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Metabolism: Clinical and Experimental Mar 2018There are four Notch transmembrane receptors that determine the fate and function of cells. Notch is activated following its interactions with ligands of the Jagged and... (Review)
Review
BACKGROUND
There are four Notch transmembrane receptors that determine the fate and function of cells. Notch is activated following its interactions with ligands of the Jagged and Delta-like families that lead to the cleavage and release of the Notch intracellular domain (NICD); this translocates to the nucleus to induce the transcription of Notch target genes. Genetic disorders of loss- and gain-of-NOTCH function present with severe clinical manifestations.
BASIC PROCEDURES
In this article, current knowledge of Hajdu Cheney Syndrome (HCS) and related disorders is reviewed.
MAIN FINDINGS
HCS is a rare genetic disorder characterized by acroosteolysis, fractures, short stature, neurological manifestations, craniofacial developmental abnormalities, cardiovascular defects and polycystic kidneys. HCS is associated with NOTCH2 gain-of-function mutations. An experimental mouse model of the disease revealed that the bone loss is secondary to increased osteoclastogenesis and bone resorption due to enhanced expression of receptor activator of nuclear factor kappa B ligand (Rankl). This would suggest that inhibitors of bone resorption might prove to be beneficial in the treatment of the bone loss associated with HCS. Notch2 is a determinant of B-cell allocation in the marginal zone of the spleen and "somatic" mutations analogous to those found in HCS are associated with B-cell lymphomas of the marginal zone, but there are no reports of lymphomas associated with HCS.
CONCLUSION
In conclusion, HCS is a serious genetic disorder associated with NOTCH2 mutations. New experimental models have offered insight on mechanisms responsible for the manifestations of HCS.
Topics: Animals; Hajdu-Cheney Syndrome; Humans; Receptor, Notch2; Receptors, Notch; Signal Transduction
PubMed: 28941602
DOI: 10.1016/j.metabol.2017.08.002 -
American Journal of Medical Genetics.... Jan 2023Hajdu-Cheney syndrome is an ultra-rare autosomal dominant disorder caused by a heterozygous variant in NOTCH2 gene. Characteristic features include osteolysis, distinct...
Hajdu-Cheney syndrome is an ultra-rare autosomal dominant disorder caused by a heterozygous variant in NOTCH2 gene. Characteristic features include osteolysis, distinct facial appearance, skull deformity, joint laxity, osteoporosis, and short stature. Associated abnormalities are congenital heart disease, congenital defects of the kidney, and neurological problems. Here, we present the first reported case of an African child with a variant in NOTCH2 gene and features of Hajdu-Cheney syndrome in whom we detected a congenital heart defect that has not been previously reported in association with the syndrome. To appropriately characterize this disease and document correct proportion of cardiovascular malformation associations, echocardiography is recommended for all cases of Hajdu Cheney syndrome.
Topics: Child; Humans; Hajdu-Cheney Syndrome; Receptor, Notch2; Osteoporosis; Heterozygote; Cardiovascular Abnormalities
PubMed: 36301051
DOI: 10.1002/ajmg.a.63013 -
Heliyon Apr 2023Frank-Ter Haar syndrome (FTHS), Winchester syndrome (WS), Torg syndrome (TS) and Multicentric Osteolysis Nodulosis and Arthropathy (MONA) are progressive skeletal...
Frank-Ter Haar syndrome (FTHS), Winchester syndrome (WS), Torg syndrome (TS) and Multicentric Osteolysis Nodulosis and Arthropathy (MONA) are progressive skeletal dysplasia consisting of acro-osteolysis. Mutation in Matrix Metalloproteinase 2 (MMP2), Matrix Metalloproteinase 14 (MMP14) and SH3PXD2B are known genetic defects in these disorders. We hereby report a 5 years and 9 months old girl suffering from progressive limb deformity. She is the first child of a relative couple, who was referred to metabolic disorders' clinic due to poor growth and bone pain. On physical examination, minor facial dysmorphism, hypertrichosis, severe hand deformity with limitation in range of motion in carpal, metacarpal and phalangeal joints, hallux valgus deformity of feet, soft tissue hypertrophy and nodule formation in palmoplantar areas were detected. Her past history indicated a cardiac defect resulting in open heart surgery at 8 months of age. Genetic study revealed a new homozygote nonsense mutation in MMP2 gene explaining her clinical manifestations. We recommend careful evaluation and follow-up of patients with congenital heart disease, as it may be the first presentation of a genetic multisystem disorder. Early differentiation of the disease from other skeletal dysplasia and rheumatologic disorders could prevent unnecessary management.
