Hajdu-Cheney Syndrome Research Articles

Anaesthesia for a patient of Hajdu Cheney syndrome scheduled for scoliosis surgery-A case study.

Anaesthesia for a patient of Hajdu Cheney syndrome scheduled for scoliosis surgery-A case study.

First case of Hajdu-Cheney syndrome in Lithuania caused by novel NOTCH2 gene likely pathogenic variant

Hajdu-Cheney syndrome (HCS) is an extremely rare autosomal dominant skeletal disorder. The prevalence rate of less than 1 case per 1,000,000 newborns and only 50 cases were reported in the medical literature. HCS is characterized by progressive bone resorption in the distal phalanges (acro-osteolysis), progressive osteoporosis, distinct craniofacial changes, dental anomalies, and occasional association with renal abnormalities. HCS is caused by pathogenic variants in the NOTCH2 gene, 34th exon. We report first familial case of HCS caused by likely pathogenic variant of NOTCH2 gene c.6449delC, p.(Pro2150LeufsTer5).

Fracture healing in a mouse model of Hajdu–Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability

Notch signaling regulates cell fate in multiple tissues including the skeleton. Hajdu–Cheney-Syndrome (HCS), caused by gain-of-function mutations in the Notch2 gene, is a rare inherited disease featuring early-onset osteoporosis and increased risk for fractures and non-union. As the impact of Notch2 overactivation on fracture healing is unknown, we studied bone regeneration in mice harboring a human HCS mutation. HCS mice, displaying high turnover osteopenia in the non-fractured skeleton, exhibited only minor morphologic alterations in the progression of bone regeneration, evidenced by static radiological and histological outcome measurements. Histomorphometry showed increased osteoclast parameters in the callus of HCS mice, which was accompanied by an increased expression of osteoclast and osteoblast markers. These observations were accompanied by inferior biomechanical stability of healed femora in HCS mice. Together, our data demonstrate that structural indices of bone regeneration are normal in HCS mice, which, however, exhibit signs of increased callus turnover and display impaired biomechanical stability of healed fractures.

A case of safe airway management by fiber-optic nasotracheal intubation in general anesthesia in a pediatric patient with Hajdu-Cheney syndrome: a case report

BackgroundHajdu-Cheney syndrome (HCS) is an extremely rare disorder characterized by progressive acro-osteolysis. A unique facial structure and deformity of the cervical spine are associated with a difficult airway. Although several reports describe general anesthesia with orotracheal intubation for patients with HCS, there have been no reports of nasotracheal intubation with a risk of skull base fracture. We describe nasotracheal intubation for oral surgery in a patient with HCS.Case presentationA 13-year-old girl with HCS was scheduled for dental surgery. Preoperative computed tomography revealed no abnormalities including fractures in the skull base or cervical spine. After confirming a lack of vocal cord paralysis by bronchofiberscopic inspection from the nose, general anesthesia was induced with sevoflurane, remifentanil, and rocuronium. Fiber-optic nasotracheal intubation was successfully performed without complications such as depletion of oxygen saturation and massive epistaxis, and the surgery was completed uneventfully. She was discharged the day after surgery with no anesthesia-related complications.ConclusionsWe were able to safely manage the airway of a patient with HCS by nasotracheal intubation under general anesthesia.

ODP132 Efficacy of Romosozumab for Osteoporosis in a Patient with Hajdu-Cheney Syndrome: A Case Report

