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1.  Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively - coincidence within one family 
BMC Medical Genetics  2010;11:110.
Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and metaphyses of the long bones, and in the carpal and tarsal bones [1]. Heterozygous LEMD3 gene mutations were shown to be the primary cause of the disease [2]. Association of the primarily asymptomatic osteopokilosis with connective tissue nevi of the skin is categorized as Buschke-Ollendorff syndrome (BOS) [3]. Additionally, osteopoikilosis can coincide with melorheostosis (MRO), a more severe bone disease characterised by the ectopic bone formation on the periosteal and endosteal surface of the long bones [4-6]. However, not all MRO affected individuals carry germ-line LEMD3 mutations [7]. Thus, the genetic cause of MRO remains unknown. Here we describe a familial case of osteopoikilosis in which a novel heterozygous LEMD3 mutation coincides with a novel mutation in EXT1, a gene involved in aetiology of multiple exostosis syndrome. The patients affected with both LEMD3 and EXT1 gene mutations displayed typical features of the osteopoikilosis. There were no additional skeletal manifestations detected however, various non-skeletal pathologies coincided in this group.
We investigated LEMD3 and EXT1 in the three-generation family from Poland, with 5 patients affected with osteopoikilosis and one child affected with multiple exostoses.
We found a novel c.2203C > T (p.R735X) mutation in exon 9 of LEMD3, resulting in a premature stop codon at amino acid position 735. The mutation co-segregates with the osteopoikilosis phenotype and was not found in 200 ethnically matched controls. Another new substitution G > A was found in EXT1 gene at position 1732 (cDNA) in Exon 9 (p.A578T) in three out of five osteopoikilosis affected family members. Evolutionary conservation of the affected amino acid suggested possible functional relevance, however no additional skeletal manifestations were observed other then those specific for osteopoikilosis. Finally in one member of the family we found a splice site mutation in the EXT1 gene intron 5 (IVS5-2 A > G) resulting in the deletion of 9 bp of cDNA encoding three evolutionarily conserved amino acid residues. This child patient suffered from a severe form of exostoses, thus a causal relationship can be postulated.
We identified a new mutation in LEMD3 gene, accounting for the familial case of osteopoikilosis. In the same family we identified two novel EXT1 gene mutations. One of them A598T co-incided with the LEMD3 mutation. Co-incidence of LEMD3 and EXT1 gene mutations was not associated with a more severe skeletal phenotype in those patients.
PMCID: PMC2912259  PMID: 20618940
2.  Osteogenesis imperfecta type V, spot diagnosis 
Polish Journal of Radiology  2010;75(1):84-87.
The first case of Osteogenesis Imperfecta Type V in the Polish literature is reported.
Case Report:
Skeletal survey of an 8 year old girl with a history of multiple fractures and bilateral dislocation of radial heads was received for consultation.
Generalised osteoporosis with multiple fractures, periosteal thickening and bilateral dislocation of the radial heads are characteristic signs of osteogenesis imperfecta Type V. The Nosology and Classification of Genetic Skeletal Disorders 2006 Revision classified Osteogenesis Imperfecta into 8 major types. Type V is recognizable on the basis of skeletal survey alone.
PMCID: PMC3389858  PMID: 22802766
osteoporosis; fractures; radial head dislocation; periosteal thickening; ectopic ossification; osteogenesis imperfecta
3.  Multifocal intracranial astrocytoma in a pediatric patient with Ollier disease 
Ollier disease (OD) is a subtype of enchondromatosis. Historically, it has been distinguished from Maffucci syndrome (MS) by the presence of vascular malformations and nonskeletal neoplasms (NSN) in the latter. However, there is an increasing number of reports of NSN in OD, and this categorization is now being questioned. We report a case of OD complicated by multifocal astrocytoma in a young patient, once again pointing to a possible association between OD and NSN. We also review the available literature and examine the similarities between the reported cases.
PMCID: PMC3354360  PMID: 22623818
Astrocytoma; IDH1 mutation; multifocal; Ollier disease
4.  Nosology and Classification of Genetic Skeletal Disorders – 2010 Revision& 
Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology.
In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene.
The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology.
