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Hajdu-Cheney syndrome

Description

Hajdu-Cheney Syndrome: A Rare Connective Tissue Disorder

Hajdu-Cheney syndrome, also known as acroosteolysis with osteoporosis and changes in skull and mandible, is a rare autosomal dominant congenital disorder of the connective tissue. This condition is characterized by severe and excessive bone resorption leading to osteoporosis and a wide range of other possible symptoms.

Key Features:

  • Bone Abnormalities: Hajdu-Cheney syndrome affects many parts of the body, particularly the bones. Loss of bone tissue from the hands and feet (acro-osteolysis) is a characteristic feature of the condition.
  • Short Stature: Individuals with Hajdu-Cheney syndrome often experience short stature due to progressive focal bone destruction.
  • Osteoporosis: Severe osteoporosis is a hallmark of this condition, leading to compression fractures and other skeletal abnormalities.
  • Craniofacial Changes: The condition also manifests with distinctive craniofacial and skull changes, including hypertelorism (increased distance between the eyes), bushy eyebrows, micrognathia (small jaw), small mouth with dental anomalies, low-set ears, and short neck.

Other Possible Symptoms:

  • Shortening of Digits: Pseudoclubbing, a condition characterized by shortening of digits, pain in digits, and other skeletal abnormalities.
  • Developmental Defects: Developmental defects of bones, teeth, and joints are also associated with Hajdu-Cheney syndrome.

Inheritance Pattern:

Hajdu-Cheney syndrome follows an autosomal dominant pattern of inheritance, meaning that only a single copy of the disease-causing gene variant is necessary to cause the condition. However, many sporadic cases occur, indicating that environmental or other genetic factors may also contribute to the development of this disorder.

Prevalence:

Fewer than 100 people are reported as having Hajdu Cheney syndrome, making it an extremely rare condition.

References:

  • [3] - Hajdu-Cheney syndrome is a rare autosomal dominant congenital disorder of the connective tissue characterized by severe and excessive bone resorption leading to osteoporosis and a wide range of other possible symptoms.
  • [2] - The condition affects many parts of the body, particularly the bones, with loss of bone tissue from the hands and feet (acro-osteolysis) being a characteristic feature.
  • [1] - Hajdu-Cheney syndrome is also associated with craniofacial changes, including hypertelorism, bushy eyebrows, micrognathia, small mouth with dental anomalies, low-set ears, and short neck.

Additional Characteristics

  • Osteoporosis
  • Short Stature
  • Bone Abnormalities
  • Craniofacial Changes
  • Shortening of Digits
  • Developmental Defects

Signs and Symptoms

Overview of Signs and Symptoms

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder that affects bone, joint, and brain development. The signs and symptoms of HCS can vary greatly among affected individuals, even within the same family.

  • Bone Abnormalities: One of the primary features of HCS is severe osteoporosis, which can lead to compression fractures, particularly in the spine, hips, and wrists [5][11]. Other bone-related issues include acroosteolysis (shortening or disappearance of distal phalanges) [7], and curvature of the spine (scoliosis) [11].
  • Craniofacial Dysmorphism: Individuals with HCS often exhibit distinctive facial features, such as micrognathia (small jaw), mid-face hypoplasia, and a narrow forehead [8]. Additionally, there may be abnormalities in the shape and size of the skull.
  • Short Stature: Many people with HCS experience short stature, which can range from mild to severe [10].
  • Brain and Kidney Issues: In some cases, HCS can lead to problems with the brain and kidneys. These issues may include cognitive impairment, seizures, and renal failure due to multiple renal cysts [3].

Timing of Symptoms

It's essential to note that the signs and symptoms of HCS can present at different times, from infancy to adulthood [12]. Some features, such as acroosteolysis and facial dysmorphisms, may not be apparent at birth but become more pronounced in childhood or later.

Variability among Affected Individuals

The severity and presentation of HCS can vary significantly among affected individuals. Even within the same family, there may be differences in the expression of symptoms [4][6].

References: [1] Context result 5 [2] Context result 10 [3] Context result 3 [4] Context result 4 [5] Context result 9 [6] Context result 12 [7] Context result 7 [8] Context result 8 [9] Context result 11 [10] Context result 1 [11] Context result 13

Additional Symptoms

  • seizures
  • cognitive impairment
  • narrow forehead
  • severe osteoporosis
  • compression fractures (spine, hips, wrists)
  • acroosteolysis (shortening or disappearance of distal phalanges)
  • scoliosis (curvature of the spine)
  • micrognathia (small jaw)
  • mid-face hypoplasia
  • abnormalities in the shape and size of the skull
  • renal failure due to multiple renal cysts
  • short stature

Diagnostic Tests

Diagnostic Tests for Hajdu-Cheney Syndrome

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder that affects bone, joint, and brain development. Diagnosing HCS can be challenging due to its rarity and diverse presentation. However, various diagnostic tests can help confirm the diagnosis.

  • Imaging Tests: X-rays of the skull can reveal characteristic changes, including open sutures and an abnormally shaped skull [1]. Radiographic features such as acroosteolysis (bone loss in hands and feet) and vertebral anomalies are also common in HCS patients [9].
  • Genetic Testing: Genetic testing is a crucial diagnostic tool for HCS. Sequence analysis of exon 34 of the NOTCH2 gene can detect nonsense mutations or deletions creating a STOP codon upstream the PEST domain, confirming the diagnosis [13]. Next-generation sequencing (NGS) tests are also available to identify genetic mutations associated with HCS [5].
  • Clinical Evaluation: A thorough clinical evaluation, including a detailed patient and family history, is essential for diagnosing HCS. Clinical features such as short stature, coarse facies, bowing of long bones, and vertebral anomalies can help suspect the diagnosis [4].

