Malignant hemangioendothelioma of the heart with hematological disorders.

An autposy case of a 30-year-old house wife with malignant hemangiothelioma of the heart was reported. This case was also accompanied by marked anemia, thrombocytopenia, leukoerythremoid reaction and hypofibrinogenemia. The spread of tumor was so wide that only the alimentary tract and the skin were free from metastases of the tumor. Many of the metastatic foci showed marked hemopoiesis intra tumori. A short discussion was made on the hematological abnormalities associated with vascular tumors.     

The Wolf-Hirschhorn syndrome

Four new cases of the Wolf-Hirschhorn syndrome are presented, two of which were due to t(4;22)mat. Review of the literature (more than 100 cases of the Wolf-Hirschhorn syndrome) showed that 13 % of all the reported cases were not mutations but segregations of parental chromosomal aberrations, primarily translocations. Similar data were obtained previously for other deletions (5p-, 18p-, 18q -). Analysis of data on some "new" deletion syndromes (4q -, 8p-, 9p-, 10p-, 11p -, 11q -) revealed that 14.5% were inherited cases. Thus, all human autosomal deletions have virtually the same genetic pattern.     

Seizure frequency in adults with Wolf-Hirschhorn syndrome

Epilepsy is a characteristic feature of Wolf-Hirschhorn syndrome (WHS) with onset usually in the first 2 years of life. There have been several reports of epilepsy ceasing as children get older. We have inspected a register of WHS cases from the UK and identified 27 adults with the condition; their mean age was 24.8 years (range 17-40 years). We conducted a telephone survey and asked parents to comment on their experience of seizures in WHS. In 18 patients (66%) a seizure had not occurred within 3 years. The mean age of those who have been seizure free for over 3 years was 23.7 years (range 17-33 years) whereas for those who had a recent seizure their mean age was 27.1 years (range 17-40 years). The mean age of the last seizure for those who were seizure free for 3 years was 11.3 years (range 2-28 years); in the majority of patients, seizures ceased within childhood years. Many parents commented that seizures were precipitated by fever. Individuals with WHS who had a deletion were more likely to be seizure free than those with a translocation. This reached statistical significance: chi(2) = 4.6, P = 0.03, odds ratio = 6.5 (95% CI 1.1-38.6). Data from this survey may be helpful when counseling families with a very young child with WHS.     

The Wolf-Hirschhorn syndrome

Most cases of Wolf-Hirschhorn syndrome occurring among children who die during the perinatal period are not diagnosed by morphologists. However, analysis of the morphological data on the Wolf-Hirschhorn syndrome reveals that association of typical external features and abnormalities of the brain (shortening of the H2 area of Ammon's horn, dystopic dysplastic gyrae in the cerebellum), eyes (colobomata, microphthalmos, retinal dysplasia) and kidneys (bilateral or unilateral agenesis, cystic dysplasia or polycystosis) with diaphragmatic hernia allows the establishment of a diagnosis of the syndrome without cytogenetic investigation.     

The Wolf-Hirschhorn syndrome in fetuses

Wolf-Hirschhorn syndrome (WHS) with partial deletion of the short arm of chromosome 4 has been exceptionally diagnosed in fetuses. We report prenatal diagnosis of five cases of monosomy 4p. The fetuses were karyotyped for severe intrauterine growth retardation (IUGR) diagnosed on routine ultrasound (US). In addition, cleft-lip and palate and diaphragmatic hernia respectively were found in two cases. The quantity of amniotic fluid was normal in all cases. At autopsy, the fetuses showed the typical craniofacial dysmorphy but without microcephaly. Major renal hypoplasia was the only constant visceral anomaly. Midline fusion defects were observed in all the fetuses, ranging from minor abnormalities such as scalp defect, hypertelorism, pulmonary isomerism, common mesentery, hypospadias and sacral dimple, to cleft palate, corpus callosum agenesis, ventricular septal defect, and diaphragmatic hernia. On post-mortem X-rays, a delayed bone age was always observed. All the placentae were hypotrophic, and two exhibited vascular lesions, although there was no maternal hypertension. Chromosomal studies showed that the breakpoints were within the 4p16 band in three cases, the 4p15 band in one case, and the 4p14 band in one case. The deletion was de novo in four cases, and resulted from a paternal translocation in one case. This study emphasizes the importance of karyotyping all fetuses with IUGR, especially when the quantity of amniotic fluid is normal, and suggests the possibility of recognizing on US the particular phenotype of WHS in utero.     