PubMed: 37025869
DOI: 10.1016/j.heliyon.2023.e14865 -
BMJ Case Reports Mar 2019
Topics: Acro-Osteolysis; Diagnosis, Differential; Female; Fingers; Humans; Middle Aged; Occupational Diseases
PubMed: 30914415
DOI: 10.1136/bcr-2018-229054 -
Innate Immunity 2013Numerous studies provide detailed insight into the triggering and amplification mechanisms of the inflammatory response associated with prosthetic wear particles,... (Review)
Review
Numerous studies provide detailed insight into the triggering and amplification mechanisms of the inflammatory response associated with prosthetic wear particles, promoting final dominance of bone resorption over bone formation in multiple bone multicellular units around an implant. In fact, inflammation is a highly regulated process tightly linked to simultaneous stimulation of tissue protective and regenerative mechanisms in order to prevent collateral damage of periprosthetic tissues. A variety of cytokines, chemokines, hormones and specific cell populations, including macrophages, dendritic and stem cells, attempt to balance tissue architecture and minimize inflammation. Based on this fact, we postulate that the local tissue homeostatic mechanisms more effectively regulate the pro-inflammatory/pro-osteolytic cells/pathways in patients with none/mild periprosthetic osteolysis (PPOL) than in patients with severe PPOL. In this line of thinking, 'particle disease theory' can be understood, at least partially, in terms of the failure of local tissue homeostatic mechanisms. As a result, we envision focusing current research on homeostatic mechanisms in addition to traditional efforts to elucidate details of pro-inflammatory/pro-osteolytic pathways. We believe this approach could open new avenues for research and potential therapeutic strategies.
Topics: Animals; Arthroplasty, Replacement, Hip; Cellular Microenvironment; Hajdu-Cheney Syndrome; Humans; Inflammation; Inflammation Mediators; Joint Prosthesis; Osteogenesis; Prosthesis Failure
PubMed: 22751380
DOI: 10.1177/1753425912451779 -
Acta Orthopaedica Et Traumatologica... Jan 2017Acro-osteolysis is a rare disease characterized by bone resorption involving the distal phalanges of the hand. We present a unique case of progressive acro-osteolysis of...
Acro-osteolysis is a rare disease characterized by bone resorption involving the distal phalanges of the hand. We present a unique case of progressive acro-osteolysis of the distal phalanges and articular calcifications in a patient with scleroderma. The calcified deposit in a proximal interphalangeal joint was excised under local anesthesia. The medical treatment was arranged under the supervision of a rheumatologist.
Topics: Acro-Osteolysis; Antirheumatic Agents; Calcinosis; Female; Finger Joint; Finger Phalanges; Glucocorticoids; Humans; Methotrexate; Middle Aged; Orthopedic Procedures; Radiography; Scleroderma, Limited; Treatment Outcome; Wrist Joint
PubMed: 28017514
DOI: 10.1016/j.aott.2015.03.003 -
Actas Dermo-sifiliograficas May 2012Leprosy, a disease caused by Mycobacterium leprae, primarily affects the skin and nerves, but the nails are also involved in as many as 3 out of 4 patients .The factors... (Review)
Review
Leprosy, a disease caused by Mycobacterium leprae, primarily affects the skin and nerves, but the nails are also involved in as many as 3 out of 4 patients .The factors that trigger nail changes in leprosy are numerous and include repeated trauma, neuropathy, vascular impairment, infections, lepra reactions, and the drugs used to manage the disease. The changes most often reported include subungual hematomas, onycholysis, onychauxis, onychogryphosis, pterygium unguis, and onychoheterotopia, most of which can be attributed to nerve damage and trauma. Furthermore, the acro-osteolysis that occurs in the advanced stages of the disease may present with brachyonychia, racquet nails, or even anonychia. Infections of the nail bed leading to paronychia and onychomycosis should also be taken into account in leprosy. Other typical changes include longitudinal striae, pitting, macrolunula, Terry nails, leukonychia, hapalonychia, and Beau lines. In this review, we describe the principal nail changes associated with leprosy. These changes, which are highly varied and diverse in origin, are in fact a reflection of the significant morbidity caused by M. leprae infection.
Topics: Humans; Leprosy; Nail Diseases
PubMed: 22056258
DOI: 10.1016/j.ad.2011.07.011 -
Prague Medical Report 2018Hajdu-Cheney syndrome (HCS) is a rare multi-system disease with autosomal dominant inheritance and skeletal involvement, resulting mostly in craniofacial dysmorphy with...
