Multicentric Carpotarsal Osteolysis Syndrome Research Articles

Clinical and genetic characteristics of multicentric carpotarsal osteolysis syndrome

BACKGROUND: Multicentric carpotarsal osteolysis (MCTO) syndrome is a rare autosomal dominant disease of skeletal dysplasias caused by heterozygous missense variants in MAFB. Clinical manifestations of the disease are characterized by pain, swelling, and hand and foot deformities as a result of progressive osteolysis of the carpal and tarsal bones. Kidney insufficiency also developed in some patients.
 CLINICAL CASES: Three Russian patients aged 2–39 years with MCTO syndrome caused by pathogenic variants c.176CT, c.184AG, c.203CT in MAFB are presented. All cases were sporadic. Two of our patients with MCTO were typically observed for several years with a diagnosis of juvenile idiopathic arthritis. All patients underwent phenotypic analysis using standard methods, radiography of the upper and lower extremities, ultrasonography of the kidneys, blood and urine tests to assess renal function, and molecular tests to clarify the diagnosis. Molecular genetic analysis included direct automatic Sanger sequencing of MAFB (NM_005461.5).
 DISCUSSION: The clinical manifestations of the disease in the patients included deformities and shortening of the hands and feet and typical signs of osteolysis of the metacarpal and metatarsal bones on radiographs. One of the examined patients had proteinuria in early childhood. Considering the rarity of MCTO syndrome, a description of the clinical and radiological characteristics of newly identified cases of the disease will help optimize its diagnosis and multidisciplinary observation of patients and improve the quality of medical and genetic counseling for affected families.
 CONCLUSIONS: The first clinical manifestations of MCTO syndrome are characterized by significant similarities with those of juvenile arthritis. For their differential diagnosis, a thorough radiographic analysis of the hands and feet for osteolysis is necessary. Early diagnosis of MCTO syndrome is essential because in recent years intensive research aimed at developing therapy for diseases caused by dysfunction of the RANK/RANKL signaling pathway, in which the protein product of MAFB functions.

Multicentric carpotarsal osteolysis syndrome with variants of MAFB gene: a case report and literature review

BackgroundMulticentric carpotarsal osteolysis (MCTO) is a rare genetic disorder characterized by the progressive loss of bone in the hands, feet, and other skeletal structures. It presents with symptoms that may resemble those of juvenile idiopathic arthritis, making diagnosis challenging for clinicians. The identification of MAF BZIP Transcription Factor B (MAFB) mutations as significant contributors to MCTO represents a major breakthrough in our understanding of the pathogenesis of this rare skeletal disorder.Case presentationOur objective was to present the phenotype, treatment, and outcome of a patient with a variant of MAFB-induced MCTO to broaden the range of clinical features associated with MCTO and share our clinical experience for improved diagnosis and treatment. In our case, early MRI examination of the bones and whole exome sequencing enabled an early and accurate MCTO diagnosis, and timely Denosumab administration resulted in no deterioration.ConclusionThis suggests that MRI examination and whole exome sequencing should be considered when MCTO is suspected, and Denosumab might be an option in the treatment of MCTO.

A report of 5 Indian families with multicentric carpotarsal osteolysis syndrome

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare autosomal dominant skeletal dysplasia characterised by swelling and restriction of movement in the wrist and ankle joints, as well as osteolysis of the carpal and tarsal bones, that can be misdiagnosed as juvenile idiopathic arthritis. We describe five Indian families with heterozygous nonrecurrent missense pathogenic variants in exon 1 of MAF bZIP transcription factor B (MAFB).

The Tomographic Study and the Phenotype of Wormian Bones.

