American Journal of Medical Genetics, Part A

The immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo‐ or agamma‐globulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café‐au‐lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations abnormalities have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases. © 2012 Wiley Periodicals, Inc.

The ICF syndrome (immunodeficiency, centromeric instability, facial anomalies) (OMIM#242860) is a rare autosomal, recessively inherited disorder. Another rare condition, ischiadic hypoplasia, renal dysgenesis, immunodeficiency, and polydactyly (IHRDIP, OMIM#243340), displays features that resemble those of the ICF syndrome. Due to the overlapping symptoms in both syndromes, we asked whether a shared underlying molecular defect exists. Two patients, each with the clinical characteristics of one of these syndromes, were subjected to conventional cytogenetic analysis and the determination of the methylation state of satellite II DNA. We found that both displayed the two hallmark features of the ICF syndrome, namely hypomethylation and centromeric instability of chromosomes 1 and 16. Therefore, we reclassified the patient previously diagnosed with the IHRDIP syndrome as an ICF patient. Since the majority of ICF patients are carriers of mutations in the methytransferase gene DNMT3B, we determined the sequence of its coding, splice site, and putative promoter region and analyzed its transcripts in both patients, without detecting any alterations. Similarly, the coding region of two DNMT3B‐interacting proteins, SUMO‐1 and UBC9, did not reveal mutations. With this study, the published number of patients that lack mutations in DNMT3B coding region increases to almost 40% of all ICF patients reported. It is, therefore, implied that a significant subset of ICF patients will have a yet unknown, alternative alteration, which may include the involvement of DNMT3B‐interacting factors or aberrations of an independent pathway. © 2005 Wiley‐Liss, Inc.

Sự liên quan giữa mức tiêu thụ folate của mẹ và nguy cơ dị tật môi miệng không hội chứng đã được nghiên cứu trong nhiều quần thể với kết quả trái ngược nhau. Gen methylenetetrahydrofolate reductase (MTHFR) đóng vai trò quan trọng trong chuyển hóa folate, và một số đa hình, bao gồm C677T, phổ biến trong các quần thể châu Âu. Dữ liệu từ một nghiên cứu ở Pháp (1998–2001) cho phép chúng tôi điều tra vai trò của mức tiêu thụ folate qua chế độ ăn của mẹ và đa hình MTHFR cũng như tương tác của chúng với nguy cơ dị tật môi với/hay không có khe hở (CL/P) và chỉ khe hở palate (CP). Chúng tôi sử dụng cả mẫu nghiên cứu trường hợp-đối chứng (164 CL/P, 76 CP, 236 đối chứng; 148, 59, 168 người trong số đó có kiểu gen có sẵn) và thiết kế nghiên cứu trường hợp-phụ huynh (143 gia đình CL/P và 56 CP) và phân biệt vai trò của kiểu gen của trẻ và tác động từ mẹ đối với nguy cơ. Nghiên cứu này quan sát thấy hiệu ứng có lợi của mức tiêu thụ folate từ chế độ ăn của mẹ đối với nguy cơ của con cái họ (tỷ lệ nguy cơ (OR)_{≤230 µg/ngày} = ref; đối với CL/P, OR_{[230–314 µg/ngày]} = 0.56, khoảng tin cậy 95% = 0.3–0.9, OR_{>314 µg/ngày} = 0.64, 0.4–1.1; đối với CP, OR_{[230–314 µg/ngày]} = 1.15, 0.6–2.2, OR_{>314 µg/ngày} = 0.70, 0.3–1.4). Chúng tôi nhận thấy nguy cơ giảm liên quan đến kiểu gen TT của trẻ trong phân tích trường hợp-đối chứng (OR_CC = ref; đối với CL/P, OR_TT = 0.54, 0.3–1.1; đối với CP, OR_TT = 0.33, 0.1–1.0); kiểu gen này, bất kể là thai nhi hay mẹ, không có tính chất thống kê có ý nghĩa trong phân tích trường hợp-phụ huynh. Tần suất kiểu gen TT cao hơn trong nhóm đối chứng của chúng tôi so với những báo cáo từ trước ở Pháp có thể lý giải một phần sự giảm nguy cơ quan sát được trong so sánh trường hợp-đối chứng. Các tương tác không có tính chất thống kê có ý nghĩa. Tuy nhiên, phân tích trường hợp-phụ huynh theo nhóm cho thấy sự không đồng nhất nhẹ trong vai trò của kiểu gen TT theo mức tiêu thụ folate. Kích cỡ mẫu khiêm tốn là một giới hạn của nghiên cứu này, nhưng vẫn cung cấp ước lượng mới về tác động có thể có của mức tiêu thụ folate qua chế độ ăn và đa hình MTHFR đối với dị tật môi miệng.

