Based on genotype-phenotype correlation analysis of 80 Wolf-Hirschhorn syndrome (WHS) patients, as well as on review of relevant literature, we add further insights to the following aspects of WHS: (1) clinical delineation and phenotypic categories; (2) characterization of the basic genomic defect, mechanisms of origin and familiarity; (3) identification of prognostic factors for mental retardation; (4) chromosome mapping of the distinctive clinical signs, in an effort to identify pathogenic genes. Clinically, we consider that minimal diagnostic criteria for WHS, defining a "core" phenotype, are typical facial appearance, mental retardation, growth delay and seizures (or EEG anomalies). Three different categories of the WHS phenotype were defined, generally correlating with the extent of the 4p deletion. The first one comprises a small deletion not exceeding 3.5 Mb, that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed. The second and by far the more frequent category is identified by large deletions, averaging between 5 and 18 Mb, and causes the widely recognizable WHS phenotype. The third clinical category results from a very large deletion exceeding 22-25 Mb causing a severe phenotype, that can hardly be defined as typical WHS. Genetically, de novo chromosome abnormalities in WHS include pure deletions but also complex rearrangements, mainly unbalanced translocations. With the exception of t(4p;8p), WHS-associated chromosome abnormalities are neither mediated by segmental duplications, nor associated with a parental inversion polymorphism on 4p16.3. Factors involved in prediction of prognosis include the extent of the deletion, the occurrence of complex chromosome anomalies, and the severity of seizures. We found that the core phenotype maps within the terminal 1.9 Mb region of chromosome 4p. Therefore, WHSCR-2 should be considered the critical region for this condition. We also confirmed that the pathogenesis of WHS is multigenic. Specific and independent chromosome regions were characterized for growth delay and seizures, as well as for the additional clinical signs that characterize this condition. With the exception of parental balanced translocations, familial recurrence is uncommon.

Wolf-Hirschhorn syndrome (WHS) is a well-known chromosomal disorder attributable to partial deletion of the short arm of chromosome 4 (4p-). Although about 120 cases have been reported so far, there is still very little data on its natural history. Information given to parents at the time of diagnosis tends to be skewed to the extreme negative. To help delineate more thoroughly the natural history of WHS, and to obtain better information to answer parents' questions in a clinical setting, we evaluated 15 patients (12 females, 3 males) in three centers with the 4p- syndrome. Four of the cases had a follow-up spanning 16 years. Thirteen cases were detected by standard cytogenetics (regular G-banding 10, high-resolution banding 3), while the remaining 2 required fluorescence in situ hybridization. A total of 5/15 (33.3%) had heart lesions; 7/15 (46. 6%) had oral facial clefts; 13/15 (86.6%) had a seizure disorder, that tended to disappear with age; and 100% had severe/profound developmental retardation. One Italian patient had sensorineural deafness and 1 Utah patient had a right split hand defect. Of note, 2 Utah patients were able to walk with support (at 4 and 12 years of age, respectively), whereas 3 Italian patients and 1 Utah patient were able to walk unassisted (at 4, 5, 5 years 9 months, and 7 years of age, respectively). Two of the 3 Italian patients also achieved sphincter control (by day). The 8 patients receiving serial electroencephalogram studies showed fairly distinctive abnormalities, usually outlasting seizures. A slow, but constant progress in development was observed in all cases, during the follow-up period. In conclusion, the combined cases of the three centers represent considerable experience, providing new information on several aspects of this important deletion syndrome.

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We report on two adolescents with 22q11 deletion. Their main clinical manifestation was chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. Neither congenital cardiac abnormality nor T cell deficiency were detected. The phenotypic manifestations of the observed patients were consistent with velo-cardio-facial syndrome (VCFS). A microdeletion of chromosome region 22q11 has been demonstrated in approximately 90% of DiGeorge syndrome (DGS) patients and in 75% of VCFS patients; the association of the deletion with a wide spectrum of clinical findings suggests the existence of a contiguous gene syndrome. The presence of certain traits of DGS/VCFS should lead to investigations of the parathyroid function and molecular analysis of the 22q11 region hybridization studies.

Children with Neurofibromatosis type 1 (NF1) are known to have cognitive, social, and behavioral deficits. Fifteen NF1-subjects (5 boys, 10 girls, mean age = 13.4), and 15 healthy controls matched for age and sex were assessed on the presence of anxiety symptoms, using the Multidimensional Anxiety Scale for Children (MASC), self-report questionnaire. Significant group differences emerged with regard to MASC total (Z = -2.058, P = 0.041) and anxiety disorder index (ADI; Z = -2.202, P = 0.026), but not with regard to single scales. When the severity and visibility of NF1 were considered, correlation between severity and social anxiety, and severity and MASC total was found. This is the first study assessing anxiety symptoms in NF1 children and youths. A precocious psychological survey and intervention in NF1 subjects, may contribute to reduce the risk of psychiatric disorders in adulthood.