Publications by authors named "Trevor Cole"

96 Publications

The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma.

Cancers (Basel) 2021 Mar 29;13(7). Epub 2021 Mar 29.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.

Retinoblastoma is a childhood eye cancer, mainly caused by mutations in the gene, which can be somatic or constitutional. Unlike many other cancers, tumour biopsies are not performed due to the risk of tumour dissemination. As a result, until recently, somatic genetic analysis was only possible if an affected eye was removed as part of a treatment. Several recent proof of principle studies have demonstrated that the analysis of tumour-derived cell-free DNA, either obtained from ocular fluid or blood plasma, has the potential to advance the diagnosis and influence the prognosis of retinoblastoma patients. It has been shown that a confirmed diagnosis is possible in retinoblastoma patients undergoing conservative treatment. In vivo genetic analysis of retinoblastoma tumours is also now possible, allowing the potential identification of secondary genetic events as prognostic biomarkers. In addition, noninvasive prenatal diagnosis in children at risk of inheriting retinoblastoma has been developed. Here, we review the current literature and discuss the potential impact of cell-free DNA analysis on both the diagnosis and treatment of retinoblastoma patients and their families.
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http://dx.doi.org/10.3390/cancers13071570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037190PMC
March 2021

Non-Invasive Prenatal Diagnosis of Retinoblastoma Inheritance by Combined Targeted Sequencing Strategies.

J Clin Med 2020 Oct 30;9(11). Epub 2020 Oct 30.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.

Retinoblastoma, the most common childhood eye cancer, presents in two forms: heritable or sporadic. Heritable retinoblastoma is caused by a germline mutation in the gene. Early diagnosis of children at risk of inheriting an mutation is crucial to achieve optimal clinical outcome. Currently, the majority of genetic testing is performed on newborns, which has multiple disadvantages for both families and the healthcare system. We have developed a non-invasive prenatal diagnosis (NIPD) service for retinoblastoma, available from 8 weeks' gestation, which uses a combination of massively parallel sequencing (MPS) techniques, dependent on the inheritance model. Detection of paternal or suspected de novo variants is achieved through amplicon-based MPS. NIPD of a fetus at risk of maternal inheritance is performed using capture-based targeted sequencing and relative haplotype dosage analysis. In addition, we show proof of principle of how capture-based sequencing can be used for de novo variants unsuitable for amplicon-based testing. In total, we report the NIPD of 15 pregnancies, results of which show 100% concordance with all postnatal testing performed at the time of publication ( = 12) with remaining pregnancies ongoing. NIPD of retinoblastoma therefore offers a viable alternative to newborn genetic testing.
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http://dx.doi.org/10.3390/jcm9113517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692133PMC
October 2020

Carpal tunnel syndrome in paediatric patients: A novel association with Kosaki overgrowth syndrome.

JPRAS Open 2020 Sep 27;25:83-87. Epub 2020 Jul 27.

Hand and Upper Limb Service, Plastic and Reconstructive Surgery, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

Carpal tunnel syndrome in a paediatric population is vanishingly rare and usually associated with lysosomal storage disorders such as mucopolysaccharidosis (MPS). Overgrowth syndromes similarly are rare and are characterised by increased skeletal growth alongside typical dysmorphic features and intellectual delay and as such the acronym OGID (overgrowth intellectual delay) is now widely used. Kosaki overgrowth syndrome (KOGS) is a newly recognised OGID with only 6 cases to date reported in the literature. Here we report a 7th case of KOGS with a new finding of carpal tunnel syndrome not previously described. We discuss similarities between the intraoperative findings during carpal tunnel decompression with findings seen in patients with MPS.
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http://dx.doi.org/10.1016/j.jpra.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451825PMC
September 2020

Clinical Service Delivery of Noninvasive Prenatal Diagnosis by Relative Haplotype Dosage for Single-Gene Disorders.

J Mol Diagn 2020 09 15;22(9):1151-1161. Epub 2020 Jun 15.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Edgbaston, United Kingdom.

