RESUMO
BACKGROUND: Opitz GBBB syndrome (GBBB) is an X-linked disease characterized by midline defects, including congenital heart defects. We present our diagnostic approach to the identification of GBBB in a consanguineous family in which two males siblings were concordant for a total anomalous connection of pulmonary veins and minor facial dysmorphias. METHODS: Targeted exome sequencing analysis of a 380-gene panel associated with cardiovascular disease was performed on the propositus. Interpretative analysis of the exome results was conducted, and 3D models of the protein changes were generated. RESULTS: We identified a NM_000381.4:c.608G>A;p.(Arg203Gln) change in MID1, affecting the conformation of the B-box 2 domain of the protein, with a zinc finger structure and associated protein interactions. This clinical phenotype is consistent with GBBB; however, the type of congenital heart disease observed in this case has not been previously reported. CONCLUSION: A new likely pathogenic variant on MID1 c.608G>A was found to be associated with Opitz GBBB syndrome.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Hipertelorismo , Hipospadia , Humanos , Masculino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipertelorismo/genética , Hipospadia/genéticaRESUMO
Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p < 0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant effect prediction tools showed 97% of the variants with potential to influence in these genes regulation. DGE analysis showed a significant reduction of ESCO2 in hPSCs after thalidomide exposure.
Assuntos
Acetiltransferases/genética , Proteínas Cromossômicas não Histona/genética , Predisposição Genética para Doença , Proteínas com Domínio T/genética , Teratogênese/genética , Talidomida/efeitos adversos , Fatores de Transcrição/genética , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/genética , Brasil , Linhagem Celular , Anormalidades Craniofaciais/induzido quimicamente , Anormalidades Craniofaciais/genética , Conjuntos de Dados como Assunto , Síndrome da Retração Ocular/induzido quimicamente , Síndrome da Retração Ocular/genética , Ectromelia/induzido quimicamente , Ectromelia/genética , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/genética , Comunicação Interatrial/induzido quimicamente , Comunicação Interatrial/genética , Humanos , Hipertelorismo/induzido quimicamente , Hipertelorismo/genética , Hanseníase/tratamento farmacológico , Deformidades Congênitas das Extremidades Inferiores/induzido quimicamente , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Mutação , Células-Tronco Pluripotentes , Polimorfismo de Nucleotídeo Único , Gravidez , Complicações na Gravidez/tratamento farmacológico , Mapas de Interação de Proteínas/genética , Teratogênese/efeitos dos fármacos , Deformidades Congênitas das Extremidades Superiores/induzido quimicamente , Deformidades Congênitas das Extremidades Superiores/genéticaRESUMO
Barber-Say syndrome is a rare autosomal dominant disease characterized by dysmorphic features, mainly of the eyelids and skin. It is caused by heterozygous mutations in gene TWIST2, localized in chromosome 2q37.3. The authors present the case of a pediatric patient with a clinical diagnosis of Barber-Say syndrome with ocular symptoms related to exposure keratitis. Molecular analysis of her DNA revealed a mutation on TWIST2 gene confirming the diagnosis of Barber-Say syndrome. Surgical treatment of the patient's eyelids resolved her signs and symptoms.
Assuntos
Doenças Palpebrais/genética , Hirsutismo/genética , Hipertelorismo/genética , Hipertricose/genética , Macrostomia/genética , Mutação , Proteínas Repressoras/genética , Anormalidades da Pele/genética , Proteína 1 Relacionada a Twist/genética , Pré-Escolar , Análise Mutacional de DNA , Doenças Palpebrais/cirurgia , Pálpebras/cirurgia , Feminino , Hirsutismo/cirurgia , Humanos , Hipertelorismo/cirurgia , Hipertricose/cirurgia , Macrostomia/cirurgia , Anormalidades da Pele/cirurgia , Transplante de Pele/métodos , Resultado do TratamentoRESUMO
Manitoba-oculo-tricho-anal (MOTA) syndrome is an uncommon condition arising from biallelic mutations of FREM1 gene and clinically characterized by a variable spectrum of eyelid malformations, aberrant hairline, bifid or broad nasal tip, and gastrointestinal anomalies. In this report, we describe a patient with a phenotype compatible with MOTA syndrome (aberrant anterior hair line, hypertelorism, unilateral anophthalmia, and bifid and broad nasal tip) in whom two novel FREM1 mutations (c.305 A > G, p.Asp102Gly; and c.2626delG, p.Val876Tyrfs*16) were identified in the compound heterozygous state, thus broadening the mutational spectrum of the disease. We performed a literature review of the clinical and genetic features of individuals carrying FREM1 mutations.
