Multiple Hereditary Exostoses


Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Prenatal Diagnosis
  • exostosin-2
  • Adolescents
  • exostosin-1
  • DNA Primers
  • Radiography
  • Infant
  • Mutation
  • Phenotype
  • Heterozygote
  • Genes, Dominant
  • Base Sequence
  • Chromosome Mapping
  • Pedigree
  • DNA Mutational Analysis
  • Bone Cancer
  • Bone and Bones
  • Thyroglobulin
  • Restriction Mapping
  • Exostoses, Multiple Hereditary
  • Chondrosarcoma
  • China
  • Exons
  • N-Acetylglucosaminyltransferases
  • Amino Acid Sequence
  • Multiple Abnormalities
  • Tumor Suppressor Gene
  • Newborns
  • Translocation
  • Chromosome Deletion
  • Polymerase Chain Reaction
  • Genotype
  • Childhood Cancer
  • Intellectual Disability
  • Genetic Linkage
  • Chromosome 8
  • Asian Continental Ancestry Group
  • Restriction Fragment Length Polymorphism
  • Genetic Predisposition
  • Genetic Markers
  • Chromosome 11
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (5)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

EXT1 8q24.11 EXT, LGS, TTV, LGCR, TRPS2 Germline
-EXT1 and Multiple Hereditary Exostoses
EXT2 11p11.2 SOTV, SSMS Germline
-EXT2 and Multiple Hereditary Exostoses
EXT3 19p EXT2 -EXT3 and Multiple Hereditary Exostoses
EXTL1 1p36.1 EXTL -EXTL1 and Exostoses, Multiple Hereditary
PTH1R 3p22-p21.1 PFE, PTHR, PTHR1 -PTH1R and Exostoses, Multiple Hereditary

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications (1 links)

    D'Ambrosi R, Ragone V, Caldarini C, et al.
    The impact of hereditary multiple exostoses on quality of life, satisfaction, global health status, and pain.
    Arch Orthop Trauma Surg. 2017; 137(2):209-215 [PubMed] Related Publications
    PURPOSE: The aim of the study was to evaluate quality of life (QOL), global health status, pain, and level of satisfaction in patients with hereditary multiple exostoses (HME), and to correlate the association between the severity of diseases and age, sex, number of surgical procedures, and number of exostoses.
    METHODS: The data of 50 patients with HME were retrospectively evaluated and recorded. QOL was evaluated with the Short-Form Health Survey (SF-12) questionnaire, the 12-Item General Health Questionnaire (GHQ-12), and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF); intensity of pain was measured using the visual analogue scale (VAS). The association of age, gender, pain, quality of life, number of exostoses, and number of surgical procedures were evaluated and correlated.
    RESULTS: Mean number of exostoses in our patient's cohort resulted 18.12 ± 8.60, and every patient underwent to a mean of 5.62 ± 5.74 surgical procedures for the exostoses. Mean VAS resulted 5.16 ± 2.90. Considering SF-12, mental (MCS) and physical (PCS) component resulted, respectively, 45.36 ± 10.76 and 38.73 ± 11.09, while GHQ-12 and Q-LES-Q-SF were 15.48 ± 4.70 and 45.28 ± 9.55, respectively. We found a significant positive correlation between the number of exostoses and the number of surgical procedures (p < 0.001), a significant positive correlation between the number of surgical procedures and GHQ-12 (p = 0.422) and VAS (p = 0.0011), and a negative correlation between the number of surgical procedures and PCS (p = 0.0257) and between age and GHQ-12 (p = 0.0385).
    CONCLUSIONS: We can conclude that HME impact on patient quality of life as measured by the MCS and PCS scores similar to the disability associated with osteoarthritis in the mental component and tumors or diabetes as regards the physical component. Moreover, we found no difference in patients' quality of life as regards number of exostoses, age, and surgical procedure, but we found that women have a worse response as regards the psychological side than men.

    McFarlane J, Knight T, Sinha A, et al.
    Exostoses, enchondromatosis and metachondromatosis; diagnosis and management.
    Acta Orthop Belg. 2016; 82(1):102-5 [PubMed] Related Publications
    We describe a 5 years old girl who presented to the multidisciplinary skeletal dysplasia clinic following excision of two bony lumps from her fingers. Based on clinical examination, radiolographs and histological results an initial diagnosis of hereditary multiple exostosis (HME) was made. Four years later she developed further lumps which had the radiological appearance of enchondromas. The appearance of both exostoses and enchondromas suggested a possible diagnosis of metachondromatosis. Genetic testing revealed a splice site mutation at the end of exon 11 on the PTPN11 gene, confirming the diagnosis of metachondromatosis. While both single or multiple exostoses and enchondromas occur relatively commonly on their own, the appearance of multiple exostoses and enchondromas together is rare and should raise the differential diagnosis of metachondromatosis. Making this diagnosis is important as the lesions in metachondromatosis may spontaneously resolve and therefore surgical intervention is often unnecessary. We discuss the diagnostic findings, genetic causes, treatment and prognosis of this rare condition of which less than thirty cases have previously been reported.

