Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia ... Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by Cappello et al., 2013). For a discussion of genetic heterogeneity of Van Maldergem syndrome, see 601390.
Mansour et al. (2012) reported 2 unrelated patients (patients 1 and 6) with Van Maldergem syndrome-2. The patients had a distinctive facial appearance that included large fontanels, maxillary hypoplasia, micrognathia, flat face, blepharophimosis, telecanthus, broad nasal bridge, and ... Mansour et al. (2012) reported 2 unrelated patients (patients 1 and 6) with Van Maldergem syndrome-2. The patients had a distinctive facial appearance that included large fontanels, maxillary hypoplasia, micrognathia, flat face, blepharophimosis, telecanthus, broad nasal bridge, and microtia and atresia of the external auditory meatus resulting in hearing loss. Patients showed neonatal hypotonia, intellectual disability, poor growth and feeding, and respiratory problems due to tracheomalacia. One patient required a tracheostomy. Skeletal abnormalities included osteopenia, thickened skull base and frontal bones, narrow thorax, short clavicles, subluxation of the radial heads, and hand and feet abnormalities with clinodactyly due to flexion deformities. Both had small kidneys. Brain MRI of 1 patient showed nodular periventricular heterotopia and a dysmorphic corpus callosum; MRI of the other patient showed agenesis of the corpus callosum. Seizures were not noted. Neuhann et al. (2012) reported a boy, born of consanguineous Caucasian parents, with Van Maldergem syndrome. He presented at age 4 years with severe developmental delay, hypotonia, inability to walk, and no speech development. Physical examination showed talipes equinovarus, finger camptodactyly with interphalangeal pterygium, joint laxity, and bilateral microtia. Dysmorphic facial features included epicanthus, telecanthus, short palpebral fissures, broad flat nasal bridge, downturned mouth, and dental malocclusion. He had a history of pharyngeal instability requiring a tracheostomy, poor feeding requiring tube feeding, inguinal hernia, hip subluxation, small kidneys, and genital abnormalities, including micropenis, cryptorchidism, and bifid scrotum. He also had a sacral dimple and an anteriorly placed anus. Brain MRI showed hypoplastic corpus callosum. Cappello et al. (2013) reported 2 sibs with VMLDS2. Features included periventricular nodular heterotopia, renal hypoplasia, hand anomalies, and skeletal dysplasia.
In 5 patients from 4 unrelated families with Van Maldergem syndrome-2, Cappello et al. (2013) identified biallelic mutations in the FAT4 gene (612411.0001-612411.0006). The first mutations were found by whole-exome sequencing and the subsequent mutations were found by ... In 5 patients from 4 unrelated families with Van Maldergem syndrome-2, Cappello et al. (2013) identified biallelic mutations in the FAT4 gene (612411.0001-612411.0006). The first mutations were found by whole-exome sequencing and the subsequent mutations were found by whole-exome sequencing or targeted Sanger sequencing. All mutations segregated with the disorder in the families. Functional studies were not performed, but animal studies suggested that loss of Fat4 resulted in defects of neocortical development similar to those observed in the patients. Two of the patients had been reported by Mansour et al. (2012) and 1 by Neuhann et al. (2012).