Letter to the Editor
2010-10-01

22 October 2009 Dear Editor, MULTIPLE SCLEROSIS IN ASSOCIATION WITH WILLIAMS–BEUREN SYNDROME Williams–Beuren syndrome (WBS) is caused by a deletion on chromosome 7q11.23 and is most often because of unequal recombination during meiosis.1 The mutation results in a lesion affecting the connective tissue and the central nervous system. Although WBS is a genetic, multi-systemic disorder with various neurological manifestations, paediatric multiple sclerosis (MS) in association with WBS has not been reported previously. We here present the clinical and molecular genetic findings of a 15-year-old girl with WBS who developed MS. The girl presented with a 1-day history of unsteady gait and eye motility disorders. At infancy, she was clinically diagnosed with WBS on the basis of the typical facial stigmata during an evaluation for growth failure. There was a history of precocious puberty. The family history was unremarkable. Facial features included a flat nasal bridge, a small mandible, prominent cheeks, a wide mouth with fleshy lips, small and widely spaced teeth, and prominent ear lobes. In addition, weight retardation below the fifth percentile and scoliosis of the spine were diagnosed. The child disclosed slight mental retardation, deficient fine motor skills, macroglossia and a hoarse voice. Cardiac ultrasound revealed a small perimembranous ventricular septal defect without haemodynamic relevance. Neurological evaluation demonstrated an ataxic gait and reduced muscle power in all extremities. Ophthalmological examination revealed a right-sided internuclear ophthalmoplegia (Fig. 1a). Because of the acute onset of ocular motility disorders and the ataxic gait, magnetic resonance imaging (MRI) of the brain was performed. It showed numerous supra- and infra-tentorial T2-hyperintense lesions consistent with demyelinating plaques, which further involved the pons, midbrain, cerebellum, corpus callosum and cerebral hemispheres (Fig. 1b,c). Some of these lesions displayed gadolinium enhancement. A lumbar puncture revealed a lymphocytic pleocytosis (22 cells/mm3), elevated protein (60 mg/dL), increased cerebrospinal fluid immunoglobulin G (IgG) synthesis rate (18.16 mg/24 h), elevated IgG index (2.1) and oligoclonal bands. According to the 2007 consensus definitions for paediatric MS, the clinical, neuroimaging and laboratory findings raised immediate suspicion of MS.2, 3 Fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) array analyses showed a microdeletion at 7q11.23 (WBS critical region) and confirmed the suspected diagnosis of WBS. The girl was treated with intravenous methylprednisolone for 3 days (1000 mg/day), followed by oral prednisone (8-day taper). On ophthalmological and neurological re-examination after 2 months, ocular motility was normal, and gait ataxia had also improved. One could argue that the clinical presentation, despite the MRI and cerebrospinal fluid findings, was a single demyelinating event (such as acute disseminated encephalomyelitis), because dissemination in time was not fulfilled. However, a repeat MRI scan 6 months later revealed a few new T2 lesions and two new periventricular gadolinium-enhancing lesions. According to the revised McDonald criteria, dissemination in time in this case was demonstrated by MRI, even in the absence of a second clinical demyelinating event; therefore, the findings were consistent with MS.3 (a) Nine cardinal gaze directions: right-sided internuclear ophthalmoplegia (on attempted left lateral gaze, the right eye fails to adduct across the midline). In the primary position, a left strabismus divergens is present. (b) Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging shows a demyelinating right dorsal paramedian pontine lesion (black arrow) causing the right-sided internuclear ophthalmoplegia and a left paramedian cerebellar lesion (white arrow). (c) Further demyelinating plaques were located in the supra-tentorial periventricular white matter. To our knowledge, this is the first reported case of MS in an adolescent female patient with WBS. WBS (OMIM 194050) is a neurodevelopmental disorder with multi-system manifestations. Usually sporadic, WBS has an estimated incidence of 1 in 20 000 live births, but new prevalence estimates are as high as 1 in 7500.1 The diagnosis of WBS in the described patient was based on the clinical features and was confirmed by FISH and SNP array. It has been recently shown that 99% of patients with WBS have a submicroscopic deletion on chromosome 7q11.23. The common ∼1.6-Mb (megabases) deletion region contains the elastin gene.1 Elastin deficiency has been implicated in the pathogenesis of some of the characteristics of WBS, such as cardiovascular disease, some of the facial features, hernias, orthopaedic problems and hoarse voice.4 Short stature because of feeding problems, prolonged colic, gastro-oesophageal reflux and constipation is often one of the early symptoms leading to a diagnosis, because of the lack of distinctive facial features at birth.4 Gait and ophthalmological abnormalities have also been reported in patients with WBS. A significant portion of adolescent WBS patients develop a degree of gait ataxia and may have noticeable appendicular ataxia along with ocular dysmetria and slow saccadic eye movements. Gait disturbances are usually attributed to primary cerebellar dysfunction or to visual–spatial processing problems.1 However, in the present case, the acute onset of gait ataxia and ophthalmoplegia set the indication for further diagnostic workup, which confirmed the coexistence of MS and WBS. MS is an inflammatory, presumed autoimmune disorder. Although the exact aetiology of MS is unknown, available evidence points to a multifactorial origin that includes genetic susceptibility and environmental factors.5 The estimated prevalence of MS is 50 per 100 000, with 2–5% of patients presenting before the age of 18 years and being defined as ‘paediatric MS’ cases.2 The diagnosis of paediatric cases should be based on the 2007 consensus definitions for paediatric MS and the revised McDonald criteria.2, 3 Similar to adult onset MS, children present most commonly with either pure sensory symptoms or optic neuritis. Diplopia, pure motor symptoms, abnormal gait including ataxia (cerebellar or vestibular), mixed sensory and motor symptoms, and sphincter disturbances are also reported.2 In the present case, we observed an association of MS with WBS. It is thus recommended that WBS children with acute onset complaints should undergo an appropriate, thorough evaluation, additionally to the regular control examinations, so that other, coexisting disorders are not overlooked. The authors would like to thank the European Union (PERACT – Marie Curie Early Stage Training MEST-CT-2004-504321).