Assuntos
Anormalidades Múltiplas , Face , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Unhas Malformadas , Humanos , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Unhas Malformadas/genética , Unhas Malformadas/congênito , Unhas Malformadas/patologia , Micrognatismo/genética , Micrognatismo/etiologia , Face/anormalidades , Deformidades Congênitas da Mão/genética , Pescoço/anormalidades , Pescoço/patologia , Masculino , Dedos/anormalidades , FemininoRESUMO
The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann-Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features (n = 3), hyperactivity and anxiety (n = 2), thick eyebrows and lower-limb hypertrichosis (n = 2), congenital heart disease (n = 1), short stature (n = 1), and velopharyngeal insufficiency (n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann-Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses.
Assuntos
Anormalidades Múltiplas , Contratura , Síndrome de DiGeorge , Fácies , Transtornos do Crescimento , Deficiência Intelectual , Microcefalia , Insuficiência Velofaríngea , Humanos , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Síndrome de DiGeorge/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genéticaRESUMO
Introducción: el síndrome del incisivo central maxilar medio único (SMMCI) es un trastorno de etiología desconocida, con base genética heterogénea, que se caracteriza por la erupción de un único incisivo central en el maxilar y que se puede relacionar con multitud de patologías y síndromes, entre los que destacan las alteraciones de la línea media, obstrucción nasal congénita, disfunción hipofisaria, talla baja y holoprosencefalia. Caso clínico: neonato mujer con síndrome dismórfico no filiado y obstrucción nasal congénita, que es diagnosticada de SMMCI tras consultar en repetidas ocasiones por cuadros de dificultad respiratoria y problemas para alimentarse. Conclusiones: el conocimiento de este raro síndrome es fundamental para la realización de un diagnóstico precoz por parte del equipo pediátrico y obstétrico, ya que un diagnóstico temprano es posible, mejorando la evaluación prenatal ecográfica, así como el adecuado manejo posnatal multidisciplinar posterior de nuestros pacientes.
Introduction: the Solitary Median Maxillary Central Incisor Syndrome (SMMCI) is a disorder of unknown etiology, with a heterogeneous genetic basis, characterized by the eruption of a single central incisor in the maxilla and that can be linked to various pathologies and syndromes, among which the alterations of the midline, congenital nasal obstruction, pituitary dysfunction, short stature and holoprosencephaly stand out. Clinical case: female newborns with unknown dysmorphic syndrome and congenital nasal obstruction, diagnosed with SMMCI after repeated consultations due to respiratory distress and feeding problems. Conclusions: understanding this rare syndrome is essential for an early diagnosis to be carried out by the pediatric and obstetric team, since it will improve the ultrasound prenatal assessment, as well as the adequate subsequent multidisciplinary postnatal patient management procedures.
Introdução: a síndrome do incisivo central maxilar médio solitário (SICMMS) é uma desordem de etiologia desconhecida, com base genética heterogênea, caracterizada pela erupção de um único incisivo central na maxila e que pode estar relacionada a uma infinidade de patologias e síndromes. onde se destacam alterações da linha média, obstrução nasal congênita, disfunção hipofisária, baixa estatura e holoprosencefalia. Caso clínico: recém-nascida com síndrome dismórfica de origem desconhecida e obstrução nasal congênita, diagnosticada com SICMSS após várias consultas por desconforto respiratório e problemas de alimentação. Conclusões: o conhecimento desta rara síndrome é essencial para que a equipe pediátrica e obstétrica possa fazer um diagnóstico precoce, pois ele pode melhorar a avaliação ultrassonográfica pré-natal, bem como o adequado manejo pós-natal multidisciplinar pós-natal dos pacientes.
Assuntos
Humanos , Feminino , Recém-Nascido , Anormalidades Múltiplas/diagnóstico por imagem , Obstrução Nasal/diagnóstico por imagem , Constrição Patológica/diagnóstico por imagem , Síndrome , Anormalidades Múltiplas/patologia , Obstrução Nasal/cirurgia , Holoprosencefalia/diagnóstico por imagem , Incisivo/anormalidades , Anodontia/complicaçõesRESUMO
FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.
