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Previous work identified rare variants in DSTYKassociated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYKvariants.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Differentiation of the human spinal cord and involution of its caudal end were investigated in 4-9-week human conceptuses using immunofluorescence and electron microscopy. In the spinal cord, several types of intermediate filament proteins and desmoglein were expressed in parallel: in early stages (4 to 6 weeks), neurofilaments were expressed in low amounts only in the neuroblast processes of the marginal layer. At 6 weeks, differences in staining intensity and distribution patterns of neurofilaments became apparent between lumbar and sacrococcygeal (tail) parts of the spinal cord. Neurofilament expression increased in the mantle and marginal layers of the lumbar spinal cord coinciding with advancing neurogenesis. In contrast, neurofilament expression decreased in the sacrococcygeal spinal cord in association with regression of all tail organs. Regression was characterized by the appearance of large amounts of dead cells and macrophages. Strong vimentin expression was found in neuroepithelial (ependymal) cells and in the radial glia of the spinal cord throughout all stages examined. Coexpression of vimentin and glial fibrillary acidic protein was found only in the radial glia in the earliest developmental stage. Desmoglein was expressed in low amounts around the central canal which was probably associated with the immature junctional complexes that were present between ependymal cells. In conclusion, temporal and spatial distribution patterns of intermediate filament proteins in specific cell populations characterizes differentiation and caudal involution of the human spinal cord.

Summary Normal and anencephalic human conceptuses were analysed histologically to investigate the role of differentiation of the intracranial notochord and its relation to the formation of the basichondrocranium. We have examined 16 normal embryos and fetuses and 4 anencephalic fetuses. Each developmental stage of formation of the normal basichondrocranium presented specific morphological changes during the course of notochord depletion. In contrast with normal specimens, anencephalic fetuses presented malformations of the basichondrocranium which were always related to an abnormal position of the notochord. Macroscopical differences between craniorachischisis and cranioschisis in fetuses with anencephaly correlated with the existence of two histologically different degrees of malformation. In fetuses with craniorachischisis we found severe disturbances in the shape, position and ossification of the basichondrocranium and in the course of the intracranial notochord. In fetuses with cranioschisis the described disturbances of the basichondrocranium and intracranial notochord were mild. In addition, marked differences in affection of the central nervous system and the hypophysis were observed. These findings suggest different periods of dysmorphogenesis. Our results underline the importance of the chordal mesoderm in the differentiation for the formation of cephalic structures in Man.

The validity of voiding cystourethrography (VCUG) for detecting vesicoureteral reflux in children and assessing its extent was compared with that of direct radionuclide cystography (DRNC). Of 131 patients with recurrent urinary tract infection, all underwent DRNC and most also VCUG. Vesicoureteral reflux was found at DRNC in nine renal units (9 patients) in which VCUG was negative. In 17 renal units (15 patients) VCUG showed reflux to the ureter, but not to the renal pelvis, whereas DRNC revealed backflow from the bladder up to the renal pelvis. Reflux visualized at DRNC but not at VCUG was defined as grade Io. In all cases with reflux of grade I according to current classifications, DRNC showed reflux up to the renal pelvis. These observations make the distinction between grades I and II reflux in presently used classification less relevant and indicated the possible pathway of renal infection in patients with grade I vesicoureteral reflux and in so-called “elusive” reflux. We propose the addition of an extra grade (Io) of vesicoureteral reflux.

Lymphoscintigraphy is not considered as a first line diagnostic procedure in abdominal or thoracic lymphorrhea of various origin. We report a patient with lymphangiectasia in whom posttraumatic lymphorrhea was diagnosed by lymphoscintigraphy only after third attempt when we applied pushups exercise with the aim to raise venous pressure and thus provoke lymph backflow in ductus thoracicus and enteric lymphytics. Lymphorrhea was clearly visible in colon ascendens and colon transversum on 9h planar scintigram. We propose exercise lymphoscintigraphy with exercise tailored to individual patient's possibility before each lymphoscintigram to enhance lymphorrhea detection in patients with suspected lymph leakage.

In the version of this article initially published, affiliation 38 incorrectly read “ICNU-Nephrology and Urology Department, Barcelona, Spain”; “Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain” is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.