ABSTRACT Introduction Scalp-Ear-Nipple syndrome is caused by pathogenic KCTD1 variants and characterised by a scalp defect, prominent ears, and rudimentary breasts. We describe here further clinical associations in the eye and kidney. Methods Fifteen affected members from two unrelated families with p.(Ala30Glu) or p.(Pro31Leu) in KCTD1 were examined for ocular and renal abnormalities. The relevant proteins were studied in the eye and kidney, and the mutation consequences determined from mouse knockout models. Results Five males and 10 females with a median age of 40 years (range 1–70) with pathogenic variants p.(Ala30Glu) (n = 12) or p.(Pro31Leu) (n = 3) in KCTD1 were studied. Of the 6 who underwent detailed ophthalmic examination, 5 (83%) had low myopic astigmatism, the mean spherical equivalent of 10 eyes was 2.38D, and one (17%) had hypermetropic astigmatism. One female had a divergent strabismus. Five individuals had renal cysts (5/15, 33%), with renal biopsy in one demonstrating a thinned glomerular basement membrane identical to that seen in Thin basement membrane nephropathy (AD Alport syndrome). In the eye, KCTD1 and its downstream targets, TFAP2, and the collagen IV α3 and α4 chains localised to the cornea and near the retinal amacrine cells. In the kidney, all these proteins except TFAP2 were expressed in the podocytes and distal tubules. TFAP2B and COL4A4 knockout mice also had kidney cysts, and COL4A3 and COL4A4 knockout mice had myopia. Conclusion Individuals with a pathogenic KCTD1 variant may have low myopic astigmatism and represent a further rare genetic cause for a thinned glomerular basement membrane.

BACKGROUND:We have previously confirmed the importance of rat chromosome 3 (RNO3) genetic loci on blood pressure elevation, pulse pressure (PP) variability and renal pathology during salt challenge in the stroke-prone spontaneously hypertensive (SHRSP) rat. The aims of this study were to generate a panel of RNO3 congenic sub-strains to genetically dissect the implicated loci and identify positional candidate genes by microarray expression profiling and analysis of next-generation sequencing data. METHOD AND RESULTS:A panel of congenic sub-strains were generated containing Wistar-Kyoto (WKY)-introgressed segments of varying size on the SHRSP genetic background, focused within the first 50 Mbp of RNO3. Haemodynamic profiling during salt challenge demonstrated significantly reduced systolic blood pressure, diastolic blood pressure and PP variability in SP.WKYGla3a, SP.WKYGla3c, SP.WKYGla3d and SP.WKYGla3e sub-strains. Only SBP and DBP were significantly reduced during salt challenge in SP.WKYGla3b and SP.WKYGla3f sub-strains, whereas SP.WKYGla3g rats did not differ in haemodynamic response to SHRSP. Those sub-strains demonstrating significantly reduced PP variability during salt challenge also demonstrated significantly reduced renal pathology and proteinuria. Microarray expression profiling prioritized two candidate genes for blood pressure regulation (Dnm1, Tor1b), localized within the common congenic interval shared by SP.WKYGla3d and SP.WKYGla3f strains, and one candidate gene for salt-induced PP variability and renal pathology (Rabgap1), located within the region unique to the SP.WKYGla3d strain. Comparison of next-generation sequencing data identified variants within additional positional genes that are likely to affect protein function. CONCLUSION:This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge.

Protein phosphatase 2A (PP2A) is a family of serine/threonine phosphatases that regulate multiple cellular signalling pathways involved in proliferation, survival and apoptosis. PP2A inhibition occurs in many cancers and is considered a tumour suppressor. Deletion/downregulation of PP2A genes has been observed in breast tumours, but the functional role of PP2A subunit loss in breast cancer has not been investigated.

