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Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygore penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by cafe-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802 [right arrow] X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.

Abstract: FG syndrome is a rare X-linked multiple congenital anomaly-cognitive impairment disorder caused by the p.R961W mutation in the MED12 gene. We identified all known patients with this mutation to delineate their clinical phenotype and devise a clinical algorithm to facilitate molecular diagnosis. We ascertained 23 males with the p.R961W mutation in MED12 from 9 previously reported FG syndrome families and 1 new family. Six patients are reviewed in detail. These 23 patients were compared with 48 MED12 mutation-negative patients, who had the clinical diagnosis of FG syndrome. Traits that best discriminated between these two groups were chosen to develop an algorithm with high sensitivity and specificity for the p.R961W MED12 mutation. FG syndrome has a recognizable dysmorphic phenotype with a high incidence of congenital anomalies. A family history of X-linked mental retardation, deceased male infants, and/or multiple fetal losses was documented in all families. The algorithm identifies the p.R961W MED12 mutation-positive group with 100% sensitivity and 90% specificity. The clinical phenotype of FG syndrome defines a recognizable pattern of X-linked multiple congenital anomalies and cognitive impairment. This algorithm can assist the clinician in selecting the patients for testing who are most likely to have the recurrent p.R961W MED12 mutation.

We present the longest known surviving case of a male infant with a mosaic complete trisomy 1q. Born at 39 weeks of gestation with respiratory distress, his weight was 3,330 g (25th centile); he had micrognathia, a posterior cleft of palate, abnormal ears and left thumb, syndactyly, and an absent corpus callosum. Initial blood karyotype was normal (46,XY). He died at age 5 months. Autopsy suggested aspiration as the primary cause of death and confirmed the antemortem findings of an absent corpus callosum and atrial septal defect. It also identified some central nervous system, cardiac, gastrointestinal, and lung anomalies not previously recognized. Cytogenetic analysis of skin fibroblasts obtained at autopsy showed a de novo unbalanced translocation between chromosomes 1 and 22: 46,XY,+1,der(1;22)(q10;q10)[25]/46,XY[65] in the cells examined. The previously reported cases had a similar phenotype with birth weight above the 50th centile for gestational age, small mouth, micrognathia, abnormal ears, abnormal fingers, microphthalmia, and hydrocephalus. The present case and a review of the literature delineates the phenotype in trisomy 1q, and reinforces the critical importance of effective communication between specialists, and obtaining permission for autopsy and skin biopsy, in the pursuit of a diagnosis. © 2009 Wiley‐Liss, Inc.

Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes. Type 1 hemochromatosis is the most common form of the disease and results from mutations in the HFEgene. Juvenile hemochromatosis (JH) is the most severe form, usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP). The autosomal dominant form of the disease, type 4, is due to mutations in the SLC40A1gene, which encodes for ferroportin (FPN). Hereditary hemochromatosis is commonly found in populations of European origin. By contrast, hemochromatosis in Asia is rare and less well understood and can be masked by the presence of iron deficiency and secondary iron overload from thalassemia. Here, we provide a comprehensive report of hemochromatosis in a group of patients of Asian origin. We have identified novel mutations in HJV, HAMP, and SLC40A1in countries not normally associated with hereditary hemochromatosis (Pakistan, Bangladesh, Sri Lanka, and Thailand). Our family studies show a high degree of consanguinity, highlighting the increased risk of iron overload in many countries of the developing world and in countries in which there are large immigrant populations from these regions.

The 5' members of the Hoxa and Hoxd gene clusters play major roles in vertebrate limb development. One such gene, HOXD13, is mutated in the human limb malformation syndrome synpolydactyly. Both polyalanine tract expansions and frameshifting deletions in HOXD13 cause similar forms of this condition, but it remains unclear whether other kinds of HOXD13 mutations could produce different phenotypes. We describe a six-generation family in which a novel combination of brachydactyly and central polydactyly co-segregates with a missense mutation that substitutes leucine for isoleucine at position 47 of the HOXD13 homeodomain. We compared the HOXD13(I47L) mutant protein both in vitro and in vivo to the wild-type protein and to an artificial HOXD13 mutant, HOXD13(IQN), which is completely unable to bind DNA. We found that the mutation causes neither a dominant-negative effect nor a gain of function, but instead impairs DNA binding at some sites bound by wild-type HOXD13. Using retrovirus-mediated misexpression in developing chick limbs, we showed that wild-type HOXD13 could upregulate chick EphA7 in the autopod, but that HOXD13(I47L) could not. In the zeugopod, however, HOXD13(I47L) produced striking changes in tibial morphology and ectopic cartilages, which were never produced by HOXD13(IQN), consistent with a selective rather than generalised loss of function. Thus, a mutant HOX protein that recognises only a subset of sites recognised by the wild-type protein causes a novel human malformation, pointing to a hitherto undescribed mechanism by which missense mutations in transcription factors can generate unexpected phenotypes. Intriguingly, both HOXD13(I47L) and HOXD13(IQN) produced more severe shortening in proximal limb regions than did wild-type HOXD13, suggesting that functional suppression of anterior Hox genes by more posterior ones does not require DNA binding and is mediated by protein:protein interactions.

The 5′ members of the Hoxa and Hoxd gene clusters play major roles in vertebrate limb development. One such gene, HOXD13, is mutated in the human limb malformation syndrome synpolydactyly. Both polyalanine tract expansions and frameshifting deletions in HOXD13 cause similar forms of this condition, but it remains unclear whether other kinds of HOXD13mutations could produce different phenotypes. We describe a six-generation family in which a novel combination of brachydactyly and central polydactyly co-segregates with a missense mutation that substitutes leucine for isoleucine at position 47 of the HOXD13 homeodomain. We compared the HOXD13(I47L) mutant protein both in vitro and in vivo to the wild-type protein and to an artificial HOXD13 mutant, HOXD13(IQN), which is completely unable to bind DNA. We found that the mutation causes neither a dominant-negative effect nor a gain of function, but instead impairs DNA binding at some sites bound by wild-type HOXD13. Using retrovirus-mediated misexpression in developing chick limbs, we showed that wild-type HOXD13 could upregulate chick EphA7in the autopod, but that HOXD13(I47L) could not. In the zeugopod, however,HOXD13(I47L) produced striking changes in tibial morphology and ectopic cartilages, which were never produced by HOXD13(IQN), consistent with a selective rather than generalised loss of function. Thus, a mutant HOX protein that recognises only a subset of sites recognised by the wild-type protein causes a novel human malformation, pointing to a hitherto undescribed mechanism by which missense mutations in transcription factors can generate unexpected phenotypes. Intriguingly, both HOXD13(I47L) and HOXD13(IQN)produced more severe shortening in proximal limb regions than did wild-type HOXD13, suggesting that functional suppression of anterior Hox genes by more posterior ones does not require DNA binding and is mediated by protein:protein interactions.

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