PMCID: PMC3166781  PMID: 21438135
5.  Osteopoikilosis: Pain as a Presenting Symptom in Three Family Members 
Osteopoikilosis is a rare asymptomatic sclerosing bony dysplasia of benign origin. It is usually found incidentally on radiological examinations. Familial occurrence indicates a genetic milieu with autosomal dominant pattern. Here, we present a case report of a young woman suffering from pelvic pain due to osteopoikilosis (OPK). The same disorder was later found in her son and daughter.
PMCID: PMC3091414  PMID: 21573035
Osteopoikilosis; pain; familial occurrence
6.  Somatic mosaic IDH1 or IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome 
Nature genetics  2011;43(12):1256-1261.
Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous IDH1 (R132C and R132H) or IDH2 (R172S) mutations in 87% of enchondromas, benign cartilage tumors, and in 70% of spindle cell hemangiomas, benign vascular lesions. In total, 35 of 43 (81%) patients with Ollier disease and 10 of 13 (77%) patients with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of sixteen patients displayed identical mutations in separate lesions. Immunohistochemistry for mutant R132H IDH1 protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors are associated with hypermethylation and downregulation of expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, enabling functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.
PMCID: PMC3427908  PMID: 22057234
7.  Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision 
Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.
PMCID: PMC3166781  PMID: 21438135
skeletal genetics; osteochondrodysplasias; nosology; dysostoses; molecular basis of disease
8.  Ollier disease 
Enchondromas are common intraosseous, usually benign cartilaginous tumors, that develop in close proximity to growth plate cartilage. When multiple enchondromas are present, the condition is called enchondromatosis also known as Ollier disease (WHO terminology). The estimated prevalence of Ollier disease is 1/100,000. Clinical manifestations often appear in the first decade of life. Ollier disease is characterized by an asymmetric distribution of cartilage lesions and these can be extremely variable (in terms of size, number, location, evolution of enchondromas, age of onset and of diagnosis, requirement for surgery). Clinical problems caused by enchondromas include skeletal deformities, limb-length discrepancy, and the potential risk for malignant change to chondrosarcoma. The condition in which multiple enchondromatosis is associated with soft tissue hemangiomas is known as Maffucci syndrome. Until now both Ollier disease and Maffucci syndrome have only occurred in isolated patients and not familial. It remains uncertain whether the disorder is caused by a single gene defect or by combinations of (germ-line and/or somatic) mutations. The diagnosis is based on clinical and conventional radiological evaluations. Histological analysis has a limited role and is mainly used if malignancy is suspected. There is no medical treatment for enchondromatosis. Surgery is indicated in case of complications (pathological fractures, growth defect, malignant transformation). The prognosis for Ollier disease is difficult to assess. As is generally the case, forms with an early onset appear more severe. Enchondromas in Ollier disease present a risk of malignant transformation of enchondromas into chondrosarcomas.
PMCID: PMC1592482  PMID: 16995932
9.  Glycogen storage disease type III-hepatocellular carcinoma a long-term complication? 
Journal of hepatology  2006;46(3):492-498.
Glycogen storage disease III (GSD III) is caused by a deficiency of glycogen-debranching enzyme which causes an incomplete glycogenolysis resulting in glycogen accumulation with abnormal structure (short outer chains resembling limit dextrin) in liver and muscle. Hepatic involvement is considered mild, self-limiting and improves with age. With increased survival, a few cases of liver cirrhosis and hepatocellular carcinoma (HCC) have been reported.
A systematic review of 45 cases of GSD III at our center (20 months to 67 years of age) was reviewed for HCC, 2 patients were identified. A literature review of HCC in GSD III was performed and findings compared to our patients.
GSD III patients are at risk for developing HCC. Cirrhosis was present in all cases and appears to be responsible for HCC transformation There are no reliable biomarkers to monitor for HCC in GSD III. Systematic evaluation of liver disease needs be continued in all patients, despite lack of symptoms. Development of guidelines to allow for systematic review and microarray studies are needed to better delineate the etiology of the hepatocellular carcinoma in patients with GSD III.
PMCID: PMC2683272  PMID: 17196294
Hepatocellular carcinoma; Glycogen storage disease type III; Liver cirrhosis; Debranching enzyme deficiency; Cori disease; Hepatomegaly; Hypoglycemia
Sleep medicine  2011;13(1):52-57.