    Ishimaru D, Gotoh M, Takayama S, et al.
    Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas.
    BMC Genet. 2016; 17:52 [PubMed] Free Access to Full Article Related Publications
    BACKGROUND: Multiple osteochondroma (MO) is an autosomal dominant skeletal disorder characterized by the formation of multiple osteochondromas, and exostosin-1 (EXT1) and exostosin-2 (EXT2) are major causative genes in MO. In this study, we evaluated the genetic backgrounds and mutational patterns in Japanese families with MO.
    RESULTS: We evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. The exons and exon/intron junctions of EXT1 and EXT2 were directly sequenced after PCR amplification. Fifty-two mutations in 47 families with MO in either EXT1 or EXT2, and 42.3% (22/52) of mutations were novel mutations. Twenty-nine families (40.8%) had mutations in EXT1, and 15 families (21.1%) had mutations in EXT2. Interestingly, three families (4.2%) had mutations in both EXT1 and EXT2. Twenty-four families (33.8%) did not exhibit mutations in either EXT1 or EXT2. With regard to the types of mutations identified, 59.6% of mutations were inactivating mutations, and 38.5% of mutations were missense mutations.
    CONCLUSIONS: We found that the prevalence of EXT1 mutations was greater than that of EXT2 mutations in Japanese MO families. Additionally, we identified 22 novel EXT1 and EXT2 mutations in this Japanese MO cohort. This study represents the variety of genotype in MO.

    DuBose CO
    Multiple Hereditary Exostoses.
    Radiol Technol. 2016 Jan-Feb; 87(3):305-21. quiz 322-5 [PubMed] Related Publications
    Multiple hereditary exostoses (MHE), also known as multiple osteochondromas, is an autosomal dominant disease that results in the development of osteochondromas throughout the body. The disease typically is diagnosed during childhood and requires lifelong monitoring and treatment of painful osteochondromas. Individuals with MHE must be monitored for complications that can arise and the potential malignant transformation of an osteochondroma into a chondrosarcoma. This article discusses the basic characteristics of MHE, genetic links, the role of medical imaging in diagnosis, and treatment options.

    Tanteles GA, Nicolaou M, Neocleous V, et al.
    Genetic screening of EXT1 and EXT2 in Cypriot families with hereditary multiple osteochondromas.
    J Genet. 2015; 94(4):749-54 [PubMed] Related Publications

    Labonne JD, Vogt J, Reali L, et al.
    A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies.
    Am J Med Genet A. 2015; 167A(12):3011-8 [PubMed] Related Publications
    In Potocki-Shaffer syndrome (PSS), the full phenotypic spectrum is manifested when deletions are at least 2.1 Mb in size at 11p11.2. The PSS-associated genes EXT2 and ALX4, together with PHF21A, all map to this region flanked by markers D11S1393 and D11S1319. Being proximal to EXT2 and ALX4, a 1.1 Mb region containing 12 annotated genes had been identified by deletion mapping to explain PSS phenotypes except multiple exostoses and parietal foramina. Here, we report a male patient with partial PSS phenotypes including global developmental delay, craniofacial anomalies, minor limb anomalies, and micropenis. Using microarray, qPCR, RT-qPCR, and Western blot analyses, we refined the candidate gene region, which harbors five genes, by excluding two genes, SLC35C1 and CRY2, which resulted in a corroborating role of PHF21A in developmental delay and craniofacial anomalies. This microdeletion contains the least number of genes at 11p11.2 reported to date. Additionally, we also discuss the phenotypes observed in our patient with respect to those of published cases of microdeletions across the Potocki-Shaffer interval.

    Knipe M, Stanbury R, Unger S, Chakraborty M
    Stuve-Wiedemann syndrome with a novel mutation.
    BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
    We describe a female infant born at term to consanguineous parents, with a suspicion of skeletal dysplasia in utero. At birth, she had short limbs, camptodactyly, dysphagia leading to nasogastric tube feeds, and skeletal survey demonstrating dysplasia of long bones and spine. During infancy, she also developed episodes of respiratory failure necessitating admission to intensive care, and periods of hyperhidrosis managed at home. A basic genetic screen did not reveal any abnormalities. Contact was made with the European Skeletal Dysplasia Network, and a provisional diagnosis of Stuve-Wiedemann syndrome was suggested based on this review. Specific genetic tests showed a previously unreported homozygous mutation of leukaemia inhibitory factor receptor gene, confirming the diagnosis. This is the first case with a novel mutation, reported from the UK. For paediatricians and neonatologists, the European Skeletal Dysplasia Network is a valuable resource to reach a specific diagnosis.

