Surprising genetic and pathological findings in a patient with giant bilateral periadrenal tumours: PEComas and mutations of PTCH1 in Gorlin-Goltz syndrome

Gorlin-Goltz syndrome (GGS) or nevoid basal cell carcinoma syndrome is a rare tumour-overgrowth syndrome associated with multiple developmental anomalies and a wide variety of tumours. Here, we describe a case of a man aged 23 years with GGS with bilateral giant tumours adjacent to both adrenals that raised the suspicion of malignancy on imaging. Histological analysis of both surgically resected tumours revealed perivascular epitheloid cell tumours (PEComas) that were independent of the adrenals. Exome sequencing of the patient’s blood sample revealed a novel germline heterozygous frameshift mutation in the PTCH1 gene. As a second hit, a somatic five nucleotide long deletion in the PTCH1 gene was demonstrated in the tumour DNA of both PEComas. To the best of our knowledge, this is the first report on PEComa in GGS, and this finding also raises the potential relevance of PTCH1 mutations and altered sonic hedgehog signalling in PEComa pathogenesis. The presence of the same somatic mutation in the bilateral tumours might indicate the possibility of a postzygotic somatic mutation that along with the germline mutation of the same gene could represent an intriguing genetic phenomenon (type 2 segmental mosaicism).

Differentiation signals from glia are fine-tuned to set neuronal numbers during development

Precise neuronal numbers are required for circuit formation and function. Known strategies to control neuronal numbers involve regulating either cell proliferation or survival. In the developing Drosophila visual system photoreceptors from the eye-disc induce their target field, the lamina, one column at a time. Although each column initially contains ~6 precursors, only 5 differentiate into neurons of unique identities (L1-L5); the extra precursor undergoes apoptosis. We uncovered that Hedgehog signalling patterns columns, such that the 2 precursors experiencing the lowest signalling activity are specified as L5s; only one differentiates while the other extra precursor dies. We showed that a glial population called the outer chiasm giant glia (xgO), which reside below the lamina, relays differentiation signals from photoreceptors to induce L5 differentiation. The precursors nearest to xgO differentiate into L5s and antagonise inductive signalling to prevent the extra precursors from differentiating, resulting in their death. Thus, tissue architecture and feedback from young neurons fine-tune differentiation signals from glia to limit the number of neurons induced.

Sterols, Oxysterols, and Accessible Cholesterol: Signalling for Homeostasis, in Immunity and During Development

In this article we discuss the concept of accessible plasma membrane cholesterol and its involvement as a signalling molecule. Changes in plasma membrane accessible cholesterol, although only being minor in the context of total cholesterol plasma membrane cholesterol and total cell cholesterol, are a key regulator of overall cellular cholesterol homeostasis by the SREBP pathway. Accessible cholesterol also provides the second messenger between patched 1 and smoothened in the hedgehog signalling pathway important during development, and its depletion may provide a mechanism of resistance to microbial pathogens including SARS-CoV-2. We revise the hypothesis that oxysterols are a signalling form of cholesterol, in this instance as a rapidly acting and paracrine version of accessible cholesterol.

The Desert Hedgehog Signalling Pathway in Human Gonadal Development and Differences of Sex Development

While the Hedgehog signalling pathway is implicated in numerous developmental processes and maladies, variants in the <i>Desert Hedgehog</i> (<i>DHH</i>) ligand underlie a condition characterised by 46,XY gonadal dysgenesis with or without peripheral neuropathy. We discuss here the role and regulation of <i>DHH</i> and its signalling pathway in the developing gonads and examine the current understanding of how disruption to this pathway causes this difference of sex development (DSD) in humans.

Indian Hedgehog release from renal epithelia drives local and remote organ fibrosis

Chronic kidney disease (CKD) and ageing inhibit tissue regeneration and increase risks of organ fibrosis and cardiovascular disease. Increased numbers of leukocytes are present in the circulation and within the kidney of ageing individuals and patients with CKD where they correlate with progressive fibrosis. The involvement of activated leukocytes in progressive renal and systemic fibrosis remains incompletely understood. Here we show that renal leukocyte derived tumour necrosis factor alpha (TNFα) promotes renal and cardiac fibrosis via downstream induction of Indian Hedgehog (IHH). We identify the Ubiquitin D expressing ‘inflammatory’ proximal tubular epithelia (iPT) population responsible for TNFα/NFκB induced IHH production. iPT cells are upregulated in the kidney in experimental murine and human renal disease and ageing. iPT derived IHH activates canonical Hedgehog signalling in Gli1+ stromal cells, inducing their activation, proliferation and fibrosis in the surrounding kidney and in remote organs including the heart. This can be inhibited by selective genetic Ihh deletion from Pax8 expressing renal epithelia, or pharmacological blockade of TNFα, NFκB or Hedgehog signalling. This data connects inflammation to progressive renal and cardiac fibrosis and identifies new targets for anti-fibrotic therapies.