Re-assigned diagnosis of D4ST1-deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) after initial diagnosis of Marden-Walker syndrome.

We report on a 16-year-old female originally diagnosed with Marden-Walker syndrome due to features such as facial dysmorphism, several musculoskeletal anomalies, and atrial septal defect in addition to hypoplasia of the inferior vermis with normal-sized cerebellum and absence of the septum pellucidum. However, an SNP array performed at age 15 years detected a total of 142 Mb of long runs of homozygosity (ROH), and put the diagnosis in doubt. Using the Genomic Oligoarray and SNP array evaluation tool (http://www.ccs.miami.edu/ROH), CHST14 provided a "hit" as a gene mapping to the largest ROH region associated with a phenotype matching our patient's (if mutated). At that time, she was a cognitively intact, thin female with growth parameters below the 3rd percentile. Craniofacial features included microcephaly, midface hypoplasia, blepharophimosis, entropion, myopia, microretrognathia, and dental malocclusion. Musculoskeletal features included kyphoscoliosis, arachnodactyly, camptodactyly, and rocker-bottom feet with interphalangeal contractures. Her skin displayed large ecchymoses and poorly healed atrophic scars. Sequencing of CHST14 revealed a complex homozygous frameshift mutation involving a 7-bp deletion and an 11-bp insertion predicted to produce a truncated protein. This mutation was not seen in 100 controls of various ethnicities. Thus, our patient represents not only a novel (homozygous) mutation in CHST14, but is also the first patient with dermatan 4-O-sulfotransferase 1-deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) (DD-EDS ATCS) documented in the Western Hemisphere. Furthermore, our patient's central nervous system anomalies have not before been described in DD-EDS (ATCS).