In an F2 cross between stroke-prone spontaneously hypertensive (SHRSP) and Wistar Kyoto (WKY) rats, we previously identified blood pressure quantitative trait loci (QTL) on rat chromosome (RNO) 2 and a pulse pressure QTL on RNO3. The aims of this study were to confirm the QTL on RNO3 and to investigate interaction between RNO2 and RNO3 loci through the generation and phenotypic assessment of single RNO3 congenic (SP.WKY(Gla)3a) and bicongenic (SP.WKY(Gla)2a/3a) strains. Hemodynamic profiling, vascular function, and renal histology were examined in these newly generated strains along with the previously reported RNO2 congenic strain (SP.WKY(Gla)2a). Our results demonstrate significant equivalent reduction in systolic, diastolic, and pulse pressure phenotypes in SP.WKY(Gla)3a and SP.WKY(Gla)2a rats, whereas greater reductions were observed with the SP.WKY(Gla)2a/3a bicongenic strain achieving blood pressure levels similar to normotensive WKY rats. Epistasis was observed between pulse pressure QTL on RNO2 and 3 at baseline and during 1% salt challenge. Vascular function and renal pathology studies indicate that QTL on RNO3 are responsible for salt-induced kidney pathology, whereas QTL on RNO2 seem to have greater impact on vascular function. RNO3 congenic and bicongenic strains have confirmed the importance of SHRSP alleles in the RNO3 congenic interval on pulse pressure variability and end-organ damage. These strains will allow interrogation of complex gene-gene and gene-environment interactions contributing to salt-sensitive hypertension and renal pathology in the SHRSP rat.

Background Metanephric stromal tumour (MST) is a purely stromal neoplasm at the benign end of the spectrum of metanephric tumours of kidney with a mean age at presentation of 2 years. Case report A 3-year-old girl presented with haematuria. Imaging revealed a non-enhancing mass in the right kidney with no evidence of distant spread. Right nephrectomy was performed. Macroscopically, a 45 mm, pale, white, tumour was present in the kidney. Microscopically, the lesion was a non-encapsulated, circumscribed, bland spindle cell tumour with vaguely nodular appearance on low power. Condensation of spindled cells was seen around entrapped tubules. Arterioles within the mass showed features of angiodysplasia. Epithelial component, heterologous tissue, necrosis and mitoses were absent. Spindle cells were positive for CD34. There was focal weak nuclear positivity for WT-1. Epithelial markers were negative. Discussion Patients with MST can present with hypertension resulting from juxtaglomerular cell hyperplasia. Rarely, morbidity has been reported due to extrarenal angiodysplasia. None of these features were present in our case. MST has a benign course and surgical resection is curative. Hence, it is importance to differentiate it from other tumours like congenital mesoblastic nephroma, clear cell sarcoma of kidney and synovial sarcoma, all of which are different histologically and do not stain for CD34.

Germline succinate dehydrogenase B (SDHB) mutation causes pheochromocytoma/paraganglioma syndrome type 4 (PGL4). PGL4 is characterized by pheochromocytoma and paraganglioma, type 2 (SDHB negative) gastrointestinal stromal tumors and renal tumors, which are usually classified as carcinoma. We report 4 kindreds with 5 PGL4-associated renal tumors. Four of the tumors occurred before the age of 30 years, 4 were in the left kidney, 3 were in female patients, and 4 demonstrated consistent but previously unrecognized morphology. The tumors were composed of cuboidal cells with bubbly eosinophilic cytoplasm and indistinct cell borders. Many of the cells displayed distinctive cytoplasmic inclusions, which were vacuolated or contained eosinophilic fluid-like material. The cells were arranged in solid nests or in tubules surrounding central spaces. The tumors were well circumscribed or lobulated and frequently showed cystic change. Benign tubules or glomeruli were often entrapped at the edges of the tumors. The fifth tumor lacked these features but displayed sarcomatoid dedifferentiation. Immunohistochemistry for SDHB was completely negative in all 4 available tumors. Death from metastatic disease occurred in the patient with dedifferentiated tumor 1 year after diagnosis, whereas the other 4 tumors were cured by local excision alone (mean follow-up, 11 y; range, 2 to 30 y). We conclude that morphology supported by negative immunohistochemistry for SDHB can be used to identify kindreds with germline SDHB mutations (PGL4 syndrome) presenting with this unique type of renal tumor. These renal tumors appear to have a good prognosis after complete excision unless there is sarcomatoid dedifferentiation.

