Notch 1 to 4 receptors are important determinants of cell fate and function, and Notch signaling plays an important role in skeletal development and bone remodeling. After direct interactions with ligands of the Jagged and Delta-like families, a series of cleavages release the Notch intracellular domain (NICD), which translocates to the nucleus where it induces transcription of Notch target genes. Classic gene targets of Notch are hairy and enhancer of split (Hes) and Hes-related with YRPW motif (Hey). In cells of the osteoblastic lineage, Notch activation inhibits cell differentiation and causes cancellous bone osteopenia because of impaired bone formation. In osteocytes, Notch1 has distinct effects that result in an inhibition of bone resorption secondary to an induction of osteoprotegerin and suppression of sclerostin with a consequent enhancement of Wnt signaling. Notch1 inhibits, whereas Notch2 enhances, osteoclastogenesis and bone resorption. Congenital disorders of loss- and gain-of-Notch function present with severe clinical manifestations, often affecting the skeleton. Enhanced Notch signaling is associated with osteosarcoma, and Notch can influence the invasive potential of carcinoma of the breast and prostate. Notch signaling can be controlled by the use of inhibitors of Notch activation, small peptides that interfere with the formation of a transcriptional complex, or antibodies to the extracellular domain of specific Notch receptors or to Notch ligands. In conclusion, Notch plays a critical role in skeletal development and homeostasis, and serious skeletal disorders can be attributed to alterations in Notch signaling.

Notch Signaling and the Skeleton.

Hajdu-Cheney syndrome is a rare, autosomal dominant disorder comprising acroosteolysis of the distal phalanges with associated digital abnormalities, distinctive craniofacial and skull changes, dental anomalies, and proportionate short stature. The clinical and radiologic characteristics of Hajdu-Cheney syndrome develop and progress with age. Many of the medical problems that arise in this syndrome cluster in specific age ranges. Case reports of six affected individuals in two additional families and a summary of the English literature is presented with emphasis on the changing physical findings and medical sequelae over time.

Hajdu‐Cheney syndrome: Evolution of phenotype and clinical problems

Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys. HCS is rare and is inherited as autosomal dominant although many sporadic cases have been reported. HCS is associated with mutations in exon 34 of NOTCH2 upstream the PEST domain that lead to the creation of a truncated and stable NOTCH2 protein with enhanced NOTCH2 signaling activity. Although the number of cases with NOTCH2 mutations reported are limited, it would seem that the diagnosis of HCS can be established by sequence analysis of exon 34 of NOTCH2. Notch receptors are single-pass transmembrane proteins that determine cell fate, and play a critical role in skeletal development and homeostasis. Dysregulation of Notch signaling is associated with skeletal developmental disorders. There is limited information about the mechanisms of the bone loss and acroosteolysis in HCS making decisions regarding therapeutic intervention difficult. Bone antiresorptive and anabolic agents have been tried to treat the osteoporosis, but their benefit has not been established. In conclusion, Notch regulates skeletal development and bone remodeling, and gain-of-function mutations of NOTCH2 are associated with HCS.

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Hajdu-Cheney syndrome: a review

Summary
The Hajdu–Cheney syndrome is a very rare disease that affects several organ system, leading to severe osteoporosis and other abnormalities. We describe clinical and genetic findings of nine patients with this disease.

Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome

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

Acro-osteolysis with diffuse osteoporosis in the absence of other associated diseases is named Hajdu-Cheney syndrome. Reduced bone formation rather than enhanced bone resorption has been indicated as the mechanism of osteoporosis. On the assumption that in this syndrome the active bone resorption which produces distal osteolysis must also predominate in generalized osteoporosis, we investigated boae histology, calcium kinetics, calciotropic hormones and bone markers in a patient suffering from sporadic Hajdu-Cheney syndrome. A radius bone biopsy taken far from the osteolytic lesions showed severe osteoporosis with a marked increase in osteoclastic bone resorption and reduced bone formation. Total body calcium clearance, performed through an analysis of the kinetics of calcium infusion, was 2.8 times higher than in normal controls, indicating the presence of active osteoclastic bone resorption. Serum parathormone, 1, 25-dihydroxycholecalciferol, alkaline phosphatase and urinary hydroxiproline were in the normal range. These data indicate that in Hajdu-Cheney syndrome trabecular osteoporosis is produced by the same mechanism that induces distal osteolysis, which suggests that it may be sustained by local acting factors stimulating osteoclastic resorption.

High turnover osteoporosis in acro-osteolysis (Hajdu-Cheney syndrome).

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High turnover osteoporosis in acro-osteolysis (Hajdu-Cheney syndrome).