Hajdu-Cheney syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Hajdu-Cheney syndrome is a rare disorder that can affect many parts of the body, particularly the bones. Bone loss from the tips of the fingers and toes (acroosteolysis) is a characteristic feature of the condition. The fingers and toes may appear short and rounded, and they may become shorter over time as the bone continues to break down. In people with Hajdu-Cheney syndrome, the fingers are more likely to be affected than the toes. Bone loss in the fingers can interfere with fine motor skills, such as picking up small objects.

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, including acroosteolysis, are not present at birth but become apparent in childhood or later.

Additional bone abnormalities are common in people with Hajdu-Cheney syndrome. Affected individuals typically develop osteoporosis, which causes the bones to be brittle and prone to fracture. Many affected individuals experience a type of fracture called a compression fracture in the spinal bones (vertebrae). Some develop an abnormal curvature of the spine (scoliosis or kyphosis). Hajdu-Cheney syndrome can also affect the shape and strength of the long bones in the arms and legs. The bone abnormalities that are associated with this condition often lead to short stature.

Hajdu-Cheney syndrome can also involve the bones of the skull. The shape of the skull is often 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. Serious complications of Hajdu-Cheney syndrome include abnormalities known as platybasia and basilar invagination. Platybasia is a flattening of the base of the skull that is caused by thinning and softening of the skull bones. Basilar invagination occurs when the softened bones allow part of the spine to protrude through the opening at the bottom of the skull and push into the lower parts of the brain. These abnormalities can lead to severe neurological problems, such as a buildup of fluid in the brain (hydrocephalus) or spinal cord (syringomyelia) and breathing difficulties. In some cases, these abnormalities can be life-threatening.

Additional signs and symptoms can include a small lower jaw (micrognathia) and an opening in the roof of the mouth called a cleft palate. Adults with Hajdu-Cheney syndrome may have facial features that are described as "coarse." These facial features can include widely spaced and downward-slanting eyes, eyebrows that grow together in the middle (synophrys), low-set ears, and a large space between the nose and upper lip (a long philtrum).

Other features of Hajdu-Cheney syndrome can include joint abnormalities, particularly an unusually large range of joint movement (hypermobility); dental problems; hearing loss; and a deep, gravelly voice. Affected individuals may also have recurrent childhood infections, heart defects, and kidney abnormalities that include 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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Hajdu-Cheney syndrome is associated with variants (also called mutations) in the NOTCH2 gene. This gene provides instructions for making a receptor protein. Other proteins, called ligands, can fit into specific sites on receptor proteins, like a key into a lock. When a ligand binds to the NOTCH2 receptor protein, it triggers a signaling pathway called the NOTCH2 signaling pathway. NOTCH2 signaling is important for the early development of bones and 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.

Variants in a specific area near the end of the NOTCH2 gene are associated with Hajdu-Cheney syndrome. These variants cause cells to produce a version of the NOTCH2 receptor protein that cannot be broken down normally. As a result, the protein accumulates, which leads to an increase in NOTCH2 signaling. It is unclear exactly how the buildup of NOTCH2 receptor proteins leads to the various features of Hajdu-Cheney syndrome. Researchers suspect that the skeletal features of the disorder, including acroosteolysis, osteoporosis, and the appearance of certain facial features, are a result of abnormal bone development and remodeling.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Hajdu-Cheney syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Many cases of this condition result from a new (de novo) variant in the gene that occurs during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development. These affected individuals typically have no history of the disorder in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal facial shape · Very frequent (99-80%)

An abnormal morphology (form) of the face or its components.

Abnormal skull morphology · Very frequent (99-80%)

An abnormality of the skull, the bony framework of the head which is comprised of the neurocranium (with eight cranial bones) and the viscerocranium (facial skeleton) that comprises fourteen facial bones with the mandible as its largest bone.

Brachydactyly · Very frequent (99-80%)

Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.

Decreased skull ossification · Very frequent (99-80%)

A reduction in the magnitude or amount of ossification of the skull.

Downslanted palpebral fissures · Very frequent (99-80%)

The palpebral fissure inclination is more than two standard deviations below the mean.

Hypertelorism · Very frequent (99-80%)

Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).

Long philtrum · Very frequent (99-80%)

Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.

Micrognathia · Very frequent (99-80%)

Developmental hypoplasia of the mandible.

Other findings in the same source

From: Orphanet

Additional reported features include Osteolysis (Very frequent (99-80%)); Osteopenia (Very frequent (99-80%)); Osteoporosis (Very frequent (99-80%)); Partial absence of toe (Very frequent (99-80%)); Periodontitis (Very frequent (99-80%)); Short distal phalanx of finger (Very frequent (99-80%)); Short stature (Very frequent (99-80%)); Short toe (Very frequent (99-80%)); Skeletal dysplasia (Very frequent (99-80%)); Thick eyebrow (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Hajdu-Cheney syndrome is Orthopaedics, with a orthopaedic specialist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• What explains the change in pain, movement or function?
• Which activities need adjustment while the diagnosis is being clarified?
• What are the roles of rehabilitation, observation and surgery in this situation?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Hajdu-Cheney syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.