Hajdu–Cheney syndrome with ventricular septal defect

Sargın, Gökhan; Çildağ, Songül; Şentürk, Taşkın

doi:10.1016/j.kjms.2012.10.009

Cited by 19 publications

(18 citation statements)

References 2 publications

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“…Platybasia and basilar invagination can result in severe neurological complications, including hydrocephalus and central respiratory arrest causing sudden death. Polycystic kidneys are present in 10% of the cases and occasionally affected subjects present with cardiac septal defects and valve abnormalities [38]. Iliac crest biopsies reveal the presence of cortical bone osteopenia, woven bone and increased osteoclast number and bone resorption [39].…”

Section: Notch and Congenital Disorders Of The Skeletonmentioning

confidence: 99%

Notch in skeletal physiology and disease

Canalis

2018

Osteoporos Int

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Notch (Notch1 through 4) are transmembrane receptors that play a fundamental role in cell differentiation and function. Notch receptors are activated following interactions with their ligands in neighboring cells. There are five classic ligands termed Jagged (Jag)1 and Jag2 and Delta-like (Dll)1, Dll3, and Dll4. Recent work has established Notch as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages and in skeletal development and bone remodeling. The effects of Notch are cell-context dependent, and the four Notch receptors carry out specific functions in the skeleton. Gain- and loss-of-function mutations of components of the Notch signaling pathway result in a variety of congenital disorders with significant craniofacial and skeletal manifestations. The Notch ligand Jag1 is a determinant of bone mineral density, and Notch plays a role in the early phases of fracture healing. Alterations in Notch signaling are associated with osteosarcoma and with the metastatic potential of carcinoma of the breast and of the prostate. Controlling Notch signaling could prove useful in diseases of Notch gain-of-function and in selected skeletal disorders. However, clinical data on agents that modify Notch signaling are not available. In conclusion, Notch signaling is a novel pathway that regulates skeletal homeostasis in health and disease.

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Section: Notch and Congenital Disorders Of The Skeletonmentioning

confidence: 99%

Notch in skeletal physiology and disease

Canalis

2018

Osteoporos Int

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“…The subject presented with a variety of skeletal abnormalities including osteoporosis with fractures, scoliosis and acroosteolysis. Polycystic kidneys and cardiovascular developmental anomalies, including patent ductus arteriosus, atrial and ventricular septal defects and valve defects can be clinical manifestations of HCS[4,26,27]. The subject of this report did not present with any cardiovascular or renal defects, but had splenomegaly, a possible consequence of increased NOTCH2 activity in the marginal zone of the spleen and not previously reported in HCS[28].…”

Section: Discussionmentioning

confidence: 68%

Hajdu Cheney Syndrome; report of a novel NOTCH2 mutation and treatment with denosumab

Adami

Rossini

Gatti

et al. 2016

Bone

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Notch receptors play a central role in skeletal development and homeostasis. Hajdu Cheney Syndrome (HCS) is a rare disease associated with mutations of NOTCH2 that lead to the translation of a truncated, presumably stable, NOTCH2 protein. As a consequence, a gain-of-NOTCH2 function is manifested. We report a subject presenting with HCS and her child, both harboring a new heterozygous mutation in Exon 34 of NOTCH2 upstream of the PEST domain. The subject presented with osteoporosis, fractures, acroosteolysis and splenomegaly but did not have neurological complications, cardiovascular defects or polycystic kidneys. Sequencing of genomic DNA revealed a previously unreported mutation at nucleotide 6667C>T leading to a Gln2223Ter protein product in the subject and her son. Preclinical studies have demonstrated that the bone loss in HCS is secondary to enhanced osteoclastogenesis and bone resorption, and the same mechanism may operate in humans. Accordingly, the case we report was treated and responded to therapy with denosumab with an increase in bone mineral density (BMD). However, acroosteolysis progressed and was not modified by denosumab. In conclusion, we report a case of HCS associated with a novel mutation in NOTCH2 and its response to denosumab on BMD.

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“…In accordance with the pronounced inhibitory effects of Notch signaling on chondrogenesis, patients with HCS exhibit short stature [45]. Cardiovascular defects, including patent ductus arteriosus, atrial and ventricular septal defects, and mitral and aortic valve abnormalities leading to valvular insufficiency or stenosis have been reported [46][47]. …”

Section: Hajdu Cheney Syndrome – Clinical Manifestationsmentioning

confidence: 99%

Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations

Canalis

Zanotti

2016

Curr Osteoporos Rep

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Notch plays an important function in skeletal homeostasis, osteoblastogenesis and osteoclastogenesis. Hajdu Cheney syndrome (HCS) is a rare disease associated with mutations in NOTCH2 leading to the translation of a truncated NOTCH2 stable protein. As a consequence, a gain-of-NOTCH2 function is manifested. HCS is inherited as an autosomal dominant disease although sporadic cases exist. HCS is characterized by craniofacial developmental defects, including platybasia and wormian bones, osteoporosis with fractures and acroosteolysis. Subjects may suffer severe neurological complications, and HCS presents with cardiovascular defects and polycystic kidneys. An experimental mouse model harboring a HCSNotch2 mutation exhibits osteopenia secondary to enhanced bone resorption suggesting this as a possible mechanism for the skeletal disease. If the same mechanisms were operational in humans, anti-resorptive therapy could correct the bone loss, but not necessarily the acroosteolysis. In conclusion, HCS is a devastating disease associated with a gain-of-NOTCH2 function resulting in diverse clinical manifestations.

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Hajdu–Cheney syndrome with ventricular septal defect

Cited by 19 publications

References 2 publications

Notch in skeletal physiology and disease

Notch in skeletal physiology and disease

Hajdu Cheney Syndrome; report of a novel NOTCH2 mutation and treatment with denosumab

Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations

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