Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents and cancer predisposition. Recent evidence for the interactions of ataxia-telangiectasia mutated protein ATM and breast cancer susceptibility proteins BRCA1 and BRCA2 (identified as FANCD1) with other known FA proteins suggests that FA proteins have a significant role in DNA repair/recombination and cell cycle control. The International Fanconi Anemia Registry (IFAR), a prospectively collected database of FA patients, allows us the unique opportunity to analyze the natural history of this rare, clinically heterogeneous disorder in a large number of patients. Of the 754 subjects in this study, 601 (80%) experienced the onset of bone marrow failure (BMF), and 173 (23%) had a total of 199 neoplasms. Of these neoplasms, 120 (60%) were hematologic and 79 (40%) were nonhematologic. The risk of developing BMF and hematologic and nonhematologic neoplasms increased with advancing age with a 90%, 33%, and 28% cumulative incidence, respectively, by 40 years of age. Univariate analysis revealed a significantly earlier onset of BMF and poorer survival for complementation group C compared with groups A and G; however, there was no significant difference in the time to hematologic or nonhematologic neoplasm development between these groups. Multivariate analysis of overall survival time shows that FANCC mutations (P ‫؍‬ .007) and hematopoietic stem cell transplantation (P ‫؍‬ < .0001) define a poor-risk subgroup. The results of this study of patients registered in the IFAR over a 20-year period provide information that will enable better prediction of outcome and aid clinicians with decisions regarding major therapeutic modalities.

In patients with FA, there is a high incidence of aggressive HNSCC at a young age. Surgery remains the mainstay of treatment because patients with FA tolerate radiation therapy and chemotherapy poorly, with significant morbidity. An increased understanding of FA-associated malignancies is not only important in the clinical management of patients with FA but can also elucidate the role of chromosomal instability in the development of HNSCC in general.

Although many of the phenotypic features of our patients are rather nonspecific in cohorts of individuals with syndromic and nonsyndromic mental retardation, the proneness to infection is quite striking because the patients had normal growth and were not physically debilitated. Although the etiology of the infections is not understood, we recommend considering MECP2 dosage studies and a genetics referral in individuals with severe developmental delay and neurologic findings, especially when a history of recurrent respiratory ailments has been documented.

The PMRP database will allow research in three areas: genetic epidemiology, pharmacogenetics, and population genetics. The size and the stability of the population as well as the relative ethnic homogeneity will help facilitate longitudinal studies with valid research results that are not biased by population stratification.

Background-A genetic predisposition for progressive enlargement of thoracic aortic aneurysms leading to type A dissection (TAAD) is inherited in an autosomal-dominant manner in up to 19% of patients, and a number of chromosomal loci have been identified for the condition. Having mapped a TAAD locus to 3p24 -25, we sequenced the gene for transforming growth factor-␤ receptor type II (TGFBR2) to determine whether mutations in this gene resulted in familial TAAD. Methods and Results-We sequenced all 8 coding exons of TGFBR2 by using genomic DNA from 80 unrelated familial TAAD cases. We found TGFBR2 mutations in 4 unrelated families with familial TAAD who did not have Marfan syndrome. Affected family members also had descending aortic disease and aneurysms of other arteries. Strikingly, all 4 mutations affected an arginine residue at position 460 in the intracellular domain, suggesting a mutation "hot spot" for familial TAAD. Despite identical mutations in the families, assessment of linked polymorphisms suggested that these families were not distantly related. Structural analysis of the TGFBR2 serine/threonine kinase domain revealed that R460 is strategically located within a highly conserved region of this domain and that the amino acid substitutions resulting from these mutations will interfere with the receptor's ability to transduce signals. Conclusion-Germline

Abnormal vertebral segmentation (AVS) in man is a relatively common congenital malformation but cannot be subjected to the scientific analysis that is applied in animal models. Nevertheless, some spectacular advances in the cell biology and molecular genetics of somitogenesis in animal models have proved to be directly relevant to human disease. Some advances in our understanding have come through DNA linkage analysis in families demonstrating a clustering of AVS cases, as well as adopting a candidate gene approach. Only rarely do AVS phenotypes follow clear Mendelian inheritance, but three genes-DLL3, MESP2, and LNFG-have now been identified for spondylocostal dysostosis (SCD). SCD is characterized by extensive hemivertebrae, trunkal shortening, and abnormally aligned ribs with points of fusion. In familial cases clearly following a Mendelian pattern, autosomal recessive inheritance is more common than autosomal dominant and the genes identified are functional within the Notch signaling pathway. Other genes within the pathway cause diverse phenotypes such as Alagille syndrome (AGS) and CADASIL, conditions that may have their origin in defective vasculogenesis. Here, we deal mainly with SCD and AGS, and present a new classification system for AVS phenotypes, for which, hitherto, the terminology has been inconsistent and confusing.

Fanconi anemia is an autosomal recessive disorder characterized by congenital malformations, bone marrow failure, and the development of squamous cell carcinomas (SCCs) and other cancers. Recent clinicopathologic evidence has raised the possibility that an environmental factor such as human papillomavirus (HPV) may be involved in the pathogenesis of SCCs in Fanconi anemia patients. Given the high prevalence of p53 mutations in SCCs among the general population and the lack of p53 mutations in HPV-related carcinogenesis, we evaluated the role of HPV and p53 mutations and polymorphisms in SCC from Fanconi anemia patients. We used polymerase chain reaction (PCR) screening and real-time PCR to detect and quantify HPV DNA in DNA extracted from microdissected SCCs obtained from 24 Fanconi anemia patients (n = 25 SCCs; case subjects) and 50 age-, sex-, and tumor site-matched SCC patients without Fanconi anemia (n = 50 SCCs; control subjects). We PCR-amplified and sequenced exons 4-9 of the p53 gene from SCC DNA. We detected HPV DNA in 84% of the SCC specimens from the case subjects and in 36% of the SCC specimens from the control subjects (P<.001). The prevalence of p53 mutations in SCCs from the case subjects (0%, 0/25) was statistically significantly lower than that of SCCs from the control subjects (36%, 12/33; P<.001). A greater proportion of patients with Fanconi anemia and SCC were homozygous for Arg72, a p53 polymorphism that may be associated with increased risk for HPV-associated human malignancies, than an ethnically-matched cohort of Fanconi anemia patients without SCC (75% versus 51%; P =.05). These data suggest that Fanconi anemia is associated with increased susceptibility to HPV-induced carcinogenesis.

Many multiple congenital anomalies (MCA) are caused by recombination between homologous segmental duplications. In this report, we describe a novel “de novo” microdeletion in male monozygotic twins presenting with aortic valve abnormality, seizure disorder, and mild mental retardation. Using array based comparative genomic hybridization, we mapped the microdeletion to the short arm of chromosome 16 at 16p11.2 and refined it using hemizygosity mapping to about 593 kb, a region that overlaps with 24 genes. The most probable mechanism for this microdeletion is through a specific intrachromosomal recombination between two, nearly identical, segmental duplications each spanning 147 kb that are flanking the microdeletion. Based on the phenotypes presented in the twins and what is known about the genes within the 16p11.2 microdeletion, we identified several genes that are strong candidates for the normal development of the aortic valve, as well as the development of seizure disorder and mental retardation. © 2007 Wiley‐Liss, Inc.