Assuntos
Anormalidades Múltiplas , Caseína Quinase I , Fissura Palatina , Exoftalmia , Proteínas da Matriz Extracelular , Variação Genética , Microcefalia , Osteosclerose , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Fissura Palatina/genética , Fissura Palatina/metabolismo , Fissura Palatina/mortalidade , Fissura Palatina/patologia , Exoftalmia/genética , Exoftalmia/metabolismo , Exoftalmia/mortalidade , Exoftalmia/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/mortalidade , Microcefalia/patologia , Osteosclerose/genética , Osteosclerose/metabolismo , Osteosclerose/mortalidade , Osteosclerose/patologiaRESUMO
Raine syndrome is a rare, often lethal autosomal recessive condition marked by congenital malformations that range in severity. Considering that several case reports of this syndrome describe cases of stillbirth or perinatal death, information about the clinical presentation and development of this condition in mild, non-lethal cases is lacking. With that in mind, in this case report, we describe the clinical, oro-dental, and skeletal findings of a 14-year-old Brazilian patient diagnosed with a mild form of non-lethal Raine syndrome. This patient has very mild facial dysmorphia, not displaying hypoplastic nose, micrognathia, low set ears or depressed nasal bridge, which is uncommon even in other mild, non-lethal cases of RS. Furthermore, this patient has bilateral brain calcifications and a series of oro-dental abnormalities, such as amelogenesis imperfecta and recurrent periodontal abcesses. Sanger sequencing of genomic DNA identified a homozygous missense variant c.1487C > T at exon 9 of FAM20C (NM_020223.4) in the patient. The patient's mother carries the same variant but is heterozygous. This variant predicts a proline to leucine substitution in position 496 (p.P496L, NP_064608.2) previously reported, which allows for the phenotypic comparison between these cases. This way, this case report calls attention to how differently RS can appear, highlighting the importance of new non-lethal Raine syndrome case reports to help further determine the phenotypic spectrum of this condition.
Assuntos
Anormalidades Múltiplas/genética , Fissura Palatina/genética , Exoftalmia/genética , Microcefalia/genética , Osteosclerose/genética , Fenótipo , Anormalidades Múltiplas/patologia , Adolescente , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Fissura Palatina/patologia , Dentição , Exoftalmia/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Masculino , Microcefalia/patologia , Mutação de Sentido Incorreto , Osteosclerose/patologiaRESUMO
Mucopolysaccharidosis type I is a rare autosomal recessive genetic disease caused by deficient activity of α-L-iduronidase. As a consequence of low or absent activity of this enzyme, glycosaminoglycans accumulate in the lysosomal compartments of multiple cell types throughout the body. Mucopolysaccharidosis type I has been classified into 3 clinical subtypes, ranging from a severe Hurler form to the more attenuated Hurler-Scheie and Scheie phenotypes. Over 200 gene variants causing the various forms of mucopolysaccharidosis type I have been reported. DNA isolated from dried blood spot was used to sequencing of all exons of the IDUA gene from a patient with a clinical phenotype of severe mucopolysaccharidosis type I syndrome. Enzyme activity of α-L-iduronidase was quantified by fluorimetric assay. Additionally, a molecular dynamics simulation approach was used to determine the effect of the Ser633Trp mutation on the structure and dynamics of the α-L-iduronidase. The DNA sequencing analysis and enzymatic activity shows a c.1898C>G mutation associated a patient with a homozygous state and α-L-iduronidase activity of 0.24 µmol/L/h, respectively. The molecular dynamics simulation analysis shows that the p.Ser633Trp mutation on the α-L-iduronidase affect significant the temporal and spatial properties of the different structural loops, the N-glycan attached to Asn372 and amino acid residues around the catalytic site of this enzyme. Low enzymatic activity observed for p.Ser633Trp variant of the α-L-iduronidase seems to lead to severe mucopolysaccharidosis type I phenotype, possibly associated with a perturbation of the structural dynamics in regions of the enzyme close to the active site.
Assuntos
Anormalidades Múltiplas/genética , Dermatan Sulfato/química , Heparitina Sulfato/química , Iduronidase/química , Mucopolissacaridose I/genética , Mutação Puntual , Anormalidades Múltiplas/enzimologia , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/terapia , Domínio Catalítico , Cristalografia por Raios X , Dermatan Sulfato/metabolismo , Terapia de Reposição de Enzimas/métodos , Expressão Gênica , Heparitina Sulfato/metabolismo , Humanos , Iduronidase/genética , Iduronidase/metabolismo , Lactente , Masculino , Simulação de Dinâmica Molecular , Mucopolissacaridose I/enzimologia , Mucopolissacaridose I/patologia , Mucopolissacaridose I/terapia , Análise de Componente Principal , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Especificidade por SubstratoRESUMO
We aim to characterize patients with Gomez-López-Hernández syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology.
