Loss of NHEJ1 Protein Due to a Novel Splice Site Mutation in a Family Presenting with Combined Immunodeficiency, Microcephaly, and Growth Retardation and Literature Review.

INTRODUCTION: Non-homologous end joining gene 1 (NHEJ1) defect is a rare form of primary immune deficiency. Very few cases have been described from around the world. PURPOSE: We are reporting the first family from the Arabian Gulf with three siblings presenting with combined immunodeficiency (CID), microcephaly, and growth retardation due to a novel NHEJ1 splice site mutation, in addition to a review of the previously published literature on this subject. METHODS: Patients' clinical, immunological, and laboratory features were examined. Samples were subjected to targeted next-generation sequencing (NGS). The pathogenic change in NHEJ1 was confirmed by Sanger sequencing, then further assessed at the RNA and protein levels. RESULTS: Patients were found to have a homozygous splice site mutation immediately downstream of exon 3 in NHEJ1 (c.390 + 1G > C). This led to two distinct mRNA products, one of which demonstrated skipping of the last 69 basepairs (bp) of exon 3 while the other showed complete skipping of the entire exon. Although both deletions were in-frame, immunoblotting did not reveal any NHEJ1 protein products in patient cells, indicating a null phenotype. CONCLUSION: Patients presenting with CID, microcephaly, and growth retardation should be screened for NHEJ1 gene mutations. We discuss our data in the context of one of our patients who is still alive at the age of 30 years, without transplantation, and who is the longest known survivor of this disease.

Novel mutation in DOCK8-HIES with severe phenotype and successful transplantation.

BACKGROUND: Hyper-IgE syndrome (HIES) due to DOCK8 deficiency is an autosomal recessive (AR) primary combined immunodeficiency which results in significant morbidity and mortality at a young age. Different mutations in the DOCK8 gene can lead to variable severity of the disease. OBJECTIVE: We evaluated the genetic mutations in three related patients with severe clinical manifestations suggestive of AR HIES. We also explored whether treatment with stem cell transplantation could lead to complete disease resolution. METHOD: We examined the clinical manifestations and immunological workup of these patients. Their DNA was also screened for causative mutation. Post transplantation, clinical and immunological data for the transplanted patient was also collected. RESULTS: All patients had a severe course of the disease with rarely reported severe complications in HIES. One patient died with lymphoma while another died with progressive multifocal leukoencephalopathy (PML) due to a slow virus. All our patients had two novel mutations in the DOCK8 gene. One of these mutations was a novel pathogenic mutation and explains the severity of the disease (homozygous splice site mutation at position 5 after the end of exon 45), while the other mutation was mostly non-pathogenic. Hematopoietic stem cell transplantation (HSCT) was performed in the youngest patient with excellent engraftment and full reversibility of the clinical manifestations. CONCLUSION: We report 3 patients from a consanguineous family diagnosed with AR-HIES due to a novel pathogenic mutation in DOCK8 gene leading to fatal outcome in 2 patients and complete resolution of the clinical and immunological features in the third patient by HSCT.

First study of pattern of anaphylaxis in a large tertiary care hospital in Saudi Arabia.

BACKGROUND: Anaphylaxis is a serious allergic reaction that may cause death. The signs and symptoms of anaphylaxis have not been examined in the Saudi population before. OBJECTIVE: The present study examined the signs, symptoms, triggers, and demographic patterns of patients treated for anaphylaxis at a large tertiary care hospital in Riyadh, Saudi Arabia. METHODS: All the patients who were prescribed new prescriptions of adrenaline auto-injectors (AAs) between February 1, 2010 and December 31, 2011 were included in this study. Information was collected using a standardized form. RESULTS: There were 238 patients who were analyzed. The median age at the time of first AA prescription was 15.5 years. Female to male ratio was 52:48 and 54% of the subjects were more than 18 years of age. There were some differences in the presenting signs and symptoms observed in our study compared with similar studies from around the world. Urticaria and angioedema were the most common at about 70% across all ages, followed by shortness of breath at 28%. Some triggers were found to be more common in our region. Food was the commonest trigger for anaphylaxis including tree nuts, egg, and sesame. Drug allergy was also a common trigger, with penicillins and nonsteroidal anti-inflammatory drugs being the commonest. Regarding insect allergy, samsam ant was the commonest trigger in our study. CONCLUSION: To our knowledge, this is the first study on anaphylaxis in Saudi Arabia. Some of the manifestations of anaphylaxis are significantly different in our population study compared to previously published data from other parts of the world. While managing anaphylaxis, we should be mindful of these differences. This improved understanding should help reduce the morbidity and mortality associated with anaphylaxis in our region.