A relative haplotype dosage (RHDO)-based method was developed and implemented into routine clinical practice for noninvasive prenatal diagnosis (NIPD) of multiple single-gene disorders: spinal muscular atrophy, Duchenne and Becker muscular dystrophies, and cystic fibrosis. This article describes the experiences of the first 152 pregnancies to have NIPD by RHDO as part of a routine clinical service. Provision of results within a clinically useful time frame (mean, 11 calendar days) was shown to be possible, with a very low failure rate (4%), none being due to a technical failure. Where follow-up confirmatory testing was performed for audit purposes, 100% concordance was seen with the NIPD result, and no discrepancies have been reported. The robust performance of the assay, together with high sensitivity and specificity, demonstrates that NIPD by RHDO is feasible for use in a clinical setting.
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http://dx.doi.org/10.1016/j.jmoldx.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471768PMC
September 2020

Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications.

Clin Genet 2020 07 4;98(1):19-31. Epub 2020 May 4.

Centre de Génétique et Centre de référence « Anomalies du Développement et Syndromes Malformatifs », Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France.

Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS-like disorders and suggest vascular imaging is indicated in these patients.
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http://dx.doi.org/10.1111/cge.13752DOI Listing
July 2020

The evolving therapeutic landscape of genetic skeletal disorders.

Orphanet J Rare Dis 2019 12 30;14(1):300. Epub 2019 Dec 30.

West Midlands Clinical Genetics Unit, Birmingham Women's and Children's NHS FT and Birmingham Health Partners, Birmingham, UK.

Background: Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials.

Methods: A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review.

Results: Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP.

Discussion: It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.
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http://dx.doi.org/10.1186/s13023-019-1222-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937740PMC
December 2019

The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.

Am J Med Genet C Semin Med Genet 2019 12 13;181(4):557-564. Epub 2019 Nov 13.

David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, California.

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.
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http://dx.doi.org/10.1002/ajmg.c.31749DOI Listing
December 2019

Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients.

Am J Med Genet C Semin Med Genet 2019 12 12;181(4):638-643. Epub 2019 Nov 12.

South West Thames Regional Genetics Service, St George's University NHS Foundation Trust, London, UK.

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.
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http://dx.doi.org/10.1002/ajmg.c.31750DOI Listing
December 2019

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.

Genet Med 2020 03 3;22(3):524-537. Epub 2019 Oct 3.

CHU de Rennes, service de génétique clinique, Rennes, France.

Purpose: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.

Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated.

Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.

Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
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http://dx.doi.org/10.1038/s41436-019-0657-0DOI Listing
March 2020

The phenotype of Sotos syndrome in adulthood: A review of 44 individuals.

Am J Med Genet C Semin Med Genet 2019 12 3;181(4):502-508. Epub 2019 Sep 3.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
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http://dx.doi.org/10.1002/ajmg.c.31738DOI Listing
December 2019

Initial Validation of IBD KNOW-IT: Measuring Patient and Caregiver Knowledge of a Child's Disease and Treatment Regimen.

J Clin Psychol Med Settings 2020 09;27(3):480-489

Division of Health Services and Outcomes Research, Children's Mercy-Kansas City, Kansas City, MO, USA.

The present study describes the development and initial validation of a newly developed measure of child and caregiver knowledge of the child's own IBD and treatment, called IBD KNOW-IT. One hundred and fifty-five children and their caregivers completed the IBD KNOW-IT as well as a scale designed to compare each dyad's perceived knowledge to their actual knowledge. Initial psychometric evaluation of IBD KNOW-IT was completed by conducting factor analysis and determining internal consistency, convergent validity, and associations with demographic and medical characteristics. Results supported the validity of a 12-item measure with 4 subscales including Symptoms, Medication Regimen, Disease Monitoring, and Medical Team. Support for the internal consistency of IBD KNOW-IT was obtained. Evidence of validity was demonstrated by significant correlations between child and caregiver scales, and high congruence between perceived and actual knowledge across all subscales. The reliability of the measure was demonstrated by good internal consistency and test-retest reliability. Preliminary psychometric evaluation suggests that IBD KNOW-IT is reliable and valid.
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http://dx.doi.org/10.1007/s10880-019-09636-0DOI Listing
September 2020

Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling.

J Clin Endocrinol Metab 2019 10;104(10):4304-4318

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts.

Context: Kisspeptin-neurokinin B (NKB)-dynorphin neurons are critical regulators of the hypothalamic-pituitary-gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear.