Abstract Introduction Hajdu–Cheney syndrome (HCS) is a genetic disease with an autosomal-dominant pattern caused by mutations of NOTCH2. This rare disease primarily causes skeletal dysplasia, including craniofacial dysmorphology, dental anomalies, and short stature accompanied by radiographic abnormalities with acroosteolysis and generalized osteoporosis. Even if a definite diagnosis of HCS could be reached as techniques for genetic testing have been advanced, the more important problem is that there is no effective pharmacological treatment for this disease at present. In this study, we aimed to evaluate the efficacy of romosozumab for improving bone fragility in our osteoporotic HCS patient. Clinical Case Report A 43-year old woman was referred to our department to evaluate skeletal dysplasia. She underwent surgical correction of valvular disease when she was 11 years old. She did not have any fracture before she was 26-years old when she got an L1 compression fracture while carrying heavy stuff. She presented with persistent pain and progressive shortening of both fingers and toes since she was 29-years old. She also has hearing difficulty. Physical examination revealed coarse facial features such as micrognathia, low-set ears, elongated philtrum, bushy eyebrows, the wide nose and short digits showing pseudo-clubbing. There were no abnormalities in her biochemical results for liver and renal function, serum calcium, phosphate, alkaline phosphatase, thyroid-stimulating hormone, estradiol, parathyroid hormone, and 25-hydroxy vitamin D. Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry showed T score of -4.2, -2.4, and -1.5 at the lumbar spine (LS), femur neck (FN), and total hip (TH), respectively. A skeletal survey revealed acro-osteolysis and deformity of all digits bilaterally and compression fracture at T8, T10, and L1. Her next-generation sequencing confirmed HCS with a mutation at nucleotide 6758G>A, leading to Trp2253Ter amino acid in NOTCH2 gene annotated as pathogenic. Romosozumab treatment (210mg injected subcutaneously every month) with calcium and vitamin D supplements was started because she had already received bisphosphonate for 10 years without preventing progressive osteolytic lesions and repeated fractures. After one year of treatment with romosozumab, BMD increased by 15.4%, 6.3%, and 1.3% to T-score of -3.5, -2.1, and -1.4 at LS, FN, and TH, respectively. Overall, C-telopeptide was suppressed by 26.4%, 0.121 to 0. 089 ng/mL, and P1NP was increased by 18.7% from 25.2 to 29.9ng/mL with transient fluctuation during the follow-up period. Follow-up radiographs of the hand and feet showed no progressive acro-osteolysis. Clinical conclusion: This is the first treatment report of romosozumab for an osteoporotic HCS patient in Korea. One year of romosozumab treatment provided substantial gains in BMD and prevented progressive acroosteolysis, which represents a promising treatment option for the rare disease of HCS. Presentation: No date and time listed

Progress and Current Status in Hajdu-Cheney Syndrome with Focus on Novel Genetic Research.

Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder caused by a mutation in the NOTCH2 gene. NOTCH signaling has variations from NOTCH 1 to 4 and maintains homeostasis by determining and regulating the proliferation and differentiation of various cells. In HCS, the over-accumulated NOTCH2 causes abnormal bone resorption due to its continuous excessive signaling. HCS is characterized by progressive bone destruction, has complex wide-range clinical manifestations, and significantly impacts the patient’s quality of life. However, no effective treatment has been established for HCS to date. There are genetic variants of NOTCH2 that have been reported in the ClinVar database of the U.S. National Institutes of Health. In total, 26 mutant variants were detected based on the American College of Medical Genetics and Genomics (ACMC). To date, there has been no comprehensive compilation of HCS mutations. In this review, we provide the most comprehensive list possible of HCS variants, nucleotide changes, amino acid definitions, and molecular consequences reported to date, following the ACMC guidelines.

Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy: A Case Report

A case report of an 11-year-old boy with a de novo variant in NOTCH2 and clinical features characteristic of Hajdu-Cheney syndrome is reported, with acroosteolysis of the distal phalanges of the feet and hands, generalized osteoporosis, musculoskeletal and craniofacial alterations, short stature, bowing of long bones, vertebral anomalies, genu recurvatum, hypertrichosis, joint and skin hyperlaxity, atopic dermatitis, megalocorneas, micrognathia and frequent respiratory infections, among others. Treatment is with bisphosphonates in the framework of bone density improvement and with focal vibration therapy for rehabilitation of the musculoskeletal system and gait improvement. The three generalities of this pathology—phenotypic variability, degenerative character and the presence of generalized osteoporosis and acroosteolysis of the distal phalanges—are seen in this case, whose diagnostic confirmation was made by genetic study.

Surgical management of high-grade lumbar spondylolisthesis associated with Hajdu-Cheney syndrome: illustrative case.

Hajdu-Cheney syndrome (HCS) is a rare connective tissue disorder characterized by severe bone demineralization. In the spine, it is associated with the early onset of severe osteoporosis and can cause spondylolisthesis. Spinal instrumentation in the setting of severe osteoporosis is challenging because of poor resistance of vertebrae to biomechanical stress. A 59-year-old woman with known idiopathic HCS presented with a grade 4 L5-S1 spondylolisthesis and right L5 pedicle fracture associated with a left L5 pars fracture, causing a progressive L5 radiculopathy that was worse on the left side than the right side and bilateral foot drop. The authors performed decompressive lumbar surgery, which included a complete L5 laminectomy and resection of the left L5 pedicle. This was followed by multilevel lumbosacral instrumentation using cement-augmented fenestrated pedicle screws as well as transdiscal sacral screws and bilateral alar-iliac fixation. Postoperatively, the radicular pain resolved, and the left foot drop partially recovered. Stabilization of high-grade spondylolisthesis in the setting of bone demineralization disorders is challenging. The use of different instrumentation techniques is important because it increases biomechanical stability of the overall instrumentation construct.

