A novel mutation in the matrix metallopeptidase 2 coding gene associated with intrafamilial variability of multicentric osteolysis, nodulosis, and arthropathy.

BACKGROUND: MONA, which stands for a spectrum of Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia, is an ultra rare autosomal recessive disorder caused by mutations in the matrix metallopeptidase 2 (MMP2) gene. To date only 44 individuals, carrying 22 different mutations have been reported. Here we report on two brothers with identical homozygous MMP2 gene mutations, but with clearly different phenotypes. METHODS: Genomic DNA was isolated from the affected brothers and the parents. An iliac crest bone biopsy was taken from the younger patient (index case). The level of matrix metallopeptidase 2 enzyme (MMP2) in serum and synovial fluid of the younger patient was analyzed using gelatin zymography. RESULTS: The DNA analysis revealed a homozygous c.1188C>A transversion on exon 8 of the gene. The affected brothers had the same homozygous variant and the parents were heterozygous to this variant. This variant has been reported as a compound heterozygous mutation on one individual resulting in scleroderma like skin thickening. Bone histomorphometry indicated increased trabecular bone remodeling and turnover. The zymography revealed that the level of MMP2 was completely nonmeasurable in the serum and only a minor gelatinolytic protein band of about similar molecular weight as MMP2 was found in the synovial fluid. CONCLUSIONS: Both the age at the onset and the phenotypic severity of the syndrome in these two brothers were different despite identical genotypes. The younger patients had corneal opacities leading to deteriorating visual acuity. For the first time in this disease, opacities were successfully treated with corneal transplantations.

Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders.

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.

Bone Structural Characteristics and Response to Bisphosphonate Treatment in Children With Hajdu-Cheney Syndrome.

Context: Hajdu-Cheney syndrome (HJCYS) is a rare, multisystem bone disease caused by heterozygous mutations in the NOTCH2 gene. Histomorphometric and bone ultrastructural analyses in children have not been reported and sparse evidence exists on response to bisphosphonate (BP) therapy. Objective: To investigate clinical and bone histomorphometric characteristics, bone matrix mineralization, and the response of bone geometry and density to BP therapy. Patients: Five children with HJCYS (three males) between 6.7 and 15.3 years of age. Interventions: Various BP regimens (pamidronate, zoledronic acid, and alendronate) were used for between 1 and 10 years. Main Outcome Measures: Pretreatment transiliac bone biopsy specimens and peripheral quantitative computed tomography results were available in four and three subjects, respectively. Bone histomorphometry and quantitative backscattered electron imaging were performed in two patients. The response to BP was monitored using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Results: Three patients had previously unreported NOTCH2 mutations. Histomorphometry demonstrated increased bone resorption and osteoclast numbers, increased heterogeneity of mineralization, and immature, woven bone. Trabecular bone formation was normal or elevated. Radius cortical thickness and density and lumbar spine bone mineral density were reduced at baseline and increased in response to BP therapy, which was not sustained after therapy discontinuation. Conclusions: Increased bone resorption and low cortical thickness are consistent with the effect of activating NOTCH2 mutations, which stimulate osteoclastogenesis. The increase in lumbar spine bone density and radial cortical thickness and density by BP therapy provides evidence of beneficial treatment effects in children with HJCYS.

Sustained Notch2 signaling in osteoblasts, but not in osteoclasts, is linked to osteopenia in a mouse model of Hajdu-Cheney syndrome.

Individuals with Hajdu-Cheney syndrome (HCS) present with osteoporosis, and HCS is associated with NOTCH2 mutations causing deletions of the proline-, glutamic acid-, serine-, and threonine-rich (PEST) domain that are predicted to enhance NOTCH2 stability and cause gain-of-function. Previously, we demonstrated that mice harboring Notch2 mutations analogous to those in HCS (Notch2HCS) are severely osteopenic because of enhanced bone resorption. We attributed this phenotype to osteoclastic sensitization to the receptor activator of nuclear factor-κB ligand and increased osteoblastic tumor necrosis factor superfamily member 11 (Tnfsf11) expression. Here, to determine the individual contributions of osteoclasts and osteoblasts to HCS osteopenia, we created a conditional-by-inversion (Notch2COIN ) model in which Cre recombination generates a Notch2ΔPEST allele expressing a Notch2 mutant lacking the PEST domain. Germ line Notch2COIN inversion phenocopied the Notch2HCS mutant, validating the model. To activate Notch2 in osteoclasts or osteoblasts, Notch2COIN mice were bred with mice expressing Cre from the Lyz2 or the BGLAP promoter, respectively. These crosses created experimental mice harboring a Notch2ΔPEST allele in Cre-expressing cells and control littermates expressing a wild-type Notch2 transcript. Notch2COIN inversion in Lyz2-expressing cells had no skeletal consequences and did not affect the capacity of bone marrow macrophages to form osteoclasts in vitro In contrast, Notch2COIN inversion in osteoblasts led to generalized osteopenia associated with enhanced bone resorption in the cancellous bone compartment and with suppressed endocortical mineral apposition rate. Accordingly, Notch2 activation in osteoblast-enriched cultures from Notch2COIN mice induced Tnfsf11 expression. In conclusion, introduction of the HCS mutation in osteoblasts, but not in osteoclasts, causes osteopenia.

Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations.

Notch plays an important function in skeletal homeostasis, osteoblastogenesis, and osteoclastogenesis. Hajdu-Cheney syndrome (HCS) is a rare disease associated with mutations in NOTCH2 leading to the translation of a truncated NOTCH2 stable protein. As a consequence, a gain-of-NOTCH2 function is manifested. HCS is inherited as an autosomal dominant disease although sporadic cases exist. HCS is characterized by craniofacial developmental defects, including platybasia and wormian bones, osteoporosis with fractures, and acro-osteolysis. Subjects may suffer severe neurological complications, and HCS presents with cardiovascular defects and polycystic kidneys. An experimental mouse model harboring a HCSNotch2 mutation exhibits osteopenia secondary to enhanced bone resorption suggesting this as a possible mechanism for the skeletal disease. If the same mechanisms were operational in humans, anti-resorptive therapy could correct the bone loss, but not necessarily the acro-osteolysis. In conclusion, HCS is a devastating disease associated with a gain-of-NOTCH2 function resulting in diverse clinical manifestations.

End-Stage Renal Disease in an Infant With Hajdu-Cheney Syndrome.

Hajdu-Cheney syndrome (HJCYS) is a rare, autosomal dominant, skeletal disorder caused by mutations in the NOTCH2 signaling pathway for which genetic testing has recently become available. Renal abnormalities are associated in at least 10% of cases. We present an 8-year-old Caucasian boy, born with multiple dysmorphic features consistent with HJCYS. Imaging of the urinary tract revealed bilateral cystic dysplastic kidneys with associated vesicoureteral reflux. Renal function has been impaired since birth and deteriorated progressively to end-stage renal disease (ESRD) by the age of two and a half years, when peritoneal dialysis was initiated and only recently renal transplantation was performed. Additional congenital abnormalities and multisystem involvement in HJCYS further complicated management, and he developed refractory anemia. Molecular diagnosis was confirmed by identification of a truncating mutation in exon 34 of NOTCH2. Although, renal abnormalities are considered an integral part of the HJCYS, published reports on ESRD are scarce. In those few published cases, where ESRD was recognized, renal failure developed either in late adolescence or adulthood. This is the first report of early ESRD occurring in a child. Patients with HJCYS may need chronic renal replacement therapy even in early childhood. The management of these children can be challenging given the multisystemic manifestations of HJCYS.

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption.

Notch receptors are determinants of cell fate and function and play a central role in skeletal development and bone remodeling. Hajdu Cheney syndrome, a disease characterized by osteoporosis and fractures, is associated with NOTCH2 mutations resulting in a truncated stable protein and gain-of-function. We created a mouse model reproducing the Hajdu Cheney syndrome by introducing a 6955C→T mutation in the Notch2 locus leading to a Q2319X change at the amino acid level. Notch2(Q2319X) heterozygous mutants were smaller and had shorter femurs than controls; and at 1 month of age they exhibited cancellous and cortical bone osteopenia. As the mice matured, cancellous bone volume was restored partially in male but not female mice, whereas cortical osteopenia persisted in both sexes. Cancellous bone histomorphometry revealed an increased number of osteoclasts and bone resorption, without a decrease in osteoblast number or bone formation. Osteoblast differentiation and function were not affected in Notch2(Q2319X) cells. The pre-osteoclast cell pool, osteoclast differentiation, and bone resorption in response to receptor activator of nuclear factor κB ligand in vitro were increased in Notch2(Q2319X) mutants. These effects were suppressed by the γ-secretase inhibitor LY450139. In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption.