Objective: To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB.

Design: Case/control.

Setting: Academic medical center.

Participants: Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice.

Interventions: Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin.

Main Outcome Measures: LH pulse characteristics.

Results: Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin.

Conclusion: The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.
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http://dx.doi.org/10.1210/jc.2019-00146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736049PMC
October 2019

Identification of new Wilms tumour predisposition genes: an exome sequencing study.

Lancet Child Adolesc Health 2019 05 16;3(5):322-331. Epub 2019 Mar 16.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK. Electronic address:

Background: Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour.

Methods: In this exome sequencing study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers.

Findings: We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p<0·0001). Finally, we identified two de-novo KDM3B mutations, supporting the role of KDM3B as a childhood cancer predisposition gene.

Interpretation: The four new Wilms tumour predisposition genes identified-TRIM28, FBXW7, NYNRIN, and KDM3B-are involved in diverse biological processes and, together with the other 17 known Wilms tumour predisposition genes, account for about 10% of Wilms tumour cases. The overlap between these 21 constitutionally mutated predisposition genes and 20 genes somatically mutated in Wilms tumour is limited, consisting of only four genes. We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing. Only a third of the familial Wilms tumour clusters we analysed were attributable to known genes, indicating that further Wilms tumour predisposition factors await discovery.

Funding: Wellcome Trust.
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http://dx.doi.org/10.1016/S2352-4642(19)30018-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472290PMC
May 2019

EED and EZH2 constitutive variants: A study to expand the Cohen-Gibson syndrome phenotype and contrast it with Weaver syndrome.

Am J Med Genet A 2019 04 21;179(4):588-594. Epub 2019 Feb 21.

Department of Clinical Genetics, St George's University of London, London, United Kingdom.

Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen-Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.
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http://dx.doi.org/10.1002/ajmg.a.61066DOI Listing
April 2019

Non-invasive diagnosis of retinoblastoma using cell-free DNA from aqueous humour.

Br J Ophthalmol 2019 Feb 11. Epub 2019 Feb 11.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

Retinoblastoma is the most common eye malignancy in childhood caused by mutations in the gene. Both alleles of the gene must be mutated for tumour development. The initial mutation may be constitutional germline or somatic (originating in one retinal cell only). Distinguishing between these alternative mechanisms is crucial, with wider implications for management of the patient and family members. Bilateral retinoblastoma is nearly always due to a constitutional mutation; however, approximately 15% of unilateral cases also carry a germline mutation, and identifying these cases is important. This can be achieved by identifying both mutation types in tumour tissue and excluding their presence in blood. Modern eye-saving chemotherapy treatment (systemic, intra-arterial and intravitreal) has resulted in fewer enucleations. As a result, tumour tissue required to identify sporadic mutation(s) is not always available. Modern intravitreal chemotherapeutic techniques for retinoblastoma involve aspiration of aqueous humour (AH), providing a novel sample source for analysis. By analysing cell-free DNA present in the AH fluid of eyes affected with retinoblastoma, we have developed a screening test capable of detecting somatic mutations that is comparable to current tests on enucleated tumour tissue. The results obtained with fluid from enucleated eyes were concordant with tumour tissue in all 10 cases analysed. In addition, AH analysis from two patients undergoing intravitreal chemotherapy successfully identified somatic variants in both cases. Our findings suggest that AH fluid is a promising source of tumour-derived DNA in retinoblastoma for analysis.
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http://dx.doi.org/10.1136/bjophthalmol-2018-313005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709774PMC
February 2019

Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing.

Genome Med 2018 12 7;10(1):95. Epub 2018 Dec 7.

Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, CB2 0PT, UK.

Background: Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation.

Methods: We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case.

Results: We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements.

Conclusions: Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.
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http://dx.doi.org/10.1186/s13073-018-0606-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286558PMC
December 2018

EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome.

Hum Mutat 2019 02 29;40(2):142-161. Epub 2018 Nov 29.

Department of Pediatrics, University of California, San Diego, La Jolla, California.

