Cerebrotendinous xanthomatosis with radiological abnormalities of the chest

Background

Cerebrotendinous xanthomatosis (CTX) is a rare genetic disease caused by a cytochrome P450 (CYP) gene abnormality that results in decreased activity of the CYP protein, sterol 27-hydroxylase (CYP27).1 CTX is associated with intractable diarrhoea, juvenile cataracts, xanthoma, juvenile arteriosclerosis, osteoporosis and psychiatric disorders such as mental retardation, cerebellar ataxia, epilepsy and extrapyramidal symptoms.2 On the other hand, pulmonary lesions caused by CTX have been reported infrequently; in particular, to the best of our knowledge, only one case of CTX with chest radiological abnormalities has been reported.3

We present the case of a patient with CTX, who presented with characteristic pulmonary lesions on radiology. We examined these lesions using chest CT imaging and MRI, and performed a transbronchial lung biopsy for definitive diagnosis. We diagnosed this lesion as being caused by CTX. We were also able to review the effects of 2 years of treatment on the lesion. To the best of our knowledge, this is the first case in which a detailed investigation of CTX-related pulmonary lesions was performed.

Case presentation

The patient was a 55-year-old Japanese man with no history of smoking. He had been diagnosed with mental retardation and muscle weakness from birth. He suffered from Stevens-Johnson syndrome, caused by treatment for the common cold, when he was 16 years old, and sustained corneal opacity. He had been admitted to another hospital because of a right tibial fracture and was diagnosed with bilateral calcaneal tendon thickening when he was 45 years old. A hereditary disease was suspected by the family doctor when he was 55 years old, and he was referred to our department. He had no history of coronary artery disease or prolonged neonatal cholestasis. He did not have any respiratory symptoms at the time of referral.

Physical examination of the patient revealed no adventitious sounds. No cyanosis or clubbing of the fingers or enlargement of superficial lymph nodes was observed. His vital signs were as follows: blood pressure 125/87 mm Hg, pulse 68 beats/min, temperature 36.2°C, respiratory rate 18 breaths/min and oxygen saturation 96% breathing room air at rest. Neurological examination revealed mental retardation; in particular, the patient’s verbal IQ had decreased to 55 on the Wechsler Adult Intelligence Scale (Fourth Edition). He achieved nearly full scores for each extremity using the Medical Research Council Scale for muscle strength. His deep tendon reflexes were increased except for that of the calcaneal tendon, which was decreased. Both Babinski reflexes were positive. He exhibited ataxia of the limbs but not of the trunk. He had no obvious abnormalities in sensory examinations.

Investigations

A complete blood count revealed a white blood cell count of 4.1×10⁹/L, haemoglobin of 128 g/L and a platelet count of 298×10⁹/L. Serum chemistry revealed the following: aspartate aminotransferase 12 U/L, alanine aminotransferase 9 U/L, lactate dehydrogenase 201 U/L, total bilirubin 0.19 mg/dL, blood urea nitrogen 16.5 mg/dL, creatinine 1.18 mg/dL, total protein 6.21 g/dL, albumin 3.44 g/dL, total cholesterol 196 mg/dL, high-density lipoprotein cholesterol 78.7 mg/dL, triglycerides 82 mg/dL and cholestanol 28 µg/mL (normal range <5 µg/mL).4 The patient’s thyroid function was within normal ranges. Genetic analysis of the patient’s blood cells for CYP27A1 revealed a known homozygous missense mutation, c.1421G>A (p.R474Q), in exon 8.

Bilateral, well-defined, elongated soft-tissue masses were discovered posterior to the distal tibias and superior to the calcanei; these were considered thickening of the calcaneal tendons (figure 1A). Head CT revealed slight hyperattenuation in both dentate nuclei (figure 1B). Fluid-attenuated inversion recovery MRI revealed symmetrical areas of decreased signal intensity in both dentate nuclei and areas of increased signal intensity surrounding the deep cerebellar nuclei (figure 1C). The patient’s lumbar-spine bone mineral density was decreased to 42% of the young adult mean.

Chest radiography revealed diffuse, small nodular opacities predominantly in the upper to middle fields of both lungs (figure 2A). On chest CT images, diffuse micronodular and reticular opacities, suggestive of a perilymphatic distribution, were observed predominantly in the upper and middle zones of both lungs (figure 2B). In the posterior segment of the upper lobe of the right lung, an ill-defined area of consolidation with calcification was also observed. One of the nodular lesions in the right lung was visualised as an area of slightly increased signal intensity on T1-weighted and T2-weighted MR images, and as an area of decreased signal intensity on short tau inversion recovery MR images (figure 2C–E).

Because of the chest radiological findings, the patient underwent bronchoscopy for definitive diagnosis of pulmonary lesions. No substantial abnormalities, such as inflammation of the bronchial mucosa or intrabronchial sputum, were observed. In bronchoalveolar lavage fluid taken from the patient’s right upper lobe (B3), the total cell counts (2.3×10⁵/mL), percentage of lymphocytes (27%) and percentage of neutrophils (10%) were increased; however, no contamination with lipid elements was observed. The bronchoalveolar lavage fluid was also negative for malignant cells, Mycobacterium and Pneumocystis staining, as well as bacterial and fungal cultures. Transbronchial lung biopsy was performed on the right lung (B2b, B6b and B9). Histological findings obtained from the biopsy revealed foamy macrophages and multinucleate giant cells in the alveolar spaces, and the permeation of lymphocytes and plasmacytes on the walls of the airways (figure 3). In addition, marked lipid crystal clefts and collagenous fibrosis were observed. On immunohistochemical staining, CD68-positive cells were observed, containing lipid crystal clefts.

Outcome and follow-up

We diagnosed his disease as CTX. Although there are few reports of patients with CTX with pulmonary lesions, we concluded from the radiological and histopathological findings that the pulmonary lesions were indeed caused by the CTX.

The patient was treated with 250 mg/day chenodeoxycholic acid (CDCA), divided into two doses. After treatment with CDCA for 2 years, the patient’s serum cholestanol concentration had decreased to 5.9 µg/mL from 28 µg/mL. The patient’s neurological findings and calcaneal tendon thickening were unchanged; however, the nodular shadows and small nodular lesions visualised using chest CT had decreased (figure 4).