Compound heterozygous mutations in the IFT140 gene cause Opitz trigonocephaly C syndrome in a patient with typical features of a ciliopathy.

〈 We report on an infant with Opitz trigonocephaly C syndrome (OTCS), who also had manifestations of ciliopathy, including short ribs (non-asphyxiating), trident acetabular roofs, postaxial polydactyly cone-shaped epiphyses, and dysplasia of the renal, hepatic and pancreatic tissues. To investigate the molecular cause, we used an exome sequencing strategy followed by Sanger sequencing. Two rare variants, both predicted to result in loss of functional protein, were identified in the IFT140 gene; a substitution at the splice donor site of exon 24 (c.723 + 1 G > T) and a 17 bp deletion, impacting the first coding exon (c.-11_6del). The variants were confirmed as being biallelic using Sanger sequencing, showing that the splice variant was inherited from the propositus mother and the deletion from the father. To date, Mainzer-Saldino syndrome, Jeune syndrome, and a form of nonsyndromic retinal dystrophy, have been identified as ciliopathies caused by IFT140 mutations. We provide the first description of an OTCS phenotype that appears to result from IFT140 mutations. The presentation of this patient is consistent with previous reports showing that OTCS already exhibited skeleletal and nonskeletal features of a ciliopathy.

Indicadores de severidad de la craneosinostosis no sindrómica: Cuantificación de malformaciones sagitales y metópicas / Severity indices for non-syndromic craniosynostosis: quantifying sagittal and metopic malformations

En este trabajo se presenta un nuevo conjunto de indicadores de severidad que combinan diversos rasgos craneales para cuantificar las craneosinostosis aisladas de tipo sagital y metópica. La utilidad de los indicadores se evaluó examinando las tomografías computarizadas del cráneo de un grupo de infantes afectados por craneosinostosis aislada y un grupo de infantes no afectados. La base de datos contiene estudios de 90 pacientes con craneosinostosis sagital, 40 con craneosinostosis metópica y 60 pacientes no afectados. Los indicadores de severidad se obtienen a partir de un conjunto de indices de severidad por medio de un método estadístico de regresión logística regularizada conocido como red elástica. Los índices de severidad son medidas univariadas de forma que se calculan a partir de tres planos de análisis. Los planos se estiman a partir de referencias anatómicas cerebrales radiológicamente identificables. El desempeño de los indicadores se midió estimando el grado de separación lineal (GSL), que cuantifica la capacidad de un indicador para distinguir cráneos sagitales o metópicos de cráneos no afectados. Los indicadores de severidad propuestos alcanzan un GSL del 95.83% y 98.9% en las poblaciones sagitales vs. controles y metópicos vs. controles, respectivamente. Los resultados obtenidos en este trabajo sugieren que es posible construir indicadores multivariables de severidad que son clínicamente reproducibles y cuantifican efectivamente aspectos de la morfología craneal codificada por medio de un conjunto de índices de severidad.

This work develops a new set of severity scores that combine several cranial features in order to quantify sagittal and metopic craniosynostosis. Computed tomography head scans were obtained from 90 children affected with single-suture sagittal synostosis, 40 children with single-suture metopic synostosis, and 60 age-matched nonsynostotic controls. Tridimensional reconstructions of the skull were used to trace image analysis planes defined in terms of skull-base plane and internal landmarks. For each patient, a new set of descriptive measures or severity indices of skull shape malformation were computed. A statistical classification approach (regularized logistic regression) was used for combining individual severity indices into summarizing severity scores. The linear separation index that measures the ability of a classification function to separate the affected (sagittal or metopic) and nonsynostotic populations was used to evaluate the severity scores. The proposed scores are sensitive measures of the calvarial malformation that achieve linear separation indices of 95.83% and 98.9% for sagittal vs. control and metopic vs. control populations, respectively. As opposed to individual severity indices, the summarizing severity scores encapsulate a number of distinctive calvarial features associated with sagittal and metopic synostoses crania. The proposed scores enable quantitative analysis in clinical settings of skull features observed in isolated sagittal and metopic synostoses that may not be accurately detected by separate analysis of individual severity indices.