RESUMO
BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type I (MOPD I, also known as Taybi-Linder syndrome) is a rare genetic disorder associated with severe intrauterine growth retardation, short stature, microcephaly, brain anomalies, stunted limbs, and early mortality. RNU4ATAC, the gene responsible for this disorder, does not encode a protein but instead the U4atac small nuclear RNA (snRNA), a crucial component of the minor spliceosome. Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. CASE REPORT: The patient described herein is an 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at the age of one, thereafter resulting in severe psychomotor disabilities. Genetic analysis using gene microarray and whole-exome sequencing could not identify the cause of her congenital anomalies. However, Sanger sequencing revealed a compound heterozygous mutation within RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity. Furthermore, antibodies against varicella-zoster, rubella, measles, mumps, and influenza were very low or negative despite having received vaccinations for these viruses. HHV-6 IgG antibodies were also undetected. DISCUSSION: The patient here exhibited a marked MOPD I phenotype complicated by various immunodeficiencies. Previous studies have not demonstrated immunodeficiency comorbidities within MOPD I subjects, but this report suggests an evident immunodeficiency in MOPD I. Patients with MOPD I should be treated with one of the immunodeficiency syndromes.
Assuntos
Cardiomiopatias/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Doenças da Imunodeficiência Primária/genética , RNA Nuclear Pequeno/genética , Doenças Retinianas/genética , Adolescente , Alelos , Cardiomiopatias/fisiopatologia , Nanismo/fisiopatologia , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Microcefalia/fisiopatologia , Mutação , Osteocondrodisplasias/fisiopatologia , Linhagem , Fenótipo , Doenças da Imunodeficiência Primária/fisiopatologia , Doenças Retinianas/fisiopatologia , Sequenciamento do ExomaAssuntos
Síndromes de Imunodeficiência/sangue , Contagem de Linfócitos , Subpopulações de Linfócitos , Receptores de Antígenos de Linfócitos T gama-delta , Verrugas/sangue , Biomarcadores , Análise Mutacional de DNA , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Imunofenotipagem , Lactente , Subpopulações de Linfócitos/metabolismo , Mutação , Período Pós-Operatório , Doenças da Imunodeficiência Primária , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores CXCR4/genética , Verrugas/diagnóstico , Verrugas/terapiaRESUMO
BACKGROUND: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. OBJECTIVE: This study aimed to identify novel genes responsible for APDS. METHODS: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. RESULTS: We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. CONCLUSION: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.