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1.
Medicina (Kaunas) ; 57(12)2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34946295

RESUMO

Background: Cleidocranial dysplasia (CCD) is a rare, autosomal dominant skeletal dysplasia with a prevalence of one per million births. The main causes of CCD are mutations in the core-binding factor alpha-1 (CBFA1) or runt-related transcription factor-2 (RUNX2), located at the 6p21 chromosomal region. RUNX2 plays important roles in osteoblast differentiation, chondrocyte proliferation and differentiation, and tooth formation. The disease is characterized by clavicular aplasia or hypoplasia, Wormian bones, delayed closure of cranial suture, brachycephalic head, maxillary deficiency, retention of primary teeth, inclusion of permanent teeth, and multiple supernumerary teeth. Materials and Methods: A 22-year-old girl suffering from cleidocranial dysplasia with short stature, narrow shoulders, craniofacial manifestations (short face, broad forehead, etc.) and dental anomalies (different lower dental elements under eruption, supernumerary and impacted multiple teeth, etc.) was examined at our service (Complex Operative Unit of Odontostomatology of Policlinico of Bari). RX Orthopantomography (OPG) and cone beam computed tomography (CBCT) were requested to better assess the position of the supernumerary teeth and their relationships with others and to evaluate the bone tissue. Results: Under eruption was probably caused by dental interferences with supernumerary teeth; hence, extractions of supernumerary upper canines and lower premolars were performed under general anaesthesia. Surgery outcome was excellent with good tissue healing and improvements in the therapeutic possibilities with future orthodontics. Conclusions: The objective of this article is to give an update about radiological, clinical, and molecular features of CCD and to alert the health team about the importance of establishing an early diagnosis and an appropriate treatment in these patients to prevent impacted teeth complications and to offer them a better quality of life.


Assuntos
Displasia Cleidocraniana , Dente Impactado , Dente Supranumerário , Adulto , Displasia Cleidocraniana/genética , Feminino , Humanos , Qualidade de Vida , Radiografia Panorâmica , Dente Impactado/diagnóstico por imagem , Dente Impactado/genética , Dente Impactado/cirurgia , Dente Supranumerário/diagnóstico por imagem , Dente Supranumerário/genética , Dente Supranumerário/cirurgia , Adulto Jovem
2.
Genes (Basel) ; 12(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200357

RESUMO

Chromosome deletions, including band 5q12, have rarely been reported and have been associated with a wide range of clinical manifestations, such as postnatal growth retardation, intellectual disability, hyperactivity, nonspecific ocular defects, facial dysmorphism, and epilepsy. In this study, we describe for the first time a child with growth retardation in which we identified a balanced t(3;10) translocation by conventional cytogenetic analysis in addition to an 8.6 Mb 5q12 deletion through array-CGH. Our results show that the phenotypic abnormalities of a case that had been interpreted as "balanced" by conventional cytogenetics are mainly due to a cryptic deletion, highlighting the need for molecular investigation in subjects with an abnormal phenotype before assuming the cause is an apparently simple cytogenetic rearrangement. Finally, we identify PDE4D and PIK3R1 genes as the two major candidates responsible for the clinical features expressed in our patient.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 5/genética , Transtornos do Crescimento/genética , Transtornos Cromossômicos/patologia , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Hibridização Genômica Comparativa , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Feminino , Transtornos do Crescimento/patologia , Humanos , Lactente , Cariotipagem , Fenótipo , Translocação Genética
3.
Clin Genet ; 99(3): 425-429, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33236357

RESUMO

mTOR dysregulation has been described in pathological conditions, such as cardiovascular and overgrowth disorders. Here we report on the first case of a patient with a complex congenital heart disease and an interstitial duplication in the short arm of chromosome 1, encompassing part of the mTOR gene. Our results suggest that an intragenic mTOR microduplication might play a role in the pathogenesis of non-syndromic congenital heart defects (CHDs) due to an upregulation of mTOR/Rictor and consequently an increased phosphorylation of PI3K/AKT and MEK/ERK signaling pathways in patient-derived amniocytes. This is the first report which shows a causative role of intragenic mTOR microduplication in the etiology of an isolated complex CHD.