To explore how insomnia symptoms are hierarchically organized in individuals reporting daytime consequences of their sleep disturbances.
This is a cross-sectional study conducted in the general population of the states of California, New York and Texas. The sample included 8,937 individuals aged 18 years or older representative of the general population. Telephone interviews on sleep habits and disorders were managed with the Sleep-EVAL expert system and using DSM-IV and ICSD classifications. Insomnia symptoms and Global Sleep Dissatisfaction (GSD) had to occur at least three times per week for at least three months.
A total of 26.2% of the sample had a GSD. Individuals with GSD reported at least one insomnia symptom in 73.1% of the cases. The presence of GSD in addition to insomnia symptoms considerably increased the proportion of individuals with daytime consequences related to insomnia. In the classification trees performed, GSD arrived as the first predictor for daytime consequences related to insomnia. The second predictor was nonrestorative sleep followed by difficulty resuming sleep and difficulty initiating sleep.
Classification trees are a useful way to hierarchically organize symptoms and to help diagnostic classifications. In this study, GSD was found to be the foremost symptom in identifying individuals with daytime consequences related to insomnia.
PMCID: PMC3249005  PMID: 22036602
11.  PTHR1 mutations associated with Ollier disease result in receptor loss of function 
Human Molecular Genetics  2008;17(18):2766-2775.
PTHR1-signaling pathway is critical for the regulation of endochondral ossification. Thus, abnormalities in genes belonging to this pathway could potentially participate in the pathogenesis of Ollier disease/Maffucci syndrome, two developmental disorders defined by the presence of multiple enchondromas. In agreement, a functionally deleterious mutation in PTHR1 (p.R150C) was identified in enchondromas from two of six unrelated patients with enchondromatosis. However, neither the p.R150C mutation (26 tumors) nor any other mutation in the PTHR1 gene (11 patients) could be identified in another study. To further define the role of PTHR1-signaling pathway in Ollier disease and Maffucci syndrome, we analyzed the coding sequences of four genes (PTHR1, IHH, PTHrP and GNAS1) in leucocyte and/or tumor DNA from 61 and 23 patients affected with Ollier disease or Maffucci syndrome, respectively. We identified three previously undescribed missense mutations in PTHR1 in patients with Ollier disease at the heterozygous state. Two mutations (p.G121E, p.A122T) were present only in enchondromas, and one (p.R255H) in both enchondroma and leukocyte DNA. Assessment of receptor function demonstrated that these three mutations impair PTHR1 function by reducing either the affinity of the receptor for PTH or the receptor expression at the cell surface. These mutations were not found in DNA from 222 controls. Including our data, PTHR1 functionally deleterious mutations have now been identified in five out 31 enchondromas from Ollier patients. These findings provide further support for the idea that heterozygous mutations in PTHR1 that impair receptor function participate in the pathogenesis of Ollier disease in some patients.
PMCID: PMC2722890  PMID: 18559376
12.  Two Cases of Pulmonary Hypertension Associated with Type III Glycogen Storage Disease 
JIMD Reports  2011;1:79-82.
Glycogen storage diseases (GSDs) comprise a large, heterogeneous group of disorders characterized by abnormal glycogen deposition. Multiple cases in the literature have demonstrated an association between GSD type I and pulmonary arterial hypertension (PAH). We now also report on two patients with GSD type III and PAH, a novel association. The first patient was a 16-year-old girl of Nicaraguan descent with a history of hepatomegaly and growth retardation. Molecular testing identified a homozygous 17delAG mutation in AGL consistent with GSD type IIIb. At the age of 16, she was found to have PAH and was started on medical therapy. Two years later, she developed acute chest pain and died shortly thereafter. The second patient is a 13-year-old girl of Colombian descent homozygous for the c.3911dupA mutation consistent with GSD IIIa. An echocardiogram at age 2 showed left ventricular hypertrophy, which resolved following the institution of a high protein, moderate carbohydrate diet during the day and continuous gastric-tube feeding overnight. At the age of 12, she was found to have pulmonary hypertension. She was started on sildenafil, and her clinical status has shown marked improvement including normalization of her elevated transaminases. PAH may be a rare association in patients with GSD IIIa and IIIb and should be evaluated with screening echocardiograms for cardiac hypertrophy or if they present with symptoms of right-sided heart failure such as shortness of breath, chest pain, cyanosis, fatigue, dizziness, syncope, or edema. Early diagnosis of PAH is important as increasingly effective treatments are now available.
