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NORD gratefully acknowledges Ernesto Canalis, MD, Professor of Orthopaedic Surgery and Medicine, Director of Center for Skeletal Research, UConn Health, Co-Director of UConn Musculoskeletal Institute, for assistance in the preparation of this report.
Summary
Hajdu-Cheney syndrome is a rare genetic disorder. The specific symptoms and the severity can vary greatly from one person to another. The breakdown of bone (osteolysis), especially the outermost bones of the fingers and toes (acroosteolysis), is a major characteristic. In addition, affected individuals frequently have skull deformities, distinctive facial features, abnormally loose joints (joint laxity), a severe reduction of bone mass (osteoporosis) and short stature. There are additional symptoms sometimes associated with the disorder including neurological problems, heart abnormalities that are present at birth (congenital), and abnormalities of the kidneys and urinary tract. Most affected individuals have normal mental development, but a small proportion show mild delays in development. Hajdu-Cheney syndrome is associated with a change (variant or mutation) in the NOTCH2 gene. This condition can be inherited in an autosomal dominant manner, but many cases occur due to a new gene variant (de novo) that is not inherited.
Introduction
A rare disorder called serpentine fibula-polycystic kidney syndrome (SFPKS) has symptoms similar to Hajdu-Cheney syndrome but was once thought to be a separate condition. Researchers now believe that these disorders are the same and that people with SFPKS have Hajdu-Cheney syndrome with some specific symptoms including malformed long bones of the legs and cysts in the kidneys.
The signs and symptoms of Hajdu-Cheney syndrome can vary greatly among affected individuals. The disorder is present at birth (congenital), but in some individuals the signs and symptoms may be more apparent during adolescence and adulthood.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
A characteristic finding is the breakdown of bone and tissue (osteolysis), particularly the outermost bones of the fingers and toes (acroosteolysis). This may be painless or can occur with inflammation, pain, swelling and abnormal sensations like burning or tingling (paresthesia). Severely affected patients may have fingers and toes that are shortened and appear clubbed or rounded. Generally, the fingers are affected worse than the toes.
Some individuals also have a reduction of bone mass (osteoporosis), which predisposes individuals to fractures. Osteoporosis can be severe, and fractures can be frequent. The bones of the spinal column, called the vertebrae, may be susceptible to compression fractures, in which the vertebrae collapse. This is extremely painful and can lead to spinal malformation. Some individuals may have abnormal sideways curvature of the spine (scoliosis) or an abnormal rounding of the spine (kyphosis) may occur. The long bones of the arms and legs can be misshapen or bowed. Because of these various skeletal problems, affected individuals may reach an adult height that is noticeably shorter than would otherwise be expected (short stature). Sometimes, these skeletal problems can become a significant impairment in daily life by late adolescent or early adulthood.
Individuals have distinctive facial features. Some features are noted during infancy or childhood, whereas others become more pronounced as affected individuals age. These features include eyes that are slightly farther apart than normal (mild hypertelorism), a wide space in between the upper and lower eyelids, a single, thick eyebrow over the eyes (synophrys), low-set ears, a high arched roof of the mouth (palate), a cleft palate, a small jaw (micrognathia), flattening of the middle portion of the face, coarse hair and a short neck. The range of motion of the neck may be limited.
There are abnormalities of the skull including open sutures. An infant’s skull has seven bones and several joints called sutures. These are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull usually fuse together until around age two or later. In affected adults, the occipital bone, which is in the back of skull, may bulge outward, a condition called bathrocephaly.
Dental abnormalities are common including permanent teeth that get blocked as they try to emerge from the gums (impacted) and upper and lower teeth may not meet correctly when biting (malocclusion). There may be early loss of permanent teeth. The gums of affected individuals may be infected and swollen and bleed (periodontal disease).
Additional symptoms can include hearing loss, and joints that can be abnormally loose and flexible (joint hypermobility) and can be moved beyond their normal range. Various heart defects have been reported in some children. Abnormalities affecting the urinary tract can also occur. Some children experience protrusion of parts of the large intestine through an opening near the bellybutton (umbilical hernia).
Some affected individuals may have flattening of the base of the skull (platybasia). This may occur because the base of the skull is pushed upward because of basilar invagination. Basilar invagination occurs when the upper bones of the spinal column are located higher than normal, blocking the hole in the base of skull through which the spinal column passes. This blocks the flow of the fluid that surrounds the brain and spinal cord (cerebrospinal fluid). These conditions can cause excessive fluid accumulation and pressure within the brain (hydrocephalus), respiratory arrest and sudden death.