Assuntos
Anormalidades Múltiplas/genética , Fosfatase Ácida/genética , Alopecia/genética , Cerebelo/anormalidades , Anormalidades Craniofaciais/genética , Sequenciamento do Exoma , Transtornos do Crescimento/genética , Síndromes Neurocutâneas/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Alopecia/diagnóstico , Alopecia/diagnóstico por imagem , Alopecia/patologia , Brasil/epidemiologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/patologia , Feminino , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/diagnóstico por imagem , Transtornos do Crescimento/patologia , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Rombencéfalo/diagnóstico por imagem , Rombencéfalo/patologia , Nervo Trigêmeo/diagnóstico por imagem , Nervo Trigêmeo/metabolismo , Nervo Trigêmeo/patologia , Adulto JovemRESUMO
Kenny-Caffey syndrome (KCS) is a rare hereditary skeletal disorder involving hypoparathyroidism. The autosomal dominant form (KCS2), caused by heterozygous pathogenic variants in the FAM111A gene, is distinguished from the autosomal recessive form (KCS1) and Sanjad-Sakati syndrome (SSS), both caused by pathogenic variants in the tubulin folding cofactor E (TBCE) gene, by the absence of microcephaly and intellectual disability. We present a patient with KCS2 caused by a de novo pathogenic variant c.1706G>A (p.Arg569His) in FAM111A gene, presenting intellectual disability and microcephaly, which are considered to be typical signs of SSS. We suggest that KCS1, KCS2, and SSS may not represent mutually exclusive clinical entities, but possibly an overlapping spectrum.
Assuntos
Anormalidades Múltiplas/patologia , Nanismo/patologia , Transtornos do Crescimento/patologia , Hiperostose Cortical Congênita/patologia , Hipocalcemia/patologia , Hipoparatireoidismo/patologia , Deficiência Intelectual/patologia , Mutação , Osteocondrodisplasias/patologia , Fenótipo , Receptores Virais/genética , Convulsões/patologia , Anormalidades Múltiplas/genética , Adolescente , Nanismo/complicações , Nanismo/genética , Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Humanos , Hiperostose Cortical Congênita/complicações , Hiperostose Cortical Congênita/genética , Hipocalcemia/complicações , Hipocalcemia/genética , Hipoparatireoidismo/complicações , Hipoparatireoidismo/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Masculino , Osteocondrodisplasias/complicações , Osteocondrodisplasias/genética , Convulsões/complicações , Convulsões/genéticaRESUMO
Seckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR and ATRIP, are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development and function of the central nervous system (CNS). Here, we investigated the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing murine neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons did not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) led to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we showed that RPCs lacking functional ATRIP exhibited higher levels of replicative stress and accumulated endogenous DNA damage that was accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevented apoptosis of Atrip-deficient progenitor cells and was sufficient to rescue retinal dysplasia, neurodegeneration and loss of vision. Together, these results reveal an essential role of ATRIP-mediated replication stress response in CNS development and suggest that the TRP53-mediated apoptosis of progenitor cells might contribute to retinal malformations in Seckel syndrome and other MPD disorders.This article has an associated First Person interview with the first author of the paper.
Assuntos
Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação a DNA/metabolismo , Degeneração Neural/patologia , Displasia Retiniana/patologia , Células-Tronco/patologia , Animais , Apoptose , Cegueira/patologia , Morte Celular , Proliferação de Células , Dano ao DNA , Modelos Animais de Doenças , Embrião de Mamíferos/patologia , Desenvolvimento Embrionário , Camundongos , Degeneração Neural/complicações , Neurogênese , Células Fotorreceptoras de Vertebrados/patologia , Retina/patologia , Displasia Retiniana/complicações , Síndrome , Proteína Supressora de Tumor p53/metabolismo , Visão OcularRESUMO
Prader-Willi syndrome (PWS) is one of the common neurogenetic disorders associated with intellectual disability. PWS involves a complex inheritance pattern and is caused by an absence of gene expression on the paternally inherited 15q11.2-q13 region, either due to deletion, maternal uniparental disomy or imprinting defect. The syndrome is characterized principally by severe neonatal hypotonia, a weak suck in infancy that is later followed by hyperphagia and obesity, developmental delay, intellectual disability and short stature. In the case of the chromosome 15q26-qter deletion syndrome or Drayer's syndrome, very few reports have been published. Its characteristics include intrauterine growth restriction, postnatal growth failure, varying degrees of intellectual disability, developmental delay, typical facial appearance and diaphragmatic hernia. The present paper describes a female patient in whom clinical findings were suggestive of PWS and deletion in the 15q26-qter region. Both karyotyping and methylation-specific polymerase chain reaction were shown to be normal. Nevertheless, fluorescence in situ hybridization showed a 15qter deletion that was later mapped by single nucleotide polymorphism (SNP)-array. The deleted genomic region involves the insulin-like growth factor-1 receptor (IGF1R) gene, which is related to short stature, developmental delay and intellectual disability. This case had various clinical characteristics in common with the cases of 15q26-qter deletionand characteristics compatible with PWS.