PURA syndrome : clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotypephenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.Peer reviewe

PURA-related neurodevelopmental disorders

Clinical characteristics. PURA-related neurodevelopmental disorders include PURA syndrome, caused by a heterozygous pathogenic sequence variant in PURA, and 5q31.3 deletion syndrome, caused by a genomic 5q31.3 deletion encompassing all or part of PURA. PURA-related neurodevelopmental disorders are characterized by moderate to severe neurodevelopmental delay with absence of speech in most and lack of independent ambulation in many. Early-onset problems can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal non-epileptic movements (dystonia, dyskinesia, and dysconjugate eye movements), and abnormal vision. Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur, but are less common.Diagnosis/testing. The diagnosis of a PURA-related neurodevelopmental disorder is established in a proband with either a heterozygous PURA pathogenic sequence variant (90% of affected individuals) or a non-recurrent deletion of 5q31.3 that encompasses all or part of PURA (10%).Management. Treatment of manifestations: Ongoing routine care by a multidisciplinary team. Treatment and/or therapy for developmental delays; neurologic findings (hypotonia, seizures, abnormal movements); feeding difficulties; apnea; visual impairment; and malformations of the heart, urogenital tract, and skeleton.Surveillance: Long-term follow up to assess psychomotor development, seizures or suspected seizures, vision, feeding for dysphagia, and musculoskeletal complications (hip dysplasia and scoliosis).Genetic counseling. PURA-related neurodevelopmental disorders, caused by either a heterozygous PURA pathogenic sequence variant or a 5q31.3 deletion encompassing all or part of PURA are inherited in an autosomal dominant manner. In almost all probands with a PURA pathogenic sequence variant the sequence variant is de novo; to date, all reported 5q31.3 deletions have been de novo. For parents of an affected child, the risk to future pregnancies is presumed to be low, as a de novo genetic alteration involving PURA is most likely in the proband. However, parents of an affected child may wish to consider prenatal testing or preimplantation genetic diagnosis as risk may be greater than in the general population owing to the possibility of parental germline mosaicism (estimated empirically at &lt;1%).</p

Gait patterns after fracture of the femoral shaft in children, managed by external fixation or early hip spica cast

The authors prospectively studied three-dimensional kinematics and kinetics of gait in children recovering from a closed, isolated, nonpathologic fracture of the femoral diaphysis, who had been randomly assigned to management by monolateral external fixation or early hip spica casting. The aims were to investigate the gait patterns soon after injury and at 2 years after injury. Children treated with external fixation, walking with the external fixator in situ, demonstrated asymmetric gait abnormalities in all three anatomic planes affecting the trunk, pelvis, hip, knee, and ankle. This appears to be a strategy to minimize movement and pain at the fixator pin sites. The gait pattern normalized rapidly after removal of the external fixator with few kinematic or kinetic abnormalities and no clinically significant disturbances of gait at 2 years after injury. In contrast, children in the early hip spica cast group developed a “crouch gait” pattern in the sagittal plane, most likely due to weakness. They also had abnormal coronal plane kinematics related to shortening of the injured side. Gait patterns improved, but at 2 years there were some persistent gait deviations, probably related to residual limb length discrepancy. (C) 2004 Lippincott Williams & Wilkins, Inc