Osteólisis multicéntrica carpotarsal / Multicentric carpotarsal osteolysis

Las osteólisis son enfermedades raras que se caracterizan por la destrucción y reabsorción ósea. De mecanismo patogénico desconocido, causan alteraciones anatómicas y dejan secuelas funcionales variables que dependen de la localización e intensidad de las lesiones. Presentamos un varón con daño neurológico previo, afecto de una osteólisis multicéntrica carpotarsal (también conocida como osteólisis multicéntrica idiopática), sin nefropatía y con patrón de herencia autosómico dominante. Aunque en principio se consideró la posibilidad de artritis idiopática juvenil, los antecedentes familiares y la ausencia de datos analíticos de inflamación llevaron a la sospecha diagnóstica de esta infrecuente forma de osteólisis, que fue confirmada con la evolución del paciente. Actualmente el niño presenta afectación carpiana bilateral y tarsiana unilateral, sin gran repercusión clínica considerando su intensa afección neurológica. El padre del niño, también afecto de osteólisis multicéntrica carpotarsal y carente de huesos carpianos, conserva buenas capacidades funcionales que le permiten una normal actividad laboral como conductor. Resulta interesante conocer esta rara enfermedad con varios objetivos: evitar diagnósticos inadecuados del tipo artritis idiopática juvenil, establecer con la familia planes de manejo y, finalmente, brindar asesoría genética a las familias afectadas (AU)

Osteolysis are rare diseases characterized by destruction and subsequent bone resorption. Although osteolysis have an unknown pathogenetic basis, they result in anatomic and functional disabilities related to the place and severity of the affected bones. A boy with previous neurologic damage is presented, affected by a multicentric carpotarsal osteolysis (also named idiopathic multicentric osteolysis) without nephropathy and with dominant transmission. Although at first the boy was believed to be affected by idiopathic chronic arthritis, the family history and the absence of inflammation biological markers aroused suspicions about osteolysis. The ulterior studies and the patient evolution confirmed this diagnosis. Nowadays, the boy is affected by carpal bilateral and tarsal unilateral bone lesions of little clinical significance considering his severe neurologic damage. His father, despite being affected by idiopathic multicentric osteolysis which caused the absence of carpal bones, shows excellent functional abilities working as a driver. This rare disease must be well-known in order to avoid wrong diagnoses develop adequate control strategies and offer genetic counseling to the affected families (AU)

The identification of MAFB mutations in eight patients with multicentric carpo-tarsal osteolysis supports genetic homogeneity but clinical variability.

Multicentric carpo-tarsal osteolysis (MCTO) with or without nephropathy is a rare osteolysis disorder beginning in early childhood and involving mainly carpal and tarsal bones. Renal disease appears later in life in the majority of cases and evolves quickly to end stage renal failure. Autosomal dominant (AD) inheritance has been demonstrated, with a high frequency of sporadic cases. Recently, mutations in a highly conserved region of the MAFB gene (v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B) have been identified in MCTO patients by exome sequencing. MafB, known as a regulator of various developmental processes, is essential for osteoclastogenesis and renal development. We report here the molecular screening of MAFB in eight MCTO patients from six families. We identified MAFB mutations in all, including three novel missense mutations clustering within the hot spot mutation region. Among the eight patients, six only presented renal disease. Our report confirms the genetic homogeneity of MCTO and provides data underlying the clinical variability of this disorder.

A case report of anesthesia for a child with Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome is an extremely rare disorder characterized by progressive skeletal acro-osteolysis, which results in extremity fractures and scoliosis often requiring surgical treatment from childhood. A unique facial structure and deformity of the cervical spine is associated with a difficult airway. We report here a 10-year-old girl with Hajdu-Cheney syndrome who developed progressive basilar impression and medullary compression for which foramen magnum decompression was performed. After slow induction of anesthesia, we were able to perform fiberoptic orotracheal intubation via a VBM bronchoscope airway. This case report contributes to the accumulation of knowledge about anesthesia for this rare syndrome.

Integrated anti-remodeling and anabolic therapy for the osteoporosis of Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome (MIM 102500) is a rare skeletal dysplasia marked by severe generalized osteoporosis and focal bone loss (acro-osteolysis). Osteoporosis treatment outcome has been reported only once previously. Reported herein is the biochemical and densitometric response to integrated anti-remodeling and anabolic therapy in a woman with Hajdu-Cheney syndrome. Results suggest dissociation of bone formation from bone resorption resulting in dramatic increases in bone mineral density without clinical evidence of activated osteoporosis.