This report describes Van Maldergem syndrome 2, which shows autosomal recessive inheritance. The human gene implicated in this disease, FAT4, is also implicated in a similar neurodevelopmental disorder, Hennekam lymphangiectasia-lymphedema syndrome 2 (FBhh0001082, MIM:616006, DOID:0060366). See the report for 'neurodevelopmental disorders, FAT4-related' (FBhh0001080) for information on experimental results using Drosophila models of this and related diseases.
[updated July 2019 by FlyBase; FBrf0222196]
[VAN MALDERGEM SYNDROME 2; VMLDS2](https://omim.org/entry/615546)
[FAT ATYPICAL CADHERIN 4; FAT4](https://omim.org/entry/612411)
VMS is characterized by intellectual disability, periventricular heterotopia, an unusual face, camptodactyly and syndactyly, small kidneys, osteoporosis and tracheal anomalies sometimes necessitating tracheostomy. (Alders et al. 2014, pubmed:24913602.)
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, pubmed:24056717).
[from MIM:615546, 2019.7.17]
In 5 patients from 4 unrelated families with Van Maldergem syndrome-2, Cappello et al. 2013 (pubmed:24056717) identified biallelic mutations in the FAT4 gene. [from MIM:615546, 2019.7.17]
VMS-1 is caused by recessive mutations in the DCHS1 gene (dachsous cadherin-related 1 [Homo sapiens]) on chromosome 11p15.4, while VMS-2 is caused by recessive mutations in the FAT4 gene (Fat tumor suppressor, Drosophila of 4), on chromosome 4q28.1. DCHS1 protein is the ligand for the FAT4 receptor. Dchs1-Fat4 influence planar cell polarity (PCP), the polarization of cell structures and behaviors (direction of movement) within the plane of a tissue. PCP is essential for the generation of tissue architecture during embryogenesis and for postnatal growth and tissue repair. (Sotos et al. 2017, pubmed:29046692.)
The FAT4 gene encodes a protein that is a member of a large family of protocadherins. DCHS1 (MIM:603057) is another protocadherin that is the ligand for FAT4; FAT4 and DCHS1 form an apically located adhesive complex in the developing brain (summary by Cappello et al. 2013, pubmed:24056717). [from MIM:612411, 2019.7.16]
