Multicentric Carpal-Tarsal Osteolysis With Nephropathy Treated Successfully With Cyclosporine A: A Case Report and Literature Review

doi:10.1053/j.ajkd.2007.06.014

American Journal of Kidney Diseases

Volume 50, Issue 4, October 2007, Pages 649-654

https://doi.org/10.1053/j.ajkd.2007.06.014 Get rights and content

Multicentric carpal-tarsal osteolysis is a rare skeletal disorder characterized by osteolysis of the metacarpal, carpal, and tarsal bones and leading to crippling joint deformities. Progressive nephropathy occurs in more than half the cases. All previously reported series with renal biopsies showed only end-stage renal disease on histological examination because of the late presentation to nephrologists. Accurate diagnosis of the underlying renal pathological state therefore has not been possible. We report the first case in which early and sequential renal biopsies were performed. These show the renal lesion to be focal and segmental glomerulosclerosis, which was treated successfully with cyclosporine A.

Section snippets

Case Report

Our patient was born to unrelated parents with no family history of bone or renal disease. At the age of 2 years, his left foot was noted to be smaller than his right. Radiographs showed an apparent delay in the development of the bones of the left foot. Deformities of his wrists and ankles developed over the following years.

Radiographs at 5 years of age showed osteolysis of the carpal and tarsal bones and proximal ends of the metacarpals. The bones were diffusely osteoporotic. Comparison with

Discussion

The first case of “disappearing bone disease” was described in 1938.¹ A number of overlapping classifications for the multicentric osteolyses exist, including the International Bone Dysplasia Registry Classification.² Autosomal dominant, autosomal recessive, and sporadic forms of essential osteolyses were described. Our case is classified as sporadic MCTO with nephropathy.

One study of a recessive form of carpal-tarsal osteolysis without nephropathy localized a disease gene at 16q12-21, encoding

Acknowledgements

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Cited by (19)

A report of 5 Indian families with multicentric carpotarsal osteolysis syndrome
2023, European Journal of Medical Genetics
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).
Multicentric carpotarsal osteolysis syndrome (MCTO) with generalized high bone turnover and high serum RANKL: Response to denosumab
2021, Bone Reports
Citation Excerpt :
Proteinuria and hypertension are the most typical renal manifestations documented (Zagury and Neto, 2001). Focal segmental glomerulosclerosis (FSGS) was reported in some children when biopsy was done early in the disease course (Connor et al., 2007; Zhuang et al., 2017). A case report described non-specific changes in the glomerular basement membrane without changes on light microscopy raising the possibility of the nephropathy being a primary issue with the glomerular basement membrane, similar to Alport syndrome (Bakker et al., 1996; Bakker et al., 1996).
MCTO is a rare disorder, caused by mutations in the MafB gene, a negative regulator of receptor activator of nuclear factor-кB ligand (RANKL). Manifestations include carpal and tarsal osteolysis and renal failure. Pathophysiology is poorly understood, and no effective treatment is available.
In this case report we describe a patient with MCTO (MafB, mutation c.206C>T, p.Ser69Leu), diagnosed at the age of 5 years. At 7 years, skeletal survey showed diffuse osteopenia. BMD was mildly reduced, and bone turnover markers increased. He was treated with denosumab, a human monoclonal RANKL inhibitor for two years. Each injection was followed by a marked reduction in C-telopeptide (CTX). Following denosumab his BMD and bone symptoms improved and the osteolysis stabilized. At the age of 13 years, osteoporosis was diagnosed using high resolution peripheral quantitative computed tomography (HRpQCT) and serum RANKL was found to be markedly increased.
This initial experience suggests that the associated osteoporosis may be ameliorated by denosumab, although further study will be needed to understand the appropriate dose, frequency, and the extent of efficacy. Monitoring of CTX and bone specific alkaline phosphatase will be especially useful in this regard. Further study in other MCTO patients is also needed to determine whether high bone turnover is specific to this mutation or more common than previously appreciated. We propose a model in which osteolysis in this condition is strongly associated with the systemic osteoporosis.
A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome
2018, Kidney International
Citation Excerpt :
Moreover, MCTO can occur with or without FSGS. When FSGS coexists, renal diseases manifest with variable expressivity in approximately 50% of all cases, likely reflecting an incomplete penetrance of the disease allele.14,28 FSGS typically appears several years after the osteolysis has manifested.
Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MAFB, a leucine zipper transcription factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MAFB recognition element. Additionally, immunohistochemistry indicated reduced MAFB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MAFB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MAFB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.
Hands and feet ulcers and bone lysis in a patient with renal failure. Diagnosis and comment
2016, Piel
Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB
2012, American Journal of Human Genetics
Citation Excerpt :
Affected individuals can also have subtle craniofacial abnormalities (triangular faces, micrognathia, and exophthalmos), and many develop a progressive nephropathy leading to end-stage renal failure. Both simplex cases and families with autosomal-dominant inheritance have been reported.5–16 However, the responsible genetic defect has remained elusive.
Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.
A case report of Gorham-Stout syndrome remission
2012, Journal of Orthopaedic Science
Gorham–Stout syndrome (GSS) is a rare disorder characterized by spontaneous bone resorption with rapid progression, occasionally after minor trauma. It is also known as massive osteolysis or vanishing bone disease [1–3]. Some patients present with relatively abrupt pain and have swelling in the affected extremity, whereas others present with a history of insidious onset of pain, limitation of motion, and progressive weakness in the involved limb. The affected bone disappears completely [4]. The degree of osseous deformity in patients with GSS becomes severe. Paraplegia occurs in patients with spinal cord compression caused by vertebral involvement. Spinal involvement increases mortality to over 30%, because of complications such as spinal cord compression [5]. Thoracic cage, pulmonary, or pleural involvement leads to compromise of respiratory function and consequent death [3, 6]. Visceral complication can occur when the disease invades the surrounding tissues [7]. Recently, interferon and bisphosphonates have been reported to have remissive effects, although the mechanisms are unclear [8, 9]. Understanding the mechanisms that contribute to spontaneous or drug-induced remission is important in the control of this severe condition.

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: Originally published online as doi:10.1053/j.ajkd.2007.06.014 on August 1, 2007.

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Case ReportMulticentric Carpal-Tarsal Osteolysis With Nephropathy Treated Successfully With Cyclosporine A: A Case Report and Literature Review

Section snippets

Case Report

Discussion

Acknowledgements

Am J Kidney Dis

A boneless arm

Boston Med Surg J

International nomenclature and classification of the osteochondrodysplasias

Pediatr Radiol

Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome

Nat Genet

Idiopathic multicentric osteolysis: Report of two new cases and a review of the literature

Am J Med Genet

Osteolysis induced by AV-fistula in idiopathic carpotarsal osteolysis

Nephrol Dial Transplant

Inherited multicentric osteolysis with carpal-tarsal localization mimicking juvenile idiopathic arthritis

Eur J Pediatr

Idiopathic carpotarsal osteolysis with Bartter’s syndromeA case report and review of the literature

Clin Orthop Relat Res

Polystrophies sequelettiques avec osteolyse progressive

Arch Franc Pédiatr

Nephropathy of idiopathic multicentric osteolysis

Nephron

Case Report
Multicentric Carpal-Tarsal Osteolysis With Nephropathy Treated Successfully With Cyclosporine A: A Case Report and Literature Review