Published: 09:04 AM, 05 November 2025
Hajdu–Cheney Syndrome: Rarest Disease in Bangladesh
SMM Musabbir Uddin
Introduction
Hajdu–Cheney syndrome (HCS) is a very rare, progressive genetic disorder that primarily affects bone and connective tissue. The hallmark findings are acro osteolysis (resorption of the distal phalanges), generalized osteoporosis with fractures, and variable craniofacial, dental and renal or cardiovascular abnormalities. Severity and the combination of features vary widely between patients and with age.
History
HCS was first described clinically in the mid-20th century and has since been sporadically reported worldwide. For many years its cause was unclear in the 2010s pathogenic truncating mutations in exon 34 of the NOTCH2 gene were identified as the principal molecular cause. That discovery helped explain many of the skeletal and developmental features through altered Notch signaling.
Clinical Features
Typical features include:
1) Acro-osteolysis of fingers and toes, often progressive.
2) Early-onset, severe osteoporosis with low bone mass and fractures.
3) Short stature, brachycephaly or other craniofacial dysmorphism.
4) Dental problems (early tooth loss, periodontitis) and wormian bones on skull X-ray.
5) Joint laxity or contractures, scoliosis, and variable hearing loss.
Less common but important manifestations include cardiac defects, polycystic kidneys, and neurologic complications from basilar invagination. The phenotype evolves with age some findings become more obvious in adolescence or adulthood.
Diagnosis
Diagnosis rests on the clinical picture (typical radiology showing acro osteolysis and osteoporosis) together with molecular confirmation when available. Genetic testing targeted to exon 34 of NOTCH2 or whole-exome sequencing can demonstrate pathogenic truncating variants and confirms the diagnosis. Because HCS overlaps with other skeletal dysplasias, clinicians often use a combination of clinical, radiologic and genetic data. Genetic counseling is recommended once a diagnosis is made.
Treatment
There is no cure. Management is multidisciplinary and symptom-directed:
1) Bone health: calcium/vitamin D, fracture prevention, physiotherapy. Anti-resorptive agents (bisphosphonates) have been used in individual cases to treat osteoporosis, with variable benefit; data are limited to case reports and small series. Monitoring for complications of low bone mass is essential.
2) Dental care and ENT/audiology follow-up for hearing loss.
3) Orthopedic management for fractures, deformities and spinal instability; neurosurgical input if basilar invagination threatens the brainstem.
4) Routine screening for cardiac and renal abnormalities and anticipatory care. Because knowledge is limited, individualized care plans and referral to a tertiary centre or a geneticist are advisable.
Prevention
Primary prevention of a genetic disorder like HCS is limited. Key measures are:
1) Genetic counselling for affected families, discussing autosomal dominant inheritance and recurrence risk (many cases are sporadic but familial transmission can occur).
2) Prenatal or preimplantation genetic testing is possible when a familial NOTCH2 pathogenic variant is known.
3) Early recognition and bone-health optimization can prevent complications.
Epidemiology in Bangladesh
HCS is ultra-rare globally (estimates place prevalence well under 1 per 1,000,000). Published literature from Bangladesh is extremely limited: the Bangladesh Journal of Child Health published what was described as the first reported case from Bangladesh in 2012, a single-case report from a tertiary hospital in Dhaka. That report underlines two realities: HCS is both rare and likely underdiagnosed in low-resource settings where genetic testing is limited. At present there are no national registries or population data from Bangladesh to suggest more than isolated case reports. Clinicians in Bangladesh should consider HCS when confronted with the characteristic radiology and severe early osteoporosis, and where possible seek genetic confirmation or referral.
Conclusion
Hajdu–Cheney syndrome is a rare, progressive disorder caused mainly by truncating NOTCH2 variants and identified by its combination of acro-osteolysis and severe osteoporosis with a variable spectrum of other findings. Management is supportive and individualized, focused on bone health, dental and hearing care, and monitoring for systemic complications. In Bangladesh, published experience is limited to case reports; improving clinician awareness, access to imaging and genetic testing, and registry efforts would help with diagnosis, family counselling and long-term care planning.