Segmental neurofibromatosis refers to individuals who have manifestations of neurofibromatosis type 1 (NF‐1) limited to one area of the body. It results from a post‐conceptional mutation in the NF‐1 gene leading to somatic mosaicism. Although it is generally considered a rare condition, this report of 39 children with segmental NF‐1 demonstrates that it is commonly seen in a pediatric NF‐1 referral center. The mean age at diagnosis was 7.8 years (range: 2–25 years). Twenty‐nine patients had only pigmentary manifestations of segmental NF‐1, including seven who had only café‐au‐lait macules and 22 who had café‐au‐lait macules and freckling. Two patients had isolated plexiform neurofibromas; a third patient had a plexiform neurofibroma of the eyelid in addition to ipsilateral dysplasia of the sphenoid wing and Lisch nodules. A 12‐year‐old girl had an isolated tibial pseudarthrosis. An 8‐year‐old boy had an isolated optic pathway tumor, which behaved both biologically and radiographically as an NF1‐associated tumor. While most children with segmental NF‐1 have only localized pigmentary changes, some children will have isolated plexiform neurofibromas, pseudarthroses, or optic pathway tumors. Accurate diagnosis of segmental NF‐1 is crucial for both management and genetic counseling. © 2003 Wiley‐Liss, Inc.

Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder with high penetrance but extreme variability of expression. Monozygotic (MZ) twins with NF1 who have phenotypic discordances are a useful tool in evaluating which traits are influenced by non‐hereditary influences such as second hit somatic events, environmental agents, epigenetic modification, or post‐zygotic mutations. We evaluated nine sets of MZ twins and one set of MZ triplets, ages 4–18 years, for NF1 features and calculated probandwise concordance (P_C) for each feature. MZ twins were highly concordant in numbers of café‐au‐lait spots (P_C = 0.89) and cutaneous neurofibromas. IQ scores were within 10 points for all twin pairs tested, and similar patterns of learning disabilities and speech disorders were observed. Twin pairs showed significant discordance for tumors, particularly plexiform neurofibromas (P_C = 0.40) and malignant peripheral nerves sheath tumors (MPNST), as expected if post‐natal second‐hit events were contributing to these features. One set of twins was concordant for multiple, large paraspinal neurofibromas, suggesting that there may be more hereditary factors involved in production of paraspinal neurofibromas. Four sets were concordant for pectus deformities of the chest (P_C = 0.80). Three sets of twins were discordant for scoliosis (P_C = 0.40); an additional set was concordant for scoliosis but differed in presence of dystrophic features and need for surgery. Our data suggest there are additional non‐hereditary factors modifying the NF1 phenotype and causing discordancies between MZ twins. Future studies may focus on differences in epigenetic changes or somatic mosaicism which have been documented for other disease genes in MZ twins. © 2011 Wiley‐Liss, Inc.

Neurofibromatosis 1 (NF1) is a common genetic disorder with an autosomal dominant mode of inheritance, an increased morbidity and mortality, and a shorter lifespan. Although the disease is fully penetrant by the age of 8, the variability in symptoms and complications is high, even among members of the same family. The aim of this study was to identify easily recognizable clinical features that may be associated with mortality in a cohort of patients affected with NF1. We used prospectively collected data from the Neurofibromatosis Institute Database (NFID) and included in our analysis 703 patients who fulfilled the NIH diagnostic criteria for NF1. Clinical, especially dermatological features were tested as potential factors associated with mortality. Among the patients, 405 (57.6%) were children and 298 (42.4%) were adults. The mean follow‐up was 2.4 years (median = 0.98, range: 0–15.3 years). Forty patients died during follow‐up, mostly due to tumor development such as sarcoma (n = 18). In the adult population, subcutaneous neurofibromas (odds ratio [OR] = 3.6, 95% confidence interval (CI): [1.2–11.3], P = 0.02) and male gender (OR = 5.6, [1.5–20.9], P = 0.004) were independent predictors of mortality after adjustment for age. Among children, the presence of facial plexiform neurofibromas and pruritus were significantly associated with mortality in univariate analysis. Our study describes independent risk factors of mortality in a large cohort of adult and pediatric patients. Close follow‐up should be obtained for patients presenting with subcutaneous neurofibromas. © 2004 Wiley‐Liss, Inc.