    Bozzola M, Gertosio C, Gnoli M, et al.
    Hereditary multiple exostoses and solitary osteochondroma associated with growth hormone deficiency: to treat or not to treat?
    Ital J Pediatr. 2015; 41:53 [PubMed] Free Access to Full Article Related Publications
    BACKGROUND: Osteochondroma generally occurs as a single lesion and it is not a heritable disease. When two or more osteochondroma are present, this condition represents a genetic disorder named hereditary multiple exostoses (HME). Growth hormone deficiency (GHD) has rarely been found in HME patients and a few data about growth therapy (GH) therapy effects in development/growth of solitary or multiple exostoses have been reported.
    CASE PRESENTATION: We describe the clinical features of 2 patients (one with osteochondroma and one with HME) evaluated before and after GH therapy. In the first patient, the single osteochondroma was noticed after the start of treatment; the other patient showed no evidence of significant increase in size or number of lesions related to GH therapy.
    CONCLUSION: It is necessary to investigate GH secretion in patients with osteochondroma or HME and short stature because they could benefit from GH replacement therapy. Moreover, careful clinical and imaging follow-up of exostoses is mandatory.

    Billings PC, Pacifici M
    Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries.
    Connect Tissue Res. 2015; 56(4):272-80 [PubMed] Free Access to Full Article Related Publications
    Heparan sulfate (HS) is a component of cell surface and matrix-associated proteoglycans (HSPGs) that, collectively, play crucial roles in many physiologic processes including cell differentiation, organ morphogenesis and cancer. A key function of HS is to bind and interact with signaling proteins, growth factors, plasma proteins, immune-modulators and other factors. In doing so, the HS chains and HSPGs are able to regulate protein distribution, bio-availability and action on target cells and can also serve as cell surface co-receptors, facilitating ligand-receptor interactions. These proteins contain an HS/heparin-binding domain (HBD) that mediates their association and contacts with HS. HBDs are highly diverse in sequence and predicted structure, contain clusters of basic amino acids (Lys and Arg) and possess an overall net positive charge, most often within a consensus Cardin-Weintraub (CW) motif. Interestingly, other domains and residues are now known to influence protein-HS interactions, as well as interactions with other glycosaminoglycans, such as chondroitin sulfate. In this review, we provide a description and analysis of HBDs in proteins including amphiregulin, fibroblast growth factor family members, heparanase, sclerostin and hedgehog protein family members. We discuss HBD structural and functional features and important roles carried out by other protein domains, and also provide novel conformational insights into the diversity of CW motifs present in Sonic, Indian and Desert hedgehogs. Finally, we review progress in understanding the pathogenesis of a rare pediatric skeletal disorder, Hereditary Multiple Exostoses (HME), characterized by HS deficiency and cartilage tumor formation. Advances in understanding protein-HS interactions will have broad implications for basic biology and translational medicine as well as for the development of HS-based therapeutics.

    Su P, Wang Y, Cooper DN, et al.
    Disclosing the Hidden Structure and Underlying Mutational Mechanism of a Novel Type of Duplication CNV Responsible for Hereditary Multiple Osteochondromas.
    Hum Mutat. 2015; 36(8):758-63 [PubMed] Related Publications
    The additional mutational complexity associated with copy number variation (CNV) can provide important clues as to the underlying mechanisms of CNV formation. Correct annotation of the additional mutational complexity is, however, a prerequisite for establishing the mutational mechanism. We illustrate this point through the characterization of a novel ∼230 kb EXT1 duplication CNV causing autosomal dominant hereditary multiple osteochondromas. Whole-genome sequencing initially identified the CNV as having a 22-bp insertion at the breakpoint junction and, unprecedentedly, multiple breakpoint-flanking micromutations on both sides of the duplication. Further investigation revealed that this genomic rearrangement had a duplication-inverted triplication-duplication structure, the inverted triplication being a 41-bp sequence synthesized from a nearby template. This permitted the identification of the sequence determinants of both the initiation (an inverted Alu repeat) and termination (a triplex-forming sequence) of break-induced replication and suggested a possible model for the repair of replication-associated double-strand breaks.

    Sarafidis K, Piretzi K, Agakidou E, et al.
    Stüve-Wiedemann syndrome in a neonate.
    Pediatr Int. 2015; 57(2):302-4 [PubMed] Related Publications
    We describe a female neonate with Stüve-Wiedemann syndrome. The facial dysmorphism, joint contracture, distinctive skeletal changes, and myotonic discharges on electromyogram raised a suspicion of the rare autosomal recessive syndrome, which was later confirmed on molecular analysis of leukemia inhibitory factor receptor. She developed recurrent attacks of hyperpyrexia and died at age 3 months.