The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane-bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3' end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Here, we report 13 novel EPCAM mutations from 17 CTE patients from two separate centers, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic missense mutations. Statistical analyses indicate that the c.499dupC (previously reported as c.498insC) frameshift mutation was associated with more severe treatment regimens and greater mortality in CTE, whereas the c.556-14A>G and c.491+1G>A splice site mutations were not correlated with treatments or outcomes significantly different than random simulation. These findings suggest that genotype-phenotype correlations may be useful in contributing to management decisions of CTE patients. Depending on the type and nature of EPCAM mutation, one of two unrelated diseases may occur, CTE or Lynch syndrome.
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http://dx.doi.org/10.1002/humu.23688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328345PMC
February 2019

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Am J Hum Genet 2018 07 14;103(1):3-18. Epub 2018 Jun 14.

North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037202PMC
July 2018

Further delineation of Malan syndrome.

Hum Mutat 2018 09 25;39(9):1226-1237. Epub 2018 Jun 25.

Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern Ireland.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
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http://dx.doi.org/10.1002/humu.23563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175110PMC
September 2018

Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes , and .

J Med Genet 2018 06 31;55(6):384-394. Epub 2018 Jan 31.

West Midlands Regional Genetics service, Birmingham Women's Hospital, Birmingham, UK.

Background: Germline pathogenic variants in / are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of / mutation carriers.

Methods: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in / (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.

Results: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in and (paternally inherited) mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).

Conclusions: Overall risks of clinically apparent tumours for mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for / mutation carriers.
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http://dx.doi.org/10.1136/jmedgenet-2017-105127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992372PMC
June 2018

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Nat Rev Endocrinol 2018 04 29;14(4):229-249. Epub 2018 Jan 29.

South West Thames Regional Genetics Service and St George's University of London and Institute of Cancer Research, London, SW17 0RE, UK.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
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http://dx.doi.org/10.1038/nrendo.2017.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022848PMC
April 2018

Heterozygous mutations affecting the protein kinase domain of cause a syndromic form of developmental delay and intellectual disability.

J Med Genet 2018 01 11;55(1):28-38. Epub 2017 Oct 11.

Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.

Introduction: Recent evidence has emerged linking mutations in to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with mutations.

Methods: Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.

Results: Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.

Conclusions: These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.
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http://dx.doi.org/10.1136/jmedgenet-2017-104620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749303PMC
January 2018

, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.

EMBO Mol Med 2017 10;9(10):1379-1397

Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital, Lausanne, Switzerland

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 () is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function mutations in 13 patients (4%). Most patients with mutations (9/13) exhibited metabolic defects. In mice, lack of led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.
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http://dx.doi.org/10.15252/emmm.201607376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623842PMC
October 2017

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability.

Am J Hum Genet 2017 May;100(5):725-736

Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. Electronic address:

To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a product that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and in DNA binding and protein-protein interactions because key residues are truncated. Functional network analyses demonstrated that epigenetic regulation is a prominent biological process dysregulated in individuals with OGID. Mutations in six epigenetic regulation genes-NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED-accounted for 44% of individuals (311/710). There was significant overlap between the 14 genes involved in OGID and 611 genes in regions identified in GWASs to be associated with height (p = 6.84 × 10), suggesting that a common variation impacting function of genes involved in OGID influences height at a population level. Increased cellular growth is a hallmark of cancer and there was striking overlap between the genes involved in OGID and 260 somatically mutated cancer driver genes (p = 1.75 × 10). However, the mutation spectra of genes involved in OGID and cancer differ, suggesting complex genotype-phenotype relationships. These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield.
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http://dx.doi.org/10.1016/j.ajhg.2017.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420355PMC
May 2017

Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect.

J Clin Endocrinol Metab 2017 06;102(6):2019-2028

Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.

Context: Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI) by dysregulating intracellular calcium flux.

Objectives: Clinical and bone material phenotype description and osteoblast differentiation studies.

Design And Setting: Natural history study in pediatric research centers.

Patients: Eight patients with type XIV OI.

Main Outcome Measures: Clinical examinations included bone mineral density, radiographs, echocardiography, and muscle biopsy. Bone biopsy samples (n = 3) were analyzed using histomorphometry, quantitative backscattered electron microscopy, and Raman microspectroscopy. Cellular differentiation studies were performed on proband and control osteoblasts and normal murine osteoclasts.

