Clinical and molecular genetic characterization of a male patient with Sensenbrenner syndrome (cranioectodermal dysplasia) and biallelic WDR35 mutations

Background: Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy first described by Judith Sensenbrenner in 1975. CED is a complex disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. The clinical symptoms are variable and the CED phenotype may present intrafamilial and interfamilial differences. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disease. Mutations in six genes: IFT122, WDR35, IFT43, WDR19, IFT52, and IFT140 have been associated with this disorder. All known CED genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia.

Case: We report a on 2-year-old male patient affected by Sensenbrenner syndrome. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, narrow chest, high forehead, epicanthal folds, telecanthus, broad nasal bridge, low-set ears, sparse hair, and widely space teeth. Craniosynostosis was surgically corrected at the age of 4 months. The patient presented chronic renal disease. Nephrologic picture showed early stages of nephronophthisis. Psychomotor development was apparently normal. Molecular analysis of the affected individual revealed compound heterozygosity for a novel nonsense p.(Arg113*) and a missense p.(Asp841Val) variant in the WDR35 gene.

Conclusions: The observations of the CED patient in this study provide additional clinical data and expand the molecular spectrum of Sensenbrenner syndrome. Moreover, the two variants identified in the proband provide further evidence for the WDR35 mutations as the most common cause of this rare syndrome.