Cognitive-behavioral features of children with Wolf-Hirschhorn syndrome: preliminary report of 12 cases

As a subset of genetic abnormalities, subtelomeric deletions have been found in 7-10% of individuals with mental retardation (MR). One subtelomeric deletion, Wolf-Hirschhorn syndrome (WHS), causes mild to severe MR, but the cognitive-behavioral features of individuals with WHS have not been studied systematically. To that end, we administered a comprehensive cognitive-behavioral battery to 12 children with WHS, ages 4-17 years, who also had some expressive language. Using the Stanford-Binet (4th Edition), we found cognitive deficits ranged from mild to severe, with mean IQ = 44.1. Interviewing parents with the Vineland Adaptive Behavior Scales, we found mean adaptive behavior score (DQ) = 37.3, with females exhibiting slightly higher scores than males. Cognitive profiles indicated relative strengths in Verbal and Quantitative Reasoning. Adaptive behavior profiles noted significant relative strengths in the Socialization Domain. These cognitive-behavioral profiles differed from children with other subtelomeric deletion syndromes, 2q37 or 8p23. Attention deficits and hyperactivity (ADHD) were observed in 7/12 (58%) of the children we tested. One child attained a score on the Child Autism Rating Scale (CARS) suggestive of mild autism. We conclude that different genetic disorders, which cause MR, produce diverse cognitive-behavioral profiles. Consequently, cognitive-behavioral profiles of children with MR need to be assessed more comprehensively.     

Mouse models of Wolf-Hirschhorn syndrome

Subtelomeric deletion syndromes represent a significant cause of mental retardation and craniofacial disease. However, for most of these syndromes the pathogenic genes have yet to be identified. Currently there is every indication that identification of these genes will be a slow process if we continue to rely strictly upon clinical data. An alternative approach is the use of mouse models to complement the patient studies. Wolf-Hirschhorn syndrome (WHS), caused by deletions in 4p16.3, is the first recognized subtelomeric deletion syndrome. As with other syndromes of this class, WHS has not yet been subjected to an intensive, systematic analysis using mouse models. Nonetheless, a significant number of targeted mutations have been introduced into mouse genomic region, 5B1, which is orthologous to 4p16.3. Included among these mutations are a series of deletions approximating the deletions in some patients. The mouse lines carrying these deletions display a remarkable concordance of phenotypes with the human patient's characteristics, strongly indicating that the mouse models can be used to phenocopy WHS. In this review, we will catalog the currently existing targeted mutations in mice in the regions orthologous to the WHS critical regions. For each mutation we will discuss the resulting phenotype and its potential relevance to the pathogenesis of the syndrome. Further, we will describe how the phenotypes of some of the mutations suggest new directions for the clinical studies. Finally we will outline approaches for the efficient creation of new mouse models of WHS going forward.     

Familial translocation resulting in Wolf-Hirschhorn syndrome in two related unbalanced individuals: Clinical evaluation of a 39-year-old man with Wolf-Hirschhorn syndrome

A chromosomal translocation between chromosomes 4 and 8 resulting in Wolf-Hirschhorn syndrome in 2 individuals has been traced through 4 generations of a family. Ascertainment of the family was through a newborn infant with evident Wolf-Hirschhorn syndrome who had an unbalanced chromosomal translocation [46,XY,?4,+der(4),t(4;8) (p15.32;p22)]. Discussion with the family documented a paternal great-uncle who also had a similar phenotype and profound mental retardation. Subsequently this individual was found to have the same unbalanced chromosome constitution as the propositus. The 39-year-old great-uncle is the oldest reported individual with the Wolf-Hirschhorn syndrome. The importance of chromosome evaluation of older individuals with mental retardation syndromes is emphasized. © 1995 Wiley-Liss, Inc.     

Fine-grained facial phenotype-genotype analysis in Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of cases are due to de novo terminal deletions, 40% from unbalanced translocations and 5% from other abnormalities. The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum. We used dense surface modelling and pattern recognition techniques to delineate the milder facial phenotype of individuals with a small terminal deletion (breakpoint within 4p16.3) compared to those with a large deletion (breakpoint more proximal than 4p16.3). Further, fine-grained facial analysis of several individuals with an atypical genotype and/or phenotype suggests that multiple genes contiguously contribute to the characteristic Wolf-Hirschhorn syndrome facial phenotype.     

