De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

Abstract

Background: Pathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713.

Methods: Here we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.

Results: From an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.

Conclusion: Our findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

Keywords: genetics; medical; nervous system diseases; pathology; plastic; stomatognathic diseases; surgery.

Figure 1

Clinical and radiological facial features of subject 1. (A, B) Facial photographs at age 11. Dysmorphic features include frontal bossing, dolichocephaly, hypertelorism, half-closed eyes, a broad and flat nasal bridge, and an asymmetric bilateral swelling at mandibular and mid-facial levels. (C, D) 3-D reconstructed CT images of the face at age 11 years show a bilateral asymmetric cystic expansion of the mandible, maxilla, ethmoid and frontal bones with medial displacement of the teeth at mandibular level. In addition, frontal bossing and dolichocephaly can be noted. (E–H) Transverse CT images of at mandibular and mid-facial levels at age 11 years show extensive osteolytic and osteoblastic lesions. Note that the lesions are not only at mandibular level but also on mid-facial level and the anterior side of the foramen magnum. (I) 3-D reconstructed CT image of the face at age 9 years shows a bilateral asymmetric cystic expansion of the mandible, maxilla, ethmoid and frontal bones with medial displacement of the teeth and bilateral orbital involvement. (J) One year after the start of pamidronate (age 11 years), small cystic lesions can be seen at mandibular and mid-facial level; note the difference in osseous tissue compared with the CT scan before the start of the therapy. (K) Five years after the start of therapy (age 14 years), more remodelling of osseous tissue has occurred, although small cystic lesions are present. (L) One year after stopping pamidronate and 2 years after shaving approximately 2.5 cm of the right maxilla (age 17 years), multiple cystic lesions at mandibular and mid-facial levels with intensive displacement of the orbita. CT 3-D reconstruction of the skull, with (M) a sagittal view and (N) a posterior view of the cervical spine showing, besides lytic lesions, abnormalities of the cervical vertebrae at the age of 6 years and (O) at 18 years. (P) Spine X-rays at the age of 7 years showing scoliosis and abnormal thoracic vertebrae. (Q) Sagittal T2-weighted MRI of the thoracolumbal spine showing the thoracic syrinx and meningomyelocele (arrow) and neurogenic bladder (asterisk).

Figure 2

Clinical features of subject 1 at the age of 6 years (A) and 16 years (B–D), showing cubitus valgus, progressive contractures of metacarpophalangeal and interphalangeal joints, contractures of the toes and pes cavus.

Figure 3

Radiological features of individual 2’s skeletal alterations. (A) Multilocular radiolucent tumour in the anterior part of the mandible causing teeth displacement. (B, C) CT image with 3-D reconstruction showing cortical bone destruction. (D) Axial CT scan showing the primary tumour in the maxilla. (E–G) Osteolytic lesions in the squamous part of the temporal bone, greater wing of the sphenoid, lateral wall of the orbit and diploe of the left occipital bone. (H) Hypoplasia of the vertebral bodies and the intervertebral disc of C2–C3, with fusion of its posterior elements characterising vertebra in block.

Figure 4

Photomicrograph of a mandibular giant cell lesion and screenshots of chromatograms of individual 2. (A) Subject 2: histopathological features of the mandibular tumour displaying numerous giant cells in a fibroblastic and haemorrhagic stroma (standard H&E staining, magnification bar: 50 μm). (B) Subject 2: screenshots of Sanger sequencing chromatograms showing the TRPV4 c.1856T>C (p.Leu619Pro) in blood DNA, which was detected in the proband and was absent in both parents. The proportion of the variant allele and wild-type allele peaks is consistent with a variant allele frequency of 21.6% detected in the whole-exome sequencing. (C) Pore view of homotetrameric TRPV4 transmembrane domain in the presence of barium (PDB ID: 6C8G) (D). Channel view of pore domain S5–S6 of TRPV4 showing two opposing subunits for clarity, with Leu619 and (E) Leu619Pro shown in stick representation. TRPV4, transient receptor potential vanilloid 4 cation channel.