RESUMO
Hajdu-Cheney syndrome or acro-dento-osteo-dysplasia syndrome is a rare disease characterized by band osteolysis of distal phalanges and facial dysmorphia, among other manifestations. We present the case of a 45-year-old male who consulted for mechanical joint pain of both hands, facial dysmorphism, cranio-facial alterations, and digital telescoping with acroosteolysis.
Assuntos
Acro-Osteólise , Síndrome de Hajdu-Cheney , Masculino , Humanos , Pessoa de Meia-Idade , Síndrome de Hajdu-Cheney/diagnóstico , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Acro-Osteólise/diagnóstico por imagem , Acro-Osteólise/etiologia , Mãos , Doenças RarasRESUMO
Signs of skeletal dysplasias are relatively common in fetuses with abnormal ultrasound (US) findings. The diversity of congenital skeletal disorders, the possibility of late-onset severe phenotypes and overlapping syndromes can be a challenge in the way of diagnosis, even if prenatal high-throuput sequencing allows for a better diagnosis, prognosis and genetic counseling. Hajdu-Cheney spectrum pathologies are rarely described in prenatal, and the signs associated remain poorly known, and do not include specific postnatal signs as acro-osteolysis and premature osteoporosis. We hereby report a couple for whom a medical termination of pregnancy was performed because a severe polymalformative syndrome associating severely short limbs with bowed long bones, severe cardiopathy, hyperechogenic kidneys and dysmorphism. After fetopathological and radiological examinations, Exome Sequencing (ES) was performed and revealed a de novo truncating mutation in the last exon of NOTCH2, responsible for Hajdu-Cheney or Serpentine Fibula Polycystic Kidney syndromes.
Assuntos
Acro-Osteólise , Síndrome de Hajdu-Cheney , Osteoporose , Feminino , Humanos , Gravidez , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Síndrome de Hajdu-Cheney/genética , Osteoporose/genética , Acro-Osteólise/genética , Éxons , Apresentação no Trabalho de Parto , Receptor Notch2/genéticaRESUMO
CASE: 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. CONCLUSION: 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.
Assuntos
Acro-Osteólise , Reabsorção Óssea , Síndrome de Hajdu-Cheney , Acro-Osteólise/diagnóstico por imagem , Acro-Osteólise/genética , Reabsorção Óssea/complicações , Feminino , Síndrome de Hajdu-Cheney/complicações , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Síndrome de Hajdu-Cheney/genética , Humanos , Mutação , GravidezRESUMO
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.
Assuntos
Artroplastia do Joelho , Síndrome de Hajdu-Cheney , Absorciometria de Fóton , Animais , Remodelação Óssea , Osso e Ossos , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Humanos , Masculino , CamundongosRESUMO
Hajdu-Cheney syndrome is a rare condition characterized by acro-osteolysis, osteoporosis, and multiple craniofacial anomalies. The goal of treatment is to reduce the associated symptoms and to prevent osteoporotic fractures. This is a report of 3 patients across consecutive generations demonstrating variable phenotypic severity. The hand surgeon was the first medical care provider visited by the patients because of the shortening of the fingers.
Assuntos
Síndrome de Hajdu-Cheney , Deformidades da Mão , Osteoporose , Fraturas por Osteoporose , Osso e Ossos , Síndrome de Hajdu-Cheney/diagnóstico por imagem , HumanosRESUMO
INTRODUCTION: 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. OBJECTIVE: We report a mutation in exon 34 of NOTCH2 gene, in a Greek pedigree, with diverse phenotypes among members. DESCRIPTION OF THE PEDIGREE: 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. GENETIC TESTING: 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. CONCLUSIONS: 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.
Assuntos
Síndrome de Hajdu-Cheney , Osteoporose , Receptor Notch2 , Feminino , Grécia , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Síndrome de Hajdu-Cheney/tratamento farmacológico , Síndrome de Hajdu-Cheney/genética , Humanos , Masculino , Mutação , Fenótipo , Gravidez , Receptor Notch2/genéticaRESUMO
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.