Pneumococcal vaccination in splenectomized patients with hematological disorders

Seventy splenectomized patients were vaccinated with Pneumovax, a pneumococcal polysaccharide vaccine. Twenty-four of the patients had a malignant and 30 a nonmalignant hematological disorder. The remaining 16 were patients with no known hematological disorder, seven with intra-abdominal carcinomas and nine with non-malignant reasons for splenectomy. About 90% of the patients with non-malignant hematological disorders responded to vaccination with a rise in antibody titres, which was significantly higher than in the other two groups studied. Malignant hematological disorders lowered the response rate to 61-67%. Patients with no known hematological disorder but with intra-abdominal carcinomas also responded less frequently, while those in this group with other surgical reasons for splenectomy had a response rate comparable to healthy individuals. No serious side-effects were reported and we therefore conclude that all splenectomized patients should be vaccinated with a pneumococcal vaccine. However, it must always be born in mind that one third of the patients with malignant disease did not respond to vaccination.     

Wolf-Hirschhorn syndrome and a split-hand malformation

Ectrodactyly has not previously been reported in children with Wolf-Hirschhorn syndrome (WHS). Based on this premise and the identification of an unbalanced translocation between chromosomes 4p15 and 10q25 in a fetus with ectrodactyly and hemimelia, a second locus for dominantly inherited split hand/foot malformation (SHFM3) was mapped to chromosome 10q24–q25. We present the clinical findings of an infant with WHS and SHFM and suggest that the presence of additional loci on 4p which modify/cause SHFM cannot be excluded. Am. J. Med. Genet. 75:351-354, 1998. © 1998 Wiley-Liss, Inc.     

Cutaneous T-cell lymphoma in a 21-year-old male with Wolf-Hirschhorn syndrome

We describe a case of cutaneous T-cell lymphoma occurring in a 21-year-old male with Wolf-Hirschhorn syndrome (WHS) due to a chromosome 4p16.3 deletion. This is the first documented case report of malignancy occurring in an adult with WHS. We also review the literature regarding patients with WHS and the joint occurrence of malignancy and discuss genetic changes involving chromosome 4 which may have contributed to the genesis of our patient's lymphoma.     

Proliferative and neoplastic disorders in children with acquired immunodeficiency syndrome

Acquired immunodeficiency syndrome (AIDS) is a multisystem disease and, besides infections, various proliferative and neoplastic disorders are seen in cytology, biopsy, and autopsy specimens from infected children. These lesions can be classified into four types: systemic lymphoproliferation, smooth muscle tumors, Kaposi sarcoma (KS), and human papilloma (HPV)-related genital lesions. In addition, isolated cases of multiple miscellaneous tumors have been reported. Proliferative and neoplastic disorders are categorized as lesions of undetermined pathogenesis; however, there are certain factors that are suggested to be related to their pathogenesis. The symptoms related to them may be atypical or difficult to appreciate, and proliferative and neoplastic disorders may clinically mimic an opportunistic infection. The type and site of proliferative and neoplastic disorder also tends to be atypical as compared with those seen in non HIV-infected children. This is a brief but detailed review of these disorders in children with AIDS.     

Health supervision and anticipatory guidance of individuals with Wolf-Hirschhorn syndrome

Pallister-Killian syndrome (PKS) is characterized by multiple congenital anomalies including pigmentary skin changes, mental retardation, and the mosaic presence of a tissue-limited isochromosome 12p [i(12p)]. Mechanism(s) of formation and parental origin of the isochromosome are not well understood. In this study, microsatellite DNA markers of chromosome 12p were used to identify the parental origin of the extra chromosome in an 8-year-old previously reported patient with PKS. The i(12p) was found to be maternally inherited. Reported cases of PKS where the parental origin of the i(12p) was determined were also reviewed. In all the cases, with one exception, the errors were found to be maternal in origin. Premeiotic mitotic error may be the most likely mechanism for i(12p) formation in this syndrome.     

Mouse models for the Wolf-Hirschhorn deletion syndrome

Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental haploidy of chromosome 4p16.3. Its hallmark features include a 'Greek warrior helmet' facial appearance, mental retardation, various midline defects and seizures. The WHS critical region (WHSCR) lies between the Huntington's disease gene, HD, and FGFR3. In mice, the homologs of these genes map to chromosome 5 in a region of conserved synteny with human 4p16.3. To derive mouse models of WHS and map genes responsible for subphenotypes of the syndrome, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size. These mice represent the first animal models for WHS. This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissection of other deletion syndromes using the mouse.