Diagnostic Teams

A diagnostic team for Hajdu-Cheney syndrome may include:

  • Genetics
  • Nephrology (for renal cysts associated with SFPKS)
  • Orthopedics (for bone abnormalities)

These teams work together to provide a comprehensive evaluation and coordinate providers as needed.

References: [1] - Search result 1: A diagnosis of Hajdu-Cheney syndrome is based upon the identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized imaging tests. [4] - Search result 4: Hajdu-Cheney syndrome (HJCYS) is a rare autosomal dominant skeletal disorder characterized by short stature, coarse and dysmorphic facies, bowing of the long bones, and vertebral anomalies. [5] - Search result 5: This is a next-generation sequencing (NGS) test appropriate for individuals with clinical signs and symptoms, suspicion of, or family history of Hajdu-Cheney syndrome. [9] - Search result 9: Feb 9, 2023 — Diagnosis involves genetic testing searching for the truncating mutation in the NOTCH2 gene and radiographic features such as acroosteolysis (bone loss in hands and feet) and vertebral anomalies. [13] - Search result 13: Hajdu Cheney syndrome (HCS) ... Hajdu Cheney Syndrome - Management. The diagnosis of HCS is verified out by sequence analysis of exon 34 of NOTCH2 in genomic DNA isolated from peripheral leukocytes, and the demonstration of a nonsense mutation or deletion creating a STOP codon upstream the PEST domain [52, 54, 70].

Treatment

Treatment Options for Hajdu-Cheney Syndrome

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder that affects the bones, skin, and other systems in the body. While there is no cure for HCS, various treatment options are available to manage its symptoms and improve quality of life.

Medications:

  • Bisphosphonates: These medications have been shown to be beneficial in treating osteoporosis associated with HCS. Studies have demonstrated significant gains in bone mineral density (BMD) and maintenance of acro-osteolytic status without deterioration [1, 2].
  • Romosozumab: A one-year treatment course provided substantial gains in BMD while maintaining the last acro-osteolytic status without deteriorating [3].

Other Treatments:

  • Surgical procedures: May be necessary to address specific symptoms or complications associated with HCS, such as fractures or craniofacial anomalies.
  • Non-steroidal anti-inflammatory drugs (NSAIDs): Can help manage pain and inflammation associated with HCS.
  • Antibiotics: May be prescribed to treat infections related to the syndrome.

Emerging Therapies:

  • Vitamin D therapy: Has been suggested as a potential treatment option for improving bone density in individuals with HCS [4].
  • Zoledronic acid: A progress report on anti-resorptive therapy using this medication has shown promising results in treating osteoporosis associated with HCS [5].

Importance of Research:

Continued research is crucial to advance our understanding of HCS and develop more effective treatment options. This includes exploring new medications, surgical techniques, and other therapeutic approaches.

References:

[1] Kim KJ (2023) - One year of romosozumab treatment provided substantial gains in BMD with maintaining the last acro-osteolytic status without deteriorating. [2] Pittaway JFH (2018) - We have described the responses of acro-osteolysis and spinal BMD to treatment with bisphosphonates in a new cohort of patients with Hajdu-Cheney syndrome. [3] Kim KJ (2023) - One year of romosozumab treatment provided substantial gains in BMD with maintaining the last acro-osteolytic status without deteriorating. [4] Giustina A. Drug-induced osteoporosis (2019) [5] Pittaway JFH (2018) - We have described the responses of acro-osteolysis and spinal BMD to treatment with bisphosphonates in a new cohort of patients with Hajdu-Cheney syndrome.

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Differential Diagnosis

Differential Diagnosis of Hajdu-Cheney Syndrome

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder that can be challenging to diagnose due to its overlapping symptoms with other conditions. The differential diagnosis for HCS includes several genetic syndromes and disorders that present with similar clinical and radiological features.

List of Differential Diagnoses:

  • Pyknodysostosis: A rare genetic disorder characterized by osteosclerosis, short stature, and distinctive facial features [1].
  • Mandibuloacral dysplasia: A rare genetic disorder that affects the development of bones and cartilage, leading to characteristic skeletal abnormalities [2].
  • Progeria: A rare genetic disorder that causes premature aging, including growth failure, aged appearance, and organ system dysfunction [3].
  • Rothmund-Thompson syndrome: A rare genetic disorder characterized by short stature, skin atrophy, cataracts, and skeletal abnormalities [4].
  • Scleroderma: An autoimmune disease that affects the skin and connective tissue, leading to thickening of the skin and internal organs [5].
  • Hyperparathyroidism: A condition caused by an overactive parathyroid gland, leading to elevated calcium levels in the blood [6].
  • Psoriasis: A chronic inflammatory skin condition characterized by red, scaly patches on the skin [7].

Key Features for Differential Diagnosis:

When considering a differential diagnosis for HCS, it is essential to look for characteristic features such as:

  • Acroosteolysis (bone loss in the hands and feet)
  • Osteoporosis
  • Short stature
  • Specific craniofacial features
  • Wormian bones
  • Neurological symptoms
  • Cardiovascular defects
  • Polycystic kidneys

Genetic Considerations:

HCS is caused by mutations in the NOTCH2 gene, which plays a crucial role in cell development and differentiation. The diagnosis of HCS can be confirmed through genetic testing, including sequence analysis of exon 34 of NOTCH2 [8].

References:

[1] Search result 10 [2] Search result 4 [3] Search result 13 [4] Search result 14 [5] Search result 12 [6] Search result 9 [7] Search result 11 [8] Search result 15

Additional Information

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