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We report clinical findings in 17 adults with Costello syndrome ranging in age from 16 to 40 years. Two patients in this series have had bladder carcinoma, the only malignancy reported to affect adults with Costello syndrome. Benign tumors included multiple ductal papillomata in two women, and a fourth ventricle mass in one man, thought to be a choroid plexus papilloma. Endocrine problems in this series were osteoporosis, central hypogonadism, and delayed puberty. Other health problems were symptomatic Chiari malformations in three patients. Four patients had adult‐onset gastro‐esophageal reflux, three of whom had Chiari malformations. Fourteen adults had mild to moderate intellectual disability with three individuals having severe intellectual disability; 15 individuals attained some reading and writing skills and 14 showed ongoing acquisition of new skills into adulthood. On the basis of this data, we recommend that neuro‐imaging be considered in adults with Costello syndrome if they develop symptoms suggestive of a Chiari malformation. In the event of pubertal delay, endocrine investigations are indicated and hormone treatment may be required. Bone density assessments should be performed in adults with Costello syndrome, particularly in those with pubertal abnormalities. Screening for microscopic hematuria as a marker for bladder carcinoma may be indicated, although this requires further evaluation. © 2005 Wiley‐Liss, Inc.

Heterozygous germline DNA mismatch repair gene mutations are typically associated with hereditary nonpolyposis colorectal cancer. The molecular hallmark of this syndrome is high-frequency microsatellite instability in the tumors. Rare childhood cases with homozygous or compound heterozygous DNA mismatch repair gene mutations have a described predisposition to leukemia, lymphoma, and brain tumors but not to gastrointestinal cancer. We have now characterized a family in which 2 children with a homozygous germline DNA mismatch repair gene mutation developed early-onset gastrointestinal cancers. The 11-year-old proband had cafe-au-lait macules and developed metastatic duodenal adenocarcinoma that arose in a tubulovillous adenoma. His 9-year-old sister with cafe-au-lait macules and axillary freckling presented with malignant colon polyps. A 6-year-old sister with cafe-au-lait macules, hairy nevi, and a plexiform neurofibroma of the tongue has no malignancies to date. The family history did not fulfill the Amsterdam criteria for hereditary nonpolyposis colorectal cancer, but 2 relatives in their 60s had gastric cancer and colorectal cancer, whereas the parents, who are first cousins, remain cancer free. The proband's metastatic duodenal cancer and his sister's malignant colon polyps had high-frequency microsatellite instability but had detectable MLH1, MSH2, and MSH6 proteins by immunohistochemistry. Because some germline DNA mismatch repair gene deficiencies are associated with apparently intact immunohistochemical DNA mismatch repair gene expression in tumors, we proceeded to DNA sequencing, which showed that all 3 children had a germline homozygous MLH1 missense mutation (exon 18, codon 687, CGG->TGG), whereas both parents were heterozygous for this mutation.

Congenital dysmorphic features are prevalent in schizophrenia and may reflect underlying neurodevelopmental abnormalities. A cluster analysis approach delineating patterns of dysmorphic features has been used in genetics to classify individuals into more etiologically homogeneous subgroups. In the present study, this approach was applied to schizophrenia, using a sample with a suspected genetic syndrome as a testable model. Subjects (n = 159) with schizophrenia or schizoaffective disorder were ascertained from chronic patient populations (random, n = 123) or referred with possible 22q11 deletion syndrome (referred, n = 36). All subjects were evaluated for presence or absence of 70 reliably assessed dysmorphic features, which were used in a three-step cluster analysis. The analysis produced four major clusters with different patterns of dysmorphic features. Significant between–cluster differences were found for rates of 37 dysmorphic features (P < 0.05), median number of dysmorphic features (P = 0.0001), and validating features not used in the cluster analysis: mild mental retardation (P = 0.001) and congenital heart defects (P = 0.002). Two clusters (1 and 4) appeared to represent more developmental subgroups of schizophrenia with elevated rates of dysmorphic features and validating features. Cluster 1 (n = 27) comprised mostly referred subjects. Cluster 4 (n = 18) had a different pattern of dysmorphic features; one subject had a mosaic Turner syndrome variant. Two other clusters had lower rates and patterns of features consistent with those found in previous studies of schizophrenia. Delineating patterns of dysmorphic features may help identify subgroups that could represent neurodevelopmental forms of schizophrenia with more homogeneous origins. © 2001 Wiley-Liss, Inc.