Assuntos
Acro-Osteólise/genética , Síndrome de Hajdu-Cheney/genética , Mutação/genética , Osteoporose/genética , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Síndrome de Hajdu-Cheney/patologia , Humanos , Fenótipo , Radiografia , Doenças Raras , Receptor Notch2RESUMO
We present five Danish individuals with Hajdu-Cheney syndrome (HJCYS) (OMIM #102500), a rare multisystem skeletal disorder with distinctive facies, generalised osteoporosis and progressive focal bone destruction. In four cases positive genetic screening of exon 34 of NOTCH2 supported the clinical diagnosis; in one of these cases, mosaicism was demonstrated, which, to our knowledge, has not previously been reported. In one case no genetic testing was performed since the phenotype was definite, and the diagnosis in the mother was genetically confirmed. The age of the patients differs widely from ten to 57 years, allowing a natural history description of the phenotype associated with this ultra-rare condition. The evolution of the condition is most apparent in the incremental bone loss leading to osteoporosis and the acro-osteolysis, both of which contribute significantly to disease burden.
Assuntos
Síndrome de Hajdu-Cheney/diagnóstico , Síndrome de Hajdu-Cheney/genética , Receptor Notch2/genética , Acro-Osteólise/congênito , Acro-Osteólise/diagnóstico por imagem , Acro-Osteólise/genética , Acro-Osteólise/fisiopatologia , Adulto , Doenças Ósseas Metabólicas/congênito , Doenças Ósseas Metabólicas/genética , Criança , Éxons , Feminino , Síndrome de Hajdu-Cheney/sangue , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Mutação , Osteoporose/congênito , Osteoporose/diagnóstico por imagem , Osteoporose/genética , Osteoporose/fisiopatologia , Linhagem , Fenótipo , Doenças Raras/genética , Doenças Raras/fisiopatologia , Sequenciamento do ExomaRESUMO
We present a natural history of a 32-year-old man with Hajdu-Cheney syndrome (HJCYS), because of the de novo truncating mutation in the exon 34 of NOTCH2 (c.6424-6427delTCTG, p.Ser2142ArgfsX4), who has been followed up for a period of 23 years (between 9 and 32 years). During follow-up, we observed abnormalities of vision, hearing, voice, and progression of craniofacial features in the form of skeletal dysplasia with affected skull, dentition, spine, limbs, fingers, and toes. Low bone mineral density and history of fragility fractures also suggested primary osteoporosis being a clinical manifestation. According to Stengel-Rutkowski, Schimanek, and Wernheimer (1984; Human Genetics, 6, 272-295), systematic data acquisition has been used for quantitative analysis of anthropological, radiographic, and clinical features at childhood, adolescence, and young adulthood separately. A detailed phenotype description together with the results of reanalysis of 14 reports so far published on patients with HJCYS and NOTCH2 mutation showed similar phenotype evolution with age. The spectrum of observed features may improve diagnostic tools for HJCYS at different periods of the lifespan.
Assuntos
Síndrome de Hajdu-Cheney/genética , Mutação/genética , Receptor Notch2/genética , Adolescente , Adulto , Sequência de Bases , Criança , Análise Mutacional de DNA , Progressão da Doença , Seguimentos , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Humanos , Masculino , Fenótipo , Adulto JovemRESUMO
Osteoarthritis is a joint disease characterized by cartilage degradation, altered gene expression and inflammation. NOTCH1 and NOTCH2 receptors and the JAGGED1 ligand regulate chondrocyte biology; however, the contribution of Notch signaling to osteoarthritis is controversial. Hajdu Cheney Syndrome (HCS) is a rare genetic disorder affecting the skeleton and associated with NOTCH2 mutations that lead to NOTCH2 gain-of-function. A murine model of the disease (Notch2tm1.1Ecan) was used to test whether the HCS mutation increases the susceptibility to osteoarthritis. The knee of three-month-old Notch2tm1.1Ecan male mice and control sex-matched littermates was destabilized by resection of the medial meniscotibial ligament, and changes in the joint analyzed two months thereafter. Expression of Notch target genes was increased in the femoral heads of Notch2tm1.1Ecan mice, documenting Notch signal activation. Periarticular bone and cartilage structures were unaffected in Notch2tm1.1Ecan mutants subjected to sham surgery, indicating that NOTCH2 gain-of-function had no discernible impact on joint structure under basal conditions. However, destabilization of the medial meniscus increased osteophyte volume and thickened subchondral bone in Notch2tm1.1Ecan mice compared to wild type littermates. Moreover, destabilized Notch2tm1.1Ecan mutants exhibited histological signs of moderate to severe cartilage degeneration, demonstrating joint sensitization to the development of osteoarthritis. Chondrocyte cultures from Notch2tm1.1Ecan mutants expressed increased Il6 mRNA levels following exposure to JAGGED1, possibly explaining the susceptibility of Notch2tm1.1Ecan mice to osteoarthritis. In conclusion, Notch2tm1.1Ecan mutants are sensitized to the development of osteoarthritis in destabilized joints and NOTCH2 activation may play a role in the pathogenesis of the disease.
