We identified two unrelated children with DSS. Their clinical features are given in Table 1 and their radiographs are shown in Figure 1. They presented with fractures, cortical thickening and widening of the diaphysis of the long bones, cranial base sclerosis, broad ribs with sclerosis and platyspondyly. Subject 1 suffered from recurrent ear and skin infections between the ages of 8 and 11 months. Subject 2 presented with a pulmonary infection at two years of age and later necessitated surgical removal of her adenoids for breathing difficulties. Bone marrow biopsies were not performed in either child. Neither child had neurological symptoms or dental anomalies. Only subject 1 had skin findings, which were recurrent transient erythematous papules on the lower abdomen (1). Dual-energy X-ray absorptiometry for subject 1 showed a lumbar spine BMD Z-score of +8.1 at 2 years of age, and +11.9 at 5 years of age. Because she has short stature, these greatly elevated bone density scores are actually underestimates (6). Table 1.Summary of clinical and radiographic characteristics of children with DSS that we studiedSubject 1Subject 2ReferencesWhyte et al. (1)This publicationConsanguinity−+GenderFFHeight−2 SD−2.8 SDHead circumference+4 SD91st percentileSkin anomalies+−Blue sclera+−Recurrent infections++Laboratory anomaliesIncreased erythrocyte sedimentation rateReactive lymphocytes on complete blood count, hypercalcemiaSerum glucose levelNormalNormalCognitionNormalNormalVisionNormalNormalHearingNormalNormalHair and pilosityNormalNormalTeeth anomalies−−Frontal bossing+−Cranial base sclerosis++Broad ribs with sclerosis++Platyspondyly++Pelvis, peripheral sclerosis++Diaphyseal widening and relative hypodensity++Cortical thickening (initially)++Fractures++Other skeletal featuresDelayed closure of fontanelle Genu valgumOpen in a separate windowOpen in a separate windowFigure 1.Radiographs of patients. Images from subject 1 at 33 months (and 22 months for the pelvis) are from Whyte et al. (1), and have been reproduced with authorization from the publisher. For subject 2, radiographs were taken at 4 years of age. Note the sclerosis at the skull base, periphery of the iliac wings and metaphyses, platyspondyly, and in the long bones cortical thickening at the diaphysis, diaphyseal enlargement with relative radiolucency and a fracture in subject 2.We performed whole-exome sequencing to identify the genetic basis of DSS. Our study was approved by the Institutional Review Board of the Baylor College of Medicine. As shown in Table 2, after discrete filtering against dBSNP129 for variants with known minor allele frequencies <5% (according to the 1000 Genomes Pilot project), only 303 genes had rare or novel protein-impacting variants in both subjects. As an initial strategy, we kept genes in which variants corresponded to an autosomal recessive model (i.e. homozygous or compound heterozygote variants). There were 132 such overlapping genes. Given the high number of false-positive INDEL calls, we preferentially explored genes that showed at least one single nucleotide polymorphism (SNP). As shown in Table 2, only 17 genes shared by the two subjects showed rare or novel protein-impacting variants. Variants were visualized and compared with 12 other exomes of subjects with unrelated conditions. After keeping only high-quality variants (e.g. removing variants in repeat regions or variants seen in unrelated conditions that are likely false positives), and considering variants predicted to be pathogenic, only SLC29A3 variants remained. Subject 1 is heterozygous for p.Ser203Pro (c.607T>C) and p.Arg386Gln (c.1157G>A).

DNA from two Syrian families with H syndrome was analyzed through direct sequencing, and the expression of hENT3 in normal human skin was investigated by in situ hybridization and immunostaining. Results: We identified two novel mutations in the SLC29A3 gene: a homozygous splice site mutation IVS1+2T>G predicted to cause a splicing error, and a homozygous missense mutation c.1157G>A (p.R386Q) which substituted highly conserved amino acid residue in a transmembrane domain of hENT3. Furthermore, we demonstrate that hENT3 is expressed in histiocytes as well as in endothelium of blood and lymphatic vessels in normal human skin.