Hajdu-Cheney syndrome (HCS) is a rare multi-system disease with autosomal dominant inheritance and skeletal involvement, resulting mostly in craniofacial dysmorphy with mid-face hypoplasia, dental anomalies, short stature, scoliosis, shortening of the digits and nail beds, acro-osteolysis and osteoporosis. We report the progression of clinical and radiographic findings in five patients with Hajdu-Cheney syndrome from two families. A custom capture array designed to capture exons and adjacent intron sequences of 230 selected genes were used for molecular analyses, and the pathogenic variants identified were confirmed by PCR and Sanger sequencing. In both families we observed age-dependent changes in the disease, with a progression of pain in older patients, a shortening of digits and nail beds on both the hands and feet, kyphoscoliosis and the persistence of Wormian bones in lambdoid sutures. Molecular analyses performed in two patients revealed that they are heterozygotes for a c.6255T>A (p.Cys2085*) variant in the NOTCH2 gene, resulting in a premature stop-codon. Bone mineral density (Z-score < -2) did not improved in a girl treated with calcium and vitamin D supplementation during childhood and bisphosphonate during adolescence. Hajdu-Cheney syndrome is a slowly progressive disease with a frequently unfavourable prognosis in elderly patients, especially for the development of dental anomalies, osteoporosis and the progression of skeletal complications requiring orthopedic surgeries.
Topics: Adolescent; Aged; Bone Density; Child; Disease Progression; Female; Hajdu-Cheney Syndrome; Humans; Osteoporosis; Prognosis
PubMed: 30779700
DOI: 10.14712/23362936.2019.3 -
Joint Bone Spine Feb 2024To assist the development of future treatments in systemic sclerosis (SSc), the development of reliable outcome measures is pivotal. We aimed to evaluate the use of...
OBJECTIVE
To assist the development of future treatments in systemic sclerosis (SSc), the development of reliable outcome measures is pivotal. We aimed to evaluate the use of high-resolution peripheral quantitative CT (HR-pQCT) for visualization and gradation of acro-osteolysis (AO) and calcinosis compared to conventional hand radiographs (CR) in patients with SSc.
METHODS
HR-pQCT scans of the 2nd to 4th fingers, CR, nail fold capillaroscopy, and a clinical examination were conducted. Images were reviewed for the presence and degree of AO and calcinosis according to semiquantitative grading scales.
RESULTS
Forty patients were included. Fourteen had AO according to CR, whereas HR-pQCT revealed AO in 18 patients. The sensitivity and specificity of classifying patients as having AO by HR-pQCT when CR was used as reference were 93% (95% CI: 66-99%) and 80% (95% CI: 59-93%), respectively. By CR and with HR-pQCT as reference, the sensitivity and specificity were 72% (95% CI: 47-90%) and 95% (95% CI: 76-99%). Patients with AO had more or larger calcifications than patients without AO according to the proposed HR-pQCT grading system, with a median grade of 2 (IQR: 1-3) versus 0 (IQR: 0-1) (P<0.01). Grade 3 changes were observed exclusively in patients with AO (n=6/14, 42.9%). Assessment of AO and calcinosis by HR-pQCT demonstrated moderate to excellent test-retest reliability.
CONCLUSION
HR-pQCT allowed precise and reliable classification and grading of acro-osteolysis and acral calcinosis. The modality could prove helpful for detecting and monitoring these lesions as well as facilitating early diagnosis and guide treatment of these patients.
PubMed: 38309517
DOI: 10.1016/j.jbspin.2024.105699 -
Journal of Radiology Case Reports Sep 2014Hajdu-Cheney syndrome is a very rare connective tissue disorder. It has autosomal dominant inheritance or may occur due to spontaneous de novo mutation. Recent research... (Review)
Review
Hajdu-Cheney syndrome is a very rare connective tissue disorder. It has autosomal dominant inheritance or may occur due to spontaneous de novo mutation. Recent research suggests that it is caused by heterozygous mutation of terminal exon of NOTCH 2. Most characteristic findings include transverse band of acro-osteolysis involving the phalanges of both hands and feet and osteoporosis and deformities involving skull, mandible, spine and other bones. Patient may progressively develop kyphoscoliosis, basilar invagination, and bone fractures due to bone softening. Treatment is symptomatic. In this case report we present clinical and radiological features of a 43-year-old female patient who presented with features of Hajdu-Cheney syndrome.
Topics: Adult; Diagnosis, Differential; Female; Foot Bones; Hajdu-Cheney Syndrome; Hand Bones; Humans; Osteolysis; Osteoporosis; Prognosis; Radiography; Skull
PubMed: 25426244
DOI: 10.3941/jrcr.v8i9.1833