How is Hajdu‑Cheney syndrome diagnosed, and what genetic tests are used?

Diagnosis starts with a detailed physical exam noting acroosteolysis, short stature, and craniofacial features. Imaging (X‑ray, CT) confirms bone loss and spinal abnormalities. Genetic testing for pathogenic variants in the NOTCH2 gene—usually via whole‑exome sequencing or targeted panel—provides definitive confirmation.

Are there treatments that can slow bone loss or improve bone density in Hajdu‑Cheney syndrome?

While no cure exists, therapies that target bone turnover can help. Bisphosphonates (e.g., alendronate) and denosumab reduce bone resorption. Some clinicians use anabolic agents like teriparatide, though evidence is limited. Early referral to a metabolic bone specialist is recommended to tailor therapy.

How does the syndrome affect speech and hearing, and what interventions are recommended?

Many patients have a deep, gravelly voice and may experience hearing loss due to ear bone changes. Speech therapy can improve articulation, while hearing aids or cochlear implants may be necessary for significant hearing loss. Regular audiology evaluations and early intervention improve communication outcomes.===

What are the most common bone complications, and how can I prevent fractures?

Patients often develop osteoporosis, vertebral compression fractures, and distal phalangeal loss. Preventive measures include calcium and vitamin D supplementation, weight‑bearing exercise, fall‑prevention strategies, and regular bone density scans. In high‑risk cases, bisphosphonates or denosumab may be prescribed to strengthen bone.

Hajdu‑Cheney syndrome

A rare genetic disorder characterized by progressive bone loss, especially acroosteolysis of the fingers, caused by pathogenic variants in the NOTCH2 gene.

Overview

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 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.

Clinical Features

Bone abnormalities

Acroosteolysis of the distal phalanges (more common in fingers)
Osteoporosis leading to brittle bones and increased fracture risk
Compression fractures of the vertebrae
Abnormal spinal curvature (kyphosis, scoliosis)
Short stature due to long‑bone involvement
Skull shape often dolichocephalic (elongated front‑to‑back)
Occipital bone protrusion (occipital bossing)
Platybasia (flattening of the skull base) and basilar invagination, which can cause hydrocephalus, syringomyelia, or breathing difficulties

Facial and craniofacial features

Small lower jaw (micrognathia)
Palatal cleft (cleft palate)
Coarse facial appearance in adults
Prominent eyes and eyebrows that may meet in the middle (synophrys)
Low‑set ears
Large nasolabial distance (increased space between nose and upper lip)

Other systemic manifestations

Joint hypermobility
Dental problems
Hearing loss
Deep, gravelly voice
Recurrent childhood infections
Congenital heart defects
Kidney abnormalities, including multiple fluid‑filled cysts
Mild developmental delays in childhood

Frequency

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.

Causes & Risk Factors

Hajdu‑Cheney syndrome is associated with variants (mutations) in the NOTCH2 gene. This gene provides instructions for making a receptor protein that participates in the NOTCH2 signaling pathway, which is important for early bone development, bone remodeling, and the development of the heart, kidneys, teeth, and other organs.

Variants located near the end of the NOTCH2 gene produce a receptor protein that cannot be broken down normally, leading to accumulation of the protein and increased NOTCH2 signaling. The exact mechanisms by which this excess signaling produces the skeletal and facial features of the disorder remain unclear, but abnormal bone development and remodeling are suspected contributors.

Learn more about the gene associated with Hajdu‑Cheney syndrome

NOTCH2

Inheritance

Hajdu‑Cheney syndrome is inherited in an autosomal dominant pattern, meaning one copy of the altered gene in each cell is sufficient to cause the disorder. Many cases result from a new (de novo) variant that arises during the formation of reproductive cells or early embryonic development, so there may be no family history.

Other Names for This Condition

Acroosteolysis dominant type
Acroosteolysis with osteoporosis and changes in skull and mandible
Arthrodentoosteodysplasia
Cheney syndrome
Hajdu‑cheney syndrome‑notch2
HJCYS
Serpentine fibula polycystic kidney syndrome
SFPKS

Additional Information & Resources

Genetic Testing Information

Genetic Testing Registry: Hajdu‑Cheney syndrome

Genetic and Rare Diseases Information Center

Hajdu‑Cheney syndrome

Patient Support and Advocacy Resources

National Organization for Rare Disorders (NORD)

Clinical Trials

ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

HAJDU‑CHENEY SYNDROME; HJCYS

Scientific Articles on PubMed

PubMed

References

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Canalis E, Zanotti S. Hajdu‑Cheney syndrome: a review. Orphanet J Rare Dis. 2014 Dec 10;9:200. doi:10.1186/s13023-014-0200-y.
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Gray MJ, Kim CA, Bertola DR, et al. Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu‑Cheney syndrome. Eur J Hum Genet. 2012 Jan;20(1):122‑124. doi:10.1038/ejhg.2011.125.
Isidor B, Lindenbaum P, Pichon O, et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet. 2011 Mar 6;43(4):306‑308. doi:10.1038/ng.778.
Majewski J, Schwartzentruber JA, Caqueret A, et al. Mutations in NOTCH2 in families with Hajdu‑Cheney syndrome. Hum Mutat. 2011 Oct;32(10):1114‑1117. doi:10.1002/humu.21546.
Narumi Y, Min BJ, Shimizu K, et al. Clinical consequences in truncating mutations in exon 34 of NOTCH2: report of six patients with Hajdu‑Cheney syndrome and a patient with serpentine fibula polycystic kidney syndrome. Am J Med Genet A. 2013 Mar;161A(3):518‑526. doi:10.1002/ajmg.a.35772.
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 Mar 6;43(4):303‑305. doi:10.1038/ng.779.
Zhao W, Petit E, Gafni RI, et al. Mutations in NOTCH2 in patients with Hajdu‑Cheney syndrome. Osteoporos Int. 2013 Aug;24(8):2275‑2281. doi:10.1007/s00198-013-2298-5.