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II. Surgical Management of Melorheostosis: General Information and Considerations. Jeffrey C. King, M.D. and James Dobyns, M.D.
This document was prepared as general guidelines to educate patients and doctors about known surgical issues associated with melorheostosis. It is not intended as a recommendation of any particular treatment or surgery, nor as a substitute for evaluation between physicians and patients. Every melorheostosis patient is unique.
Surgery to alleviate mechanical effects from melorheostosis in adults seems to be fairly effective. This is particularly true when the mechanical effects are mostly due to asymmetric bone growth, producing a deformity that can be corrected with bone procedures alone. As soft tissue causes of deformity increase, the need for osseous, soft tissue, and skin correction increases. In this case, surgery is less likely to produce satisfactory results, unless amputation is deemed an appropriate procedure.
— Surgery for the sole purpose of relieving pain (non-mechanical) in melorheostosis is rarely effective, unless that pain is a direct result of nerve pressure or irritation.
— Healing of osteotomies in melorheostotic bone is unpredictable and can be problematic. Bone stimulators or BMP products do not seem to help. Nevertheless, the most commonly used procedures for correction of melorheostotic deformity involve corrective osteotomies of bone.
— Contracture releases are more effective in adults than in children, and the results seem to improve with the use of rotation flaps, where possible. Pinning the involved joints may help, but does not assure that the contractures will not recur. The use of external fixators spanning the contracture area to provide corrective stretching may be preferable as a preliminary to surgery or even as sole treatment, but experience to date is very limited.
— Soft tissue releases alone in skeletally immature patients have a 100% "failure" rate in the literature. This statistic does not necessarily mean that they should not be done, but families need to be advised that the procedure may need to be repeated in the future. Soft tissue releases in the skeletally mature patient are not as affected by aggressive scar formation as is the case with children’s tissues, but are best suited to release if the deformity is relatively recent.
— Melorheostosis has rarely been reported in the skull, face, ribs or spine.
If this information does not seem particularly encouraging, that is because the available information leads us to believe that surgical management for the orthopedic manifestations of melorheostosis is unpredictable and fraught with complications. This does not mean that surgery should never be undertaken, rather that the surgeon and the family must have a clear understanding of the risks and benefits involved and clear and realistic expectations about the proposed procedures. ________________________________ The above observations are based on a retrospective review of 15 cases of surgery for the manifestations of melorheostosis in the upper extremities, review of the available English literature, a non-scientific review of 41 patient reported results of surgeries for melorheostosis from the www.melorheostosis.org website and the professional experience of the authors.
It is the authors’ hope that this information will provide a basic framework of our current knowledge of this disease with regard to surgical management. Please consult your doctor to discuss the role of surgery in your specific situation. |
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2005 Conference Papers |
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Abstract and Slide Presentations from the Third International Conference of the Melorheostosis Association — St. Louis, MO; July 17-29, 2005
NOTE: Click on “READ PAPER” to see a PDF of the full paper. Some papers are not available online.
Melorheostosis: Current Understanding and Recent Developments Robert E. Fleming Pediatrics, Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO
This presentation was an overview to acquaint patients with the current scientific understanding of melorheostosis and to review the scientific and medical terminology that would be discussed in the scientific talks. READ PAPER click here for PDF.
Synchronizing the Process of Bone Formation and Angiogenesis Jill A. Helms Department of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA
Endochondral ossification requires precise coordination among programs regulating chondrocyte maturation, osteoblast differentiation, and angiogenesis. Our long-term research goal is to understand how these events are synchronized during skeletal development, and how a disruption to any of these processes adversely impacts the biology of bone formation.
Over the years we have gained a deeper understanding of the biological regulation of angiogenesis through analyses of matrix metalloproteinase 9-(MMP9) and Indian hedgehog (Ihh) deficient mice. In recent years we have focused more closely on the role of Ihh in regulating the behavior of the skeletal vascular endothelium during fetal bone formation, as well as its function in defining and fine-tuning the boundary between the cartilage and perichondrium. We continue to pursue the hypothesis that disruptions in this cartilage-perichondrium boundary have adverse consequences on later stages of skeletal tissue formation and remodeling, and will discuss this concept in light of the disease process of melorheostosis.
