ABSTRACT
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.
Subject(s)
Abnormalities, Multiple , Casein Kinase I , Cleft Palate , Exophthalmos , Extracellular Matrix Proteins , Genetic Variation , Microcephaly , Osteosclerosis , Phenotype , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Abnormalities, Multiple/mortality , Abnormalities, Multiple/pathology , Casein Kinase I/genetics , Casein Kinase I/metabolism , Cleft Palate/genetics , Cleft Palate/metabolism , Cleft Palate/mortality , Cleft Palate/pathology , Exophthalmos/genetics , Exophthalmos/metabolism , Exophthalmos/mortality , Exophthalmos/pathology , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Humans , Microcephaly/genetics , Microcephaly/metabolism , Microcephaly/mortality , Microcephaly/pathology , Osteosclerosis/genetics , Osteosclerosis/metabolism , Osteosclerosis/mortality , Osteosclerosis/pathologyABSTRACT
BACKGROUND: The clinical manifestations of microcephaly/congenital Zika syndrome (microcephaly/CZS) have harmful consequences on the child's health, increasing vulnerability to childhood morbidity and mortality. This study analyzes the case fatality rate and child-maternal characteristics of cases and deaths related to microcephaly/CZS in Brazil, 2015-2017. METHODS: Population-based study developed by linkage of three information systems. We estimate frequencies of cases, deaths, case fatality rate related to microcephaly/CZS according to child and maternal characteristics and causes of death. Multivariate logistic regression models were applied. RESULTS: The microcephaly/CZS case fatality rate was 10% (95% CI 9.2-10.7). Death related to microcephaly/CZS was associated to moderate (OR = 2.15; 95% CI 1.63-2.83), and very low birth weight (OR = 3.77; 95% CI 2.20-6.46); late preterm births (OR = 1.65; 95% CI 1.21-2.23), Apgar < 7 at 1st (OR = 5.98; 95% CI 4.46-8.02) and 5th minutes (OR = 4.13; 95% CI 2.78-6.13), among others. CONCLUSIONS: A high microcephaly/CZS case fatality rate and important factors associated with deaths related to this syndrome were observed. These results can alert health teams to these problems and increase awareness about the factors that may be associated with worse outcomes.
Subject(s)
Microcephaly/mortality , Pregnancy Complications, Infectious/virology , Zika Virus Infection/mortality , Adolescent , Adult , Brazil/epidemiology , Female , Humans , Logistic Models , Male , Medical Records , Middle Aged , Pregnancy , Retrospective Studies , Risk Factors , Young Adult , Zika Virus Infection/congenital , Zika Virus Infection/epidemiologyABSTRACT
Neu-Laxova syndrome (NLS) is a lethal genetic multiple congenital anomaly syndrome of unknown prevalence representing the severe spectrum of serine biosynthesis defects associated with PHGDH, PSAT1, or PSP gene mutations. The purpose of this study was to describe clinical/molecular and pathologic features of a NLS case caused by novel heterozygous missense variant in PHGDH gene identified in his consanguineous parents.