PMCID: PMC3509822  PMID: 23430832
Amylo-1,6-glucosidase; Genetic; Hepatomegaly; Metabolic
13.  Cardiac Involvement in Glycogen Storage Disease Type IV: Two Cases and the Two Ends of a Spectrum 
Case Reports in Medicine  2012;2012:764286.
Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder due to the deficiency of α 1,4-glucan branching enzyme, resulting in an accumulation of amylopectin-like polysaccharide in various systems. We describe two cases, a 23-year-old girl with dilated cardiomyopathy who presented with progressive dyspnea and fatigue and a 28-year-old girl with hypertrophic cardiomyopathy who was asymptomatic, secondary to the accumulation of amylopectin-like fibrillar glycogen, in heart. In both patients, the diagnosis was confirmed by enzyme assessment. Our patients showed that GSD IV is not only liver or skeletal muscle disease, but also it can be presented in different form of the spectrum of cardiomyopathy from dilated to hypertrophic and from asymptomatic to decompensated heart failure. Also, to our knowledge, this is the first hypertrophic cardiomyopathy case due to GSD IV in the literature.
PMCID: PMC3463931  PMID: 23056054
14.  Incidence, Predictive Factors, and Prognosis of Chondrosarcoma in Patients with Ollier Disease and Maffucci Syndrome: An International Multicenter Study of 161 Patients 
The Oncologist  2011;16(12):1771-1779.
The results of a European retrospective, multicenter study led by the European Musculoskeletal Oncology Society on the clinical behavior and characteristics of enchondromas in patients with Ollier disease and Maffucci syndrome are reported, with the goals of better defining the presentation and characteristics of enchondromas in these patients, estimating the cumulative probability of secondary transformation of enchondromas over a lifetime, and finding variables significantly associated with this latter outcome and mortality.
Learning Objectives
After completing this course, the reader will be able to: Describe major enchondroma distribution patterns that were identified in this study.Identify variables that are predictive for the secondary transformation of enchondroma over the lifetime of individuals with Ollier disease or Maffucci syndrome.
This article is available for continuing medical education credit at
Enchondromatosis is characterized by the presence of multiple benign cartilage lesions in bone. While Ollier disease is typified by multiple enchondromas, in Maffucci syndrome these are associated with hemangiomas. Studies evaluating the predictive value of clinical symptoms for development of secondary chondrosarcoma and prognosis are lacking. This multi-institute study evaluates the clinical characteristics of patients, to get better insight on behavior and prognosis of these diseases.
A retrospective study was conducted using clinical data of 144 Ollier and 17 Maffucci patients from 13 European centers and one national databank supplied by members of the European Musculoskeletal Oncology Society.
Patients had multiple enchondromas in the hands and feet only (group I, 18%), in long bones including scapula and pelvis only (group II, 39%), and in both small and long/flat bones (group III, 43%), respectively. The overall incidence of chondrosarcoma thus far is 40%. In group I, only 4 patients (15%) developed chondrosarcoma, in contrast to 27 patients (43%) in group II and 26 patients (46%) in group III, respectively. The risk of developing chondrosarcoma is increased when enchondromas are located in the pelvis (odds ratio, 3.8; p = 0.00l).
Overall incidence of development of chondrosarcoma is 40%, but may, due to age-dependency, increase when considered as a lifelong risk. Patients with enchondromas located in long bones or axial skeleton, especially the pelvis, have a seriously increased risk of developing chondrosarcoma, and are identified as the population that needs regular screening on early detection of malignant transformation.
PMCID: PMC3248776  PMID: 22147000
Enchondroma; Chondrosarcoma; Ollier disease; Maffucci syndrome
15.  Refinement of the 12q14 microdeletion syndrome: primordial dwarfism and developmental delay with or without osteopoikilosis 
European Journal of Human Genetics  2009;17(9):1141-1147.
