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1.
J Bone Miner Res ; 38(12): 1822-1833, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37823782

RESUMO

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range <1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Calcitonina , Querubismo , Criança , Humanos , Masculino , Feminino , Calcitonina/efeitos adversos , Estudos de Coortes , Querubismo/tratamento farmacológico , Estudos Retrospectivos , Minerais
2.
J Clin Lipidol ; 17(2): 291-296, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36604244

RESUMO

Homozygous familial hypercholesterolemia (HoFH) is a rare, potentially life-limiting, inherited disorder of lipoprotein metabolism characterized by extremely high low-density lipoprotein cholesterol levels. When both parents have heterozygous FH, there is a 25% chance they will conceive a child with HoFH. Here we describe our clinical experience with two such prospective parent couples who were counseled regarding reproductive options and prenatal testing for HoFH. These cases showcase how, in consultation with a molecular geneticist and pediatric cardiologist, parents may be informed of the prognosis and treatment outlook of HoFH based on the FH-variants carried, to ultimately make personal decisions on reproductive options. One couple opted for prenatal testing and termination of pregnancy in case HoFH was found, while the other accepted the risk without testing. We review the available literature on preconception counseling for HoFH and provide practical guidance to clinicians counseling at-risk couples. Optimal counseling of prospective parents may help prevent future physical and psychological problems for both parent and child.


Assuntos
Hipercolesterolemia Familiar Homozigota , Hiperlipoproteinemia Tipo II , Humanos , Criança , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Fenótipo , Estudos Prospectivos , Aconselhamento , Homozigoto
3.
Prenat Diagn ; 42(13): 1612-1621, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36336875

RESUMO

OBJECTIVE: Noninvasive Prenatal Diagnosis has recently been introduced for a limited number of monogenetic disorders. However, the majority of DNA diagnostics still require fetal material obtained using an invasive test. Recently, a novel technique, TRIC (Trophoblast Retrieval and Isolation from the Cervix), has been described, which collects fetal trophoblast cells by endocervical sampling. Since this technique has not been successfully replicated by other groups, we aimed to achieve this in the current study. METHOD: Pregnant women referred for transvaginal chorionic villous sampling (CVS) were asked for an endocervical sample prior to CVS. The TRIC samples were processed to isolate trophoblast DNA. TRIC DNA was used in ForenSeq to determine the amount of maternal DNA contamination, and for Sanger sequencing in case of a monogenic disorder. RESULTS: 23%-44% of samples had a sufficiently high fetal DNA fraction to allow genetic testing, as calculated by Sanger sequencing and ForenSeq, respectively. CONCLUSION: We have been able to successfully replicate the TRIC protocol, although with a much lower success rate as described by the original study performing TRIC. As we obtained the samples in the actual clinical setting envisioned, the method in its current setup is not advisable for use in prenatal diagnostics.


Assuntos
Colo do Útero , Trofoblastos , Gravidez , Feminino , Humanos , Diagnóstico Pré-Natal/métodos , Testes Genéticos , Amostra da Vilosidade Coriônica
4.
Am J Hum Genet ; 109(6): 1140-1152, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35659929

RESUMO

In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weight <2.3rd percentile (13.6% [24/177] vs 2.5% [3,892/155,491]; RR 5.5) were significantly increased compared to the general obstetric population. Of the 90 maternal findings, 12 (13.3%) were malignancies and 32 (35.6%) (mosaic) pathogenic copy number variants, mostly associated with mild or no clinical phenotypes. Data from this large cohort study provide crucial information for deciding if and how to implement GW-NIPT in screening programs. Additionally, these data can inform the challenging interpretation, counseling, and follow-up of additional findings.


Assuntos
Diagnóstico Pré-Natal , Trissomia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Mosaicismo , Placenta , Gravidez , Diagnóstico Pré-Natal/métodos
5.
J Clin Oncol ; 40(22): 2426-2435, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35394817