We describe patients who were recognized via conventional radiographs of the skull as manifesting wormian bones. Wormian bones are not a specific diagnostic entity and can be seen in variable forms of syndromic disorders. Seven children and three adults (of 10-28 years) were seen and diagnosed in our departments. The principal complaints for the pediatric and adult group were: ligamentous hyperlaxity, a history of delayed walking and occasional fractures, which later in life started to manifest a constellation of neurological symptoms such as nystagmus, persistent headache, and apnea. Conventional radiographs were the first traditional tools used to recognize wormian bones. We performed 3D reconstruction CT scans to further understand the precise etiology and the nature of these wormian bones and attempted to connect them with a broad spectrum of unpleasant clinical presentations. Our group of patients was consistent with the phenotypic and genotypic diagnoses of osteogenesis imperfecta type I and type IV as well as patients with multicentric carpotarsal osteolysis syndrome. Three-dimensional reconstruction CT scan of the skulls confirmed that these worm-like phenotypes are in fact stemmed from the progressive softening of the sutures. The overall phenotype of the melted sutures is akin to overly stretched pastry. The most concerning sutures in this pathological process are the lambdoid. The overstretching of the lambdoid sutures was responsible for the development of sub-clinical basilar impression/invagination. Patients with certain forms of skeletal dysplasia such as osteogenesis imperfecta type I and IV manifested the heterozygous mutation of COL1A1/COLA2, shown as typical overstretching of the sutures. Similarly, patients with multicentric carpotarsal osteolysis syndrome with a heterozygous missense mutation of MAFB also manifested the phenotype of overly stretched pastry along the skull sutures. What we encountered via 3D reconstruction CT scan in our group of patients was entirely different than the traditional description that can be found in all relevant literature of the last decades. The worm-like phenomenon is in fact a pathological sequel occurring as a result of a progressive softening of the sutures, which results in the overstretching of the lambdoid sutures, a pathological process roughly similar to an overly stretched soft pastry. This softening is totally connected to the weight of the cerebrum (the occipital lobe of the cerebrum). The lambdoid sutures represent the weight-bearing zone of the skull. When these joints are loose and soft, they adversely alter the anatomical structures of the skull and lead to a highly hazardous derangement of the craniocervical junction. The latter causes the pathological upward invasion of the dens into the brain stem, leading to the development of morbid/mortal basilar impression/invagination.

Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of MAFB Gene and Literature Review.

Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment.

Monogenic disorders as mimics of juvenile idiopathic arthritis

BackgroundJuvenile idiopathic arthritis is the most common chronic rheumatic disease of childhood. The term JIA encompasses a heterogenous group of diseases. The variability in phenotype of patients affected by the disease means it is not uncommon for mimics of JIA to be misdiagnosed.Case presentationWe present four cases who were treated in single tertiary rheumatology centre for JIA who were subsequently diagnosed with a rare monogenic disease. All four patients shared the unifying features of presenting in early childhood and subsequently suffered with refractory disease, not amenable to usual standards of treatment. Multicentric Carpotarsal Osteolysis Syndrome and Camptodactyly-arthropathy-coxa vara-pericarditis syndrome are non-inflammatory conditions and patients typically present with arthropathy, normal inflammatory markers and atypical radiological features. Blau syndrome is an autosomal dominant condition and patients will typically have symmetrical joint involvement with a strong family history of arthritis, signifying the genetic aetiology.ConclusionsWe share our learning from these cases to add to the growing portfolio of JIA mimics and to highlight when to consider an alternative diagnosis. In cases of refractory disease and diagnostic uncertainty further imaging and genetic testing can play a crucial role in establishing the aetiology. In all of these cases the correct diagnosis was made due to careful, longitudinal clinical phenotyping and a close working relationship between rheumatology, radiology and clinical genetics; highlighting the importance of the multidisciplinary team in managing complex patients.

O18 When joints vanish

O18 When joints vanish

MON-LB72 Multicentric Carpotarsal Osteolysis Syndrome (MCTO) Has a Generalized High Turnover Bone Phenotype, High S RANKL and Responds to Denosumab