Subject(s)
Abnormalities, Multiple/genetics , Brain Diseases/genetics , Congenital Abnormalities/genetics , Fetal Growth Retardation/genetics , Ichthyosis/genetics , Limb Deformities, Congenital/genetics , Microcephaly/genetics , Phosphoglycerate Dehydrogenase/genetics , Stillbirth/genetics , Abnormalities, Multiple/mortality , Abnormalities, Multiple/pathology , Brain Diseases/mortality , Brain Diseases/pathology , Brazil/epidemiology , Congenital Abnormalities/mortality , Congenital Abnormalities/pathology , Consanguinity , Female , Fetal Growth Retardation/mortality , Fetal Growth Retardation/pathology , Genes, Lethal/genetics , Genetic Predisposition to Disease , Humans , Ichthyosis/mortality , Ichthyosis/pathology , Limb Deformities, Congenital/mortality , Limb Deformities, Congenital/pathology , Microcephaly/mortality , Microcephaly/pathology , Mutation, Missense/genetics , Pregnancy , Stillbirth/epidemiologyABSTRACT
Introduction: We present temporal and spatial variation of deaths from microcephaly in children under 1 year of age is analyzed at regional, state, and municipal level in the pre-Zika period in Brazil. Materials and Methods: Data on births and deaths of infants with microcephaly was obtained from DATASUS from 1996 to 2013. Infant mortality rate from microcephaly (IMR-M) was estimated at Region, Federative Unit (UF), and Municipality level. Secular trend (ST) and risk of death variation were estimated using a Poisson regression model. Satscan software was used to obtain a statistic spatial scan for the Poisson model. Results: IMR-M shows a non-significant negative ST in the Southeast, South and Central West Regions of Brazil. A greater IMR-M risk of death variation is found in the North and Northeast Regions. Most UFs in the Southeast, South and Central West Regions showed a negative ST, in contrast to what occurs in the UFs of the North and Northeast Regions showed a positive ST. Six high risk significant clusters were found: 3 in the North-Northeast and 3 in the South-SouthWest-Center-West. Conclusions: The North and Northeast Regions showed positive ST for IRM-M and higher death risk, which was not observed in the other regions. Cluster distribution for higher IMR-M and risk resembles the distribution of the microcephaly and Zika cases in the outbreak period.
Introducción: Presentamos la variación temporal y espacial de las muertes por microcefalia en niños menores de 1 año de edad que se analizan a nivel regional, estatal y municipal en el período pre-Zika en Brasil. Materiales y métodos: Los datos sobre nacimientos y muertes de niños con microcefalia se obtuvieron de DATASUS de 1996 a 2013. La tasa de mortalidad infantil por microcefalia (TMI-M) se estimó a nivel de Región, Unidad de Federativa (UF) y Municipio. La tendencia secular (TS) y la variación del riesgo de muerte se estimaron utilizando un modelo de regresión de Poisson. El análisis estadístico espacial fue realizado por un modelo de Poisson utilizando el software Satscan. Resultados: La TMI-M muestra un TS negativo no significativo en las regiones sudeste, sur y centro-oeste de Brasil. Una mayor variación de riesgo de muerte se encuentra en las regiones Norte y Noreste. La mayoría de las UF en las regiones Sureste, Sur y Centro-Oeste mostraron un TS negativa, en contraste con lo que ocurre en las UF de las Regiones Norte y Noreste mostraron una TS positiva. Se encontraron seis agrupamientos significativos de alto riesgo: 3 en el Norte-Noreste y 3 en el Sur-Sur-Oeste-Centro-Oeste. Conclusiones Las regiones Norte y Noreste mostraron una TS positiva para la TMI-M y un mayor riesgo de muerte, que no se observó en las otras regiones. La distribución de los agrupamientos de mayor TMI-M y riesgo se asemeja a la distribución de los casos de microcefalia y Zika en el período del brote. Conclusiones: Las regiones Norte y Noreste mostraron una TS positiva para la TMI-M y un mayor riesgo de muerte, que no se observó en las otras regiones. La distribución de los agrupamientos de mayor TMI-M y riesgo se asemeja a la distribución de los casos de microcefalia y Zika en el período del brote.
Subject(s)
Infant Mortality , Microcephaly/mortality , Microcephaly/virology , Zika Virus Infection/epidemiology , Zika Virus Infection/mortality , Brazil/epidemiology , Disease Outbreaks , Humans , Infant , Infant, Newborn , Spatio-Temporal AnalysisABSTRACT
In the present case series, the cause of death of infants diagnosed with congenital Zika syndrome (CZS) was lung disease (pneumonia and sepsis with massive pulmonary aspiration), probably secondary to dysphagia and reflux. The main findings in infants with a confirmed diagnosis of CZS who died were as follows: (1) calcification and hypoplasia of the lentiform nuclei, hypoplasia of the caudate nuclei, and calcification at the cortical-subcortical junction was noted in all cases (100%) and calcification of the caudate nuclei was noted in 66.7% of cases; (2) calcification in the brainstem and along the lateral wall of the lateral ventricles was noted in only the case with arthrogryposis (33.3%); and (3) lesions in the posterior fossa (hypoplasia of the brainstem and cerebellum) were noted in two cases (66.7%), including the case with arthrogryposis. The findings concerning calcifications and brain malformations obtained from non-contrast computed tomography (CT) demonstrated good agreement with findings obtained from the postmortem pathological analysis; however, CT failed to detect discontinuity of the pia mater with heterotopia, invasion of the cerebral tissue into the subarachnoid space, and discontinuity of the ependyma in the lateral ventricles with gliosis; this last feature was only imaged in the most severe case of extreme microcephaly with a simplified gyral pattern. Only histopathology showed grouped calcifications associated with scattered calcifications suggestive of the neuron morphology.
