Van Maldergem syndrome: further characterisation and evidence for neuronal migration abnormalities and autosomal recessive inheritance

Abstract

We present six patients from five unrelated families with a condition originally described by Van Maldergem et al and provide follow-up studies of the original patient. The phenotype comprises a distinctive facial appearance that includes blepharophimosis, maxillary hypoplasia, telecanthus, microtia and atresia of the external auditory meatus, intellectual disability, digital contractures and skeletal anomalies together with subependymal and subcortical neuronal heterotopia. Affected patients typically have neonatal hypotonia, chronic feeding difficulties and respiratory problems. In our cohort, we have observed one instance of sibling recurrence and parental consanguinity in three of the families, indicating that autosomal recessive inheritance is likely.

Figure 1

Facial characteristics of VMS. (a) patient 1 (b) patient 2 (c) patient 3 (d) patient 4 and (e) patient 5 (f) patient 6. The faces are characterised by blepharophimosis, telecanthus, a broad nasal bridge, flat facial profile (maxillary hypoplasia) and a progressive thickening of the alae nasi. Three subjects (patients 1, 2 and 5) required a tracheostomy due to airway collapse. (g–l) auricular anomalies in VMS. (g) patient 1; (h) and (i) patient 2; (j) patient 3; (k) patient 5 and (l) patient 6. There is microtia with thickening sometimes cystic of the crura and superior and inferior helical folds and atresia of the external auditory meatus with mixed conductive and sensorineural hearing loss.

Figure 2

Digital abnormalities camptodactyly and palmar contractures and webbing in VMS. (a) patient 1; (b) and (c) patient 2; (d) patient 3 and (e) patient 4.

Figure 3

Radiographic anomalies in VMS. (a–d) Patient 2. (a) Brachy–turricephaly with relative maxillary hypoplasia and underbite. Cochlear implants are present. (b) Long, narrow thorax with a tracheostomy tube in situ. (c) Flexion deformities at the proximal interphalangeal joints, distal pointing of the terminal phalanges and soft tissue syndactyly. (d) Hypoplastic third and fourth metatarsals resulting in short third and fourth toes. Patient 5 (e–i). Large anterior fontanelle, widened metopic suture, thickened frontal bone, absent pneumatisation of the mastoid air cells and a hypoplastic mandibular condyle. (g, h) Subluxation of the radial head; (i) camptodactyly with flexion deformities at the proximal interphalangeal joints, soft tissue syndactyly and a short fourth metacarpal.

Figure 4

MRI anomalies noted in individuals with VMS syndrome. (Patient 1 a–c) (a) axial T2 image showing extensive laminar heterotopia (arrowed) extending from the occipital into the temporal horns of the lateral cerebral ventricles; (b) patient 1; axial T2 demonstrating linear lesions iso-intense with cortical grey matter adjacent to the lateral walls of the bodies of the lateral ventricles; (c) patient 1; sagittal midline T1 demonstrating a mildly dysplastic corpus callosum but normal hindbrain and brainstem structures; (d–f) patient 2 (d) axial T2 showing thick bands of heterotopic grey matter extending along the entire inferiolateral wall of the temporal horns of the cerebral ventricles (arrowed). Overlying these lesions posteriorly are localised areas of cortical thickening and gyral simplification indicative of pachygyria (asterisks); (e) axial T2 image showing linear heterotopic tissue similar to that depicted in (b) anteriorly in the bodies of the lateral ventricles (arrowheads); (f) (coronal T1 just posterior to the trigone) demonstrating bilateral periventricular heterotopia (PH) inferiolaterally in the posterior horns (arrows); (g–i) MRI scan of case 3 at 18 months of age. (g) Coronal T2 slice demonstrating alternating bands of grey (*) and white (w) matter within the posterolateral cortex, (h) extending into the temporal lobes and around the anterior convexities of the cerebral cortex (arrowheads) although the appearances are less pronounced anteriorly; (i) nodular PH within the walls of the lateral ventricles. The cerebral cortex demonstrates a simplified gyral pattern, more so posteriorly than anteriorly. (j) Patient 5, axial T1 image demonstrating laminar PH lining the occipital horns and peritrigonal region of the ventricles (arrows).