SMM Musabbir Uddin is a
student of Universal
Medical College, Dhaka.
Hajdu–Cheney syndrome (HCS) is a very rare, progressive genetic disorder that primarily affects bone and connective tissue. The hallmark findings are acro osteolysis (resorption of the distal phalanges), generalized osteoporosis with fractures, and variable craniofacial, dental and renal or cardiovascular abnormalities. Severity and the combination of features vary widely between patients and with age.
History
HCS was first described clinically in the mid-20th century and has since been sporadically reported worldwide. For many years its cause was unclear in the 2010s pathogenic truncating mutations in exon 34 of the NOTCH2 gene were identified as the principal molecular cause. That discovery helped explain many of the skeletal and developmental features through altered Notch signaling.
Clinical Features
Typical features include:
1) Acro-osteolysis of fingers and toes, often progressive.
2) Early-onset, severe osteoporosis with low bone mass and fractures.
3) Short stature, brachycephaly or other craniofacial dysmorphism.
4) Dental problems (early tooth loss, periodontitis) and wormian bones on skull X-ray.
5) Joint laxity or contractures, scoliosis, and variable hearing loss.
Less common but important manifestations include cardiac defects, polycystic kidneys, and neurologic complications from basilar invagination. The phenotype evolves with age some findings become more obvious in adolescence or adulthood.
Diagnosis
Diagnosis rests on the clinical picture (typical radiology showing acro osteolysis and osteoporosis) together with molecular confirmation when available. Genetic testing targeted to exon 34 of NOTCH2 or whole-exome sequencing can demonstrate pathogenic truncating variants and confirms the diagnosis. Because HCS overlaps with other skeletal dysplasias, clinicians often use a combination of clinical, radiologic and genetic data. Genetic counseling is recommended once a diagnosis is made.
Treatment
There is no cure. Management is multidisciplinary and symptom-directed:
1) Bone health: calcium/vitamin D, fracture prevention, physiotherapy. Anti-resorptive agents (bisphosphonates) have been used in individual cases to treat osteoporosis, with variable benefit; data are limited to case reports and small series. Monitoring for complications of low bone mass is essential.
2) Dental care and ENT/audiology follow-up for hearing loss.
3) Orthopedic management for fractures, deformities and spinal instability; neurosurgical input if basilar invagination threatens the brainstem.
4) Routine screening for cardiac and renal abnormalities and anticipatory care. Because knowledge is limited, individualized care plans and referral to a tertiary centre or a geneticist are advisable.
Prevention
Primary prevention of a genetic disorder like HCS is limited. Key measures are:
1) Genetic counselling for affected families, discussing autosomal dominant inheritance and recurrence risk (many cases are sporadic but familial transmission can occur).
2) Prenatal or preimplantation genetic testing is possible when a familial NOTCH2 pathogenic variant is known.
3) Early recognition and bone-health optimization can prevent complications.
Epidemiology in Bangladesh
HCS is ultra-rare globally (estimates place prevalence well under 1 per 1,000,000). Published literature from Bangladesh is extremely limited: the Bangladesh Journal of Child Health published what was described as the first reported case from Bangladesh in 2012, a single-case report from a tertiary hospital in Dhaka. That report underlines two realities: HCS is both rare and likely underdiagnosed in low-resource settings where genetic testing is limited. At present there are no national registries or population data from Bangladesh to suggest more than isolated case reports. Clinicians in Bangladesh should consider HCS when confronted with the characteristic radiology and severe early osteoporosis, and where possible seek genetic confirmation or referral.
Conclusion
Hajdu–Cheney syndrome is a rare, progressive disorder caused mainly by truncating NOTCH2 variants and identified by its combination of acro-osteolysis and severe osteoporosis with a variable spectrum of other findings. Management is supportive and individualized, focused on bone health, dental and hearing care, and monitoring for systemic complications. In Bangladesh, published experience is limited to case reports; improving clinician awareness, access to imaging and genetic testing, and registry efforts would help with diagnosis, family counselling and long-term care planning.
SMM Musabbir Uddin is a
student of Universal
Medical College, Dhaka.