Subject(s)
Brain/diagnostic imaging , Pregnancy Complications, Infectious/mortality , Tomography, X-Ray Computed/methods , Zika Virus Infection/congenital , Zika Virus Infection/mortality , Autopsy , Brain/ultrastructure , Brain/virology , Calcinosis/diagnostic imaging , Calcinosis/etiology , Calcinosis/mortality , Cause of Death , Female , Humans , Infant , Lung Diseases/etiology , Lung Diseases/mortality , Microcephaly/etiology , Microcephaly/mortality , Microcephaly/virology , Pregnancy , Sepsis/etiology , Sepsis/mortality , Syndrome , Zika Virus , Zika Virus Infection/diagnostic imagingABSTRACT
Considering the currently confirmed cases of microcephaly and related deaths associated with Zika virus in Brazil, the estimated case fatality rate is 8.3% (95% confidence interval: 7.2-9.6). However, a third of the reported cases remain under investigation. If the confirmation rates of cases and deaths are the same in the future, the estimated case fatality rate will be as high as 10.5% (95% confidence interval: 9.5-11.7).
Subject(s)
Disease Outbreaks , Microcephaly/epidemiology , Perinatal Mortality/trends , Pregnancy Complications, Infectious/epidemiology , Zika Virus Infection/epidemiology , Adult , Brazil/epidemiology , Female , Fetus , Humans , Infant , Infant, Newborn , Microcephaly/etiology , Microcephaly/mortality , Microcephaly/virology , Pregnancy , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/mortality , Pregnancy Complications, Infectious/virology , Survival Analysis , Zika Virus/pathogenicity , Zika Virus/physiology , Zika Virus Infection/complications , Zika Virus Infection/mortality , Zika Virus Infection/virologyABSTRACT
Due to the increase in cases of microcephaly caused by Zika virus in Brazil, the Ministry of Health of Argentina recommends increasing surveillance of this malformation. In order to deepen the knowledge of the epidemiological behavior of microcephaly in the country, infant mortality by microcephaly is analyzed between 1998 and 2012. The data come from the Direction of Statistics and Health Information (DEIS). The infant mortality rate by microcephaly (IMR-M) was calculated by provinces and regions and a clustering analysis was performed at the departmental level. The highest rates were observed in the regions and provinces of the north of the country. The spatial distribution of IMR-M is related to the prevalence of microcephaly in newborns. This distribution is related to the greater poverty and consanguinity of the north of Argentina, synergic factors predisposing to the occurrence of congenital malformations in general and microcephaly in particular.
Debido al incremento de casos de microcefalia por virus Zika en Brasil el Ministerio de Salud de Argentina recomienda incrementar la vigilancia de esta malformación. A fin de profundizar el conocimiento del comportamiento epidemiológico de microcefalia en el país se analiza la mortalidad infantil por microcefalia entre 1998-2012. Los datos proceden de la Dirección de Estadísticas e Información de Salud (DEIS). Se calculó por provincias y regiones la tasa de mortalidad infantil por microcefalia (TMI-M) y se realizó un análisis de agrupamiento a nivel departamental. Las tasas más elevadas se observaron en las regiones y provincias del norte del país. La distribución espacial de la TMI-M guarda relación con las prevalencias de microcefalia en recién nacidos. Esta distribución se relaciona con la mayor pobreza y consanguinidad del norte de la Argentina, factores sinérgicos predisponentes de la ocurrencia de malformaciones congénitas en general y de microcefalia en particular.