A subset of affected individuals has polycystic kidney disease, which is the formation of cysts within the kidneys. This can cause pain on both sides of the body between the last rib and hip (flank pain), blood in urine and progressively poor function of the kidneys, which means that the kidneys will not be able to effectively remove waste products from the blood and excrete them in the urine.
Hajdu-Cheney syndrome is associated with a change (variant or mutation) in the NOTCH2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, absent or have increased function. When there is increased function, this is called a gain-of-function variant. In Hajdu-Cheney syndrome there is a gain of NOTCH2 protein function and increased activity of the protein. Depending upon the functions of the protein, and where the protein is made can affect many organ systems of the body.
The NOTCH2 gene produces a protein that is essential for the proper growth and development of the body. Because of the variants in the NOTCH2 gene, the protein is stable and more effective. The exact manner that these gene changes result in the symptoms of Hajdu-Cheney syndrome is partially understood.
Hajdu-Cheney syndrome follows an autosomal dominant pattern of inheritance, but many sporadic cases occur. Dominant genetic disorders occur when only a single copy of disease-causing gene variant is necessary to cause a particular disease. The variant can be inherited from either parent or can be the result of a new variant (de novo) in the affected individual. The risk of passing the gene variant from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Hajdu-Cheney syndrome is an extremely rare disorder. More than 80 affected individuals have been described in the medical literature. The exact prevalence or incidence of the disorder is unknown. Rare disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
A diagnosis of Hajdu-Cheney syndrome is based upon the identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized imaging tests.
Clinical Testing and Workup
X-rays of the skull can reveal characteristic changes including open sutures and an abnormally flattened base of the skull. X-rays of the spine can show fractures and bone loss. A test known as dual-energy X-ray absorptiometry (DXA) can be used to measure bone mineral density and detect the presence of osteoporosis.
Molecular genetic testing for variants in the NOTCH2 gene can confirm a diagnosis of Hajdu-Cheney syndrome and is available as a diagnostic service at specialized laboratories.
Treatment
The treatment of Hajdu-Cheney syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat disorders of the skeleton (orthopedists or orthopedic surgeons and endocrinologists), specialists who assess and treat disorders of the heart (cardiologists), dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists) and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Hajdu-Cheney syndrome.
Some individuals have been treated with medications that prevent bone resorption to treat osteoporosis. Normally, bone gradually breaks down (bone resorption) and then reforms, a process called bone turnover. It appears that excessive or accelerated bone turnover contributes to the bone loss in Hajdu-Cheney syndrome. The benefit of these medications has not been established.
Surgery may be necessary to treat various complications of Hajdu-Cheney syndrome including hydrocephalus, spinal cord abnormalities, cleft palate and congenital heart defects. Hearing aids may be used to treat hearing loss.
A few patients have been treated with denosumab, a type of biologic therapy known as a monoclonal antibody. A monoclonal antibody is artificially created in a laboratory. In selected individuals, denosumab increased bone mineral density, but agents that decrease bone remodeling, such as denosumab or bisphosphonates do not stop the progression of acroosteolysis.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Toriello HV. Genetic Hearing Loss Associated With Musculoskeletal Disorders. In: Hereditary Hearing Loss and Its Syndromes, 3rd ed. Toriello HV, Smith SD, eds. 2013 Oxford University Press, New York, NY. pp. 322-442.
Michels VV. Hajdu-Cheney syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:11-12.
Hajdu-Cheney Syndrome (Acroosteolysis). Gorlin RJ, Cohen MM, Hennekam RCM, eds. In: Syndromes of the Head and Neck, 4th ed. Oxford University Press, New York, NY. 2001:315-318.