    Huegel J, Enomoto-Iwamoto M, Sgariglia F, et al.
    Heparanase stimulates chondrogenesis and is up-regulated in human ectopic cartilage: a mechanism possibly involved in hereditary multiple exostoses.
    Am J Pathol. 2015; 185(6):1676-85 [PubMed] Free Access to Full Article Related Publications
    Hereditary multiple exostoses is a pediatric skeletal disorder characterized by benign cartilaginous tumors called exostoses that form next to growing skeletal elements. Hereditary multiple exostoses patients carry heterozygous mutations in the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2, but studies suggest that EXT haploinsufficiency and ensuing partial HS deficiency are insufficient for exostosis formation. Searching for additional pathways, we analyzed presence and distribution of heparanase in human exostoses. Heparanase was readily detectable in most chondrocytes, particularly in cell clusters. In control growth plates from unaffected persons, however, heparanase was detectable only in hypertrophic zone. Treatment of mouse embryo limb mesenchymal micromass cultures with exogenous heparanase greatly stimulated chondrogenesis and bone morphogenetic protein signaling as revealed by Smad1/5/8 phosphorylation. It also stimulated cell migration and proliferation. Interfering with HS function both with the chemical antagonist Surfen or treatment with bacterial heparitinase up-regulated endogenous heparanase gene expression, suggesting a counterintuitive feedback mechanism that would result in further HS reduction and increased signaling. Thus, we tested a potent heparanase inhibitor (SST0001), which strongly inhibited chondrogenesis. Our data clearly indicate that heparanase is able to stimulate chondrogenesis, bone morphogenetic protein signaling, cell migration, and cell proliferation in chondrogenic cells. These properties may allow heparanase to play a role in exostosis genesis and pathogenesis, thus making it a conceivable therapeutic target in hereditary multiple exostoses.

    Cammarata-Scalisi F, Cozar M, Grinberg D, et al.
    [Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses].
    Arch Argent Pediatr. 2015; 113(2):e109-12 [PubMed] Related Publications
    Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.

    Sohn YB, Yim SY, Cho EH, Kim OH
    The first Korean patient with Potocki-Shaffer syndrome: a rare cause of multiple exostoses.
    J Korean Med Sci. 2015; 30(2):214-7 [PubMed] Free Access to Full Article Related Publications
    Potocki-Shaffer syndrome (PSS, OMIM #601224) is a rare contiguous gene deletion syndrome caused by haploinsufficiency of genes located on the 11p11.2p12. Affected individuals have a number of characteristic features including multiple exostoses, biparietal foramina, abnormalities of genitourinary system, hypotonia, developmental delay, and intellectual disability. We report here on the first Korean case of an 8-yr-old boy with PSS diagnosed by high resolution microarray. Initial evaluation was done at age 6 months because of a history of developmental delay, hypotonia, and dysmorphic face. Coronal craniosynostosis and enlarged parietal foramina were found on skull radiographs. At age 6 yr, he had severe global developmental delay. Multiple exostoses of long bones were detected during a radiological check-up. Based on the clinical and radiological features, PSS was highly suspected. Subsequently, chromosomal microarray analysis identified an 8.6 Mb deletion at 11p11.2 [arr 11p12p11.2 (Chr11:39,204,770-47,791,278)×1]. The patient continued rehabilitation therapy for profound developmental delay. The progression of multiple exostosis has being monitored. This case confirms and extends data on the genetic basis of PSS. In clinical and radiologic aspect, a patient with multiple exostoses accompanying with syndromic features, including craniofacial abnormalities and mental retardation, the diagnosis of PSS should be considered.

    Malini K, Gudi NS, Kutty AV, Balakrishna S
    Mutational Analysis of Exostosin 1 and 2 Genes in Multiple Osteochondroma.
    Indian J Pediatr. 2015; 82(7):649-50 [PubMed] Related Publications

