Hajdu-Cheney Syndrome

What is Hajdu Cheney Syndrome (HCS) ?

First of all, sorry you are here if you are looking for info on this terrible disease. Nobody should have to suffer with painful conditions. But, those of us brave souls who do are important. We are a part of life.

More than likely something called Acro-Osteolysis has resulted in odd finger tips.

Acro-Osteolysis: Acro-osteolysis is basically the fancy medical term for when the tips of your fingers or toes start to lose bone. Imagine if the very ends of your bones, like where your nails sit, slowly start to disappear or melt away. That’s what’s happening with acro-osteolysis. It makes those areas thinner and can even make your fingers or toes look shorter over time. At first, It’s not painful in itself. It can lead to other problems because the bone structure isn’t as strong or normal as it should be. Partial dislocations are common as the joints degenerate over time. Once the connective tissues have nothing strong enough to hold them they get very painful and eventually pull away from the joint. This leads to further loss of strength and dexterity which leads to more damages.

HCS is the result of our immune system reaction and type of HCS. Some of us are born and diagnosed right away while others can escape diagnosis their whole lives. I have heard of people over 40 getting diagnosed. It’s caused by mutations in the NOTCH2 gene, inherited in an autosomal dominant pattern usually. There’s no cure, so treatment focuses on managing symptoms and complications.

Every site has nearly the exact same introductory paragraph on HCS. Nord – The National Organization of Rare Disorders describes it as “… a rare genetic disorder. The specific symptoms and the severity can vary greatly from one person to another. The breakdown of bone (osteolysis), especially the outermost bones of the fingers and toes (acroosteolysis), is a major characteristic. In addition, affected individuals frequently have skull deformities, distinctive facial features, abnormally loose joints (joint laxity), a severe reduction of bone mass (osteoporosis) and short stature. There are additional symptoms sometimes associated with the disorder including neurological problems, heart abnormalities that are present at birth (congenital), and abnormalities of the kidneys and urinary tract. Most affected individuals have normal mental development, but a small proportion show mild delays in development. Hajdu-Cheney syndrome is associated with a change (variant or mutation) in the NOTCH2 gene. This condition can be inherited in an autosomal dominant manner, but many cases occur due to a new gene variant (de novo) that is not inherited.”

AI use to get a better understanding: Move over Dr. Google!!!

In this day and age we are fortunate to have the advances in medicine, science, and AI. AI such as Grok or Cloud or ChatGPT can offer fairly current studies and analyze multiple sites. This creates a comprehensive outline on anything specific you want to know. For example: I asked Grok to tell me about HCS, then asked for more details on Notch2 and then I asked to get more info on RANK-L. Here is what it said, it is intimidating jargon that i have roughly translated after:

“Here’s an updated and detailed summary of Hajdu-Cheney Syndrome (HCS), focusing on case studies, current research involving the NOTCH2 gene, and the connection with RANK-L:

Overview of Hajdu-Cheney Syndrome (HCS):

Clinical Features:

Skeletal: Acro-osteolysis (resorption of distal phalanges), generalized osteoporosis, craniofacial abnormalities (e.g., micrognathia, wormian bones), spinal deformities, and dental issues.
Other Systems: Includes cardiovascular abnormalities, renal cysts, neurological complications, and hearing loss. Growth retardation and developmental delays are also common.

Inheritance: While HCS is autosomal dominant, many cases are due to spontaneous mutations, explaining the lack of family history in many patients.

Autosomal Dominance from affected father to children

Case Studies:

Pakistan’s First Case Report:
- A 36-year-old male with multiple fragility fractures and juvenile osteoporosis, diagnosed with a pathogenic variant in NOTCH2. This case emphasizes the global distribution of HCS and the importance of genetic testing for diagnosis.
Novel NOTCH2 Mutation in a Child:
- An 11-year-old boy from Spain with a unique NOTCH2 mutation, showcasing the variability in presentation and the potential of vibrotherapy as a treatment for musculoskeletal issues.
Early-Onset Severe Case:
- A Chinese child with early and severe manifestations of HCS, highlighting the spectrum of severity even with the same mutation (c.6426dupT), suggesting the influence of other genetic or environmental factors.
Cardiovascular Anomalies:
- An African child with HCS who had an atypical congenital heart defect, emphasizing the need for comprehensive cardiovascular assessments in HCS patients.
Surgical Management:
- A 59-year-old woman with HCS underwent spinal surgery for high-grade spondylolisthesis, showcasing the surgical challenges due to bone fragility in HCS patients.

