Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.

Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR.

Facial recognition is central to the diagnosis of many syndromes, and craniofacial patterns may reflect common etiologies. In the pleiotropic Bardet-Biedl syndrome (BBS), a primary ciliopathy with intraflagellar transport dysfunction, patients have a characteristic facial ''gestalt'' that dysmorphologists have found difficult to characterize. Here, we use dense surface modeling (DSM) to reveal that BBS patients and mouse mutants have mid-facial defects involving homologous neural crest-derived structures shared by zebrafish morphants. These defects of the craniofacial (CF) skeleton arise from aberrant cranial neural crest cell (NCC) migration. These effects are not confined to the craniofacial region, but vagal-derived NCCs fail to populate the enteric nervous system, culminating in disordered gut motility. Furthermore, morphants display hallmarks of disrupted Sonic Hedgehog (Shh) signaling from which NCCs take positional cues. We propose a model whereby Bbs proteins modulate NCC migration, contributing to craniofacial morphogenesis and development of the enteric nervous system. These migration defects also explain the association of Hirschsprung's disease (HD) with BBS. Moreover, this is a previously undescribed method of using characterization of facial dysmorphology as a basis for investigating the pathomechanism of CF development in dysmorphic syndromes.sonic hedgehog ͉ Wnt ͉ cilia ͉ cell migration R ecognition of the facial ''gestalt'' is central to diagnosis of many genetic disorders, but the great variability of features often hinders successful classification (1). Recently, noninvasive 3D surface imaging has characterized dysmorphology in syndromes (2, 3). None, however, has been used to either define subtle facial dysmorphism or aid investigation of mechanisms for craniofacial dysmorphology.Bardet-Biedl syndrome (BBS) causes retinal degeneration, postaxial polydactyly, obesity, renal dysfunction, and cognitive impairment. Twelve BBS genes (BBS1-BBS12) have been discovered, and pathogenesis lies in primary cilia dysfunction (4). BBS4, BBS6, and BBS8 (investigated in this study) are expressed in ciliated epithelia and localize to the centrosome and basal bodies of ciliated cells (5-7). Subtle craniofacial abnormalities in patients have been reported (8-10). Among the many additional features of BBS is Hirschsprung's disease (HD), a disorder of the enteric nervous system (ENS) (11).Streams of neural crest cells (NCCs) from the caudal brain form most of the craniofacial (CF) skeleton (see ref. 12 for review). Cranial NCCs (CNCC) follow defined paths to populate the frontonasal prominence and branchial arch mesenchyme. Here, they proliferate and differentiate into structures of the face and cranium. Sonic Hedgehog (Shh) expressed in the ventral brain and oral ectoderm is essential for the formation of most facial structures (12). Shh-deficient mice have severe loss of craniofacial bones, and, in humans, SHH mutations cause midline CF defects with holoprosencephaly (HPE) (12).The ENS regulates gastrointestina...

IMPORTANCE A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis.OBJECTIVE To characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy. DESIGN, SETTING, AND PARTICIPANTSIn this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed.

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