What Is Hajdu-Cheney Syndrome?

Introduction

Hajdu-Cheney (HC) syndrome, also known as Orpha 955, is a rare genetic disease affecting connective tissue. Less than 100 cases have been reported worldwide.

Connective tissue composes many of the body’s components and is key for maintaining bodily structure. Therefore, in HC syndrome, a condition where connective tissue undergoes destruction, bodily structures, particularly bones, are altered. The brain and Kidney can also be affected. Ruling out other conditions affecting the skeletal system is critical in confirming a diagnosis of HC syndrome.

 A physical inspection from a doctor, x-rays, and genetic testing can all aid in diagnosing the condition. HC syndrome cannot be cured; however, there are multiple management and treatment options to help reduce the burden of the condition’s signs and symptoms, typically involving a variety of medical specialists to address the different aspects of the body that are affected.^{1 2 3 4}

Causes of hajdu-cheney syndrome

Hajdu-Cheney syndrome results from a mutation in the NOTCH2 gene, a gene which leads to proteins being made that help ensure the body functions as it should. In HC syndrome, the mutation in the NOTCH2 gene causes these proteins to become overactive, causing the signs and symptoms of HC syndrome.

 Though the exact mechanisms through which this happens are not yet fully understood. The mutation in the NOTCH2 gene can be passed from a parent to their child, which carries a 50% chance when the parent carries the mutated gene or can occur spontaneously after conception.³ 

Signs and symptoms of Hajdu-Cheney syndrome

HC syndrome can cause a range of signs and symptoms that vary across patients, but they primarily affect bone and can also cause problems with the brain and kidneys.¹

Signs and symptoms can present at different times, with them arising from infancy to adulthood.² It includes:

Breakdown of bones

It is a characteristic feature of HC syndrome and can cause several signs and symptoms:³

• Shorter fingers and toes 
• Rounded fingers and toes
• Pain, burning, tingling, and swelling at the sites of bone breakdown

Reduced bone mass

It can occur in patients with HC syndrome and can be a major cause of bone breaks:⁴

• Bones of the spinal column can break and crush each other, which can be very painful and cause a curve of the spine to the side or a hunchback
• Abnormal bending of the arms and legs
• Short height

Facial deformities

HC syndrome can cause the following deformities of the face:³

• Eyes that are farther apart than normal
• A wide space between the upper and lower eyelids
• A thick unibrow
• Ears positioned lower than normal
• The roof of the mouth has a high arch
• Cleft palate
• Small jaw
• Short neck with limited neck movement Coarse hair

Skull abnormalities

The skull is composed of various bones that are fused together by a joint called a suture. In HC syndrome, these sutures may not be properly formed, and this can cause a bone at the back of the skull, called the occipital bone, to bulge out from the back of the head.³

Dental problems

HC syndrome can cause the teeth to be unable to break through the gums as they grow. In addition to this, those with HC may have an abnormal arrangement of teeth where the top and bottom do not meet each other in a straight line. There may also be swollen and bleeding gums.

Brain damage

Bones of the spinal column can be positioned higher in individuals with HC syndrome compared to those without the condition, and this can cause bones of the skull to be pushed upwards. When bones of the skull are pushed upwards, the fluid that surrounds the brain can be blocked from the brain.  As a result, excess fluids and pressure can build up inside the brain, causing one to stop breathing and die..³

Kidney disease

Some patients with HC syndrome have polycystic kidney disease (PKD), where pockets of fluid form in the kidney. PKD can cause abdominal pain and blood in the urine.³

Diagnosis of hajdu-cheney syndrome

A diagnosis of HC syndrome typically involves a physical inspection, scans, and genetic testing, as well as ruling out disorders with similar signs and symptoms, such as osteogenesis imperfecta, Melnick-Needles syndrome, Ehlers-Danlos syndrome, and cleidocranial dysplasia.³

Physical inspection

A physical inspection involves a doctor checking for any visible abnormalities in the body. In HC syndrome, these abnormalities may be able to be observed from birth, but some may only be observable in childhood, adolescence, and adulthood. So, more than one physical inspection may be needed to confirm a diagnosis of the condition. 

X-rays

Skull X-ray

X-rays are a quick, painless procedure involving images being taken of the body. In HC syndrome, the skull bones may not fuse as they’re supposed to. This lack of fusion can be observed with a skull x-ray and aid in confirming a diagnosis of HC syndrome.^{3 5}

Dual-energy x-ray absorptiometry

Dual-energy x-ray absorptiometry, also known as DEXA or a bone density scan, measures bone mass. It is a quick painless procedure which involves a patient lying on their back on a table where they will then be scanned. This scan can detect reduced bone mass, which may occur in patients with HC syndrome and lead to spinal fractures, a hunchback, abnormal bending of the arms and legs, and short height.^{3 6}

Genetic testing

A diagnosis of HC syndrome can be confirmed with genetic testing. Specifically, genetic testing can reveal a mutation in the NOTCH2 gene that is the cause of HC syndrome. Genetic testing typically involves the collection of a sample of blood or saliva, which will then be sent to a laboratory to be analyzed to determine whether a genetic mutation is present.^{3 7}

Management and treatment of hajdu-cheney syndrome

HC syndrome cannot be cured; however, management and treatment can help alleviate the condition’s signs and symptoms. As signs and symptoms of HC syndrome can vary across patients, management and treatment may vary, too, being specific to a patient’s particular situation. With HC syndrome affecting various regions of the body at different stages of life, a team of medical specialists may be needed to coordinate the management and treatment of the condition.

 The team managing this condition includes paediatricians, orthopedists, neurologists, nephrologists, dentists, and surgeons, among others.^{2 3}

FAQs

How common is hajdu-cheney syndrome?

HC syndrome is a rare disease, with less than 100 cases having been reported globally.¹

Is there a cure for hajdu-cheney syndrome?

HC syndrome cannot be cured. However, management and treatment can help alleviate signs and symptoms as much as possible.^{2 3}

Are there any specific complications associated with hajdu-cheney syndrome?

HC syndrome has some associated complications, and these include bone fractures due to reduced bone mass, excess fluid in the brain, which causes brain damage and may cause the stopping of breath and death, and polycystic kidney disease. Patients with HC syndrome can present with different signs and symptoms and, therefore, face different complications.³

How does hajdu-cheney syndrome affect bone density and skeletal development?

HC syndrome causes reduced bone density. This can make patients more susceptible to fractures, cause a hunchback, and reduce height. Abnormal bending of arms and legs can also result from reduced bone density. Furthermore, some patients may have improperly fused bones in their skull, which can cause a bone at the back of the skull, called the occipital bone, to bulge out from the back of the head.³

Can genetic testing be done to determine whether someone is a carrier of the hajdu-cheney syndrome gene?

Genetic testing can be done to determine whether someone has the mutated NOTCH2 gene, which is the gene that causes HC syndrome. This typically involves the analysis of a sample of blood or saliva in a laboratory.^{3 7}

Summary

HC syndrome is a rare genetic disease caused by a mutation in the NOTCH2 gene. This condition causes signs and symptoms that can commence in the newborn but also appear in childhood, adolescence, and adulthood and include disorders of the bone, skeletal deformities, facial abnormalities, brain damage, and kidney disease. Confirming a diagnosis of HC syndrome can involve a physical inspection, scans, and genetic testing. There isn’t a cure for HC syndrome, but management and treatment can help alleviate signs and symptoms, which can vary across patients.