RESUMO

PURPOSE: Noninvasive prenatal testing (NIPT) for fetal aneuploidy screening using cell-free DNA derived from maternal plasma can incidentally raise suspicion for cancer. Diagnostic routing after malignancy suspicious-NIPT faces many challenges. Here, we detail malignancy suspicious-NIPT cases, and describe the clinical characteristics, chromosomal aberrations, and diagnostic routing of the patients with a confirmed malignancy. Clinical lessons can be learned from our experience. METHODS: Patients with NIPT results indicative of a malignancy referred for tumor screening between April 2017 and April 2020 were retrospectively included from a Dutch nationwide NIPT implementation study, TRIDENT-2. NIPT profiles from patients with confirmed malignancies were reviewed, and the pattern of chromosomal aberrations related to tumor type was analyzed. We evaluated the diagnostic contribution of clinical and genetic examinations. RESULTS: Malignancy suspicious-NIPT results were reported in 0.03% after genome-wide NIPT, and malignancies confirmed in 16 patients (16/48, 33.3%). Multiple chromosomal aberrations were seen in 23 of 48 patients with genome-wide NIPT, and a malignancy was confirmed in 16 patients (16/23, 69.6%). After targeted NIPT, 0.005% malignancy suspicious-NIPT results were reported, in 2/3 patients a malignancy was confirmed. Different tumor types and stages were diagnosed, predominantly hematologic malignancies (12/18). NIPT data showed recurrent gains and losses in primary mediastinal B-cell lymphomas and classic Hodgkin lymphomas. Magnetic resonance imaging and computed tomography were most informative in diagnosing the malignancy. CONCLUSION: In 231,896 pregnant women, a low percentage (0.02%) of NIPT results were assessed as indicative of a maternal malignancy. However, when multiple chromosomal aberrations were found, the risk of a confirmed malignancy was considerably high. Referral for extensive oncologic examination is recommended, and may be guided by tumor-specific hallmarks in the NIPT profile.


Assuntos
Neoplasias , Diagnóstico Pré-Natal , Aneuploidia , Aberrações Cromossômicas , Feminino , Seguimentos , Humanos , Gravidez , Diagnóstico Pré-Natal/métodos , Estudos Retrospectivos
6.
Prenat Diagn ; 40(8): 972-983, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333414

RESUMO

OBJECTIVE: The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging. METHODS: In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7). RESULTS: A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases. CONCLUSIONS: These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.


Assuntos
Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Sequenciamento do Exoma , Ultrassonografia Pré-Natal , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Tomada de Decisões , Feminino , Feto/diagnóstico por imagem , Testes Genéticos/métodos , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal/métodos , Reprodutibilidade dos Testes , Adulto Jovem
7.
Am J Hum Genet ; 105(6): 1091-1101, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31708118

RESUMO

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.


Assuntos
Síndrome de Down/diagnóstico , Testes Genéticos/métodos , Genoma Humano , Implementação de Plano de Saúde , Diagnóstico Pré-Natal/métodos , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Adolescente , Adulto , Aberrações Cromossômicas , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Gravidez , Primeiro Trimestre da Gravidez , Prognóstico , Síndrome da Trissomia do Cromossomo 13/epidemiologia , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/epidemiologia , Síndrome da Trissomía do Cromossomo 18/genética , Adulto Jovem
8.
Am J Med Genet A ; 173(5): 1383-1389, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28371265

RESUMO

Oral-facial-digital syndrome type 1 (OFD1; OMIM# 311200) is an X-linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post-mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left-right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.


Assuntos
Cardiopatias Congênitas/genética , Síndromes Orofaciodigitais/genética , Proteínas/genética , Feto Abortado , Autopsia , Feminino , Genes Ligados ao Cromossomo X , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/fisiopatologia , Humanos , Masculino , Mutação , Síndromes Orofaciodigitais/complicações , Síndromes Orofaciodigitais/fisiopatologia , Linhagem , Fenótipo , Gravidez , Transdução de Sinais
9.
Eur J Public Health ; 27(2): 372-377, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27485720

RESUMO

Background: Carrier screening for autosomal recessive disorders aims to facilitate reproductive decision-making by identifying couples with a 1-in-4 risk in every pregnancy of having an affected child. Except for a few countries or regions, carrier screening is not widely offered and is mostly ancestry-based. Technological advances enable carrier screening for multiple diseases simultaneously allowing universal screening regardless of ancestry (population-based expanded carrier screening). It is important to study how this can be successfully implemented. This study therefore aims to identify critical factors involved in successful implementation, from a user perspective, by learning from already implemented initiatives. Methods: Factors associated with successful implementation were identified by: (i) a literature review and (ii) two case studies; studying experiences with carrier screening in two high-risk communities (a Dutch founder population and the Ashkenazi Jewish population), including a survey among community members. Results: Factors identified were familiarity with (specific) genetic diseases and its availability, high perceived benefits of screening (e.g. screening avoids much suffering), acceptance of reproductive options, perceived risk of being a carrier and low perceived social barriers (e.g. stigmatization). In contrast to the Jewish community, the initial demand for screening in the Dutch founder population did not entirely come from the community itself. However, the large social cohesion of the community facilitated the implementation process. Conclusion: To ensure successful implementation of population-based expanded carrier screening, efforts should be made to increase knowledge about genetic diseases, create awareness and address personal benefits of screening in a non-directive way.


