Unveiling cerebrotendinous xanthomatosis of young adult: A case report

A 21-year-old male presented with bilateral swelling in the ankle region for 3 years, insidiously increasing in size, with no pain or diurnal variation. No walking difficulties or other joint involvement were reported. He has learning disabilities. His sister displayed similar symptoms and cognitive impairment. Occasional blurred vision; no neurological or traumatic history nor prior treatment.

A c. 9x4x4 cm swelling over both Achilles tendons, hard and immobile on palpation, with limited dorsiflexion and plantar flexion but no pain. Peripheral pulse palpable, active toe movements present (Figures 1a, 1b).

Plain radiograph was initially done for both ankles of the patient and showed diffuse, well-defined fusiform soft tissue thickening noted in the posterior aspect of both ankle joints (right > left). No obvious calcifications were noted within (Figure 2).

On ultrasound, a well-defined heterodense thickened area is noted adjacent to the calcaneal insertion of the bilateral Achilles tendon (Figure 3).

On MRI of both ankles, both the Achilles tendons showed fusiform thickening with T1 and T2 hypointensity and STIR hetero-intensity within (Figures 4a, 4b, 4c, 4d, 4e).

On MRI brain, T2, FLAIR hyperintensities are noted in bilateral centrum semiovale and bilateral parietal regions, which is an uncommon finding than the usual sites (Figures 5a, 5b, 5c).

Retrospectively analyzing and correlating with clinical history and imaging findings, a lipid profile test was done, and the results were:

- Cholesterol level: 153 mg/dl; Triglyceride: 361 mg/dl; HDL: 30 mg/dl; LDL: 87 mg/dl; VLDL: 72 mg/dl; Triglycerides, LDL, and VLDL are elevated.

USG-guided biopsy from the right Achilles tendon showed cholesterol clefts with foreign body giant cells and Touton-type giant cells. No evidence of atypia in the sections studied – features of Tendinous Xanthoma (Figures 6a, 6b).

Background

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder resulting from mutations in the CYP27A1 gene on chromosome 2, causing a deficiency in the sterol 27-hydroxylase enzyme [2]. This leads to cholesterol and cholestanol accumulation in various tissues, with significant variations in estimated incidence. Recent genetic studies suggest an incidence of 1 in 134,970 to 461,358 for Europeans and 1 in 64,267 to 64,712 for East Asians, challenging the previously reported rare prevalence of 0.13 per 100,000 people according to 2018 Orphanet data. Van Bogaert first identified CTX in 1937 [3].

Clinical Perspective

Tendon xanthomas are most prevalent in bilateral ankles, knees, elbows, fingers, and tibia. Children may initially exhibit cataracts, intellectual disability, and diarrhoea, often leading to delayed diagnosis [4]. These xanthomas typically develop in the second or third decade, with palpebral xanthelasma also occurring due to lipid deposition. Azoospermia in CTX patients can result from cholesterol accumulation in the scrotal sac, affecting male reproductive function [5]. This condition is often associated with familial hypercholesterolemia. In our patient, Achilles tendon swelling and learning disabilities were found, and imaging studies were done to reach a diagnosis.

Imaging Perspective

Ultrasound shows loss of tendon architecture, with thickening and symmetric hypoechoic infiltration. Using ultrasound, xanthomas that seem hypoechoic or hyperechoic can be distinguished from a normal tendon that appears isoechoic with a fibrillar structure. According to Steinmetz et al., swollen tendons exceed two standard deviations from a mean of 5.7 + 7.1 mm [3]. MRI hypo intensity indicates tendon hypertrophy and T1/T2 hypointensity suggests soft tissue xanthomas [6].

Tendon xanthomas appear hypointense on T1 and T2 due to cholesterol and cholestanol deposition, while a healthy tendon is hyperintense on T1WI [9].

CTX has documented T2-weighted localized and diffuse high-signal-intensity lesions predominantly in the cerebellar white matter and associated with atrophy [1]. In our case, elevated lipid levels and brain MRI confirmed cerebrotendinous xanthomatosis via biopsy.

Outcome

Early treatment with HMG-CoA reductase inhibitors and CDCA normalizes bile acid synthesis, cholestanol levels, and clinical symptoms in cerebrotendinous xanthomatosis, even during pregnancy [7]. Surgical removal of Achilles tendon xanthomas is considered for severe discomfort or disfigurement, with complete xanthoma removal or excision options.

Our patient was not operated on as he did not have a functional disability at present. Treatment included weight-bearing and physiotherapy exercises.

Take Home Message / Teaching Points

Patient’s complaints initially pointed to Achilles tendinopathy, but intellectual disability and occasional blurred vision raised xanthomatosis suspicion. Elevated triglycerides, LDL, and VLDL levels in a lipid profile reinforced this suspicion. Brain MRI revealed peculiar T2 and FLAIR hyperintensities in the bilateral parietal regions. A guided biopsy confirmed the diagnosis of cerebrotendinous xanthomatosis.

Written informed patient consent for publication has been obtained.