In their studies on the molecular basis of osteopoikilosis, Menten et al have identified three individuals with microdeletions on chromosome 12q14.4, which removed several genes including LEMD3, the osteopoikilosis gene. In addition to osteopoikilosis, affected individuals had growth retardation and developmental delay. We now report a smaller 12q14.4 microdeletion in a boy with severe pre and postnatal growth failure, and mild developmental delay; the patient was small at birth and presented with poor feeding and failure to thrive during the first 2 years of life, similar to the phenotype of primordial dwarfism or severe Silver-Russell syndrome (SRS). The 12q14 deletion did not include LEMD3, and no signs of osteopoikilosis were observed on skeletal radiographs. Among the deleted genes, HMGA2 is of particular interest in relationship to the aberrant somatic growth in our patient, as HMGA2 variants have been linked to stature variations in the general population and loss of function of Hmga2 in the mouse results in the pygmy phenotype that combines pre and postnatal growth failure, with resistance to the adipogenic effect of overfeeding. Sequencing of the remaining HMGA2 allele in our patient showed a normal sequence, suggesting that HMGA2 haploinsufficiency may be sufficient to produce the aberrant growth phenotype. We conclude that the 12q14.4 microdeletion syndrome can occur with or without deletion of LEMD3 gene; in LEMD3-intact cases, the phenotype includes primordial short stature and failure to thrive with moderate developmental delay, but osteopoikilosis is absent. Such cases will likely be diagnosed as Silver-Russell-like or as primordial dwarfism.
PMCID: PMC2986596  PMID: 19277063
HMGA2; silver-russell phenotype; primordial dwarfism; 12q14 microdeletion; array-CGH
16.  Bone scintigraphy in Ollier's disease: A rare case report 
Ollier's disease is characterized by multiple skeletal enchondroma. There are published data regarding Ollier's disease being associated with vascular malformations and non-skeletal neoplasms. We report a case of Ollier's disease in a young male associated with osteochondroma, low grade glioma in the insular cortex of brain and Gilbert's syndrome. Technetium-99m methylene diphosphonate whole body bone scan is a sensitive investigation to ascertain the complete extent of skeletal involvement particularly the asymptomatic sites.
PMCID: PMC3866668  PMID: 24379533
Bone scan; glioma; Ollier's disease; osteochondroma; technetium-99m methylene diphosphonate
17.  A Review of the Principles of Radiological Assessment of Skeletal Dysplasias 
There are more than 450 well-characterized skeletal dysplasias classified primarily on the basis of clinical, radiographic, and molecular criteria. In the latest 2010 revision of the Nosology and Classification of Genetic Skeletal Disorders, an increase from 372 to 456 disorders had occurred in the four years since the classification was last revisited in 2007. These entities in total represent about 5% of children with birth defects. An accurate diagnosis of a skeletal dysplasia is still based on detailed evaluation of clinical and radiographic [as well as chondro-osseous] findings. Regardless of the specific diagnosis, skeletal dysplasias in general share clinical and radiological findings helping us to group them in several ways. This review aims to outline the diagnostic approach to disproportionate short stature with special emphasis on radiological findings.
Conflict of interest:None declared.
PMCID: PMC3245489  PMID: 22155458
Skeletal dysplasia; disproportionate short stature; Radiology
18.  Involvement of endocrine system in a patient affected by Glycogen storage disease 1b: speculation on the role of autoimmunity 
Glycogen storage disease type 1b (GSD1b) is an inherited metabolic defect of glycogenolysis and gluconeogenesis due to mutations of the SLC37A4 gene and to defective transport of glucose-6-phosphate. The clinical presentation of GSD1b is characterized by hepatomegaly, failure to thrive, fasting hypoglycemia, and dyslipidemia. Patients affected by GSD1b also show neutropenia and/or neutrophil dysfunction that cause increased susceptibility to recurrent bacterial infections. GSD1b patients are also at risk for inflammatory bowel disease. Occasional reports suggesting an increased risk of autoimmune disorders in GSD1b patients, have been published. These complications affect the clinical outcome of the patients. Here we describe the occurrence of autoimmune endocrine disorders including thyroiditis and growth hormone deficiency, in a patient affected by GSD1b. This case further supports the association between GSD1b and autoimmune diseases.
