NOTCH2 genetic mutation and acro-osteolysis—the Hajdu–Cheney syndrome

Jerzakowski, Grzegorz; Lasek, Tomasz; Binkiewicz-Glińska, Anna; Krygier, Magdalena; Zawadzki, Piotr

doi:10.1093/qjmed/hcw211

Cited by 2 publications

(3 citation statements)

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“…Because of the limitations of our model, the impact of anti‐resorptive treatment on other aspects of the Hajdu‐Cheney syndrome such as acro‐osteolysis or renal cysts could not be addressed. However, there are reports indicating that existing acro‐osteolysis are not influenced by anti‐resorptive treatment . Nonetheless, it is conceivable, although at this point purely speculative, that pre‐symptomatic treatment with anti‐resorptives might prevent this pathology.…”

Section: Discussionsupporting

confidence: 84%

“…However, there are reports indicating that existing acro-osteolysis are not influenced by anti-resorptive treatment. (45,46) Nonetheless, it is conceivable, although at this point purely speculative, that pre-symptomatic treatment with antiresorptives might prevent this pathology. Independent of these symptoms, an improvement of systemic bone mass and bone microarchitecture as a result of the treatment should be considered beneficial for the patients because of a likely decrease in fracture risk.…”

Section: Discussionmentioning

confidence: 99%

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High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome

Vollersen

Hermans‐Borgmeyer

Cornils

et al. 2017

Journal of Bone and Mineral Research

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Hajdu-Cheney syndrome (HCS) is a rare autosomal-dominant disorder primarily characterized by acro-osteolysis and early-onset osteoporosis. Genetically, HCS is caused by nonsense or deletion mutations within exon 34 of the NOTCH2 gene, resulting in premature translational termination and production of C-terminally truncated NOTCH2 proteins that are predicted to activate NOTCH2-dependent signaling. To understand the role of Notch2 in bone remodeling, we developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) into the murine Notch2 gene. By mCT and undecalcified histology, we observed generalized osteopenia in two independent mouse lines derived by injection of different targeted embryonic stem (ES) cell clones, yet acro-osteolysis did not occur until the age of 52 weeks. Cellular and dynamic histomorphometry revealed a high bone turnover situation in Notch2 þ/HCS mice, since osteoblast and osteoclast indices were significantly increased compared with wild-type littermates. Whereas ex vivo cultures failed to uncover cell-autonomous gain-of-functions within the osteoclast or osteoblast lineage, an unbiased RNA sequencing approach identified Tnfsf11 and Il6 as Notch-signaling target genes in bone marrow cells cultured under osteogenic conditions. Because we further observed that the high-turnover pathology of Notch2 þ/HCS mice was fully normalized by alendronate treatment, our results demonstrate that mutational activation of Notch2 does not directly control osteoblast activity but favors a pro-osteoclastic gene expression pattern, which in turn triggers high bone turnover.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome

Vollersen

Hermans‐Borgmeyer

Cornils

et al. 2017

Journal of Bone and Mineral Research

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“…These signs guide diagnosis: they can be bone manifestations (fragility, deformities, malformations, worm-like bones), skin signs (pachydermia, hyperhydrosis, lipodystrophy), neurological signs (loss of sensitivity, neuropathy, muscle weakness) or haematological signs [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. The best known is the Hajdu-Cheney syndrome linked to a NOTCH2 mutation [16,17]. Although these syndromes are numerous, they affect only a few patients.…”

Section: Introductionmentioning

confidence: 99%

Is an association of acro-osteolysis, bone fragility, and enchondromatosis a newfound disease caused by an amplification of PTHLH? A case report

et al. 2022

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Background Acro-osteolysis (AO) refers to resorption of the distal finger and toe phalanges. It displays two patterns: (i) diffuse AO and (ii) transverse or bandlike AO. AO can be a sign of local distress (e.g. of toxic origin), but is very often a sign of a constitutional or systemic acquired disorder. Case presentation A 15-year-old girl was referred to a paediatric rheumatologist for recurrent pain in her fingertips. She presented a particular cross-sectional AO associated with the presence of intraosseous cysts and bone fragility with atypical fractures. Initial laboratory tests and radiological examination did not allow an etiological diagnosis. Genetic studies revealed a 12p11.22-p11.23 microduplication of 900 kb including the PTHLH (parathyroid hormone-like hormone) gene, which encodes for a hormone involved in the regulation of endochondral ossification and differentiation of chondrocytes, via its PTHLH receptor. Conclusions To date, 12p11.22-p11.23 duplications have been reported in five families with skeletal abnormalities, and in particular AO and enchondromatosis associated with bone fragility. This new observation, added to the other reported cases, suggests a close relationship between the presence of this microduplication and the skeletal abnormalities found in the patient. We suggest the descriptive name ABES (acro-osteolysis, bone fragility and enchondromatosis syndrome) to designate this disorder.

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NOTCH2 genetic mutation and acro-osteolysis—the Hajdu–Cheney syndrome

Cited by 2 publications

References 1 publication

High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome

High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome

Is an association of acro-osteolysis, bone fragility, and enchondromatosis a newfound disease caused by an amplification of PTHLH? A case report

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