Van Maldergem Syndrome 1

A number sign (#) is used with this entry because of evidence that Van Maldergem syndrome-1 (VMLDS1) is caused by homozygous mutation in the DCHS1 gene (603057) on chromosome 11p15.

Description

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).

Genetic Heterogeneity of Van Maldergem Syndrome

See also VMLDS2 (615546), caused by mutation in the FAT4 gene (612411) on chromosome 4q28.

Clinical Features

Van Maldergem et al. (1992) described a mentally retarded girl with facial abnormalities (tele- and epicanthus, ptosis, broad nasal bridge, inverted W-shaped upper lip, everted lower lip, macrostomia, malformed ears), abnormal extremities (camptodactyly, genu recurvatum, interdigital webbing), and hyperlaxity of major joints. The same complex was found by Zampino et al. (1994) in a 5-year-old girl. MRI of the brain in the latter patient showed hypoplastic optic chiasm, inferiorly beaked frontal horns, and hypoplasia of the posterior part of the corpus callosum. Both cases were sporadic. Paternal age was 38 years in one case (Van Maldergem et al., 1992) and 36 years in the other (Zampino et al., 1994). Zampino et al. (1994) proposed the term cerebrofacioarticular syndrome for this complex. Mansour et al. (2012) provided follow-up of the patient reported by Van Maldergem et al. (1992). At age 32 years, she had autism with hand stereotypies, no language development, severe intellectual disability, and self-injurious behavior. She had poor growth, no breast development or secondary sexual characteristics, and no menarche.

Mansour et al. (2012) reported 4 patients from 3 families with Van Maldergem syndrome-1 (patients 2, 3, 4, and 5). All patients had a distinctive facial appearance that included large fontanels, maxillary hypoplasia, micrognathia, flat face, blepharophimosis, telecanthus, broad nasal bridge, thickening of the nasal alae, 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. Several patients 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. More variable features included small kidneys, anal stenosis, anteriorly placed anus, sacral dimples, abnormal teeth, high-arched palate, choanal atresia, thick gums, and hypospadias. Brain MRI showed subependymal and subcortical neuronal heterotopia, often with a dysmorphic corpus callosum or simplified gyral pattern, consistent with a neuronal migration defect. None of the patients had seizures.

Inheritance

The transmission pattern of Van Maldergem syndrome in the families reported by Mansour et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 3 unrelated consanguineous families with Van Maldergem syndrome-1 (VMLDS1; 601390), Cappello et al. (2013) identified 3 different homozygous mutations in the DCHS1 gene (603057.0001-603057.0003). The mutations were found by autozygosity mapping combined with targeted genome capture of the region. Two of the mutations resulted in premature termination. The patients had previously been reported by Mansour et al. (2012) as patients 2, 3, 4, and 5.