PMCID: PMC3974180  PMID: 24646511
Glycogen storage disease 1b; Autoimmunity; Thyroiditis; Growth hormone deficiency; Inflammatory bowel disease
19.  A rare benign disorder mimicking metastasis on radiographic examination: a case report of osteopoikilosis 
Rheumatology International  2010;31(8):1113-1116.
Osteopoikilosis (OPK) is a rare, autosomal dominant bone disorder, characterized by multiple, discrete round or ovoid radio densities scattered throughout the axial and appendicular skeleton. OPK is usually asymptomatic but rarely there may be slight articular pain and joint effusions. OPK is generally diagnosed incidentally on radiographic examinations and may mimic different bone pathologies, including bone metastases. Radionuclide bone scan has a critical role in distinguishing OPK from osteoblastic bone metastases. In this case report, we present a young man with right hip pain due to OPK, whose plain radiogram and computerized tomography findings thought cancer metastasis.
PMCID: PMC3141847  PMID: 21120491
Osteopoikilosis; Computerized tomography; Sclerotic bone lesions; Metastasis
20.  Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib 
Genetics and Molecular Biology  2013;36(4):502-506.
Glycogen storage disease (GSD) comprises a group of autosomal recessive disorders characterized by deficiency of the enzymes that regulate the synthesis or degradation of glycogen. Types Ia and Ib are the most prevalent; while the former is caused by deficiency of glucose-6-phosphatase (G6Pase), the latter is associated with impaired glucose-6-phosphate transporter, where the catalytic unit of G6Pase is located. Over 85 mutations have been reported since the cloning of G6PC and SLC37A4 genes. In this study, twelve unrelated patients with clinical symptoms suggestive of GSDIa and Ib were investigated by using genetic sequencing of G6PC and SLC37A4 genes, being three confirmed as having GSD Ia, and two with GSD Ib. In seven of these patients no mutations were detected in any of the genes. Five changes were detected in G6PC, including three known point mutations (p.G68R, p.R83C and p.Q347X) and two neutral mutations (c.432G > A and c.1176T > C). Four changes were found in SLC37A4: a known point mutation (p.G149E), a novel frameshift insertion (c.1338_1339insT), and two neutral mutations (c.1287G > A and c.1076-28C > T). The frequency of mutations in our population was similar to that observed in the literature, in which the mutation p.R83C is also the most frequent one. Analysis of both genes should be considered in the investigation of this condition. An alternative explanation to the negative results in this molecular study is the possibility of a misdiagnosis. Even with a careful evaluation based on laboratory and clinical findings, overlap with other types of GSD is possible, and further molecular studies should be indicated.
PMCID: PMC3873180  PMID: 24385852
DNA-based diagnosis; glycogen storage disease; G6PC; SLC37A4; mutation
21.  Osteopoikilosis: a case report of a symptomatic patient 
Osteopoikilosis (OP) is a very rare benign sclerosing bony dysplasia with an autosomal dominant inheritance. We describe the morphology of an osteopoikilosis male patient, associated with severe pain on wrist and hand joints, report on the relative literature and focus on clinical significance, due to mimicking capability of other more severe conditions such as bone metastases.
PMCID: PMC3303288  PMID: 22470634
Osteopoikilosis; severe pain; differential diagnosis
22.  Genotype-phenotype correlation in hereditary multiple exostoses 
Journal of Medical Genetics  2001;38(7):430-434.
Hereditary multiple exostoses (HME) is a genetically heterogeneous autosomal dominant disorder characterised by the development of bony protuberances mainly located on the long bones. Three HME loci have been mapped to chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3). The EXT1 and EXT2 genes encode glycosyltransferases involved in biosynthesis of heparan sulphate proteoglycans. Here we report on a clinical survey and mutation analysis of 42 HME French families and show that EXT1 and EXT2 accounted for more than 90% of HME cases in our series. Among them, 27/42 cases were accounted for by EXT1 (64%, four nonsense, 19 frameshift, three missense, and one splice site mutations) and 9/42 cases were accounted for by EXT2 (21%, four nonsense, two frameshift, two missense, and one splice site mutation). Overall, 31/36 mutations were expected to cause loss of protein function (86%). The most severe forms of the disease and malignant transformation of exostoses to chondrosarcomas were associated with EXT1 mutations. These findings provide the first genotype-phenotype correlation in HME and will, it is hoped, facilitate the clinical management of these patients.