    Goud AL, Wuyts W, Bessems J, et al.
    Intraosseous atypical chondroid tumor or chondrosarcoma grade 1 in patients with multiple osteochondromas.
    J Bone Joint Surg Am. 2015; 97(1):24-31 [PubMed] Related Publications
    BACKGROUND: The autosomal dominant condition multiple osteochondromas, formerly called multiple hereditary exostoses, is associated with a risk of malignant progression of osteochondroma into secondary peripheral chondrosarcoma. Most patients with multiple osteochondromas have exostosin-1 or exostosin-2 gene mutations. To our knowledge, it has not been previously reported that patients may also harbor intraosseous (central) chondroid neoplasms, enchondromas, or atypical chondroid tumors or central chondrosarcomas. The combination of osteochondroma and enchondromas also exists in patients with metachondromatosis, a disorder associated with a protein tyrosine phosphatase non-receptor type 11 gene mutation. This study aims to establish any correlation between multiple osteochondromas and intraosseous cartilaginous neoplasms.
    METHODS: We retrospectively reviewed all histologically proven intraosseous atypical chondroid tumors or chondrosarcomas in our prospective nationwide Dutch tertiary referral multiple osteochondromas database. Demographic, clinical, radiographic, histological, and genetic data were recorded. The institutional medical ethics review board approved the study.
    RESULTS: From 195 adult patients, seven (3.6%) were identified with intraosseous atypical chondroid tumor or chondrosarcoma World Health Organization grade 1 and had a mean age of forty-two years; five of these patients were male. In all cases, radiographic and genetic findings were consistent with multiple osteochondromas, not metachondromatosis; three patients had an exostosin-1 mutation, four patients had an exostosin-2 mutation, and no patients had a protein tyrosine phosphatase, non-receptor type 11 mutation. Six patients underwent successful operative treatment without complications or recurrences after a mean follow-up duration of forty-eight months (range, twelve to 144 months). One patient was scheduled for surgery after biopsy and histologic confirmation. Of the seven patients, five (71%) also developed a peripheral chondrosarcoma in a known osteochondroma during the study period.
    CONCLUSIONS: Apart from osteochondromas or peripheral chondrosarcomas, multiple osteochondromas are also associated with intraosseous chondroid neoplasms, potentially resulting in central chondrosarcoma. Therefore, intraosseous lesions should not automatically be regarded as innocuous in this patient population.

    Bernelot Moens SJ, Mooij HL, Hassing HC, et al.
    Carriers of loss-of-function mutations in EXT display impaired pancreatic beta-cell reserve due to smaller pancreas volume.
    PLoS One. 2014; 9(12):e115662 [PubMed] Free Access to Full Article Related Publications
    Exotosin (EXT) proteins are involved in the chain elongation step of heparan sulfate (HS) biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF) in EXT1 and EXT2 result in hereditary exostoses (HME). Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT) followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS) in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI). OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46-1.16] vs. controls 1.53 [0.69-3.36] nmol·l-1·min-1, p<0.05). Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22-10.5] vs. controls 10.2 [7.91-12.70] nmol·l-1·min-1 p<0.05), indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0±15.8 vs. controls 96.5±26.0 cm3 p = 0.04). In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors.

    Sgariglia F, Pedrini E, Bradfield JP, et al.
    The type 2 diabetes associated rs7903146 T allele within TCF7L2 is significantly under-represented in Hereditary Multiple Exostoses: insights into pathogenesis.
    Bone. 2015; 72:123-7 [PubMed] Free Access to Full Article Related Publications
    Hereditary Multiple Exostoses (HME) is an autosomal-dominant disorder characterized by benign cartilage tumors (exostoses) forming near the growth plates, leading to severe health problems. EXT1 and EXT2 are the two genes known to harbor heterozygous loss-of-function mutations that account for the vast majority of the primary genetic component of HME. However, patients present with wide clinical heterogeneity, suggesting that modifier genes play a role in determining severity. Our previous work has pointed to an imbalance of β-catenin signaling being involved in the pathogenesis of osteochondroma formation. TCF7L2 is one of the key 'gate-keeper' TCF family members for Wnt/β-catenin signaling pathway, and TCF7L2 and EXT2 are among the earliest associated loci reported in genome wide appraisals of type 2 diabetes (T2D). Thus we investigated if the key T allele of single nucleotide polymorphism (SNP) rs7903146 within the TCF7L2 locus, which is strongly over-represented among T2D cases, was also associated with HME. We leveraged genotype data available from ongoing GWAS efforts from genomics and orthopedic centers in the US, Canada and Italy. Collectively 213 cases and 1890 controls were analyzed and, surprisingly, the T allele was in fact significantly under-represented in the HME patient group [P = 0.009; odds ratio = 0.737 (95% C.I. 0.587-0.926)]; in addition, the direction of effect was consistent within each individual cohort. Immunohistochemical analyses revealed that TCF7L2 is differentially expressed and distributed in normal human growth plate zones, and exhibits substantial variability in human exostoses in terms of staining intensity and distribution. In summary, the data indicate that there is a putative genetic connection between TCF7L2 and EXT in the context of HME. Given this observation, we suggest that these loci could possibly modulate shared pathways, in particular with respect to β-catenin, and their respective variants interplay to influence HME pathogenesis as well as T2D.