Nursing Care Plan for Patients with Hajdu-Cheney Syndrome.

Hajdu–Cheney syndrome is a rare genetic disease. Its main features include phenotypic variability, age-dependent progression and the presence of acroosteolysis of the distal phalanges and generalized osteoporosis, which have significant disabling potential. Currently, there is no effective curative treatment, so nursing care is essential to ensure the maintenance of the quality of life of these patients. The main objective of this study was to establish a specific standardized nursing care plan using the NANDA–NIC–NOC taxonomy. The application of a care plan as such would improve the quality of life of patients affected by this rare disease, will contribute to increasing healthcare professionals’ knowledge on this matter and will support future studies on this disease.

Premature Loss of Deciduous Teeth as a Symptom of Systemic Disease: A Narrative Literature Review.

Background: Premature loss of primary teeth can occur as a consequence of dental trauma, neonatal tooth extraction, early childhood caries, or periodontal problems, or it can be a manifestation of systemic disease. This review aims to present systemic disorders that can lead to premature loss of deciduous teeth in children and to provide a comprehensive resource for clinical practice for both physicians and dentists. Methods: This study is a narrative review of original studies and case reports published in English and Polish between 1957 and 2021 that was conducted by searching electronic scientific resources: PubMed, Google Scholar, Web of Science, and Science Direct. The schema of the qualification process is represented by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). In total, 196 articles were identified; after provisional assessment of the titles and abstracts by two reviewers, 46 were found to be relevant to the topic, including 1 review, 16 original papers, and 27 case reports regarding systemic disease resulting in premature tooth loss. Results: In this study, 16 systemic diseases were linked to premature primary tooth loss in children: Papillon–Lefèvre syndrome, mucocutaneous dyskeratosis, Coffin–Lowry syndrome, congenital adrenal hyperplasia, Langerhans cell histiocytosis, cherubism, hypophosphatasia, acatalasia, Chediak–Higashi syndrome, cyclic neutropenia, erythromelalgia, Down syndrome, Hajdu–Cheney syndrome, short bowel syndrome, leukocyte adhesion deficiency type 1 (LAD-1), and Wiedemann–Steiner syndrome (WSS).

Craniospinal Surgery in Hajdu-Cheney Syndrome: A Review of Case Reports

Hajdu-Cheney syndrome (HCS) is a rare metabolic bone disorder that results in severe osteoporosis and various skeletal deformities. Craniospinal pathology is commonly associated with it, but surgical management is challenging due to the distorted anatomy, reduced bone strength, and fusion failure due to osteolysis. Hence, the surgical difficulty in these patients requires careful consideration. In this study, we systematically review all published operative cases and complications to provide a comprehensive review pertaining to the spine and/or cranium in patients with HCS. By highlighting these cases and their associated complications, we aim to prepare practitioners who treat this difficult pathology.

Hairy and enhancer of split 1 is a primary effector of NOTCH2 signaling and induces osteoclast differentiation and function