Assuntos
Anormalidades Múltiplas/genética , Canal Anal/anormalidades , Coloboma/genética , Hipertelorismo/genética , Receptores de Interleucina/genética , Pré-Escolar , Pálpebras/anormalidades , Feminino , Humanos , FenótipoRESUMO
Submicroscopic chromosomal anomalies play an important role in the etiology of craniofacial malformations, including midline facial defects with hypertelorism (MFDH). MFDH is a common feature combination in several conditions, of which Frontonasal Dysplasia is the most frequently encountered manifestation; in most cases the etiology remains unknown. We identified a parent to child transmission of a 6.2 Mb interstitial deletion of chromosome region 2q36.1q36.3 by array-CGH and confirmed by FISH and microsatellite analysis. The patient and her mother both presented an MFDH phenotype although the phenotype in the mother was much milder than her daughter. Inspection of haplotype segregation within the family of 2q36.1 region suggests that the deletion arose on a chromosome derived from the maternal grandfather. Evidences based on FISH, microsatellite and array-CGH analysis point to a high frequency mosaicism for presence of a deleted region 2q36 occurring in blood of the mother. The frequency of mosaicism in other tissues could not be determined. We here suggest that the milder phenotype observed in the proband's mother can be explained by the mosaic state of the deletion. This most likely arose by an early embryonic deletion in the maternal embryo resulting in both gonadal and somatic mosaicism of two cell lines, with and without the deleted chromosome. The occurrence of gonadal mosaicism increases the recurrence risk significantly and is often either underestimated or not even taken into account in genetic counseling where new mutation is suspected.
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Hipertelorismo/genética , Mosaicismo , Atrofia Muscular/genética , Fenótipo , Adulto , Criança , Anormalidades Craniofaciais , Fácies , Feminino , Haplótipos , Humanos , Hipertelorismo/diagnóstico , LinhagemRESUMO
Midline facial defects with hypertelorism (MFDH) are mainly characterized by ocular hypertelorism and bifid nose. They are often associated with structural and functional anomalies of the central nervous system similar to those found in 22q11.2 deletion syndromes. In addition, there are some isolated reports of MFDH and 22q11.2 deletion. These findings suggest that MFDH may be part of the spectrum of 22q11.2 deletion syndromes. To test this hypothesis, 10 individuals with MFDH were analyzed by fluorescent in situ hybridization (FISH), but no 22q11.2 deletion was detected. In view of this result, the TBX1 gene located within the 22q11.2 candidate region was screened. A new sequence variant (1132GA) was identified in one patient. This variant was not found in 110 control individuals genotyped. Considering the rarity of this condition and results of this study, the involvement of the 22q11.2 chromosomal region in the pathogenesis of MFDH could not be excluded.