Background:MCTO is a rare disorder, caused by mutations in the MABF gene, a negative regulator of RANKL. Manifestations include carpal tarsal osteolysis and subsequent renal failure in some. Pathophysiology is poorly understood, and no effective treatment is available. Clinical case:A 5y old boy presented (2011) with R wrist pain and diffuse swelling. MRI showed pan-carpal synovitis with joint effusion. He did not respond to different anti-inflammatory medications. Plain films showed central loss of the proximal row of carpal bones. His mother was followed as an adolescent with presumed juvenile rheumatoid arthritis. Genetic testing confirmed MAFB gene mutation (c.206C>T,p.Ser69Leu) in both patient and mother.At 7y, skeletal survey showed diffuse osteopenia and mild height loss in T1. DXA (L1-4) Z-score was -0.7. Calcium phosphate metabolism indices were within reference ranges. Bone Specific Alk Pi was modestly increased and C-telopeptide markedly increased.He received Denosumab (0.5-0.75 mg/Kg) 4-monthly for two years and experienced less pain and increased daily activities with improved R wrist function. Osteolysis stabilized and none was noted in the L wrist or ankles. BMD Z-score was -0.2. A year following treatment (2016) he received two more injections of Denosumab following pain and movement restriction of R elbow, R knee and L ankle. In 2019 (13y) he fell and radiology showed, R knee osteopenia, R wrist almost complete destruction of the carpal bones. Neither ankle nor L wrist showed osteolysis. R upper limb musculature was wasted when compared with the left. Shoulder and elbow strength were preserved. BMD Z-score was -1.2. Serum calcium, 25(OH)Vitamin D and PTH were normal. Bone specific alkaline phosphatase and C-Telopeptide were elevated. Serum creatinine was normal, eGFR 150 ml/min/1.73m2, ACR (6.6 [normal< 3.5] mg/mmol)) with no hypercalciuria or nephrocalcinosis. He was normotensive.High resolution peripheral quantitative computerized tomography (HRpQCT) of the L distal radius and distal tibia compared with 7 age-matched healthy males showed reduced total volumetric BMD (186.4;198.2-306.4), normal trabecular volumetric BMD and markedly reduced cortical volumetric BMD (320.4;636.5-792.5). Cortical thickness was below the expected range. HRpQCT measurements of the R wrist and tibia were similar. sRANKL, 6 weeks after Denosumab were markedly increased in both undiluted (35.4 pmol/L) and averaged diluted samples (83.73 pmol/L) when compared with healthy age-matched children (0.21-0.41pmol/L). Conclusions/Clinical Lessons:MCTO (MAFB, mutation c.206C>T,p.Ser69Leu), has a generalized high turnover skeletal phenotype (osteoporosis), likely driven by very high levels of sRANKL. Denosumab is a targeted treatment for the osteoporosis, which may help stabilize the osteolysis.

Three cases of multicentric carpotarsal osteolysis syndrome: a case series

BackgroundMulticentric carpotarsal osteolysis syndrome (MCTO) is characterized by progressive destruction and disappearance of the carpal and tarsal bones associated with nephropathy. MCTO is caused by loss-of-function mutations in the MAF bZIP transcription factor B (MAFB) gene.Case presentationThis report describes three unrelated patients with MAFB mutations, including two male and one female patient. Osteolytic lesions in the carpal and tarsal bones were detected at 2 years, 12 years, and 14 months of age, respectively. Associated proteinuria was noted at 4 years, 12 years, and 3 months of age, respectively. Kidney biopsy was performed in two of them and revealed focal segmental glomerulosclerosis (FSGS). One patient showed progression to end-stage renal disease, that is by 1 year after the detection of proteinuria. The second patient had persistent proteinuria but maintained normal renal function. In the third patient, who did not undergo a kidney biopsy, the proteinuria disappeared spontaneously. The bony lesions worsened progressively in all three patients. Mutational study of MAFB revealed three different mutations, two novel mutations [c.183C > A (p.Ser61Arg) and c.211C > G (p.Pro71Ala)] and one known mutation [c.212C > T (p.Pro71Leu)].ConclusionWe report three cases with MCTO and two novel MAFB mutations. The renal phenotypes were different among the three patients, whereas progressive worsening of the bony lesions was common in all patients. We also confirmed FSGS to be an early renal pathologic finding in two cases. A diagnosis of MCTO should be considered in patients with progressive bone loss concentrated primarily in the carpal and tarsal bones and kidney involvement, such as proteinuria.