A Comprehensive Analysis of the Melorheostosis Database Jeffrey King and Scott Lewis College of Human Medicine, Michigan State University, East Lansing, MI
Drs. King and Lewis analyzed each patient history on the www.melorheostosis.org website and provided a demographic of how patients were affected by melorheostosis.
SANE/XMan1 Inhibits BMP Signaling by Binding To and Inhibiting Two Components of the BMP Signaling Pathway G. Praveen Raju, Peter S. Klein, and Hui-Chuan Huang University of Pennsylvania School of Medicine, Philadelphia, PA
Bone morphogenetic proteins (BMPs) are members of the TGF-ß superfamily that play important roles in bone formation, embryonic patterning, and epidermal-neural cell fate decisions. BMPs signal through pathway specific mediators such as Smads1 and 5, but the upstream regulation of BMP-specific Smads has not been fully characterized. Here we report the identification of SANE (Smad1 Antagonistic Effector), a novel gene with significant sequence similarity to the nuclear envelop protein MAN1. SANE binds to Smad1/5 and to BMP type I receptors to regulate BMP signaling. SANE specifically blocks BMP-dependent signaling in Xenopus embryos and in a mammalian cell culture model of bone formation, but does not significantly inhibit the TGF-ß/Smad2 pathway in these assays. Inhibition of BMP signaling by SANE requires interaction between SANE and Smad1, since a SANE mutant that does not bind Smad1 does not inhibit BMP signaling. Furthermore, SANE inhibits BMP-induced Smad1 phosphorylation, blocking ligand-dependent nuclear translocation of Smad1. These studies define a new mode of regulation for BMP/Smad1 signaling. Since publication of this work, Taira and colleagues have identified an identical gene in Xenopus which they named Xman1 based on the similarity to human MAN1. They also demonstrated that depletion of SANE enhances BMP signaling, further supporting the conclusion that SANE/Xman1 is an inhibitor of BMP signaling. The identification by Hellemans et al of mutations in human LEMD3 associated with osteopoikilosis, Buschke-Ollendorff syndrome, and melorheostosis provides strong support for the hypothesis that endogenous SANE/Man1 functions as a BMP inhibitor in other species including humans.
Mechanisms of Suppressed Bone Formation Laura McCabe, Sergiu Botolin, Gavin Gibson, Regina Irwin. Michigan State University, East Lansing, MI
In contrast to melorheostosis, diabetes type I is a disease that is associated with bone loss. Type I diabetic mice are a very interesting model to study because they lose a significant amount of bone within 4 weeks of being diagnosed as diabetic. Histomorphometry, dynamic measures of bone formation and serum markers of osteoblast and osteoclast activities indicate that the pathology lies in osteoblast function. Specifically, bone synthesis by osteoblasts is reduced. This can result from several scenarios including: a decrease in the number of pluripotent marrow cells selecting the osteoblast lineage or a decrease in the ability of osteoblasts to mature and differentiate into bone producing cells. Gene expression analyses of mouse tibias suggest that both possibilities may be occurring. Mature osteoblast markers, osteocalcin, are decreased while adipogenic markers, PPARgamma and aP2, are increased. Consistent with these findings, histology demonstrates an increase in the number of fat cells in the diabetic bone. Given that melorheostosis is associated with increased bone formation and potentially increased activity of TGF-beta and BMP signaling, we examined if these pathways were modified in diabetic mouse bone. Our findings suggest that the activity of these pathways may be suppressed in type I diabetes and may contribute to its associated bone loss. These results support a critical role for properly regulated TGF and BMP signaling pathway activities in maintaining optimum bone mass and phenotype.