Assuntos
Cromossomos Humanos Par 22 , Face/anormalidades , Hipertelorismo/genética , Deleção de Sequência , Mapeamento Cromossômico , Feminino , Variação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Tiorredoxinas/genéticaRESUMO
Robinow syndrome is a genetically heterogeneous condition characterized by mesomelic limb shortening associated with facial and genital anomalies that can be inherited in an autosomal dominant or recessive mode. We characterized these two variants clinically, with the aim of establishing clinical criteria to enhance the differential diagnosis between them or other similar conditions. The frequencies of clinical signs considered important for the discrimination of the dominant or recessive variants were estimated in a sample consisting of 38 patients personally examined by the authors and of 50 affected subjects from the literature. Using the presence of rib fusions as diagnostic of the recessive variant, and also based on the inheritance pattern in familial cases, we classified 37 patients as having the recessive form and other 51 as having the dominant form. The clinical signs present in more than 75% of patients with either form, and therefore the most important for the characterization of this syndrome were hypertelorism, nasal features (large nasal bridge, short upturned nose, and anteverted nares), midface hypoplasia, mesomelic limb shortening, brachydactyly, clinodactyly, micropenis, and short stature. Hemivertebrae and scoliosis were present in more than 75% of patients with the recessive form, but in less than 25% of patients with the dominant form. Umbilical hernia (32.3%) and supernumerary teeth (10.3%) were found exclusively in patients with the dominant form.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/diagnóstico , Genitália/anormalidades , Deformidades Congênitas dos Membros/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Diagnóstico Diferencial , Feminino , Genes Dominantes , Genes Recessivos , Humanos , Hipertelorismo/genética , Lactente , Deformidades Congênitas dos Membros/genética , Masculino , SíndromeRESUMO
Aarskog-Scott syndrome (ASS) is an X-linked disorder characterized by facial, skeletal and genital anomalies, including penoscrotal transposition in males. We report on a girl from a family with ASS who exhibits a transposition of the clitoris.
Assuntos
Anormalidades Múltiplas/genética , Clitóris/anormalidades , Face/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/genética , Pré-Escolar , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Hipertelorismo/genética , Recém-Nascido , Masculino , Pênis/anormalidades , SíndromeRESUMO
Aarskog-Scott syndrome (ASS) is an X-linked disorder characterized by facial, skeletal and genital anomalies, including penoscrotal transposition in males. We report on a girl from a family with ASS who exhibits a transposition of the clitoris.
Assuntos
Pré-Escolar , Feminino , Humanos , Recém-Nascido , Masculino , Anormalidades Múltiplas/genética , Clitóris/anormalidades , Face/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Hipertelorismo/genética , Pênis/anormalidades , SíndromeRESUMO
A Mexican family is presented with the main clinical features of camptodactyly, a distinctive facial appearance because of ocular hypertelorism, telecanthus, symblepharon and spinal defects. Other clinical manifestations included: multiple nevi, simplified ears, retrognathia, congenital shortness of the sternocleidomastoid muscle, thin hands and feet, a small penis and mild mental retardation. Radiographic studies revealed spina bifida occulta at cervical and dorso-lumbar levels, increased bone trabeculae, cortical thickening and delayed bone age. The presence of five affected members through four generations suggests autosomal dominant inheritance although no male-to-male transmission was documented. The authors propose this as a new entity, and have designated it Guadalajara camptodactyly type III.
Assuntos
Anormalidades Múltiplas/genética , Dedos/anormalidades , Hipertelorismo/genética , Coluna Vertebral/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Fácies , Saúde da Família , Feminino , Genes Dominantes , Humanos , Hipertelorismo/patologia , Masculino , México , Linhagem , Disrafismo Espinal/genética , Disrafismo Espinal/patologiaAssuntos
Transtorno Autístico/complicações , Deficiência Intelectual/genética , Transtorno Autístico/diagnóstico , Estatura , Criança , Pré-Escolar , Transtornos da Comunicação/diagnóstico , Transtornos da Comunicação/genética , Diagnóstico Diferencial , Ligação Genética , Humanos , Hipercinese/genética , Hipertelorismo/genética , Masculino , Síndrome , Cromossomo X/genéticaRESUMO
Se reporta una paciente de 2 años y 9 meses de edad con el diagnóstico de Síndrome de Weaver. La propósita presenta sobrecrecimiento pre y postnatal, maduración ósea acelerada asincrónica, patrón característico de signos dismórficos facial (macrocefalia, hipertelorismo, micrognatia, pabellones auriculares grandes), ensanchamiento bilateral de las metáfisis distales de fémures, persistencia de almohadillas embrionarias digitales, clinodactilia, tibia vara bilateral, retraso del desarrollo intelectual, llanto y voz roncos y bajo, atrofia cortical difusa, dilatación ventricular e hipoplasia del vermix cerebeloso. Se revisa el diagnóstico diferencial con otros síndromes de sobrecrecimiento y se plantea la posibilidad de isodisomía uniparental e impronta genómica como causa de este trastorno. La paciente aquí reportada constituye el primer caso de Síndrome de Weaver reportado en Venezuela
Assuntos
Pré-Escolar , Humanos , Hipertelorismo/genética , Micrognatismo/patologia , SíndromeRESUMO
We report on 12 Brazilian boys with the Optiz G/BBB syndrome associated with CNS midline anomalies, namely, Dandy-Walker anomaly (two patients), enlarged cisterna magna (four patients), enlarged 4th ventricle (four patients), and callosal a/hypoplasia (two patients). These signs clearly show the involvement of the CNS midline in the Opitz G/BBB syndrome.
