Fuad Al Mutairi

Background: Transcobalamin II (TC II) deficiency is a rare autosomal recessive disorder that typically manifests in early infancy. Symptoms include failure to thrive, vomiting, weakness, and pancytopenia. If left undiagnosed and untreated, it can be life-threatening. TC II is crucial for transporting cobalamin (vitamin B12), which plays a vital role in homocysteine and methylmalonic acid metabolism. It serves as a cofactor in neurotransmitter synthesis and protein methylation processes. Methods: In this study, we reviewed the clinical presentation, treatment approaches, and long-term outcomes of four patients with confirmed TC II deficiency. All subjects were born to consanguineous parents and exhibited symptoms between birth and four months of age. Results: All patients presented with hematological abnormalities, elevated methylmalonic acid (MMA), and increased total homocysteine (tHcy) levels. Whole Exome Sequencing (WES) confirmed TC II deficiency in all cases, revealing diverse mutation spectra, primarily frameshift mutations (leu320Valfs*51, and IIe330Hisfs*9). No clear genotype-phenotype correlations were observed. The majority of patients were treated with intramuscular hydroxocobalamin (OH-Cbl), resulting in clinical and biochemical improvements. Conclusion: This study underscores the importance of early detection and appropriate management of TC II deficiency to prevent permanent morbidity and potentially fatal outcomes. Regular monitoring of clinical and neurological status, as well as MMA and tHcy levels, is essential to ensure adequate therapy. Intramuscular treatment is the preferred route to prevent neurological deficits and optimal markers normalization.

Background: Consanguinity, or the practice of marrying close relatives, is a common cultural tradition in Saudi Arabia, with rates among the highest in the world. This practice has significant implications for the prevalence and distribution of major single genetic defects and chromosomal abnormalities within the Saudi population. Methods: Herein, using the BESTCare electronic medical record system (designed to streamline hospital operations, enhance patient care, and improve the overall efficiency of healthcare services; bestcare.ezcaretech.com) in a single tertiary centre, King Abdullah Specialized Children Hospital (KASCH) in Riyadh, Saudi Arabia, we performed a cross-sectional study for all patients referred to the hospital from the 1st January 2020 until 1st January 2022. Results: The present study, which included 1100 individuals, found a high prevalence of consanguinity (64%) and a significant proportion of third-degree relatives (69%). The mean age of participants was 12.24 years, and the diagnostic rate using advanced molecular genetics techniques was 45%, with whole exome sequencing (WES) being the most common method (43%). The study also noted a significant delay in diagnosis for more than a year in 16% of cases, with a common neurodevelopmental phenotype (18%). Conclusion: In conclusion, we revealed the prevalence of consanguineous marriages in the KASCH hospital in Riyadh, Saudi Arabia. We also highlighted the most frequently referred phenotype. These findings are consistent with previous research on the prevalence and impact of consanguinity on rare genetic disorders.

Background: Genetic microcephaly is linked to an increased risk of developmental disabilities, epilepsy, and motor impairment. The aim of this study is to describe the spectrum of identifiable genetic etiologies, clinical characteristics, and radiologic features of genetic microcephaly in patients referred to a tertiary center in Saudi Arabia. Method: This is a retrospective chart review study of all patients with identifiable genetic microcephaly presenting to a tertiary center in Saudi Arabia. The patients’ demographics, clinical, laboratory, radiologic, and molecular findings were collected. Results: Of the total 128 cases referred, 52 cases (40%) had identifiable genetic causes. Monogenic disorders were found in 48 cases (92%), whereas chromosomal disorders were found in only 4 cases (8%). Developmental disability was observed in 40 cases (84%), whereas only 8 cases (16%) had borderline IQ or mild developmental delay. Epilepsy was seen in 29 cases (56%), and motor impairment was seen in 26 cases (50%). Brain magnetic resonance imaging (MRI) revealed abnormalities in 26 (50%) of the cohort. Hereditary neurometabolic disorders were seen in 7 (15%) of the 48 cases with monogenic disorders. The most common gene defect was ASPM, which is responsible for primary microcephaly type 5 and was seen in 10 cases (19%). A novel PLK1 gene pathogenic mutation was seen in 3 cases (6%). Conclusion: Single gene defect is common in this Saudi population, with the ASPM gene being the most common. Hereditary neurometabolic disorders are a common cause of genetic microcephaly. Furthermore, we propose the PKL1 gene mutation as a possible novel cause of genetic microcephaly.

Background: Atopic dermatitis (AD) is one of the most common diseases encountered in pediatric practice. Genetic factors play a role in the development of this condition. Topical corticosteroids are the cornerstone of AD management, but with potentially serious adverse events. Misuse of these medications is not uncommon. Case Presentation: We describe a case of severe AD with inadvertent overuse of topical steroids. The patient presented with multisystem involvement and a cushingoid appearance. Laboratory tests showed thrombocytosis and abnormal liver function test, among other findings. A whole exome test showed mutations in two genes, a homozygous pathogenic variant c.317C>T p.(Pro106Leu) in the protooncogene, thrombopoietin receptor (MPL) gene (NM_005373.2) inherited from both parents and a de novo heterozygous c.139C>T p.(Arg- 47Cys) in the CARD11 gene (NM_001324281.1), that explain her combined presentation. Conclusion: The aim of this report is to share our experience with the diagnosis and treatment of a challenging case. This report also shows the association between the MPL, CARD11 genes, and severe AD. In addition, this case is consistent with the published literature on systemic involvement in severe AD and variable response to routine management.