Assuntos
Predisposição Genética para Doença , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Cromossomos Humanos Par 1 , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Cardiopatias Congênitas/diagnóstico , Humanos , Lactente , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
4.
Mol Genet Genomic Med ; 7(5): e634, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30916492

RESUMO

BACKGROUND: Glycogen storage disease type III (GSDIII) is caused by mutations of AGL gene with debranching enzyme deficiency. Patients with GSDIII manifest fasting hypoglycemia, hepatomegaly, hepatopathy, myopathy, and cardiomyopathy. We report on an 18-year-old boy with a profound growth retardation (<3 SD) besides typical clinical features of GSDIII, whereby endocrinological studies were negative. METHODS AND RESULTS: Molecular analysis of AGL gene revealed the homozygous reported variant c.3903_3904insA. Since discordant results from segregation studies showed the carrier status in one parent only, SNP array and short tandem repeats analyses were performed, revealing a paternal disomy of chromosome 1 (UPD1). CONCLUSION: This study describes the first case of GSDIII resulting from UPD1. UPD can play an important role even in case of imprinted genes. DIRAS3 is a maternally imprinted tumor suppressor gene, located on chromosome 1p31, and implicated in growth and oncogenesis. It can be speculated that DIRAS3 overexpression might have a role in the severe short stature of our patient. The study emphasizes the importance of parental segregation analysis especially in patients with recessive conditions to look for specific genetic causes of disease and to estimate properly the risk of family recurrence.


Assuntos
Cromossomos Humanos Par 1/genética , Nanismo/genética , Doença de Depósito de Glicogênio Tipo III/genética , Fenótipo , Dissomia Uniparental/genética , Adolescente , Nanismo/patologia , Doença de Depósito de Glicogênio Tipo III/patologia , Humanos , Masculino , Dissomia Uniparental/patologia
5.
Clin Genet ; 95(1): 165-171, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30288735

RESUMO

Biallelic exostosin-2 (EXT2) pathogenic variants have been described as the cause of the Seizures-Scoliosis-Macrocephaly syndrome (OMIM 616682) characterized by intellectual disability, facial dysmorphisms and seizures. More recently, it has been proposed to rename this disorder with the acronym AREXT2 (autosomal recessive EXT2-related syndrome). Here, we report the third family affected by AREXT2 syndrome, harboring compound missense variants in EXT2, p.Asp227Asn, and p.Tyr608Cys. In addition, our patients developed multiple exostoses, which were not observed in the previously described families. AREXT2 syndrome can be considered as a multiorgan Congenital Disorder of Glycosylation caused by a significant, but non-lethal, decrease in EXT2 expression, thereby affecting the synthesis of the heparan sulfate proteoglycans, which is relevant in many physiological processes. Our finding expands the clinical and molecular spectrum of the AREXT2 syndrome and suggests a possible genotype/phenotype correlation in the development of the exostoses.


Assuntos
Exostose Múltipla Hereditária/genética , Deficiência Intelectual/genética , N-Acetilglucosaminiltransferases/genética , Convulsões/genética , Adulto , Ecocardiografia , Exostose Múltipla Hereditária/diagnóstico por imagem , Exostose Múltipla Hereditária/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Adulto Jovem
6.
Eur J Med Genet ; 58(8): 400-5, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26117585

RESUMO

We report on a 3-year-old male with intellectual disability (ID), characteristic facial features, polydactyly and epilepsy carrying a paternally inherited 3q28 deletion of 1.9 Mb. The father, carrying the same deletion, presents with cleft palate, nail dystrophy and learning difficulties. The deleted region in this family is one of the smallest so far reported among genomic deletions affecting 3q27-3q28 for which some phenotypic descriptions are available. In particular, since the phenotype of our proband is strikingly similar to that previously described in a patient with a 9.3 Mb deletion, the deletion identified in this report contributes to the definition of the molecular boundaries of a genomic region responsible for a distinct clinical phenotype. Within the deleted interval there are 9 annotated genes, including TP63. Gain of function mutations of TP63 are known to be responsible for a group of conditions with distal limb and ectodermal involvement, such as ADULT, EEC, LMS, and SHFM4 syndromes. Interestingly, our cases demonstrate a milder phenotypic effect for loss of function of this gene.


Assuntos
Epilepsia/genética , Haploinsuficiência , Deficiência Intelectual/genética , Fenótipo , Polidactilia/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Sequência de Bases , Pré-Escolar , Cromossomos Humanos Par 3 , Epilepsia/diagnóstico , Epilepsia/patologia , Fácies , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Dados de Sequência Molecular , Polidactilia/diagnóstico , Polidactilia/patologia , Deleção de Sequência , Fatores de Transcrição/deficiência , Proteínas Supressoras de Tumor/deficiência
7.
Eur J Hum Genet ; 23(11): 1499-504, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25712080

RESUMO

MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype.


Assuntos
Mutação da Fase de Leitura/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Complexo Mediador/genética , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Fissura Palatina/genética , Fissura Palatina/fisiopatologia , Fácies , Feminino , Heterogeneidade Genética , Haploinsuficiência/genética , Cardiopatias Congênitas/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Deleção de Sequência
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