Assuntos
Síndrome de Hajdu-Cheney/genética , Síndrome de Hajdu-Cheney/metabolismo , Mutação/fisiologia , Osteoartrite/genética , Osteoartrite/metabolismo , Receptor Notch2/genética , Animais , Células Cultivadas , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoartrite/diagnóstico por imagemAssuntos
Síndrome de Hajdu-Cheney/complicações , Neoplasias Meníngeas/complicações , Meningioma/complicações , Adulto , Craniotomia/métodos , Feminino , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Síndrome de Hajdu-Cheney/cirurgia , Humanos , Imageamento por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Radiografia , Sela Túrcica/patologia , Base do Crânio/diagnóstico por imagem , Base do Crânio/patologia , Transtornos da Visão/etiologiaAssuntos
Pérnio/diagnóstico , Síndrome de Hajdu-Cheney/diagnóstico , Lúpus Eritematoso Cutâneo/diagnóstico , Sarcoidose/diagnóstico , Pérnio/diagnóstico por imagem , Pérnio/fisiopatologia , Feminino , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Síndrome de Hajdu-Cheney/fisiopatologia , Humanos , Lúpus Eritematoso Cutâneo/diagnóstico por imagem , Lúpus Eritematoso Cutâneo/fisiopatologia , Pessoa de Meia-Idade , Sarcoidose/diagnóstico por imagem , Sarcoidose/fisiopatologiaRESUMO
Acro-osteolysis is an osteolysis of the distal phalanges of the hands and feet and can affect the terminal tuft or the shaft of the distal phalanx (transverse or band acro-osteolysis). It is often associated with distal digital ischemia, digital calcinosis, or severe sensory neuropathy. Acro-osteolysis has been associated with a heterogeneous group of disorders, including occupational activities, infections, rheumatic disorders (systemic sclerosis, psoriatic arthritis), endocrinopathies, genetic disorders, and lysosomal storage disorders. Plain radiography is the gold standard for the detection of acro-osteolysis.
