NORD gratefully acknowledges Ernesto Canalis, MD, Professor of Orthopaedic Surgery and Medicine, Director of Center for Skeletal Research, UConn Health, UConn Musculoskeletal Institute, for assistance in the preparation of this report.
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 are also common. 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 mutations in the NOTCH2 gene. These mutations are inherited in an autosomal dominant manner.
For some time, a rare disorder called Serpentine Fibula-Polycystic Kidney syndrome (SFPKS) shared similar symptoms with Hajdu-Cheney syndrome. 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 on 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). In severe instances, the fingers and toes may be 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, while others become more pronounced as affected individuals age. These features include eyes that are slightly farther apart than normal (mild hypertelorism); an abnormally 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 also abnormalities of the skull including open sutures. An infant’s skull has seven bones and several joints called sutures. Sutures 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 located 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 recurrent respiratory infections in childhood, hearing loss, and joints that can be abnormally loose and flexible (joint hypermobility), and can be moved beyond their normal range. Some adults may have a deep voice and an excessive amount of hair growth on the body. 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 high blood pressure (hypertension), 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.
Inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) has also been reported. This condition can lead to poor kidney function and potentially kidney failure.
Hajdu-Cheney syndrome is associated with the mutation by a change (mutation) in the NOTCH2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation 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 mutation. In Hajdu-Cheney syndrome there is a gain of NOTCH2 function and increased activity of the protein. Depending upon the functions of the particular protein, this 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 alterations to 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 not fully understood.
The changes in the NOTCH2 gene that are associated with Hajdu-Cheney syndrome are inherited in an autosomal dominant manner but many sporadic cases occur. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In most individuals, physicians believe that the disorder occurs because of sporadic (de novo) genetic mutations that occur in the egg or sperm cell. In such situations, the disorder is not inherited from the parents and occurs randomly.
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 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
Common 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 radiodensitometry (DEXA) or dual-energy X-ray absorptiometry (DXA) can be used to measure bone mineral density and detect the presence of osteoporosis.
Molecular genetic testing can confirm a diagnosis of Hajdu-Cheney syndrome. Molecular genetic testing can detect mutations in the NOTCH2 gene known to be associated with the disorder, but is available as a diagnostic service at specialized laboratories.
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 asses and treat disorders of the skeleton (orthopedists), orthopedic surgeons, specialists who assess and treat disorders of the heart (cardiologists), dental specialists, speech pathologists, specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit 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 very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Hajdu-Cheney syndrome. Because the underlying way that the altered genes associated with the disorder cause bone loss is not known, treatment efforts are hampered.
Some individuals have been treated with medications that prevent bone resorption in order to treat osteoporosis. Normally, bone gradually breaks down (bone resorption) and then reforms, a process called bone turnover. One theory is that excessive or accelerated bone turnover contributes to 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.
One individual in the medical literature was treated with denosumab, a type of biologic therapy known as a monoclonal antibody. A monoclonal antibody is artificially-created in a laboratory. In this individual, denosumab increased bone mineral density, but did 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:
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For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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