Hajdu-Cheney syndrome

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Alternate names

Acroosteolysis with osteoporosis and changes in skull and mandible; Arthrodentoosteodysplasia; Cheney syndrome; Acroosteolysis dominant type ; Serpentine fibula-polycystic kidneys syndrome


Hajdu-Cheney syndrome is a rare disorder that can affect many parts of the body, particularly the bones. Loss of bone tissue from the hands and feet (acro-osteolysis) is a characteristic feature of the condition. The fingers and toes are short and broad, and they may become shorter over time as bone at the tips continues to break down. Bone loss in the fingers can interfere with fine motor skills, such as picking up small objects.


Hajdu-Cheney syndrome is a rare disease; its prevalence is unknown. Fewer than 100 affected individuals have been described in the medical literature.


  • Hajdu-Cheney syndrome is associated with mutations in the NOTCH2 gene.
  • This gene provides instructions for making a receptor called Notch2.
  • Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. When a ligand binds to the Notch2 receptor, it triggers signals that are important for the normal development and function of many different types of cells.
  • Studies suggest that signaling through the Notch2 receptor is important for the early development of bones and later for bone remodeling, a normal process in which old bone is removed and new bone is created to replace it.
  • Notch2 signaling also appears to be involved in the development of the heart, kidneys, teeth, and other parts of the body.

Gene mutations

  • Mutations in a specific area near the end of the NOTCH2 gene are associated with Hajdu-Cheney syndrome.
  • These mutations lead to a version of the Notch2 receptor that cannot be broken down normally.
  • As a result, the receptor continues to be active even after signaling should stop.
  • Researchers are unsure how excessive Notch2 signaling is related to the varied features of Hajdu-Cheney syndrome.
  • They suspect that the skeletal features of the disorder, including acro-osteolysis, osteoporosis, and distinctive facial features, likely result from abnormal bone development and remodeling.
  • Excess signaling through the overactive Notch2 receptor may increase the removal of old bone, reduce the formation of new bone, or both.
  • It is less clear how the overactive receptor contributes to the other signs and symptoms of this condition.


Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered NOTCH2 gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family. Less commonly, an affected person inherits the mutation from one affected parent.

Signs and symptoms

  • Bone abnormalities throughout the body are common in Hajdu-Cheney syndrome.
  • Affected individuals develop osteoporosis, which causes the bones to be brittle and prone to fracture. Many affected individuals experience breakage (compression fractures) of the spinal bones (vertebrae). Some also develop abnormal curvature of the spine (scoliosis or kyphosis).
  • Hajdu-Cheney syndrome also affects the shape and strength of the long bones in the arms and legs.
  • The abnormalities associated with this condition lead to short stature.
  • Hajdu-Cheney syndrome also causes abnormalities of the skull bones, including the bones of the face.
  • The shape of the skull is often described as dolichocephalic, which means it is elongated from back to front.
  • In many affected individuals, the bone at the back of the skull bulges outward, causing a bump called a prominent occiput.
  • Distinctive facial features associated with this condition include widely spaced and downward-slanting eyes, eyebrows that grow together in the middle (synophrys), low-set ears, a sunken appearance of the middle of the face (midface hypoplasia), and a large space between the nose and upper lip (a long philtrum).
  • Some affected children are born with an opening in the roof of the mouth called a cleft palate or with a high arched palate.
  • In affected adults, the facial features are often described as "coarse."
  • Other features of Hajdu-Cheney syndrome found in some affected individuals include joint abnormalities, particularly an unusually large range of joint movement (hypermobility); dental problems; hearing loss; a deep, gravelly voice; excess body hair; recurrent infections in childhood; heart defects; and kidney abnormalities such as the growth of multiple fluid-filled cysts (polycystic kidneys).
  • Some people with this condition have delayed development in childhood, but the delays are usually mild.
  • The most serious complications of Hajdu-Cheney syndrome, which occur in about half of all affected individuals, are abnormalities known as platybasia and basilar invagination.
  • Platybasia is a flattening of the base of the skull caused by thinning and softening of the skull bones.
  • Basilar invagination occurs when the softened bones allow part of the spine to protrude abnormally through the opening at the bottom of the skull, pushing into the lower parts of the brain.
  • These abnormalities can lead to severe neurological problems, including headaches, abnormal vision and balance, a buildup of fluid in the brain (hydrocephalus), abnormal breathing, and sudden death.
  • The signs and symptoms of Hajdu-Cheney syndrome vary greatly among affected individuals, even among members of the same family.
  • Many of the disorder's features, such as acro-osteolysis and some of the characteristic facial features, are not present at birth but become apparent in childhood or later.
  • The risk of developing platybasia and basilar invagination also increases over time.
  • The features of Hajdu-Cheney syndrome overlap significantly with those of a condition called serpentine fibula-polycystic kidney syndrome (SFPKS).
  • Although they used to be considered separate disorders, researchers discovered that the two conditions are associated with mutations in the same gene.
  • Based on these similarities, many researchers now consider Hajdu-Cheney syndrome and SFPKS to be variants of the same condition.


  • 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.


  • 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 afflicted 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. T
  • hey are classified as single-pass transmembrane receptors.


  • 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.

NIH genetic and rare disease info

Hajdu-Cheney syndrome is a rare disease.

Latest research - Hajdu-Cheney syndrome

Clinical trials


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