A 42-year-old man presented with a 6-year history of mild evening fatigability in all four limbs followed by slowly progressive gait imbalance and recurrent diplopia, despite an unremarkable cerebral and orbital magnetic resonance imaging (MRI) as well as a negative single fiber electromyography. During the last 3 years, he had progressively developed limb incoordination, slurred speech and dysphagia, and lost approximately 20% of his body weight. His family history was positive for rheumatoid arthritis, Sjögren’s syndrome, pancreatic cancer, but negative for ataxia, myasthenia gravis, neuropathy, tremors, and dementia. His medical history was significant for allergic asthma, increased blood pressure, and left retinal macular degeneration. At the time of presentation to our Institution, the general physical examination was unremarkable apart from bilateral xanthelasma, vitiligo on the dorsal aspect of hand fingers and yellowish papulae on both feet and the left pectoral region. Neurologic examination revealed acalculia (mini mental state examination: 23/30), horizontal gaze nystagmus, normal fundoscopic and pupillary examinations, slow start, hypermetric saccades mainly in the horizontal plane and mild bilateral neurosensorial hypoacusia. Romberg’s sign was present, and a marked ataxic gait, tight-rope walking inability, dysdiadochokinesia, arms dysmetria, tremor, dysarthria, rhinolalia, and motor hindrance of the hands were also observed.
A biopsy of one of the skin papulae showed nodular infiltration of the dermis by mononuclear histiocytes (CD163+, CD68+, CD14+, CD4+, CD1a−, CD207−, S100−, phosphorylated extracellular signal-regulated kinases+). Several histiocytes showed a foamy cytoplasm (Fig. 1).
Extensive laboratory workup including complete blood count, complete metabolic panel, hormonal profile, inflammation markers, immunoglobulins, interferon alpha, angiotensin-converting enzyme, Quantiferon, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and syphilis testing was unremarkable, except for persistent monocytosis. Low levels of both testosterone and circulating T regulatory lymphocytes were found, and high levels of vascular endothelial growth factor (x2 upper limit of normal-ULN) and anti-thyroid peroxidase (x2 ULN), in the presence of anti-nucleus Antibodies (Abs; titer: 1:640) with positive anti-dense fine speckled 70 Abs. To rule out a possible diagnosis of cerebrotendineous xanthomatosis or Gaucher’s disease, plasma cholestanol and chitotriosidase levels were measured, resulting normal and slightly increased (1.8x), respectively. Genetic analysis of spino-cerebellar ataxia (SCA)1, SCA2, SCA3, SCA6, SCA7 and SCA36 genes did not reveal any mutations, nor was the Friedreich’s ataxia (FRDA) trinucleotide repeat disorder identified. MRI of the brain revealed atrophy of the midbrain, cerebellum, superior and middle cerebellar peduncles (Fig. 2A, B). Hyperintense signals were observed in T2 and fluid-attenuated inversion recovery (FLAIR) sequences within the pons, cerebellar white matter, dentate nuclei (DN), and globi pallidi in the absence of any contrast enhancement (Fig. 2C,D,G). Both the retro-orbital space and the pituitary gland appeared normal. Susceptibility weighted imaging (Fig. 2E,F) demonstrated paramagnetic compound accumulation in the DN, caudate nuclei, and globi pallidi. Spectroscopy MRI showed a reduction of N-acetyl aspartate in the DN and globi pallidi (Fig. 2G,H). Whole-body bone scintigraphy with 99technetium-methylene diphosphonate (99Tc-MDP) showed intense, abnormal radiotracer activity in the distal femurs and whole tibiae bilaterally, with additional areas of weak uptake in the ulnae, radii, right mandible, and left maxilla (Fig. 3A,B). This pattern of skeletal colonization was further confirmed by fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging (Fig. 3E), and high resolution computed tomography (CT) of the femurs and tibiae consistently showed the presence of granulomatous lesions characterized by central demineralization and peripheral osteosclerosis (Fig. 3C,D). A brain 18F-Florbetaben PET was carried out to detect the presence of β-amyloid, but was unrevealing, as were CT scan of the thorax and abdomen and MRI of the heart.
The presence of xanthelasma, the biopsy findings, cerebellar degeneration and skeletal findings raised the diagnostic suspicion of ECD. Genetic testing of the formalin-fixed paraffin-embedded skin lesion identified the V600E, GTC > GAG mutation of the BRAF gene, further corroborating the diagnostic suspicion. To rule out a concomitant diagnosis of Rosai-Dorfman-Destombes disease (Razanamahery et al., 2020), a sternal fine-needle biopsy of bone marrow was performed and demonstrated the absence of emperipolesis. Immunostaining for S100 was negative, whereas a Kirsten rat sarcoma (KRAS) mutation was found in 1% of nucleated marrow blood cells.
Given the extensive CNS involvement, the patient was started on the BRAF inhibitor Vemurafenib at 960 mg bid. After 15 months, the patient is continuing on the same treatment. Multiple dose adjustments have been necessary in this timeframe as a result of the poor individual drug tolerance. Asthenia, weight loss, and palmoplantar fibromatosis have been the main adverse events. Clinically, the patient has benefited from the BRAF blockade, with disappearance of the xanthelasma and a progressive improvement of the cerebellar symptoms. Nonetheless, the CNS and skeletal findings have remained substantially unchanged, as demonstrated by follow-up imaging. The possibility of combining an anti-MAP2K1 agent with Vemurafenib was recently refused by the patient.