Notch2tm1.1Ecan mice, which harbor a mutation replicating that found in Hajdu–Cheney syndrome, exhibit marked osteopenia because of increased osteoclast number and bone resorption. Hairy and enhancer of split 1 (HES1) is a Notch target gene and a transcriptional modulator that determines osteoclast cell fate decisions. Transcript levels of Hes1 increase in Notch2tm1.1Ecan bone marrow–derived macrophages (BMMs) as they mature into osteoclasts, suggesting a role in osteoclastogenesis. To determine whether HES1 is responsible for the phenotype of Notch2tm1.1Ecan mice and the skeletal manifestations of Hajdu–Cheney syndrome, Hes1 was inactivated in Ctsk-expressing cells from Notch2tm1.1Ecan mice. Ctsk encodes the protease cathepsin K, which is expressed preferentially by osteoclasts. We found that the osteopenia of Notch2tm1.1Ecan mice was ameliorated, and the enhanced osteoclastogenesis was reversed in the context of the Hes1 inactivation. Microcomputed tomography revealed that the downregulation of Hes1 in Ctsk-expressing cells led to increased bone volume/total volume in female mice. In addition, cultures of BMMs from CtskCre/WT;Hes1Δ/Δ mice displayed a decrease in osteoclast number and size and decreased bone-resorbing capacity. Moreover, activation of HES1 in Ctsk-expressing cells led to osteopenia and enhanced osteoclast number, size, and bone resorptive capacity in BMM cultures. Osteoclast phenotypes and RNA-Seq of cells in which HES1 was activated revealed that HES1 modulates cell–cell fusion and bone-resorbing capacity by supporting sealing zone formation. In conclusion, we demonstrate that HES1 is mechanistically relevant to the skeletal manifestation of Notch2tm1.1Ecan mice and is a novel determinant of osteoclast differentiation and function.

Acro-osteolysis in Hajdu Cheney syndrome: A case report with review of literature

Objectives: We present a case report and review the literature on Hajdu Cheney syndrome (HCS), an extremely rare connective tissue disorder with <100 cases reported in the last 72 years. We have emphasized on the patterns of acro-osteolysis (acrosteolysis) in the literature review to conclude if the syndrome follows any particular pattern like in our case. Material and Methods: All major databases were searched for all cases of HCS. One hundred and eighty-eight hand radiographs were analyzed and detailed analysis of all digits was carried out with emphasis on the pattern of acrosteolysis. Results: Acrosteolysis may not be a mandatory association in HCS as 18.8% did not have acrosteolysis at all. The first finger to be involved in 90/96 (93.7%) of the cases was the index finger, followed by the middle finger and then the thumb. The 4th digit (ring finger) was involved in only 11/96 (11.4%) of the cases, of which 9/11 (81.8%) were above the age of 25. Incidence of acrosteolysis of the 4th digit when in comparison to all other finger has a P < 0.05 and a P < 0.001 with the index finger. Newborn with HCS evaluated for acrosteolysis at birth was negative. Conclusion: There was statistical evidence to conclude that in a majority of the cases the 4th digit was involved the least. A rough timeline of the onset and progression of acrosteolysis was made. An attempt was made to shed light on the possible lesser-known manifestations of the syndrome such as retroflexed odontoid, Arnold Chiari I, middle phalanx osteolysis, and first carpometacarpal joint osteolysis. As very little is known about the disease and awareness about it is pertinent for early management and to differentiate it from other less-lethal causes of acrosteolysis.

Association of Hadju Cheney syndrome with adrenal insufficiency in a diabetic patient: A rare association

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Hajdu-Cheney Syndrome: A Report on Successful Halting of Acro-osteolysis.

The phenomenon of acro-osteolysis often intrigues clinicians and patients alike, as it causes bone resorption. One such condition is Hajdu-Cheney syndrome. We report our experience in identifying and halting the active bone resorption in a patient and his father with 2-year follow-up results. Management included identification of the NOTCH2 mutation and treatment with antiresorptive measures. In addition, genetic counseling and antenatal counseling are recommended to explain the risk of inheritance.

Skeletal characterization in a patient with Hajdu-Cheney syndrome undergoing total knee arthroplasty

Hajdu-Cheney syndrome (HCS) is a rare genetic connective tissue disorder caused by gain-of-function mutations in the NOTCH2 gene. We report a 38-year-old male HCS patient with a history of multiple pathologic fractures, poor bone stock under intermittent antiresorptive therapy, and secondary osteoarthritis (OA) of the knee, in which we successfully performed total knee arthroplasty (TKA). Next to a detailed skeletal assessment including laboratory bone metabolism markers, dual energy X-ray absorptiometry (DXA), and high-resolution peripheral quantitative computed tomography (HR-pQCT), undecalcified histologic and histomorphometric analysis was performed on intraoperatively obtained tibial cut sections. This multiscale assessment revealed a severe, combined trabecular-cortical microarchitectural deterioration, increased bone turnover indices, and advanced cartilage degeneration, thus demonstrating the crucial role of Notch2 in skeletal and cartilage homeostasis, which is in line with the findings of previous mouse models.

Correction to: A mutation in NOTCH2 gene first associated with Hajdu–Cheney syndrome in a Greek family: diversity in phenotype and response to treatment

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hajdu-Cheney Syndrome: A Systematic Review of the Literature.