Trio Clinical Exome Sequencing in a Patient With Multicentric Carpotarsal Osteolysis Syndrome: First Case Report in the Balkans

Exome sequencing can interrogate thousands of genes simultaneously and it is becoming a first line diagnostic tool in genomic medicine. Herein, we applied trio clinical exome sequencing (CES) in a patient presenting with undiagnosed skeletal disorder, minor facial abnormalities, and kidney hypoplasia; her parents were asymptomatic. Testing the proband and her parents led to the identification of a de novo mutation c.188C>T (p.Pro63Leu) in the MAFB gene, which is known to cause multicentric carpotarsal osteolysis syndrome (MCTO). The c.188C>T mutation lies in a hotspot amino acid stretch within the transactivation domain of MAFB, which is a negative regulator of RANKL-induced osteoclastogenesis. MCTO is an extremely rare autosomal dominant (AD) disorder that typically arises spontaneously and causes carpotarsal osteolysis, often followed by nephropathy. To the best of our knowledge, this is the first study reporting genetically diagnosed MCTO in the Balkans.

Remarkable improvement of articular pain by biologics in a Multicentric carpotarsal osteolysis patient with a mutation of MAFB gene.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare autosomal dominant disorder, characterized by aggressive osteolysis of the carpal and tarsal bone, and progressive nephropathy leading to end-stage renal disease. Recently, heterozygous mutations in MAFB gene within a short region of the amino-terminal transcriptional activation domain had been reported to cause MCTO. Although affected patients suffer from early childhood with a clinical appearance mimicking juvenile idiopathic arthritis, most of anti-rheumatic agents are ineffective to control their pain.

Multicentric carpotarsal osteolysis syndrome is caused by only a few domain-specific mutations in MAFB, a negative regulator of RANKL-induced osteoclastogenesis.

Multicentric carpotarsal osteolysis syndrome (MCTO), an autosomal dominant disorder that often presents sporadically, features carpal-tarsal lysis frequently followed by nephropathy and renal failure. In 2012, mutations in the single-exon gene MAFB were reported in 13 probands with MCTO. MAFB is a negative regulator of RANKL-mediated osteoclastogenesis. We studied nine MCTO patients (seven sporadic patients and one affected mother and son) for MAFB mutation. We PCR-amplified and selectively sequenced the MAFB region that contains the transactivation domain in this 323 amino acid protein, where mutations were previously reported for MCTO. We found five different heterozygous missense defects among eight probands: c.176C > T, p.Pro59Leu; c.185C > T, p.Thr62Ile; c.206C > T, p.Ser69Leu (four had this defect); c.209C > T, p.Ser70Leu; and c.211C > T, p.Pro71Ser. All 5 mutations are within a 13 amino acid stretch of the transactivation domain. Four were identical to the previously reported mutations. Our unique mutation (c.185C > T, p.Thr62Ile) involved the same domain. DNA available from seven parents of the seven sporadic patients did not show their child's MAFB mutation. The affected mother and son had an identical defect. Hence, the mutations for 7/8 probands were suspected to have arisen spontaneously as there was no history of features of MCTO in either parent. Penetrance of MCTO seemed complete. Lack of nonsense or other truncating mutations suggested a dominant-negative pathogenesis. Our findings indicate that only a few transactivation domain-specific mutations within MAFB cause MCTO.

An incompletely penetrant novel MAFB (p.Ser56Phe) variant in autosomal dominant multicentric carpotarsal osteolysis syndrome

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare autosomal dominant skeletal dysplasia usually presenting in early childhood with variable phenotypic features and course. Clinical manifestations comprise aggressive osteolysis of the carpal and tarsal bones in particular, an often progressive nephropathy leading to end-stage renal disease, craniofacial anomalies and mental impairment. Recently, heterozygous missense mutations in the V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (avian) (MAFB) gene have been causally related to MCTO patients in 13 unrelated families investigated. Contrary to these findings suggesting complete penetrance, in the present study, we identified a novel missense MAFB variant present not only in the patient, but also in his unaffected mother, sister and maternal grandmother. This observation demonstrates an incomplete penetrance for some MAFB mutations, thereby suggesting that modifier genes, epigenetic mechanisms or environmental factors may modulate the MCTO phenotype. This should be considered in diagnosis and genetic counseling.