Research on NOTCH2 in HCS:

Genetic Mutations: Most mutations in HCS occur in Exon 34 of the NOTCH2 gene, leading to a stable, truncated NOTCH2 protein. These mutations are gain-of-function, causing enhanced NOTCH2 signaling.
Mechanistic Insights: Studies using mouse models have shown that these mutations increase the expression of RANKL (Receptor Activator of Nuclear Factor Kappa-B Ligand) in osteoblasts, leading to excessive osteoclast activity and bone resorption. This is pivotal in understanding bone loss in HCS.
Therapeutic Approaches:
- Denosumab: A monoclonal antibody that inhibits RANKL has been used in some HCS cases, showing some improvement in bone mineral density but not in acro-osteolysis. This suggests that while RANKL inhibition can manage bone density, it might not address all aspects of bone degradation in HCS.
- Bisphosphonates: Commonly used to manage osteoporosis, but their effectiveness in HCS varies, reflecting the complexity of bone pathology in this syndrome.
Ongoing Research: There is a focus on understanding how specific NOTCH2 mutations affect different tissues and exploring targeted therapies that could normalize NOTCH2 signaling without affecting other NOTCH pathways crucial for normal physiology.

Connection Between HCS and RANK-L:

Pathophysiological Link: The mutant NOTCH2 in HCS patients is thought to increase RANK-L expression in bone cells, particularly osteoblasts, leading to an imbalance favoring osteoclastogenesis and bone resorption over bone formation.
Research Implications:
- Studies have confirmed that NOTCH2 signaling influences the RANK/RANKL/OPG (Osteoprotegerin) pathway, which is central to bone remodeling. In HCS, this leads to a net bone loss due to unopposed osteoclast activity.
- The connection suggests potential therapeutic avenues through RANKL inhibitors, although more research is needed to tailor these treatments to HCS’s unique pathology.

Future Directions:

Genetic Therapies: Exploring gene editing or silencing strategies to correct or mitigate the effects of NOTCH2 mutations.
Comprehensive Management: A multidisciplinary approach combining medical management, surgical interventions for complications, and supportive therapies for quality of life improvement.
Research: Continuation of detailed genetic studies to uncover all possible mutations associated with HCS and their clinical correlations, alongside developing more targeted treatments for bone health.

Translation:

Hajdu Cheney Syndrome is a connective tissue and bone disorder caused by a mutation to our DNA. The mutation removes the “Stop” or “Off” switch on the gene responsible for bone destruction. When bone needs repaired or replaced the gene turns on to remove the old damaged bone. It is also responsible for the development of other parts of the body.

Some of us inherit the gene from one of our parents. Some of us get the gene from a mutation anywhere along the line in our development in the womb. The mutation can occur early, before pregnancy, or it can occur after any number of early cell divisions. Some of us are quite mild with symptoms compared to others who are born fighting for life.

Treatment is often with Bisphosphonates such as Zolendronate and with a monoclonal antibody such as Denosumab. Denosumab works by binding to the bone degenerator. Zolendronate boosts the ability to generate more bone to counter the degeneration caused by too much RANK-L (degenerator).

Romosozumab – NEWEST Drug in the defence against rogue bone growth control.

Drug Name and Class: Romosozumab, marketed as EVENITY™, is a sclerostin inhibitor representing the first new therapeutic approach for osteoporosis and fracture risk in nearly a decade. It is approved by Health Canada for treating osteoporosis in postmenopausal women at high risk of fracture, such as those with a history of osteoporotic fracture or multiple risk factors.

Mechanism of Action: Romosozumab functions by increasing bone formation while simultaneously decreasing bone resorption. It significantly and rapidly elevates bone mineral density (BMD) in the lumbar spine, total hip, trabecular bone, and cortical bone over a 12-month period, thereby enhancing bone strength and reducing fracture risk.

Efficacy: Clinical trials demonstrate that romosozumab achieves superior results compared to other treatments, effectively reducing the risk of fractures at the spine, hip, and other sites in women with postmenopausal osteoporosis.

Administration: The drug is administered via two subcutaneous injections, given one after the other, once monthly for a total of 12 doses. Following completion of the treatment course, consideration of an anti-resorptive agent is recommended to preserve the gains in bone density.

Side Effects and Risks: Common adverse effects include joint pain and headaches. Other potential risks encompass an increased likelihood of heart attack, stroke, or cardiovascular-related death; hypocalcemia (low blood calcium levels); osteonecrosis of the jaw; and atypical femoral fractures. Overall adverse reactions are balanced relative to other treatments, with the exception of a slightly elevated cardiovascular risk.

Additional Considerations: Osteoporosis Canada supports the availability of this treatment for high-risk individuals, noting that benefits may outweigh risks, though a comprehensive consultation with a physician is essential prior to initiation.

Some treatment has been done with Vibrotherapy, though I am unsure how that is going. It sounds good to me, I may enjoy it, same with the gentle rocking of sleeping in a boat. Better circulation in the joints that we can’t move properly is important for pain relief!

To view a comprehensive report of my own HCS experience check out this post/doc.

HCS Post

HCS & Me PDF Download