Assuntos
Osteólise/diagnóstico por imagem , Reumatologia/métodos , Acro-Osteólise/diagnóstico por imagem , Falanges dos Dedos da Mão/diagnóstico por imagem , Dedos/diagnóstico por imagem , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Mãos/diagnóstico por imagem , Humanos , Hiperparatireoidismo/diagnóstico por imagem , Isquemia/diagnóstico por imagem , Hanseníase/diagnóstico por imagem , Hanseníase/genética , Doenças por Armazenamento dos Lisossomos/diagnóstico por imagem , Mutação , Doenças Reumáticas/diagnóstico por imagem , Escleroderma Sistêmico/diagnóstico por imagemRESUMO
Notch receptors play a central role in skeletal development and homeostasis. Hajdu Cheney Syndrome (HCS) is a rare disease associated with mutations of NOTCH2 that lead to the translation of a truncated, presumably stable, NOTCH2 protein. As a consequence, a gain-of-NOTCH2 function is manifested. We report a subject presenting with HCS and her child, both harboring a new heterozygous mutation in Exon 34 of NOTCH2 upstream of the PEST domain. The subject presented with osteoporosis, fractures, acroosteolysis and splenomegaly but did not have neurological complications, cardiovascular defects or polycystic kidneys. Sequencing of genomic DNA revealed a previously unreported mutation at nucleotide 6667C>T leading to a Gln2223Ter protein product in the subject and her son. Preclinical studies have demonstrated that the bone loss in HCS is secondary to enhanced osteoclastogenesis and bone resorption, and the same mechanism may operate in humans. Accordingly, the case we report was treated and responded to therapy with denosumab with an increase in bone mineral density (BMD). However, acroosteolysis progressed and was not modified by denosumab. In conclusion, we report a case of HCS associated with a novel mutation in NOTCH2 and its response to denosumab on BMD.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Síndrome de Hajdu-Cheney/tratamento farmacológico , Síndrome de Hajdu-Cheney/genética , Mutação/genética , Receptor Notch2/genética , Adulto , Pré-Escolar , Feminino , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Humanos , Masculino , Resultado do TratamentoRESUMO
Acro-osteolysis is not uncommon and occurs in several conditions. Additional clinical and paraclinical findings and sometimes the performance of molecular tests can help to clarify the diagnosis. Here, we report the case of a 36-year-old woman who was referred to our department because of acute pain in the extremity of the left index finger. However, subsequent clinical examination also revealed short digits with pseudo-clubbing related to acro-osteolysis. Furthermore, severe osteoporosis, a moderate dysmorphic face, joint hypermobility, biological variables within normal ranges and her clinical history led us to consider the diagnosis of Hajdu-Cheney syndrome. Molecular analysis confirmed the diagnosis with the identification of a mutation in the NOTCH2 gene. The patient received bisphosphonate therapy, which resulted in some clinical and biological improvement 12 months later.
Assuntos
Síndrome de Hajdu-Cheney/tratamento farmacológico , Adulto , Difosfonatos/uso terapêutico , Feminino , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Síndrome de Hajdu-Cheney/genética , Deformidades da Mão/diagnóstico por imagem , Deformidades da Mão/tratamento farmacológico , Deformidades da Mão/genética , Humanos , Mutação , Radiografia , Receptor Notch2/genéticaRESUMO
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.
Assuntos
Síndrome de Hajdu-Cheney/diagnóstico por imagem , Adulto , Diagnóstico Diferencial , Feminino , Ossos do Pé/diagnóstico por imagem , Síndrome de Hajdu-Cheney/complicações , Síndrome de Hajdu-Cheney/etiologia , Ossos da Mão/diagnóstico por imagem , Humanos , Osteólise/diagnóstico por imagem , Osteoporose/etiologia , Prognóstico , Radiografia , Crânio/diagnóstico por imagemAssuntos
Síndrome de Hajdu-Cheney/diagnóstico por imagem , Receptor Notch2/genética , Sequência de Bases , Análise Mutacional de DNA , Progressão da Doença , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Síndrome de Hajdu-Cheney/genética , Síndrome de Hajdu-Cheney/patologia , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , RadiografiaRESUMO
We describe a case of Hajdu-Cheney syndrome affecting the scaphotrapeziotrapezoid joint presently being treated non-operatively. This syndrome poses the problem of non-union when surgical intervention is required.
Assuntos
Artrite/etiologia , Síndrome de Hajdu-Cheney/complicações , Articulação do Punho , Feminino , Síndrome de Hajdu-Cheney/diagnóstico por imagem , Humanos , Radiografia , Articulação do Punho/diagnóstico por imagem , Adulto JovemRESUMO
Hajdu-Cheney syndrome is a very rare, inherited, autosomal dominant, skeletal dysplasia associated with characteristic craniofacial and dental features, primary acroosteolysis of the terminal phalanges and generalized osteoporosis. A 37-year-old male patient presented with features of osteomyelitis of the right mandible and typical features of Hajdu-Cheney syndrome. The patient also had calcification of the falx cerebri and an unusual median palatal groove, which has not been reported in Hajdu-Cheney syndrome before. The clinical and radiological features, differential diagnosis, and management of the patient are presented.