    Mooij HL, Cabrales P, Bernelot Moens SJ, et al.
    Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function.
    J Am Heart Assoc. 2014; 3(6):e001274 [PubMed] Free Access to Full Article Related Publications
    BACKGROUND: Heparanase is the major enzyme involved in degradation of endothelial heparan sulfates, which is associated with impaired endothelial nitric oxide synthesis. However, the effect of heparan sulfate chain length in relation to endothelial function and nitric oxide availability has never been investigated. We studied the effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo.
    METHODS AND RESULT: Flow-mediated dilation, a marker of nitric oxide bioavailability, was studied in Ext1(+/-) and Ext2(+/-) mice versus controls (n=7 per group), as well as in human subjects with heterozygous loss of function mutations in EXT1 and EXT2 (n=13 hereditary multiple exostoses and n=13 controls). Endothelial function was measured in microvascular endothelial cells under laminar flow with or without siRNA targeting EXT1 or EXT2. Endothelial glycocalyx and maximal arteriolar dilatation were significantly altered in Ext1(+/-) and Ext2(+/-) mice compared to wild-type littermates (glycocalyx: wild-type 0.67±0.1 μm, Ext1(+/-) 0.28±0.1 μm and Ext2(+/-) 0.25±0.1 μm, P<0.01, maximal arteriolar dilation during reperfusion: wild-type 11.3±1.0%), Ext1(+/-) 15.2±1.4% and Ext2(+/-) 13.8±1.6% P<0.05). In humans, brachial artery flow-mediated dilation was significantly increased in hereditary multiple exostoses patients (hereditary multiple exostoses 8.1±0.8% versus control 5.6±0.7%, P<0.05). In line, silencing of microvascular endothelial cell EXT1 and EXT2 under flow led to significant upregulation of endothelial nitric oxide synthesis and phospho-endothelial nitric oxide synthesis protein expression.
    CONCLUSIONS: Our data implicate that heparan sulfate elongation genes EXT1 and EXT2 are involved in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability.

    Li L, Li X, Liu Y, et al.
    [Mutation analysis of EXT2 gene in a family with hereditary multiple exostosis].
    Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(6):743-6 [PubMed] Related Publications
    OBJECTIVE: To investigate EXT1 and EXT2 genes mutations in a family with hereditary multiple osteochondromas (HME).
    METHODS: A four-generation family with HME from Linyi city of Shandong Province was studied. There were 6 affected individuals among the 17 family members. Physical examination and radiographical evaluations were carried out for all family members. Genomic DNA was extracted from peripheral venous blood and the samples were subjected to mutation screening by PCR of the coding regions of EXT1 and EXT2 genes.
    RESULTS: The family has featured an autosomal dominant inheritance pattern. Sequencing of the EXT1 and EXT2 genes suggested the causative gene in this family was in linkage with the second exon of EXT2. A c.244delG mutation was detected, which has resulted in a frameshift mutation p.Asp81IlefsX30. The mutation was found in all of the 6 affected individuals but not in normal family members. And the mutation has co-segregated with the phenotype.
    CONCLUSION: The mutation c.244delG in the EXT2 gene is the probably the cause of the disease in this family.

    Liu H, Wu S, Duan L, et al.
    Identification of a novel EXT1 mutation in patients with hereditary multiple exostosis by exome sequencing.
    Oncol Rep. 2015; 33(2):547-52 [PubMed] Free Access to Full Article Related Publications
    Hereditary multiple exostosis (HME) is an autosomal inherited skeletal disease whose etiology is not fully understood. To further understand the genetic spectrum of the disease, we analyzed a five-generation Chinese family with HME that have observable inheritance. Exome sequencing was performed on three HME individuals and three unaffected individuals from the family. A downstream study confirmed a new C deletion at codon 442 on exon 5 of the exostosin-1 (EXT1) gene as the only pathogenic site which generated a stop codon and caused the truncation of the protein. We rediscovered the deletion in other affected individuals but not in the unaffected individuals from the family. Upon immunohistochemistry assay, we found that the EXT1 protein level of the patients with the novel mutation in our study was less than the level in the patients without the EXT1 mutation from another unrelated family. For a deeper understanding, we analyzed the mutation spectrum of the EXT1 gene. The present study should facilitate a further understanding of HME.

    Delgado MA, Martinez-Domenech G, Sarrión P, et al.
    A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG.
    Sci Rep. 2014; 4:6407 [PubMed] Free Access to Full Article Related Publications
    Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG.

