Hajdu-Cheney Syndrome: Comprehensive Imaging Guide and Clinical Overview
Overview
Hajdu-Cheney syndrome (HCS) is a rare, autosomal dominant connective tissue disorder primarily affecting the skeletal system. It was first described as cranioskeletal dysplasia and characterized by acro-osteolysis, craniofacial abnormalities, and osteoporosis. The syndrome is caused by mutations in the NOTCH2 gene, which disrupts bone remodeling and connective tissue homeostasis. Clinically, HCS presents with progressive resorption of distal phalanges, distinctive facial dysmorphism, joint laxity, short stature, and dental abnormalities such as premature tooth loss. Less than 100 cases have been reported worldwide, emphasizing its rarity and diagnostic challenge.
Key Imaging Features
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Acro-osteolysis: Transverse band-like resorption of the distal and middle phalanges of hands and feet, often sparing some digits such as the fourth finger.
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Skull radiographs show delayed closure of sutures, persistent wormian bones especially in the lambdoid suture, dolichocephaly, bathrocephaly (bulging of the occipital bone), and thickened skull base including mastoids.
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Anomalies in the skull base such as elongated, enlarged J-shaped sella turcica, aplastic or hypoplastic frontal sinuses, and platybasia with or without basilar invagination.
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Spinal imaging reveals osteoporosis with biconcave vertebrae (“fish vertebrae”), compression fractures, spondylolisthesis, and kyphoscoliosis.
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Morphological changes of the facial bones include hypoplastic maxilla and mandible with widening of the mandibular angle, premature tooth loss, periodontal disease, and alveolar bone resorption.
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Long bones may exhibit osteoporosis, occasional longitudinal striations near epiphyses, and joint subluxations due to associated laxity.
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Renal ultrasound may show multiple small cysts in the cortex and medulla, indicating extra-skeletal manifestations.
Pathophysiology
The pathophysiology of Hajdu-Cheney syndrome centers around truncating mutations in the terminal exon of the NOTCH2 gene, leading to dysregulated signaling that impairs normal bone formation and remodeling. This disrupts osteoclast and osteoblast balance, resulting in progressive osteolysis, particularly of the distal phalanges (acro-osteolysis) and generalized osteoporosis. The delayed suture closure and wormian bones arise due to defective cranial bone ossification. Thickening of the skull base and enlarged sella represent compensatory bone remodeling changes. Joint laxity and subluxations reflect defective connective tissue matrix in ligaments and tendons. Progressive bone resorption leads to characteristic radiological features evolving over time, with increasing severity of osteoporosis, vertebral deformities, and craniofacial anomalies as patients age.
Differential Diagnosis
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Other causes of acro-osteolysis: Idiopathic acro-osteolysis, autoimmune connective tissue diseases (e.g., systemic sclerosis), hyperparathyroidism, and progeria. Unlike HCS, these typically lack the extensive craniofacial abnormalities and NOTCH2 mutation.
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Cleidocranial dysplasia: Shares features such as delayed suture closure and wormian bones but usually shows absent or hypoplastic clavicles and prominent dental anomalies without acro-osteolysis.
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Pyknodysostosis: Shows generalized osteosclerosis and acro-osteolysis but differs in having short stature with open sutures and increased bone density rather than osteoporosis.
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Other skeletal dysplasias: Conditions like spondyloepiphyseal dysplasia can have spine and bone abnormalities, but lack the distinct pattern of acro-osteolysis and jaw changes seen in HCS.
Imaging Protocols and Techniques
A comprehensive skeletal survey is critical for diagnosis and monitoring of Hajdu-Cheney syndrome. Recommended imaging modalities include:
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Conventional radiography (X-rays): Essential initial imaging for detection of acro-osteolysis in hands and feet, skull sutures, vertebrae morphology, and long bone evaluation.
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Computed tomography (CT): High-resolution CT of the skull base is valuable to assess complex bony anatomy including platybasia, basilar invagination, and sella turcica morphology. Useful for surgical planning if complications occur.
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Magnetic resonance imaging (MRI): Helpful for evaluation of spinal cord and neurological complications, visualization of soft tissues around joints for subluxations, and assessment of associated renal cystic changes.
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Dual-energy X-ray absorptiometry (DEXA): Recommended for bone mineral density measurement to quantify osteoporosis severity and guide management.
Imaging pearls: The transverse “band-like” acro-osteolysis pattern is a hallmark diagnostic feature. Early skull imaging may reveal persistent wormian bones and open sutures before overt osteoporosis becomes apparent. Monitoring vertebral architecture over time helps assess fracture risk and deformity progression.
Imaging pitfalls: Overlapping features with other osteolytic conditions require correlation with clinical presentation and genetic testing. Misinterpreting wormian bones or delayed suture closure as nonspecific variants can delay diagnosis. Distal phalangeal changes can be subtle on early radiographs; high-quality images and multiple views improve detection sensitivity.
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