sis (LCH), pneumoconiosis, Rosai–Dorfman (RDD) and Erdheim–Chester diseases (ECD), and storage diseases). Ionescu et al. proposed a practical scheme including the main differential diagnoses when dealing with a pulmonary nodular histiocytic proliferation. Therapy should be directed to the underlying haematological disorder, but complete excision of pulmonary nodule(s) seems to be recommended. The main differential diagnosis includes pleural localized mesothelioma (LM) and metastasis, or other histiocytic disorders possibly involving the pleura, such as RDD, ECD and LCH. LM is exceedingly rare, but immunohistochemical features (positivity for cytokeratins and calretinin or other mesothelial cell markers) do not differ from the most common diffuse variant, even when lymphohistiocytoid or deciduoid morphology occurs. Based on the protean appearance of thyroid medullary carcinoma, a metastasis was considered, but immunonegativity for calcitonin and cytokeratins ruled out this possibility. Among histiocytic disorders, ECD and LCH basically involve the lung, as diffuse interstitial lung diseases rarely showing pleural thickening, while a single case of RDD has been so far reported in the pleura. However, the plump and pale eosinophilic histiocytes of RDD are positive for CD68 and S100. Careful clinical, laboratory and imaging workup coupled with bone marrow biopsies is mandatory in recognizing an unknown haematological disorder and adopting appropriate therapeutic strategies.

Background Our previous studies demonstrated reduced rat glutathione S-transferase μ type 1 (Gstm1) expression in stroke-prone spontaneously hypertensive rats (SHRSPs), when compared with the normotensive Wistar–Kyoto rat. Methods This study investigated the effects of angiotensin II type 1 receptor blocker (ARB) and a diuretic/vasodilator combination on the expression levels of rat Gstm1 and other Gstm isoforms. Results Antihypertensive treatments of young and mature SHRSPs with an ARB and a diuretic/vasodilator combination improved SBP but did not affect the expression levels of Gstm1. Although Gstm1 is a member of a family of highly homologous genes, with the exception of Gstm2, there was no evidence for compensatory increase in expression of other Gstm isoforms. In contrast, we observed reduced expression of several other Gstm isoforms in untreated SHRSPs. Untreated SHRSPs demonstrated increased renal and vascular oxidative stress, both of which were not significantly affected by the antihypertensive treatments. Untreated SHRSPs scored significantly higher when assessed for renal histopathological damage, and this was improved by antihypertensive treatments. Conclusion These results suggest that reduced Gstm1 expression in SHRSPs is due to strain-dependent genetic abnormalities, playing a causative role in the development of hypertension, probably through oxidative stress pathway. Renal changes occur as a consequence of increased blood pressure and can be improved when treated with antihypertensive drugs. In silico comparative genome analysis combined with expression studies in rat and human vascular tissue revealed that there are possible four human homologues (GSTM1, GSTM2, GSTM4 and GSTM5) for rat Gstm1.

BACKGROUND:UK native renal biopsy incidence is unknown. Biopsy registries in other countries indicate that the incidence of renal biopsy varies widely. Indications for renal biopsy are largely opinion based.METHODS:The Scottish Renal Biopsy Registry aimed to analyse the incidence of native renal biopsy in Scotland and examine indications and diagnoses obtained where practice varied widely.RESULTS:Consecutive native adult renal biopsies performed in eight of the nine Scottish regions that include 82.4% of the population between 2002 and 2006 were examined. A total of 2480 native renal biopsies were performed equating 126.3 biopsies per million population per year (PMP/year). A total of 56.9% of patients were male, mean age 55.6 years (SD 1.3). The centres varied widely, from a lowest mean annual incidence of 65.8 PMP/year in Fife to the highest of 170.7 PMP/year in Tayside. The prospectively recorded indications and diagnoses were compared between Greater Glasgow, Clyde and Forth Valley (GC&FV) (population 1.56 million, 101.6 biopsies PMP/year) and Tayside (population 0.39 million, 177.4 biopsies PMP/year). Differing incidence of renal biopsy in these regions was mainly explained by patients with proteinuria and preserved renal function in the absence of nephrotic syndrome (19.2 PMP/year in GC&FV versus 60.8 PMP/year in Tayside), probably due to variation in nephrologists' opinion about the utility of biopsy for this indication. Tayside diagnosed more primary glomerulopathies, diabetic nephropathy and chronic ischaemia than GC&FV.CONCLUSIONS:We have demonstrated wide regional variability in incidence of native renal biopsy within a single country, with analysis suggesting that this is mainly explained by uncertainty about the utility of renal biopsy for patients with proteinuria and preserved renal function. Further studies are required to determine the value of renal biopsy in this setting.