    Guran T, Guran O, Paketci C, et al.
    Effects of leukemia inhibitory receptor gene mutations on human hypothalamo-pituitary-adrenal function.
    Pituitary. 2015; 18(4):456-60 [PubMed] Related Publications
    BACKGROUND: Stuve-Wiedemann syndrome (STWS) (MIM #601559) is a rare autosomal recessive disorder caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene. STWS has a diverse range of clinical features involving hematopoietic, skeletal, neuronal and immune systems. STWS manifests a high mortality due to increased risk of sudden death. Heterodimerization of the LIFR mediates leukemia inhibitory factor (LIF) signalling through the intracellular Janus kinase (JAK)/STAT3 signalling cascade. The LIF/LIFR system is highly expressed in and regulates the hypothalamo-pituitary-adrenal (HPA) axis.
    OBJECTIVES: HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function.
    DESIGN: Six genetically proven STWS patients from four unrelated Turkish families were included in the study. Sudden death occurred in three before 2 years of age. Basal adrenal function tests were performed by measurement of early morning serum cortisol and plasma ACTH concentrations on at least two different occasions. Low dose synacthen stimulation test and glucagon stimulation tests were performed to explore adrenal function in three patients who survived.
    RESULTS: All patients carried the same LIFR (p.Arg692X) mutation. Our oldest patient had attenuated morning serum cortisol and plasma ACTH levels at repeated measurements. Two of three patients had attenuated cortisol response (<18 μg/dl) to glucagon, one of whom also had borderline cortisol response to low dose (1 μg) ACTH stimulation consistent with central adrenal insufficiency.
    CONCLUSIONS: STWS patients may develop central adrenal insufficiency due to impaired LIF/LIFR signalling. LIF/LIFR system plays a role in human HPA axis regulation.

    Nakane T, Goi K, Oshiro H, et al.
    Pre-B-cell acute lymphoblastic leukemia in a boy with hereditary multiple exostoses caused by EXT1 deletion.
    Pediatr Hematol Oncol. 2014; 31(7):667-9 [PubMed] Related Publications

    Mitsui T, Kim OH, Hall CM, et al.
    Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2.
    Am J Med Genet A. 2014; 164A(10):2529-34 [PubMed] Related Publications
    Acroscyphodysplasia (OMIM250215) is a distinctive form of metaphyseal dysplasia characterized by the distal femoral and proximal tibial epiphyses embedded in cup-shaped, large metaphyses known as metaphyseal scypho ("scypho" = cup) deformity. It is also associated with severe growth retardation and brachydactyly. The underlying molecular mechanism of acroscyphodysplasia has not yet been elucidated, although scypho-deformity of the knee has been reported in three patients with acrodysostosis due to a mutation in the PDE4D gene. We report on the clinical, radiological, and molecular findings of five female patients with acroscyphodysplasia; two were diagnosed as pseudohypoparathyroidism (PHP) or Albright hereditary osteodystropy, and the other three as acrodysostosis. They all had radiological findings consistent with severe metaphyseal scypho-deformity and brachydactyly. Heterozygous mutations were identified in the PHP patients consisting of one novel (p.Q19X) and one recurrent (p.R231C) mutation of the GNAS gene, as well as, in the acrodysostosis patients consisting of two novel mutations (p.T224I and p.I333T) of the PDE4D gene. We conclude that metaphyseal acroscyphodysplasia is a phenotypic variation of PHP or acrodysostosis caused by either a GNAS or PDE4D mutation, respectively.

    Yeşil G, Lebre AS, Santos SD, et al.
    Stuve-Wiedemann syndrome: is it underrecognized?
    Am J Med Genet A. 2014; 164A(9):2200-5 [PubMed] Related Publications
    Stuve-Wiedemann Syndrome (SWS) (OMIM #601559) is an autosomal recessive disorder characterized by skeletal changes, bowing of the lower limb, severe osteoporosis and joint contractures, episodic hyperthermia, frequent respiratory infections, feeding problems and high mortality in early life. It is caused by mutation in the leukemia inhibitory factor receptor gene (LIFR; 151443) on chromosome 5p13. We provide the clinical follow-up and molecular aspects of six new patients who carried the same novel mutation in the LIFR gene (p.Arg692X) and three patients carried a common haplotype at the LIFR locus supporting a founder effect in the Turkish population. The probable pathogenesis of the features is also discussed. Osseous findings in the presence of other above-mentioned morbid conditions should raise the suspicion of SWS in neonates especially in Arabic and Eastern Mediterranean countries with high rate of consanguineous marriages like in Turkey. Severe osteoporosis, bone deformities, milias, leukocoria, inflammatory lesions on distal extremities, tongue biting behavior and oral ulcers could be more prominent features of the survivors beyond the neonatal period while respiratory and feeding problems are remitting. It is of crucial importance to diagnose such babies earlier in order to prevent extensive laboratory workup and to provide proper genetic counseling.

