Some of us want to know everything we can learn about HCS. Unfortunately a lot of case studies are behind paywalls — still, there are a number that are free. I broke it into four sections: case studies of patients and family members, the discovery of the mutations on Chromosome 1 that result in a defective Notch2 pathway, research into RANK-L over-expression driven by the HCS mutation on the Notch2 gene, and links and documents that are simply insightful.
I did not realize there is so much research going on into RANK-L, but I cannot say I am surprised — there is a lot of potential there for therapeutic medications for osteoporosis and arthritis. A lot of the earlier studies are into the side effects of HCS and the complications from surgeries: anesthesia, the non-fusion of bone, and the use of bisphosphonates. Every link below opens the paper on its publisher or archive, in a new tab.
Case studies — patients & families
Case reports documenting how HCS has presented in individual patients and families — the dental, skeletal, kidney, spinal, and ocular findings that make up the disease.
- Hajdu-Cheney syndrome with serpentine fibula–polycystic kidney syndrome
- Hajdu-Cheney syndrome: a case report with review of literature
- A case of Hajdu-Cheney syndrome and the use of bisphosphonates
- Hajdu-Cheney syndrome and syringomyelia: a case report
- Hajdu-Cheney syndrome with extreme proximal junctional kyphosis: a case report
- Hajdu-Cheney syndrome: report of a case with unusual dental findings
- A novel NOTCH2 mutation in a patient with Hajdu-Cheney syndrome
- Hajdu-Cheney syndrome: a case with new radiological findings
- Hajdu-Cheney syndrome: a novel NOTCH2 mutation in a Spanish child treated with vibrotherapy
- Distinct severity of phenotype in Hajdu-Cheney syndrome: a case report
- Hajdu-Cheney syndrome: report of a case in Spain
- Hajdu-Cheney syndrome: a case report and review of the literature
- Hajdu-Cheney syndrome with a focus on foot deformities
- Congenital glaucoma: a novel ocular manifestation of Hajdu-Cheney syndrome
Research into the NOTCH2 pathway
The discovery of the mutations on Chromosome 1 that result in a defective Notch2 pathway — clustered in exon 34 of NOTCH2 — and the genetics and biology that followed, roughly in the order it was published.
- 2011 — Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss
- Mutations in NOTCH2 in families with Hajdu-Cheney syndrome
- 2013 — Mutations in NOTCH2 in patients with Hajdu–Cheney syndrome
- 2014 — Hajdu-Cheney syndrome: a review
- 2016 — Hajdu Cheney syndrome: report of a novel NOTCH2 mutation and treatment with denosumab
- Hajdu-Cheney syndrome, a disease associated with NOTCH2 mutations
- 2017 — Clinical and experimental aspects of Notch receptor signaling: Hajdu-Cheney syndrome and related disorders
- 2018 — An antibody to Notch2 reverses the osteopenic phenotype of Hajdu-Cheney mutant male mice
- 2019 — Discovery of a novel NOTCH2 mutation causing Hajdu Cheney syndrome in a kindred with remarkable phenotypic diversity
- 2020 — Distinct severity of phenotype in Hajdu-Cheney syndrome: a case report and literature review
- Clinical consequences of truncating mutations in exon 34 of NOTCH2: six patients with Hajdu-Cheney syndrome and a patient with serpentine fibula polycystic kidney syndrome
- 2021 — Hajdu Cheney syndrome due to NOTCH2 defect – first case report from Pakistan and review of literature
- 2022 — Progress and current status in Hajdu-Cheney syndrome, with a focus on novel genetic research
- 2023 — A 23-year follow-up of a male with Hajdu-Cheney syndrome due to NOTCH2 mutation
- Hajdu Cheney syndrome: report of a novel NOTCH2 mutation and treatment with denosumab
- Hajdu-Cheney syndrome with atypical cardiovascular abnormalities
- Distinct severity of phenotype in Hajdu-Cheney syndrome: a case report and literature review
- 2024 — First case of Hajdu-Cheney syndrome in Lithuania caused by a novel NOTCH2 likely pathogenic variant
- NOTCH2 promotes osteoclast maturation and metabolism and modulates the transcriptome profile during osteoclastogenesis
- Regulation of bone homeostasis: signaling pathways and therapeutic targets
- TNFα has differential effects on the transcriptome profile of selected populations in murine cartilage
- Anaesthesia for a patient with Hajdu Cheney syndrome scheduled for scoliosis surgery — a case study
- Solitary band acro-osteolysis in Hajdu-Cheney syndrome
- The age-dependent progression of Hajdu-Cheney syndrome in two families
Research into RANK-L over-expression
RANK-L (receptor activator of nuclear factor κB ligand) sits downstream of the Notch2 problem and drives the osteoclasts that take bone apart. It is a busy research area — far beyond HCS — because of its role in osteoporosis, arthritis, and cancer.
- The anti-tumor effect of RANKL inhibition in malignant solid tumors – a systematic review
- Development and disease of mouse muscular and skeletal systems
- Role of receptor activator of nuclear factor-κB ligand and osteoprotegerin in bone cell biology
- The role of receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin: clinical implications
- Receptor activator of nuclear factor-κB (RANK) signaling pathway inhibitors
- RANKL stimulates bone-associated tumors through functional RANK expressed on bone-associated cancer cells
- RANK ligand activates nuclear factor-κB in osteoclast precursors
- RANK and RANK ligand are expressed in giant cell tumors of bone
- The RANKL/RANK/osteoprotegerin system in bone and other tissues (review)
- Serum level of RANK ligand in patients with psoriasis
- RANK ligand is a novel inducer of myocardial inflammation
- Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) — overview
- Nuclear factor-κB regulation of osteoclastogenesis and osteoblastogenesis
- A role for nuclear factor κB/Rel transcription factors in the regulation of the recombinase activator genes
- Biological role of heparan sulfate in osteogenesis: a review
- RANK ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort
- RANKL — Wikipedia overview
- RANK ligand, but not sclerostin or gene polymorphisms, is related to joint destruction in early rheumatoid arthritis
- Inhibition of the RANK ligand pathway for the management of aggressive osteosarcoma
- Expression of RANK ligand in bladder cancer
- Circulating RANK ligand levels predict response to immune checkpoint inhibitors in advanced non-small-cell lung cancer
- RANK ligand and osteoprotegerin: regulation of bone remodeling in health and disease
- Nuclear factor κB: important transcription factor and therapeutic target
- RANK ligand and osteoprotegerin regulate proinflammatory cytokine production in mice
Worth reading — a thesis by one of us
Fairly recently, in 2022, Elizabeth Bombal completed her thesis, Assessment and Development of Educational Resources for Hajdu-Cheney Syndrome. Elizabeth has HCS herself, so it was a real treat to read the culmination of her hard work and perseverance.
More of the rare-disease and HCS writing — the patient guide, my own story, the broader resources — lives on Bare Your Rare.