Hajdu-Cheney syndrome

Iwaya, Tsutomu; Taniguchi, Koichi; Watanabe, Junzo; Iinuma, Kazuso; Hamazaki, Yoko; Yoshikawa, S

doi:10.1007/bf00389701

Cited by 20 publications

(15 citation statements)

References 8 publications

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“…However, Notch2 +/HCS mice did not develop acro‐osteolyses, a specific hallmark of HCS. Because it has been suggested that the underlying mechanisms causing acro‐osteolyses involve external stimuli, such as microdamages or inflammatory events, it is conceivable to speculate that the mice analyzed in our study did not experience sufficient mechanical loading and abrasion or pathogen exposure on their phalanges to trigger development of this symptom. In addition, we observed no incidences of renal cysts; however, this symptom is reported to occur only in 18% of human cases.…”

Section: Discussionmentioning

confidence: 96%

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: Discussionmentioning

confidence: 96%

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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“…Besides the skeletal lesions, the clinical course is determined by the development of neurological complications (5)(6)(7)(8)(9) due to anomalies of the craniovertebral junction, which may cause basiliar invagination. Fortunately our patient did not have respective complications during followup until the age of 39 years.…”

Section: Discussionmentioning

confidence: 99%

“…H AJDU-CHENEY SYNDROME (hereditary osteodysplasia with acro-osteolysis) is a rare disorder characterized by the typical findings of acro-osteolysis, brachydactyly, a distinctive facies with micrognathia, early loss of teeth, and short stature. The syndrome occurs sporadically (1)(2)(3)(4)(5)(6)(7)(8)(9) or familial with autosomal dominant inheritance. (10)(11)(12)(13)(14)(15) Acroosteolysis usually develops in late childhood in the distal phalanges of the fingers and, less frequently, of the toes.…”

Section: Introductionmentioning

confidence: 99%

Severe Osteoporosis in Familial Hajdu–Cheney Syndrome: Progression of Acro-Osteolysis and Osteoporosis During Long-Term Follow-up

Leidig-Bruckner

Pfeilschifter

Penning

et al. 1999

Journal of Bone and Mineral Research

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Hajdu-Cheney syndrome is an autosomal dominant inherited osteodysplastic bone disease with the hallmarks of acro-osteolysis, skull deformations, and generalized osteoporosis. Very few patients have been followed long-term with respect to the prognosis of acro-osteolysis and osteoporosis. Here we describe a 39-year-old woman and her 19-year-old daughter who are both affected with the Hajdu-Cheney syndrome. Skeletal lesions were followed in the mother between the ages of 22 and 39 years. The acro-osteolytic lesions progressed markedly and caused shortening of several fingers; some end phalanges had completely disappeared. Severe spinal osteoporosis with serial vertebral fractures was found at the age of 22 years. New vertebral fractures developed until the age of 33 years, but did not progress afterward. High turnover osteoporosis was found in the bone histology of iliac crest biopsies performed at the ages of 22 and 34 years. Bone mineral content (BMC) was strikingly decreased at the age of 34 years (T score -5.1 SD) and did not significantly change during further follow-up. In the daughter, BMC failed to increase between the ages of 12 and 19 years and was also markedly decreased (T score -4.4 SD). This suggests that osteoporosis in Hajdu-Cheney syndrome is related to a low peak bone mass and a high bone turnover, leading to insufficient bone formation compared with the increased bone

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“…It has also been shown to have both oncogenic and tumor suppressor roles in different types of cancers . Mutations in the Notch2 gene can cause Alagille and Hajdu‐Cheney syndromes, two autosomal‐dominant genetic conditions that affect skeletal, cardiovascular, neural, and gastrointestinal system development . An association between the mutation of the Notch4 gene and susceptibility to schizophrenia has been described .…”

Section: Introductionmentioning

confidence: 99%