Hajdu–Cheney syndrome (HCS) is a rare genetic disease that causes acroosteolysis and generalized osteoporosis, accompanied by a series of developmental skeletal disorders and multiple clinical and radiological manifestations. It has an autosomal dominant inheritance, although there are several sporadic non-hereditary cases. The gene that has been associated with Hajdu-Cheney syndrome is NOTCH2. The described phenotype and clinical signs and symptoms are many, varied, and evolve over time. As few as 50 cases of this disease, for which there is currently no curative treatment, have been reported to date. The main objective of this systematic review was to evaluate the results obtained in research regarding Hajdu–Cheney Syndrome. The findings are reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and were registered on the web PROSPERO under the registration number CRD42020164377. A bibliographic search was carried out using the online databases Orphanet, PubMed, and Scielo; articles from other open access sources were also considered. Finally, 76 articles were included, and after their analysis, we have obtained a series of hypotheses as results that will support further studies on this matter.

A mutation in NOTCH2 gene first associated with Hajdu-Cheney syndrome in a Greek family: diversity in phenotype and response to treatment.

Hajdu-Cheney Syndrome (HCS) is a rare genetic autosomal dominant disorder, characterized by distinctive facial features, acroosteolysis, and severe osteoporosis. Very rarely HCS is associated with polycystic kidney disease, splenomegaly or Crohn's disease (CD). It is caused by gain-of-function mutations in NOTCH2 gene. Treatment with bisphosphonates or denosumab is reported to result in BMD increase. We report a mutation in exon 34 of NOTCH2 gene, in a Greek pedigree, with diverse phenotypes among members. The 48-year-old mother had a history of a T12 vertebral fracture, postpartum at the age of 21 and two subsequent uneventful full-term pregnancies and never received treatment. Her 29-year-old son, presented with severe osteoporosis and multiple morphological vertebral fractures. Her 21-year-old daughter had recurrent vertebral fractures starting at 10 years of age. At 17 years, she developed severe CD, resistant to treatment with biologic agents, and functional hypothalamic hypogonadism. One male pedigree died of cystic fibrosis. All subjects bore the typical facial characteristics and acroosteolysis, while none had splenomegaly or renal defects. Zoledronate infusion led to BMD increase. Mutation in c.6758 G > A (NM_008163.1), leading to a Trp2253Ter replacement. This mutation has been reported as possibly pathogenic (SCV000620308), but not in association with HCS. Bone involvement can present with diverse severity in the same pedigree, ranging from low BMD to multiple fragility fractures. Antiresorptive therapy improves BMD, but its anti-fracture efficacy remains to be shown. The presence of CD might indicate the significant role of NOTCH2 signaling in different tissues.

Notch signaling regulates Akap12 expression and primary cilia length during renal tubule morphogenesis.

Alagille syndrome patients present with loss of function mutations in either JAG1 or NOTCH2. About 40%-50% of patients have kidney abnormalities, and frequently display multicystic, dysplastic kidneys. Additionally, gain-of-function mutations in NOTCH2 are associated with cystic kidneys in Hajdu-Cheney syndrome patients. How perturbations in Notch signaling cause renal tubular cysts remains unclear. Here, we have determined that reduced Notch signaling mediated transcription by ectopic expression of dominant-negative mastermind-like (dnMaml) peptide in the nephrogenic epithelia from after the s-shaped body formation and in the developing collecting ducts results in proximal tubular and collecting duct cysts, respectively. An acute inhibition of Notch signaling for two days during kidney development is sufficient to disrupt tubule formation, and significantly increases Akap12 expression. Ectopic expression of Akap12 in renal epithelia results in abnormally long primary cilia similar to that observed in Notch-signaling-deficient epithelia. Both loss of Notch signaling and elevated Akap12 expression disrupt the ability of renal epithelial cells to form spherical structures with a single lumen when grown embedded in matrix. Interestingly, Akap12 can inhibit Notch signaling mediated transcription, which likely explains how both loss of Notch signaling and ectopic expression of Akap12 result in similar renal epithelial abnormalities. We conclude that Notch signaling regulates Akap12 expression while also ensuring normal primary cilia length and renal epithelial morphogenesis, and suggest that one aspect of diseases associated with defective Notch signaling, such as Alagille syndrome, maybe mechanistically related to ciliopathies.