Keywords: hereditary multiple exostoses; EXT1; EXT2; chondrosarcoma
PMCID: PMC1757186  PMID: 11432960
23.  Anatomical variation of co-existence of 4th and 5th short metacarpal bones, sesamoid ossicles and exostoses of ulna and radius in the same hand: a case report 
Cases Journal  2008;1:281.
The anatomical variations of bones in the hand are common. The existence of exostosis and shortening of metacarpal bones has been described in the literature as part of the hereditary multiple exostosis syndrome but no case has been reported with the co-existence of sesamoid ossicles in the same patient.
Case presentation
We report a case with co-existence of distal ulnar and radial exostoses, 4th and 5th short metacarpals and sesamoid ossicles in the wrist area.
This variation may help the interpretation of pain or sensory disorders in the hand and wrist areas.
PMCID: PMC2586011  PMID: 18959780
24.  The prevalence of thanatophoric dysplasia and lethal osteogenesis imperfecta type II in Northern Ireland - a complete population study 
The Ulster Medical Journal  2010;79(3):114-118.
The minimum prevalence of lethal Osteogenesis imperfecta type II, thanatophoric dysplasia and achondroplasia were derived following detailed case note review of all perinatal lethal skeletal dysplasias (SD) in Northern Ireland over a 12 year period. Multiple sources of ascertainment, including genetic notes, radiological reports and post mortem findings, were used. 39 cases were identified. Thanatophoric dysplasia was the commonest diagnosis made (22), followed by osteogenesis imperfecta type II (four children) and achondroplasia (two children). Eleven other diagnoses each occurred once in the 12 year period. The minimum prevalence range, per live births, of each of the common skeletal dysplasias in Northern Ireland has been calculated; thanatophoric dysplasia 0.80/10,000, osteogenesis imperfecta type II 0.15/10,000 and achondroplasia 0.07/10,000. The prevalence range for thanatophoric dysplasia is much higher than reported in previous studies. We discuss reasons for the prevalence figures obtained.
PMCID: PMC3284715  PMID: 22375084
Thanatophoric dysplasia; osteogenesis imperfecta type II; achondroplasia; prevalence; lethal skeletal dysplasias
25.  The Size of Endotracheal Tube and Sore Throat after Surgery: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(10):e74467.
Recent studies showed that sore throat following endotracheal intubation was a common problem following surgery. The objective of this systematic review and meta-analysis of published randomized controlled trials (RCTs) or cohort studies was to estimate whether the size of endotracheal tube (ETT) affects the incidence of postoperative sore throat (POST) after general anesthesia.
The following databases were searched electronically: PubMed (updated to Dec 2012), EMBASE (updated to 15 Dec 2012), Google scholar, World Health Organization International Clinical Trials Registry Platform (Jul 2011), Chinese BioMedical Literature Database (1978 to Jul 2011), and China National Knowledge Infrastructure (1994 to Jul 2011). Studies comparing the size of endotracheal tube for elective surgery were included.
Three trials with a total of 509 female patients were included in the current analysis. The size of ETT used were 6.0 mm and 7.0 mm. Pooled studies from these trials showed that the smaller size of ETT (6.0 mm) significantly decreased the incidence of POST in post-anesthesia care unit (PACU) (RR = 0.56, 95% CI 0.42–0.75, P<0.01) and at 24 h after surgery (RR = 0.69, 95% CI 0.48–0.99, P<0.05). A smaller size of ETT (6.0 mm) was associated with a lower incidence of PH in PACU (RR = 0.69, 95% CI 0.55–0.87, P<0.01), but did not affect the incidence of PH at 24 h after surgery (RR = 0.73, 95% CI 0.46–1.15, P>0.05).
Our meta-analysis suggests that patients under general anesthesia with a smaller size of ETT (6.0 mm) were associated with a lower incidence of POST in female patients. More studies with adequate numbers of patients were warranted to evaluate other size of ETT on the incidence of PH and POST after general surgery among different populations.
PMCID: PMC3790787  PMID: 24124452

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