Assuntos
Anormalidades Múltiplas/genética , Sistema Nervoso Central/anormalidades , Adolescente , Adulto , Brasil , Criança , Pré-Escolar , Síndrome de Dandy-Walker/genética , Feminino , Humanos , Hipertelorismo/genética , Lactente , Masculino , Anormalidades da Boca/genética , Nariz/anormalidades , SíndromeRESUMO
El síndrome de Robinow es poco frecuente; hasta la fecha se han descrito alrededor de 15 casos con variabilidad en el tipo de herencia. Las características más relevantes son: talla baja, facies peculiar (cara fetal), braquimelia mesomélica, hemivértebras e hipoplasia de genitales. El presente informe describe dos hermanos, un masculino de siete años y diez meses y otor femenino de seis años de edad, donde el análisis familiar indica un tipo de herencia autosómico recesivo. Se revisa la literatura y se discuten los hallazgos
Assuntos
Criança , Humanos , Masculino , Feminino , Aberrações Cromossômicas/genética , Ectromelia/genética , Genitália/anormalidades , Hipertelorismo/genética , SíndromeAssuntos
Disostose Craniofacial/genética , Genes Dominantes , Hipertelorismo/genética , Hipospadia/genética , Adulto , Brasil , Criança , Feminino , Ligação Genética , Humanos , Lactente , Masculino , Linhagem , Síndrome , Cromossomo XRESUMO
Four boys of the same family (three first cousins and their uncle) had the same syndrome of multiple malformations. They had hypertelorism, antimongolian slant of the palpebral fissures, low-set ears, and Pierre Robin syndrome. The ossification of the skull vault was defective, with broad sutures and fontanelles. The ribs were sinuous, the clavicles were long, thin, and sloping, and the vertebrae were flattened. There were abnormal bowing with hyperostosis of the long bones, faulty ossification of the bones of hand and feet, and "fanned-out" toes. The disorder was lethal within a few weeks. The karyotype was normal. The mothers of affected boys had a mild form of the same abnormal facies. Transmission of this disorder appears to be linked to the X chromosome.
Assuntos
Anormalidades Múltiplas/genética , Fissura Palatina/genética , Disostose Craniofacial/genética , Face/anormalidades , Hipertelorismo/genética , Síndrome de Pierre Robin/genética , Osso e Ossos/anormalidades , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Síndrome de Pierre Robin/diagnóstico por imagem , Radiografia , Cromossomo XRESUMO
Eight patients in three families had mental retardation, characteristic facies and hands, and skeletal changes; the clinical features suggested to us that they had a syndrome previously thought to represent two entities described by Lowry and associates and by Coffin and associates, respectively. New findings include skeletal, orodental, and dermatoglyphic abnormalities and histopathologic changes suggesting that the syndrome is a heritable disorder of connective tissue. Severe expression in males and transmission through mildly affected females suggest X-linked or sex-influenced autosomal dominant inheritance.