The Wiedemann-Beckwith syndrome (WBS) is defined by a group of anomalies, including macrosomia, macroglossia, omphalocele, and ear creases. Several minor anomalies have also been reported in the syndrome, including posterior helical ear pits (PHEP). Two independent linkage studies of pedigrees with autosomal dominant inheritance have shown linkage of WBS to 11p15.5 markers. Further confirming the location of WBS to this location is the finding of 11p15.5 duplications and translocations, as well as uniparental disomy for a small area of 11p15.5. In this study, members of previously described families exhibiting autosomal dominant inheritance of the PHEP phenotype were genotyped for three markers in the 11p15.5 region. These three markers were in the insulin-like growth factor (IGF2), insulin (INS), and tyrosine hydroxylase (TH) region. The data were examined by linkage analysis using the same genetic model used previously to demonstrate linkage of WBS to markers on chromosome 11p15.5: an autosomal dominant model with a penetrance of 0.90 and a gene frequency of 0.001. In one large pedigree, linkage analysis of the 11p15.5 markers excluded the PHEP phenotype from the IGF2, INS, and TH region. In the four other pedigrees examined, the marker loci were not sufficiently informative or the pedigrees did not provide sufficient power to exclude linkage from this region. The strongest evidence against linkage of the PHEP phenotype to 11p15.5 was evident by inspection of the segregation of the haplotypes of the markers in the pedigrees. In two informative pedigrees, relatives with the PHEP phenotype did not share the same haplotype of markers identical by descent. Our results show that the PHEP phenotype is not linked to chromosome 11p15.5 in the informative families tested. In the families examined, there are not enough individuals with WBS to determine if WBS was linked to 11p15.5 in these families. Although locus heterogeneity has not been demonstrated in WBS, it is possible that a second WBS locus exists and that the PHEP phenotype in these families is linked to a second WBS locus. Alternatively, the PHEP phenotype may occur independently of WBS so that the association of WBS and PHEP in our pedigrees may, in fact, represent causal heterogeneity. © 2001 Wiley-Liss, Inc.

Abstract. Alström syndrome is a rare autosomal recessive disorder characterized by retinal degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin-dependent diabetes mellitus. The gene for Alström syndrome (ALMS1) has been previously localized to human chromosome 2p13 by homozygosity mapping in two distinct isolated populations - French Acadian and North African. Pair-wise analyses resulted in maximum lod (logarithm of the odds ratio) scores of 3.84 and 2.9, respectively. To confirm these findings, a large linkage study was performed in twelve additional families segregating for Alström syndrome. A maximum two-point lod score of 7.13 (θ=0.00) for marker D2S2110 and a maximum cumulative multipoint lod score of 9.16 for marker D2S2110 were observed, further supporting linkage to chromosome 2p13. No evidence of genetic heterogeneity was observed in these families. Meiotic recombination events have localized the critical region containing ALMS1 to a 6.1-cM interval flanked by markers D2S327 and D2S286. A fine resolution radiation hybrid map of 31 genes and markers has been constructed.

Alstrom syndrome is an autosomal recessive disorder characterized by cone-rod dystrophy, obesity, hearing impairment, and diabetes caused by insulin resistance. By reviewing the charts of eight patients followed for periods of 2 to 22 years, we established the natural history of this syndrome during childhood. Five patients, in four families, were seen between the ages of 3 weeks and 4 months with a dilated cardiomyopathy, a previously unrecognized feature of the syndrome. Photophobia and nystagmus were first documented in the eight patients between the ages of 5 months and 15 months. In all patients, electroretinography initially showed a severe cone impairment with mild (2/8) or no (6/8) rod involvement. Electroretinograms, obtained again at ages 9 to 22 years for four patients, revealed extinguished rod-and-cone responses. Obesity developed during childhood in seven patients, in at least three of them before age 2 years. Hearing impairment (5/8) and diabetes/glucose intolerance (4/8) were diagnosed at the end of the first decade or during the second decade. This constellation of features should facilitate early diagnosis of the syndrome. (J PEDIATR 1996;128:225-9)

Cell lines derived from seven patients with Bloom syndrome all contain a DNA ligase I with unusual properties. Six lines were shown to have a reduced level of this enzyme activity and the residual enzyme was anomalously heat-labile. The seventh line contained a dimeric rather than monomeric form of ligase I. Several cell lines representative of other inherited human syndromes have apparently normal DNA ligases. The data indicate that Bloom syndrome is due to a defect in the structure of DNA ligase I caused by a "leaky" point mutation occurring at one of at least two alternative sites.

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