Results: Type XIV OI clinical phenotype ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara, and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband lumbar spine bone density z score was reduced [median -3.3 (range -4.77 to +0.1; n = 7)] and increased by +1.7 (1.17 to 3.0; n = 3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast, and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone matrix mineralization is normal and nanoporosity low. We demonstrate a complex osteoblast differentiation defect with decreased expression of early markers and increased expression of late and mineralization-related markers. Predominance of trimeric intracellular cation channel type B over type A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover.

Conclusions: OI type XIV has a bone histology, matrix mineralization, and osteoblast differentiation pattern that is distinct from OI with collagen defects. Probands are responsive to bisphosphonates and some show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities.
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http://dx.doi.org/10.1210/jc.2016-3766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470761PMC
June 2017

Non-invasive prenatal diagnosis of spinal muscular atrophy by relative haplotype dosage.

Eur J Hum Genet 2017 04 25;25(4):416-422. Epub 2017 Jan 25.

West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.

Although technically possible, few clinical laboratories across the world have implemented non-invasive prenatal diagnosis (NIPD) for selected single-gene disorders, mostly owing to the elevated costs incurred. Having previously proven that NIPD for X-linked disorders can be feasibly implemented in clinical practice, we have now developed a test for the NIPD of an autosomal-recessive disorder, spinal muscular atrophy (SMA). Cell-free DNA was extracted from maternal blood and prepared for massively parallel sequencing on an Illumina MiSeq by targeted capture enrichment of single-nucleotide polymorphisms across a 6 Mb genomic window on chromosome 5 containing the SMN1 gene. Maternal, paternal and proband DNA samples were also tested for haplotyping purposes. Sequencing data was analysed by relative haplotype dosage (RHDO). Six pregnant SMA carriers and 10 healthy pregnant donors were recruited through the NIPSIGEN study. Inheritance of the maternally and paternally derived alleles of the affected SMN1 gene was determined in the foetus by RHDO analysis for autosomal-recessive disorders. DNA from the proband (for SMA carriers) or an invasively obtained foetal sample (for healthy pregnant donors) was used to identify the maternal and paternal reference haplotypes associated with the affected SMN1 gene. Results for all patients correlated with known outcomes and showed a testing specificity and sensitivity of 100%. On top of showing high accuracy and reliability throughout the stages of validation, our novel test for NIPD of SMA is also affordable and viable for implementation into clinical service.
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http://dx.doi.org/10.1038/ejhg.2016.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386415PMC
April 2017

Assault-related shame mediates the association between negative social reactions to disclosure of sexual assault and psychological distress.

Psychol Trauma 2017 03 8;9(2):166-172. Epub 2016 Sep 8.

VA Central Iowa Health Care System.

Objective: Several studies have identified associations between social reactions to disclosure of sexual assault and psychological distress; however, no studies have evaluated shame as a mediator of this association. This study evaluated assault-related shame as a mediator of the associations between negative social reactions to disclosure of sexual assault and symptoms of posttraumatic stress disorder (PTSD), depression, and global distress and hypothesized that there would be an indirect effect of social reactions to disclosure upon symptoms of psychopathology via assault-related shame.

Method: Participants were 207 female psychology undergraduates who reported past history of completed or attempted sexual assault and had disclosed the assault to at least 1 other person. Participants completed self-report measures of social reactions to sexual assault disclosure, assault-related shame, and symptoms of psychopathology.

Results: Participants reported significant histories of attempted or completed sexual assault and indicated clinically significant symptoms of depression and subthreshold symptoms of PTSD and global distress, on average. Evaluation of structural models confirmed the hypothesized indirect effect of negative social reactions to sexual assault disclosure upon symptoms of PTSD (z = 5.85, p < .001), depression (z = 4.56, p < .001), and global distress (z = 4.82, p < .001) via assault-related shame.

Conclusions: These findings offer new insight concerning the intervening role of assault-related shame and highlight the importance of shame as a target for therapeutic intervention. This study suggests the need for future research concerning the role of shame in the etiology of PTSD and process of disclosure among survivors of attempted or completed sexual assault. (PsycINFO Database Record
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http://dx.doi.org/10.1037/tra0000186DOI Listing
March 2017

Exostoses, enchondromatosis and metachondromatosis; diagnosis and management.

Acta Orthop Belg 2016 Mar;82(1):102-5

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.
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March 2016
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