Osteogenesis imperfecta (OI) is a family of heritable disorders of bone fragility. Most individuals with OI have mutations in the genes encoding type I collagen; at least 17 other genes have been associated with OI. Biallelic loss-of-function mutations in WNT1 cause severe OI. Heterozygous missense variants in WNT1 are responsible for early-onset osteoporosis with variable bone phenotypes. Herein we report a 3-generation family with four affected individuals, some presenting with multiple low-impact fractures in childhood and others presenting with early-onset osteoporosis without a striking fracture history. A WNT1 variant (c. 1051>C; p.Trp351Arg) was identified in the proband and segregated with a bone phenotype in three additional family members, consistent with autosomal dominant inheritance. In the proband, whole genome sequencing also revealed a de novo duplication (434 kb) of 22q11.2 that involves 25 genes, 4 of which are associated with human disease when haploinsufficient. Though smaller than the typical (1.5 Mb) 22q11.2 duplication, the duplication in the proband may be responsible for additional non-osseous aspects of his phenotype (hypotonia, developmental delay, small genitalia, strabismus, and depression in pre-adolescence). This case demonstrates the variability of bone phenotype conferred by a WNT1 variant and extends the spectrum of bone phenotypes associated with heterozygous WNT1 mutations.

Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer’s disease, Parkinson’s disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain. Such interactions typically occur either systemically, through the production of small molecules in the gut that are released into circulation, or through signaling via the vagus nerves which directly connect the enteric nervous system to the central nervous system. Collectively, this system of communication is now commonly referred to as the gut-microbiota-brain axis. While equally important, little attention has focused on the causes of the alterations in the composition of gut microbiota. Although several factors can contribute, mucosal immunity plays a significant role in shaping the microbiota in both healthy individuals and in association with several diseases. The purpose of this review is to provide a brief overview of the components of mucosal immunity that impact the gut microbiota and then discuss how altered immunological conditions may shape the gut microbiota and consequently affect neuroimmune diseases, using a select group of common neuroimmune diseases as examples.

Abstract Background: X-linked agammaglobulinemia type 1 or XLA is one of the most common pediatric inborn errors of immunity affecting the humoral immune system. The condition is caused by a mutation in the Bruton tyrosine kinase gene (BTK), located in the long arm of the X-chromosome. BTK is crucial for B lymphocyte differentiation and activation. Therefore, a defect in BTK results in B lymphocytes maturation arrest, absence of plasma cells, and failure of immunoglobulins (Igs) production. XLA affected individuals present with a history of frequent sever pyogenic infections such as pneumonia, conjunctivitis, otitis media, and bacteremia. Laboratory evaluation classically reveals undetectable Igs and the absence of B-cells. The mainstay treatment is immunoglobulins replacement which can be administered intravenously (IVIG) or subcutaneously (SCIG). In addition to, aggressive antimicrobial treatment to reduce complications such as bronchiectasis or invasive bacterial infections during active infections. Aim: To report the clinical presentation, immune features, and genetic mutation in one case of a four-year-old boy with a novel mutation in the BTK gene leading to XLA. Results: The Patient’s chart was reviewed. We describe the phenotypical and diagnostic characteristics of an established case in a four-year-old boy who suffered from recurrent infections. The genetic reading report revealed a pathogenic novel mutation in the BTK gene (c.1953C>A: p Tyr651*), and the flow-cytometry result of 0% C19+ (B-cells), and low Is serum levels. Discussion: We report the clinical presentation, immune features, and genetic mutation in a patient with novel mutations in the BTK gene causing XLA. Genetic analysis along with patient history and physical examination and laboratory results are necessary to identify and diagnose XLA with pathogenic mutation in the BTK gene.