonly seen bilaterally in the lateral ventricles; they areasymptomatic because they are too small to obstruct the ventricles. However, those occurring in the third ventricle are more likely to present with non-communicating hydrocephalus. Hypointensity on T2 weighted MR sequence is classical of xanthomatous tissue. Similardemonstration of bilateral choroid plexus xanthogranuloma in a patient with CTX was reported by Fiorelli et al. [22].

Magnetic resonance spectroscopy reveals diffuse mitochondrial dysfunction and axonal damage, with large amounts of lactate and decreased N -acetylaspartate in the periventricular white matter andcerebellar hemispheres [16]. Similar findings can as well be reflected in the affected xathomatous tissues.

Isolated spinal cord white matter disease has been described [20-23]. MRI may reveal increased intensity in the lateral and dorsal columns, even in mainly cerebral forms of the disease[16]. Magnetization transfer imaging has been found to be a reliable quantitative indicator of the extent of damage in the brain parenchyma [23]. MRI can also be used to evaluate possible tendon xanthomata outside the central nervous system; enlargement of the tendons and xanthomas of eyelids as evident in our case.

Treatment of this disease includes the combination of CDCA (300mg/day) and HMG Co A inhibitor (Simvastatin/Pravastatin 10 mg/ day) is more effective in reducing cholestanol levels and normalizing LDL cholesterol [24,25], LDL pheresis, and dietary modifications. The results of treatment are variable, there was either arrest of the disease progression or partial improvement of clinical, biochemical, and MRI abnormalities. Genetic analysis is important in identifying the carriers of the disease. Early institution of CDCA therapy can prevent development of CTX phenotype. It improves bile acid metabolism and decreases cholestanol levels. The drug CDCA is not available in India and is very expensive.