Expanding the clinical features of autoinflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation by description of a novel patient.

BACKGROUND: Autoinflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation (APLAID) is an exceedingly rare monogenic autoinflammatory disease. To date, only five cases have been reported with four distinct pathogenic mutations. OBJECTIVES: We present a novel case of APLAID, corroborated by molecular analysis, with newly described clinical findings including central nervous system vasculitis (CNSV); and distinctive histopathological characteristics that may expand our knowledge of this rare disease's phenotype. METHODS: This is a case report presentation of a 3-year-old boy, seen at a reference paediatric hospital in Mexico. His parents authorized the use of his clinical information and photographs. RESULTS: A 3-day-old boy presented to the emergency department with a vesiculo-pustular rash that resolved within 1 week. Two months later, he developed widespread papules and pseudovesicles that evolved into infiltrated plaques. He also had periodical flares of conjunctivitis, diarrhoea and erythematous blistering acral plaques triggered by upper respiratory infections. By the age of 10 months, he experienced seizures and CNSV. Laboratory work-up showed mild neutropenia, decreased serum levels of immunoglobulins and B-cell lymphopenia. A skin biopsy revealed a dense, perivascular and interstitial histiocytic and granulomatous infiltrate, with palisading granulomas, and leucocytoclastic vasculitis with karyorrhexis. APLAID syndrome was confirmed by Sanger sequencing of PLCG2 gene [heterozygous genotype LRG_376t1:c.2543T>C or p.(Leu848Pro)]. CONCLUSIONS: Presence of CNSV has not been previously described in APLAID, however as the number of reported patients with APLAID is very small, it is possible that the overall spectrum of clinical manifestations has not been completely elucidated. The herein identified p.(Leu848Pro) variant was also documented in a Portuguese patient, suggesting that it could be a PLCG2 gene 'hot-spot'.

Gene Interactions Provide Evidence for Signaling Pathways Involved in Cleft Lip/Palate in Humans.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common craniofacial birth defect that has a complex etiology. Genome-wide association studies have recently identified new loci associated with NSCL/P, but these loci have not been analyzed in a Mexican Mestizo population. A complex etiology implies the presence of genetic interactions, but there is little available information regarding this in NSCL/P, and no signaling pathway has been clearly implicated in humans. Here, we analyzed the associations of 24 single nucleotide polymorphisms (SNPs) with NSCL/P in a Mexican Mestizo population (133 cases, 263 controls). The multifactorial dimensionality reduction method was used to examine gene-gene and gene-folic acid consumption interactions for the 24 SNPs analyzed in this study and for 2 additional SNPs that had previously been genotyped in the same study population. Six SNPs located in paired box 7, ventral anterior homeobox 1, sprouty RTK signaling antagonist 2, bone morphogenetic protein 4, and tropomyosin 1 genes were associated with higher risks of NSCL/P (P = 0.0001 to 0.04); 2 SNPs, 1 each in netrin 1 and V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B, were associated with a lower risk of NSCL/P (P = 0.013 to 0.03); and 2 SNPs, 1 each in ATP binding cassette subfamily A member 4 (ABCA4) and noggin, showed associations with NSCL/P that approached the threshold of significance (P = 0.056 to 0.07). In addition, 6 gene-gene interactions (P = 0.0001 to 0.001) and an ABCA4-folic acid consumption interaction (P < 0.0001) were identified. On the basis of these results, combined with those of previous association studies in the literature and biological characterizations of murine models, we propose an interaction network in which interferon regulatory factor 6 plays a central role in the etiology of NSCL/P.