Keywords
Cerebrotendinous xanthomatosis - cholestanol - dentate nucleus
Introduction
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder resulting from a defective enzyme in bile acid synthesis pathway with deposition of cholestanol and cholesterol in brain, tendons, soft tissues and eyes leading to cerebellar dysfunction, early cataract formation, tendon, and soft tissue xanthomas. Around 300 cases of CTX have been reported worldwide to date. The disease is potentially treatable with chenodeoxycholic acid. Early diagnosis and treatment is essential to prevent the neurological sequelae of the disease.
Case History
A 32-year-old, mentally retarded female presented with gait instability and right malar eminence swelling as well as swelling along the posterior aspect of both ankle joints. Patient had undergone surgery for cataracts in both eyes 10 years back. On examination patient was found to have ataxia, soft, non-tender swelling along the posterior aspect of both ankle joints, as well as right malar emminence [[Figure 1A]]. A preliminary diagnosis of cerebrotendinous xanthomatosis was made and evaluation was started.
Figure 1 (A and B): Photograph of bilateral ankles revealing swelling along the posterior aspect of both ankles (A) with corresponding lateral radiograph of both ankles revealing soft tissue radio-opacities posterior to calcaneal bones and tibia in the region of Achilles tendons (B)
Lipid profile revealed total cholesterol of 306 mg/dl (LDL 205 mg/dl, VLDL 46mg/dl, HDL 55 mg/dl) and triglycerides of 526 mg/dl. Rest of the blood chemistry was normal. Radiograph of ankle joints revealed soft tissue swellings along the posterior aspect of both ankle joints and calcaneal bones [[Figure 1B]]. MRI of ankle joints revealed fusiform enlargement of bilateral Achilles tendons with signal intensity similar to muscle with speckled appearance on axial images consistent with tendinous xanthomatosis [[Figure 2]]. MRI brain revealed hyperintensity of bilateral dentate nuclei, deep cerebellar white matter with hyperintensity of posterior limbs of internal capsules on T2W and FLAIR images with corresponding hypointensity on T1W images [[Figure 3]]. Susceptibility weighted images [[Figure 4C]] revealed comma shaped hypointense signal of bilateral dentate nuclei. Hyopintense T1W and T2W round lesion was found in subcutaneous tissues of right malar eminence [[Figure 4A] and [B]] which was subjected to FNAC which revealed a xanthoma [[Figure 4D]]. Serum cholestanol levels were raised (14 1 micromole/liter).
Figure 2 (A-D): Sagittal proton density image (A) and T1-weighted image (B) showing diffuse enlargement of Achilles tendon with axial proton density (C) and MEDIC (D) showing enlarged Achilles tendon with widely spaced tendon fibers interposed with fat (speckled appearance)
Figure 3 (A-D): Axial T2-weighted and FLAIR images (A and B) reveal hyperintensity of bilateral dentate nuclei and deep cerebellar white matter. Hyperintensity of posterior limb of bilateral internal capsules is also seen on T2-weighted and FLAIR images (C and D)
Figure 4 (A-D): Axial T2-weighted and T1-weighted images (A and B respectively) reveal a hypointense nodule (arrows) in the subcutaneous tissues of right malar eminence. Susceptibility weighted image (C) reveal comma shaped hypointensity (arrow) in the region of bilateral dentate nuclei. High power view photomicrograph (D) reveals multiple giant cells and cholesterol crystals consistent with diagnosis of xanthoma
With a combined spectrum of clinical, biochemical and radiological findings, a diagnosis of cerebrotendinous xanthomatosis(CTX) was made.
Discussion
CTX is an autosomal recessive disorder characterized by defective sterol 27-hydroxylase enzyme which is responsible for conversion of cholesterol into bile acids (cholic and chenodeoxycholic acid). Defect in this enzyme pathway results in accumulation of precursors of bile acids namely cholestanol and bile alcohols.[[1],[2],[3]] Abnormally elevated cholesterol and cholestanol compounds get deposited in soft tissues leading to early cataract formation, soft tissue and tendon xanthomas, early atherosclerosis. Subnormal intelligence, learning difficulties, cerebellar dysfunction and neuropathy comprise the neurological spectrum of the disease. Serum cholesterol and cholestanol levels are elevated in CTX.[[1],[3],[4]] Diagnosis is clinched by the characteristic combination of neurological, ocular and musculoskeletal symptoms supplemented by neuroimaging and biochemical results. In CTX, MRI of brain reveals hyperintensity of dentate nuclei and deep cerebellar white matter on T2-weighted and FLAIR sequences with associated cerebellar atrophy. Microcalcifications can occur within dentate nuclei which can be demonstrated as hypointensity of dentate nuclei on susceptibility weighted imaging. Cerebral atrophy with T2W and FLAIR hyperintensity of supratentorial white matter and deep grey nuclei can also be seen. Involvement of internal capsule as T2W/FLAIR hyperintensity.[[1],[2],[3],[5],[6]] All these areas of signal intensity change exhibit increased diffusivity on DWI. Tendon xanthomascan be demonstrated by MRI as enlargement of tendons with hypointense signal intensity. Soft tissue xanthomas also exhibit hypointense signal intensity on both T1W and T2W images.
CTX has a myriad of differential diagnosis. It mimics hypercholesterolemia and sitosterolemia which share xanthoma as a clinical feature with it. Sitosterolemia is differentiated from CTX by absence of neurological symptoms and cataract formation. Hypercholesterolemia is characterized by formation of xanthomas with elevated cholesterol levels but with normal cholestanol levels. CTX also resembles Marinesco-Sjogren syndrome which also presents with triad of cataract formation, ataxia and mental retardation but the absence of tendon xanthomas and presence of scoliosis, short small bones of hand and feet reliably differentiate this disorder from CTX. On neuroimaging those disorders which exhibit hyperintensity of dentate nuclei on T2W images need to be differentiated from CTX. These include metronidazole toxicity and acutely decompensated maple syrup urine disease. These two disorders present with acute encephalopathy unlike CTX which has an insidious presentation.[[1],[5],[7]]
Treatment consists of chenodeoxycholic acid which suppresses the formation of cholestanol. Treatment must be started at the earliest to halt the neurological deterioration.[[1],[4],[7],[8]] Though this is a typical case of CTX but the fact that patient had not been diagnosed previously has led to permanent neurological damage in the form of subnormal intelligence and cerebellar ataxia. The fact that patient was operated for juvenile cataracts a decade back should have alerted the physician to ascertain the etiology of early cataract formation and early institution of appropriate therapy to avert the neurological sequelae of this otherwise treatable condition.
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