JOURNAL ARTICLES
Canalis E, Grossman TR, Carrer M, Schilling L, Yu J. Antisense oligonucleotides targeting Notch2 ameliorate the osteopenic phenotype in a mouse model of Hajdu-Cheney syndrome. J Biol Chem. 2020;295(12):3952-3964. doi:10.1074/jbc.RA119.011440
Yu, J. and Canalis, E. The Hajdu Cheney mutation sensitizes mice to the osteolytic actions of tumor necrosis factor α.J Biol Chem. 2019 Sep 27;294(39):14203-14214. https://www.ncbi.nlm.nih.gov/pubmed/31371452
Canalis, E. Notch in skeletal physiology and disease. Osteoporos Int. 2018 Dec;29(12):2611-2621. https://www.ncbi.nlm.nih.gov/pubmed/30194467
Canalis E, Zanotti S. Hajdu-Cheney syndrome, a disease associated with NOTCH2 mutations. Curr Osteoporos Res. 2016;14:126-131. https://www.ncbi.nlm.nih.gov/pubmed/27241678
Adami G, Rossini M, Gatti D, et al. Hajdu Cheney syndrome; report of a novel NOTCH2 mutation and treatment with denosumab. Bone. 2016;92:150-156. https://www.ncbi.nlm.nih.gov/pubmed/27592446
Zanotti S, Canalis E. Notch signaling and the skeleton. Endocr Rev. 2016;37:223-253. https://www.ncbi.nlm.nih.gov/pubmed/27074349
Canalis E, Schilling L, Yee SP, Lee SK, Zanotti S. Hajdu Cheney mouse mutants exhibit osteopenia, increased osteoclastogenesis, and bone resorption. J Biol Chem. 2016;291:1538-1551. https://www.ncbi.nlm.nih.gov/pubmed/26627824
Deprouw C, Feydy A, Giraudet Le Quintrec JS, et al. A very rare cause of acro-osteolysis: Hajdu-Cheney syndrome. Joint Bone Spine. 2015;82:455-459. https://www.ncbi.nlm.nih.gov/pubmed/26184537
Descartes M, Rojnueangnit K, Cole L, et al. Hajdu-Cheney syndrome: phenotypical progression with de-novo NOTCH2 mutation. Clin Dysmorphol. 2014;23:88-92. https://www.ncbi.nlm.nih.gov/pubmed/24608068
Canalis, E., Clinical and experimental aspects of Notch receptor signaling: Hajdu-Cheney syndrome and related disorders. Metabolism. 2018;80-48-56. https://www.ncbi.nlm.nih.gov/pubmed/28941602
Gray MJ, Kim CA, Betola DR, et al. Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome. Eur J Hum Genet. 2012;20:122-124. https://www.ncbi.nlm.nih.gov/pubmed/21712856
Simpson MA, Irving MD, Asilmaz E, et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet. 2011;43:303-305. https://www.ncbi.nlm.nih.gov/pubmed/21378985
Currarino G. Hajdu-Cheney syndrome associated with serpentine fibulae and polycystic kidney disease. Pediatr Radiol. 2009;39:47-52. https://www.ncbi.nlm.nih.gov/pubmed/18815778
McKiernan FE. Integrated anti-remodeling and anabolic therapy for the osteoporosis of Hajdu-Cheney syndrome. Osteoporosis Int. 2007;18:245-249. https://www.ncbi.nlm.nih.gov/pubmed/17103298
Drake WM, Hiorns MP, Kendler Dl. Hajdu-Cheney syndrome: response to therapy with bisphosphonates in two patients. J Bone Miner Res. 2003;18:131-133. https://www.ncbi.nlm.nih.gov/pubmed/12510814
Antoniades K, Kaklamanos E, Kavadia S, Hatzistilianou M, Antoniades V. Hajdu-Cheney syndrome (acro-osteolysis): a case report of dental interest. Oral Surg Oral Med Oral Path Oral Radiol Endod. 2003;95:725-31. https://www.ncbi.nlm.nih.gov/pubmed/12789155
Brennan AM, Pauli RM. Hajdu-Cheney syndrome: evolution of a phenotype and clinical problems. Am J Med Genet. 2001;100:292-310. https://www.ncbi.nlm.nih.gov/pubmed/11343321
Leidig-Bruckner G, Pfeilschifter J, Penning N, et al. Severe osteoporosis in familial Hajdu-Cheney syndrome: progression of acro-osteolysis and osteoporosis during long-term follow-up. J Bone Miner Res. 1999;14:2036-41. https://www.ncbi.nlm.nih.gov/pubmed/10620062.
INTERNET
Nishimura G. Acroosteolysis Dominant Type. Orphanet. June 2021. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=955 Accessed Jan 30, 2024.
Hajdu-Cheney syndrome. Genetics Home Reference. Feb. 2015. Available at: https://ghr.nlm.nih.gov/condition/hajdu-cheney-syndrome Accessed Jan 30, 2024.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:102500; Last Update: 09/21/2022. Available at: https://omim.org/entry/102500 Accessed Jan 30, 2024.
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