Jorge Davila

Homozygous mutation in the eukaryotic translation initiation factor 2alpha phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability

Protein translation is an essential cellular process initiated by the association of a methionyl–tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors and mRNA, which together comprise the translational initiation complex. This process is regulated by the phosphorylation status of the α subunit of eIF2 (eIF2α); phosphorylated eIF2α attenuates protein translation. Here, we report a consanguineous family with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings. Whole-exome sequencing identified a homozygous missense mutation, c.1972G>A; p.Arg658Cys, in protein phosphatase 1, regulatory subunit 15b (PPP1R15B), a protein which functions with the PPP1C phosphatase to maintain dephosphorylated eIF2α in unstressed cells. The p.R658C PPP1R15B mutation is located within the PPP1C binding site. We show that patient cells have greatly diminished levels of PPP1R15B–PPP1C interaction, which results in increased eIF2α phosphorylation and resistance to cellular stress. Finally, we find that patient cells have elevated levels of PPP1R15B mRNA and protein, suggesting activation of a compensatory program aimed at restoring cellular homeostasis which is ineffective due to PPP1R15B alteration. PPP1R15B now joins the expanding list of translation-associated proteins which when mutated cause rare genetic diseases.

Late diagnosis of cerebral folate deficiency: Fewer seizures with folinic acid in adult siblings

Cerebral folate deficiency is a genetically heterogeneous condition.1 Mutations in FOLR1 are responsible for a rare but treatable form of cerebral folate deficiency (OMIM #613068).1 The gene codes for folate receptor alpha (FRα), a specific CNS folate transporter. Individuals with FOLR1-related folate deficiency present with ataxia, dyskinesia, spasticity, seizures, and regression in cognitive abilities and motor skills during early childhood.2 Seizures commonly observed include generalized tonic-clonic, atonic, and myoclonic.3 To date, there have been 18 individuals with FOLR1-related cerebral folate deficiency diagnosed in childhood and reported in the literature.3–5 Early diagnosis is crucial, as high-dose folinic acid (2–5 mg/kg/day) has been reported to be an effective treatment that can ameliorate or even prevent further neurodegeneration, although no long-term treatment studies have been performed.1,3,5,6 We present the late diagnosis of adult siblings with cerebral folate deficiency due to FOLR1 mutations and their subsequent treatment.

Current concepts in radiologic assessment of pediatric brain tumors during treatment, part 1

Pediatric brain tumors differ from those in adults by location, phenotype and genotype. In addition, they show dissimilar imaging characteristics before and after treatment. While adult brain tumor treatment effects are primarily assessed on MRI by measuring the contrast-enhancing components in addition to abnormalities on T2-weighted and fluid-attenuated inversion recovery images, these methods cannot be simply extrapolated to pediatric central nervous system tumors. A number of researchers have attempted to solve the problem of tumor assessment during treatment in pediatric neuro-oncology; specifically, the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group was recently established to deal with the distinct challenges in evaluating treatment-related changes on imaging, but no established criteria are available. In this article we review the current methods to evaluate brain tumor therapy and the numerous challenges that remain. In part 1, we examine the role of T2-weighted imaging and fluid-attenuated inversion recovery sequences, contrast enhancement, volumetrics and diffusion imaging techniques. We pay particular attention to several specific pediatric brain tumors, such as optic pathway glioma, diffuse midline glioma and medulloblastoma. Finally, we review the best means to assess leptomeningeal seeding.

Bilateral Piriform sinus fistulas: a case study and review of management options

BackgroundPiriform sinus fistulas occur due to developmental abnormalities of the third and fourth branchial arches, and almost always occur unilaterally. They generally present as recurrent abscesses in the anterior-inferior neck, with concurrent thyroiditis. They have conventionally been managed with complete removal of the sinus tract, and thyroidectomy if required; however, endoscopic approaches have been increasingly favored. Herein we describe a case of bilateral piriform sinus fistulas, and present a review of the literature concerning their endoscopic management.Case presentationOur patient was determined to have bilateral piriform sinus fistulas based on computer tomography, magnetic resonance imaging and microlaryngoscopy. We performed electrocauterization of the proximal fistula tracts, followed by injection of fibrin sealent. Our patient has not had a recurrence in the ten months since his procedure. There were no complications.Twenty-three articles describing an endoscopic approach to these fistulas were identified through PubMed, and a search through the references of related articles was completed.ConclusionOf one hundred and ninety-five patient cases we reviewed, an endoscopic procedure success rate of 82% and complication rate of 5.6% was determined. Piriform sinus fistulas that occur bilaterally are a rare congenital abnormality of the neck. Endoscopic approaches are an acceptable alternative option to open procedures, with similar success and a lower rate of complications.

Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome

White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN‐related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals.

Brief Review on Metabolic Bone Disease

Metabolic bone disease (MBD) is a broad term that describes a clinically heterogeneous group of diseases that are only united by a common denominator of an aberrant bone chemical milieu leading to a defective skeleton and bone abnormalities. From a forensic pathologist’s perspective, MBDs create a challenging diagnostic dilemma in differentiating them from child abuse, particularly when the victim is an infant. Through this brief narrative review on MBD, bone pathophysiology and two relatively challenging pediatric MBDs will be discussed.

Rickets: Historical, Epidemiological, Pathophysiological, and Pathological Perspectives

Rickets was a common metabolic disease of bone a century ago in Europe, North America, and East Asia (mainly due to vitamin D deficiency) but was largely eradicated in growing children by use of cod liver oil and the introduction of vitamin D fortification of milk in the 1930s in the United States. Vitamin D deficiency (VDD) remains the most common form of metabolic bone disease that is entirely preventable and treatable. Historically, rickets has appeared in sporadic epidemics and, despite the introduction of numerous preventive strategies, VDD has remained a global health problem amongst children. Moreover, developed countries such as Canada, Australia, the United Kingdom, and the United States have not been exempt from this. The radiological and histological features of rickets are both distinctive and characteristic and they reflect the underlying pathophysiological issue of decreased mineralization of bone as a result of VDD. The radiological features include 1) metaphyseal cupping and fraying, 2) poor mineralization of epiphyseal centers, 3) irregular and widened epiphyseal plates, 4) increased distance between the end of shaft and epiphyseal center, 5) cortical spurs at right angles to the metaphysis, 6) coarse trabeculation, and 7) periosteal reactions. Fractures may also be evident. The histological features of rickets reflect the failure of cartilage to mineralize and undergo resorption. This results in 1) disordered proliferation of chondrocytes in the hypertrophic zone secondary to a lack of apoptosis, 2) loss of the columnar arrangement of chondrocytes that results in thickening and disorganization of the hypertrophic zone, 3) tongue-like projections of cartilage that extend into the spongiosa, 4) irregularity of the limit between the proliferative and hypertrophic zones, and 5) penetration of blood vessels into the hypertrophic zone. The case of a premature 3-month-old female infant, born in the winter months in the arctic region of Canada who died from a lobar pneumonia with an incidental finding of radiological and pathological evidence of rickets, is presented. The case is used to review the entity of rickets from historical, pathophysiological, radiological, and histological perspectives.