The Role of LEMD3 in the Pathogenesis of Melorheostosis Geert Mortier Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are rare sclerosing bone dysplasias. Osteopoikilosis is a benign, usually asymptomatic condition characterized by multiple round foci of increased bone density. BOS combines the characteristic bone lesions of osteopoikilosis with connective tissue nevi. Osteopoikilosis and BOS both show autosomal dominant inheritance whereas melorheostosis usually occurs sporadically. However, the co-occurrence of melorheostosis and osteopoikilosis in the same individual or family has been reported on several occasions. Melorheostosis is characterized by a linear hyperostosis of cortical bone, resembling dripping candle wax. The hyperostosis is often accompanied by abnormalities of the adjacent soft tissues. Melorheostosis often causes chronic pain and functional limitation of the affected limb. We recently have identified LEMD3 mutations in patients with one or more of these three conditions. The LEMD3 gene codes for a protein of the inner nuclear membrane and we have shown that it inhibits both the BMP and TGFβ signaling pathways. Loss-of-function mutations were identified in 3 unrelated patients with osteopoikilosis and in 3 families where osteopoikilosis was associated with either BOS or melorheostosis. To further explore the allelic heterogeneity within this group of disorders, we subsequently screened a larger series of patients. We confirmed the presence of inactivating germline mutations in 6/7 osteopoikilosis patients with or without BOS skin lesions and in 1 additional family with the co-occurrence of melorheostosis and osteopoikilosis/BOS. However, only in 1/11 sporadic patients with melorheostosis a germline mutation in the LEMD3 gene was found. The possibility of a somatic mutation in the remaining patients was explored but not found in biopsies of affected skin and bone from 2 patients with melorheostosis. Several explanations are possible for these observations. First, since the biopsies may contain a mixture of both mutant and normal cells, the possibility of a somatic mutation can not totally be excluded if the culturing procedures would have selected against mutant cells. Second, the somatic mutation may reside outside the coding region and therefore be missed in our screening strategy. Third, the co-occurrence of osteopoikilosis and melorheostosis may be a coincidence without a causal relationship. However three families and more than 20 cases with this association have been reported so far. Fourth, haploinsufficiency for LEMD3 may be just a predisposing factor for the development of melorheostosis lesions and perhaps another genetic defect in the LEMD3-TGFB/BMP pathway is responsible for melorheostosis. Finally, melorheostosis could be genetically heterogeneous with only a minor fraction of patients carrying a LEMD3 mutation. Further studies are necessary to identify the major genetic factor underlying isolated and sporadic melorheostosis.
Dysregulation of the BMP Signaling Pathway in Two Rare Bone Disorders Eileen M. Shore and Frederick S. Kaplan University of Pennsylvania
Increased bone formation in melorheostosis is characterized by “flowing” regions of high bone density in the skeleton. Recently, loss-of-function mutations in the LEMD3 gene have been suggested as a cause of melorheostosis. LEMD3 (also known as MAN1 or SANE) encodes a protein that acts to block activity of the bone morphogenetic protein (BMP) cellular signaling pathway. Alterations in the BMP pathway are also being investigated in another rare bone disorder, fibrodysplasia ossificans progressiva (FOP), which is characterized by extensive bone formation at extra-skeletal (heterotopic) sites. Investigations of BMP signaling in FOP may suggest research strategies to characterize altered signaling events that lead to melorheostosis pathophysiology and/or that can be used to identify cellular targets for melorheostosis treatment.
Deactivating Germline Mutations in LEMD3 Cause Osteopoikilosis and Buschke-Ollendorff Syndrome, But Not Melorheostosis Michael P. Whyte1,2, Xiafang Zhang2, William H. McAlister3, Deborah Wenkert1, Steven Mumm1,2. 1Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children; 2Division of Bone and Mineral Diseases and 3Mallinckrodt Institute of Radiology, Washington University School of Medicine; St. Louis, MO, USA.