Assuntos
Testes Genéticos/métodos , Heterozigoto , Programas de Rastreamento/métodos , Adolescente , Adulto , Feminino , Humanos , Judeus/genética , Masculino , Países Baixos , Adulto Jovem
10.
Adv Clin Chem ; 74: 63-102, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27117661

RESUMO

Cell-free DNA (cfDNA) testing has recently become indispensable in diagnostic testing and screening. In the prenatal setting, this type of testing is often called noninvasive prenatal testing (NIPT). With a number of techniques, using either next-generation sequencing or single nucleotide polymorphism-based approaches, fetal cfDNA in maternal plasma can be analyzed to screen for rhesus D genotype, common chromosomal aneuploidies, and increasingly for testing other conditions, including monogenic disorders. With regard to screening for common aneuploidies, challenges arise when implementing NIPT in current prenatal settings. Depending on the method used (targeted or nontargeted), chromosomal anomalies other than trisomy 21, 18, or 13 can be detected, either of fetal or maternal origin, also referred to as unsolicited or incidental findings. For various biological reasons, there is a small chance of having either a false-positive or false-negative NIPT result, or no result, also referred to as a "no-call." Both pre- and posttest counseling for NIPT should include discussing potential discrepancies. Since NIPT remains a screening test, a positive NIPT result should be confirmed by invasive diagnostic testing (either by chorionic villus biopsy or by amniocentesis). As the scope of NIPT is widening, professional guidelines need to discuss the ethics of what to offer and how to offer. In this review, we discuss the current biochemical, clinical, and ethical challenges of cfDNA testing in the prenatal setting and its future perspectives including novel applications that target RNA instead of DNA.


Assuntos
DNA/sangue , Testes Genéticos/métodos , Diagnóstico Pré-Natal/métodos , RNA/sangue , Aneuploidia , DNA/genética , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Feto , Testes Genéticos/ética , Testes Genéticos/instrumentação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Achados Incidentais , Polimorfismo de Nucleotídeo Único , Guias de Prática Clínica como Assunto , Gravidez , Diagnóstico Pré-Natal/ética , Diagnóstico Pré-Natal/instrumentação , RNA/genética , Sistema do Grupo Sanguíneo Rh-Hr/sangue
11.
Genet Med ; 16(6): 448-59, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24232412

RESUMO

PURPOSE: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1. METHODS: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions. RESULTS: Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions. CONCLUSION: In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.


Assuntos
Manchas Café com Leite/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Neoplasias Ósseas/genética , Manchas Café com Leite/patologia , Células Cultivadas , Criança , Pré-Escolar , Cromograninas , Feminino , Fibroma/genética , Mutação em Linhagem Germinativa , Humanos , Lactente , Masculino , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Razão de Masculinidade , Adulto Jovem
12.
J Med Genet ; 50(5): 309-23, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23456818

RESUMO

BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.


Assuntos
Dineínas do Citoplasma/genética , Síndrome de Ellis-Van Creveld/genética , Exoma/genética , Modelos Moleculares , Conformação Proteica , Sequência de Bases , Dineínas do Citoplasma/química , Componentes do Gene , Humanos , Microscopia de Fluorescência , Dados de Sequência Molecular , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA
13.
Hum Mutat ; 33(8): 1261-6, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22539336

RESUMO

Desbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of ß-D-xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism.


Assuntos
Nucleotidases/metabolismo , Proteoglicanas/metabolismo , Células Cultivadas , Cromatografia em Gel , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Nanismo/genética , Nanismo/metabolismo , Glicosídeos/metabolismo , Humanos , Instabilidade Articular/genética , Instabilidade Articular/metabolismo , Mutação , Nucleotidases/genética , Ossificação Heterotópica/genética , Ossificação Heterotópica/metabolismo , Polidactilia/genética , Polidactilia/metabolismo , Sulfotransferases , Carboidrato Sulfotransferases
15.
Br J Oral Maxillofac Surg ; 45(6): 499-500, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16713042

RESUMO

A mutation of the SH3BP2 gene is known to cause cherubism. As there are clinical and histopathological similarities between central giant cell granuloma and cherubism, we made a constitutional DNA analysis of the SH3BP2 gene in four patients with aggressive giant cell granuloma (having one or more of the following features pain, paraesthesia, rapid growth, or root resorption). We found no mutations in the SH3BP2 gene, which indicates that cherubism is a separate entity. However, a somatic mutation in a specific group of cells could cause the focal lesions in giant cell granuloma. Further DNA analysis of the tissue of giant cell granulomas therefore seems indicated.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Granuloma de Células Gigantes/genética , Doenças Maxilomandibulares/genética , Querubismo/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Granuloma de Células Gigantes/sangue , Humanos , Doenças Maxilomandibulares/sangue , Masculino , Mutação , Reação em Cadeia da Polimerase
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