    Bowen ME, Ayturk UM, Kurek KC, et al.
    SHP2 regulates chondrocyte terminal differentiation, growth plate architecture and skeletal cell fates.
    PLoS Genet. 2014; 10(5):e1004364 [PubMed] Free Access to Full Article Related Publications
    Loss of PTPN11/SHP2 in mice or in human metachondromatosis (MC) patients causes benign cartilage tumors on the bone surface (exostoses) and within bones (enchondromas). To elucidate the mechanisms underlying cartilage tumor formation, we investigated the role of SHP2 in the specification, maturation and organization of chondrocytes. Firstly, we studied chondrocyte maturation by performing RNA-seq on primary chondrocyte pellet cultures. We found that SHP2 depletion, or inhibition of the ERK1/2 pathway, delays the terminal differentiation of chondrocytes from the early-hypertrophic to the late-hypertrophic stage. Secondly, we studied chondrocyte maturation and organization in mice with a mosaic postnatal inactivation of Ptpn11 in chondrocytes. We found that the vertebral growth plates of these mice have expanded domains of early-hypertrophic chondrocytes that have not yet terminally differentiated, and their enchondroma-like lesions arise from chondrocytes displaced from the growth plate due to a disruption in the organization of maturation and ossification zones. Furthermore, we observed that lesions from human MC patients also display disorganized chondrocyte maturation zones. Next, we found that inactivation of Ptpn11 in Fsp1-Cre-expressing fibroblasts induces exostosis-like outgrowths, suggesting that loss of SHP2 in cells on the bone surface and at bone-ligament attachment sites induces ectopic chondrogenesis. Finally, we performed lineage tracing to show that exostoses and enchondromas in mice likely contain mixtures of wild-type and SHP2-deficient chondrocytes. Together, these data indicate that in patients with MC, who are heterozygous for inherited PTPN11 loss-of-function mutations, second-hit mutations in PTPN11 can induce enchondromas by disrupting the organization and delaying the terminal differentiation of growth plate chondrocytes, and can induce exostoses by causing ectopic chondrogenesis of cells on the bone surface. Furthermore, the data are consistent with paracrine signaling from SHP2-deficient cells causing SHP2-sufficient cells to be incorporated into the lesions.

    Romeike BF, Shen Y, Nishimoto HK, et al.
    Spectrum of genes involved in a unique case of Potocki Schaffer syndrome with a large chromosome 11 deletion.
    Clin Neuropathol. 2014 May-Jun; 33(3):238-44 [PubMed] Free Access to Full Article Related Publications

    Tian C, Yan R, Wen S, et al.
    A splice mutation and mRNA decay of EXT2 provoke hereditary multiple exostoses.
    PLoS One. 2014; 9(4):e94848 [PubMed] Free Access to Full Article Related Publications
    BACKGROUND: Hereditary multiple exostoses (HME) is an autosomal dominant disease. The classical paradigm of mutation screening seeks to relate alterations in the exostosin glycosyltransferase genes, EXT1 and EXT2, which are responsible for over 70% of HME cases. However, the pathological significance of the majority of these mutations is often unclear.
    METHODS: In a Chinese family with HME, EXT1 and EXT2 genes were screened by direct sequencing. The consequence of a detected mutant was predicted by in silico analysis and confirmed by mRNA analysis. The EXT1 and EXT2 mRNA and protein levels and the HS patterns in the HME patients were compared with those in healthy controls.
    RESULTS: A heterozygous transition (c.743+1G>A) in the EXT2 gene, which co-segregated with the HME phenotype in this family, was identified. The G residue at position +1 in intron 4 of EXT2 was predicted to be a 5' donor splice site. The mRNA analysis revealed an alternative transcript with a cryptic splice site 5 bp downstream of the wild-type site, which harbored a premature stop codon. However, the predicted truncated protein was not detected by western blot analysis. Decay of the mutant mRNA was shown by clone sequencing and quantification analysis. The corresponding downregulation of the EXT2 mRNA will contribute to the abnormal EXT1/EXT2 ratio and HS pattern that were detected in the patients with HME.
    CONCLUSION: The heterozygous mutation c.743+1G>A in the EXT2 gene causes HME as a result of abnormal splicing, mRNA decay, and the resulting haploinsufficiency of EXT2.

    Mikelonis D, Jorcyk CL, Tawara K, Oxford JT
    Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology.
    Orphanet J Rare Dis. 2014; 9:34 [PubMed] Free Access to Full Article Related Publications
    Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes. STWS usually results in infant mortality, yet some STWS patients survive into and, in some cases, beyond adolescence. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomally recessive pattern. Most LIFR mutations resulting in STWS are null mutations which cause instability of the mRNA and prevent the formation of LIFR, impairing the signaling pathway. LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines. STWS is managed on a symptomatic basis since there is no treatment currently available.

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