In 2004 (Nat. Genet. 36:1213, 2004), heterozygous loss-of-function mutations in the LEMD3 gene (also called MAN1), encoding an inner nuclear membrane protein, were shown to be a cause of osteopoikilosis (a benign, autosomal dominant, skeletal dysplasia featuring multiple round or oval hyperostotic lesions symmetrically throughout the skeleton) and Buschke-Ollendorff syndrome (BOS) (a benign, autosomal dominant disorder combining osteopoikilosis with disseminated connective tissue nevi). In some of these families, additional unusually large areas of dense bone were called “melorheostosis” which typically refers to a troublesome sporadic (considered non hereditary) skeletal dysostosis characterized by asymmetrical “flowing hyperostosis” of the cortex of long bones often with overlying soft tissue abnormalities. Earlier, in 1995, others had proposed that melorheostosis results from a second, post-zygotic, somatic mutation (Am J. Med Genet 58:199, 1995) in the putative osteopoikilosis gene
We investigated patients representing 9 separate families with sclerosing bone disorders where LEMD3 represented a candidate gene abnormality: 1 osteopoikilosis, 2 BOS, 2 melorheostosis, 1 previously reported by others with both osteopoikilosis and “melorheostosis” (Am J Med Genet. 72:43-46, 1997), and 3 additional patients with other bone sclerosing disorders including 1 mixed-sclerosing-bone dystrophy (features of osteopathia striata with cranial sclerosis), osteomesopyknosis, and 1 unique patient with polycystic osteosclerosis with hypercalcemia. Genomic DNA, isolated from blood lymphocytes, was amplified by PCR and sequenced for all the coding exons and adjacent splice site regions for the LEMD3 gene. We did not study lesional tissue. A heterozygous nonsense mutation (T1433A, Leu478Stop) was found in exon 1 for the osteopoikilosis patient, and a heterozygous nonsense mutation (exon 1, C1323A, Tyr441Stop) and another heterozygous mutation (insertion or deletion in exon 1) were found in the 2 BOS patients. Likewise, a heterozygous nonsense mutation (C1963T, Arg655 Stop) in exon 7 was detected for the patient with osteopoikilosis and "melorheostosis". However, no LEMD3 mutations were detected for any other patient, including the 2 patients with classic melorheostosis. We conclude that osteopoikilosis and BOS can be caused by heterozygous deactivating LEMD3 mutations, however, melorheostosis remains of unknown etiology.
Nuclear Envelope, MAN1 (LEMD3) and Signal Transduction Howard J. Worman Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY
Mutations in nuclear envelope proteins have been shown to cause a wide variety of human diseases. MAN1 (also known as LEMD3) is an integral protein of the inner nuclear membrane first characterized by our group as an antigen recognized by autoantibodies from a subject with a collagen vascular disorder. Recently, mutations in MAN1 have been shown to result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. We have shown that the nucleoplasmic, carboxyl-terminal domain of human MAN1 binds to Smad2 and Smad3 and antagonizes signaling by transforming growth factor-ß (TGF-ß). In a yeast two-hybrid screen using the carboxyl-terminal domain of MAN1 as bait, positive clones were obtained that encoded Smad3. In direct two-hybrid assays, this portion of MAN1 bound to Smad2 and Smad3. In glutathione-S-transferase precipitation assays, the carboxyl-terminal domain of MAN1 bound to Smad2 and Smad3 under stringent conditions. Antibodies against MAN1 were able to co-immunoprecipiate Smad2 from cells, demonstrating they reside in the same complex in vivo. TGF-ß treatment stimulated transcription from a reporter gene in control cells but reporter gene stimulation was significantly inhibited in cells overexpressing MAN1 or its carboxyl-terminal domain but not its amino-terminal domain. TGF-ß-induced cell proliferation arrest was also inhibited in stable cell lines overexpressing MAN1. Our results show that the nuclear envelope regulates a signal transduction pathway and have implications for how mutations in nuclear envelope proteins cause different human diseases, including melorheostosis. |