Hajdu–Cheney syndrome
Hajdu–Cheney syndrome | |
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Other names | Acrodentoosteodysplasia, Arthrodentoosteodysplasia |
Hajdu-Cheney | |
Specialty | Rheumatology, medical genetics |
Hajdu–Cheney syndrome, also called acroosteolysis with osteoporosis and changes in skull and mandible, arthrodentoosteodysplasia and Cheney syndrome,
Signs and symptoms
Hajdu–Cheney syndrome causes many issues with an individual's connective tissues. Some general characteristics of an individual with Hajdu–Cheney syndrome include bone flexibility and deformities, short stature, delayed
Genetics
Hajdu–Cheney syndrome is a monogenic disorder. The disorder is inherited and controlled by a single pair of genes. A single copy of the mutant gene on an autosome causes HCS. HCS is an autosomal dominant disorder, only one parent with the defective gene is needed to pass the disorder to the offspring.[citation needed]
Mutations within the last coding exon of
The NOTCH2 gene is ubiquitously expressed in all embryonic tissue. When researching HCS in mice, the homozygous deletion of NOTCH2 leads to death. This observation is important because it explains how the HCS phenotype is not isolated to only one system of the body. NOTCH2 is also shown to regulate RANK-L osteoclastogenesis, which is the production of functional osteoclasts. Osteoclasts are the component that breaks bone down. This is why bone loss is observed in HCS patients, due to the overactivation of RANK-L.[citation needed]
Pathogenesis
The mechanism thought to cause HCS is an abnormality in osteoblast and osteoid function. These are major components of bone development, and the low function of each leads to the weak bones that characterize HCS.[citation needed]
Diagnosis
One of the main methods of pinpointing a NOTCH2 mutation that leads to HCS is through whole genome sequencing. This is then followed by exome capture by means of in-solution hybridization. The exome part of the genome consists of exons. Parallel sequencing follows the hybridization, which results in about 3.5 Gb of sequence data. These sequence data are then analyzed. Through sequence analysis and symptom presentation in HCS patients, this proves to be the most definitive method of diagnosis.[citation needed]
Types
Laboratory testing reveals multiple mutations of HCS. Two genetic variants result in sporadic HCS symptoms, which are HCS-02 and HCS-03. These mutations produce symptoms that come and go, but have been present de novo. HCS-03 was identified as the variant that is passed through affected family members and presents symptoms throughout the lifetime of the individual. All variants of HCS lead to the same premature termination of PEST sequences which compromise normal function of NOTCH2. NOTCH has four different receptors, which have an affinity for similar ligands. They are classified as single-pass transmembrane receptors.[citation needed]
Treatment
Since about 2002, some patients with this disorder have been offered drug therapy with bisphosphonates (a class of osteoporosis drugs) to treat problems with bone resorption associated with the bone breakdown and skeletal malformations that characterize this disorder. Brand names include Actonel (risedronate/alendronate), made by Merck Pharmaceuticals. Other drugs include Pamidronate, made by Novartis and Strontium Ranelate, made by Eli Lilly. However, for more progressive cases, surgery and bone grafting are necessary.[citation needed]
Eponym
It is named after Nicholas Hajdu (1908–1987), a Hungarian-English radiologist working in the UK and William D. Cheney, MD (1899–1985), a US radiologist.[citation needed]
References
Further reading
- Adès LC, Morris LL, Haan EA (February 1993). "Hydrocephalus in Hajdu-Cheney syndrome". Journal of Medical Genetics. 30 (2): 175. PMID 8445627.
- Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (September 2011). "Exome sequencing as a tool for Mendelian disease gene discovery". Nature Reviews. Genetics. 12 (11): 745–55. S2CID 15615317.
- Brennan AM, Pauli RM (May 2001). "Hajdu--Cheney syndrome: evolution of phenotype and clinical problems". American Journal of Medical Genetics. 100 (4): 292–310. PMID 11343321.
- Cremin B, Goodman H, Spranger J, Beighton P (1982). "Wormian bones in osteogenesis imperfecta and other disorders". Skeletal Radiology. 8 (1): 35–8. S2CID 21578356.
- Iwaya T, Taniguchi K, Watanabe J, Iinuma K, Hamazaki Y, Yoshikawa S (1979). "Hajdu-Cheney syndrome". Archives of Orthopaedic and Traumatic Surgery. 95 (4): 293–302. S2CID 2104135.