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7 January 2015 - Case of the Week #338

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Establishing the spatial / cellular context of gene expression and validating NGS gene discoveries using RNA in situ Hybridization

Pronin et al. used RNA-seq to sequence the entire transcriptome of the mouse cornea and identified ~10,000 actively transcribed genes. Among them there were 194 GPCRs, of which 96 were putative olfactory receptors (Olfrs). They went on to validate the 20 Olfrs by RT-PCR and RNA in situ hybridization (ISH) via RNAscope® technology.

Join a webinar on Tues, Jan 20th, 2015 at 11 am (Pacific US Time), 2 pm (Eastern US Time) and understand new molecular techniques to:

  • Validate RNA-Seq results
  • Get spatial and quantitative gene expression information in complex tissues
  • Visualize RNA targets in the full context of tissue architecture

    Expression of Olfr558 in vessels of the choroid and retina (Pronin et al., 2014). In situ hybridization of the mouse choroid slices with Olfr558 probe (red dots). Nuclei staining is DAPI (blue dots).


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Case of the Week #338

Clinical History:
2 week old 'female' infant presents with nephrotic syndrome and renal failure. A renal biopsy was perfomed.

Due to the patient's syndrome (discussed below), genetic testing was performed, which revealed a 46XY karyotype and WT1 mutation. Bilateral nephrectomies were performed, which showed multiple, ill-defined, firm, tan nodules distributed throughout the cortex and medulla.

Gross images:

Micro images:

Question 1: What is the syndrome (from the initial biopsy)?
Question 2: What is your diagnosis (from the nephrectomies)?

Syndrome: Denys-Drash syndrome

Diagnosis: Multifocal hyperplastic intralobar rests


The renal biopsy shows diffuse mesangial sclerosis, a component of Denys-Drash syndrome, which is characterized by a germline WT1 mutation, male pseudohermaphroditism, diffuse mesangial sclerosis, and subsequent Wilm tumor (see Kidney Tumor Chapter > Childhood neoplasms > Wilms' tumor of children). The nephrogenic rests in the nephrectomy specimens are persistent foci of embryonal cells seen after normal nephrogenesis. When diffuse or multifocal, they are termed nephroblastomatosis. WT1 is a transcriptional regulator that mediates the mesenchymal-epithelial transition and differentiation during kidney and gonad morphogenesis. It normally represses genes that encode cell proliferation factors and activates genes that encode epithelial cell differentiation (eMedicine). WT1 point mutations cause result in loss of its regulatory function and the abnormalities in glomerular formation and gonadal differentiation indicated above.

Nephrogenic rests may be inapparent on gross examination but may also appear as nodules or foci of capsular thickening / scar beneath the capsule or in the deep cortex or medulla. Microscopically, they are tightly packed nests or diffuse sheets of primitive but non-anaplastic blastemal / primitive epithelial cells with scanty stroma. There is no cartilage or primitive mesenchyme. Patterns include intralobar (randomly distributed throughout cortex and medulla with irregular margins, more stroma than blastema or tubules) and perilobar (peripheral with sharply demarcated margins, composed of blastema and tubules with scanty or sclerotic stroma, often solitary). Intralobar rests have an increased rate of progression to Wilm tumor, and are more commonly associated with WT1 mutations, Denys-Drash syndrome and WAGR syndrome. Perilobar rests are seen in sporadic tumors and are associated with idiopathic hemihypertrophy and Beckwith-Wiedemann syndrome (Adv Anat Pathol 2014;21:166).

Nephrogenic rests are seen in 1% of neonatal kidneys and if incidental, a "wait and see" policy is appropriate, because they spontaneously disappear (J Pediatr Hematol Oncol 2007;29:361). In Denys-Drash syndrome patients, most patients undergo bilateral nephrectomy, as they are otherwise destined to develop Wilm tumor.

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