Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q.

Deletions of chromosome 18q are among the most common segmental aneusomies compatible with life. The estimated frequency is approximately 1/40,000 live births [Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. 1997. Am. J. Med. Genet. 69:280-286]. Most deletions are terminal encompassing as much as 36 Mb, but interstitial deletions have also been reported. We have evaluated 42 subjects with deletions of 18q at our institution. This is the largest number of individuals with this chromosome abnormality studied by one group of investigators. Here we report the physical findings in these individuals. We have compared our findings with those of previously reported cases and have found a significantly different incidence of several minor anomalies in our subjects. We also describe here several anomalies not previously reported in individuals with deletions of 18q, including short frenulum, short palpebral fissures, disproportionate short stature, overlap of second and third toes, and a prominent abdominal venous pattern. Characteristics found in subjects were analyzed for correlation with cytogenetic breakpoints. Several traits were found to correlate with the extent of the deletion. Large deletions were associated with significantly decreased head circumference and ear length as well as the presence of proximally placed and/or anomalous thumbs. Individuals with the smallest deletions were more likely to have metatarsus adductus. Although relatively few genotype/phenotype correlations were apparent, these data demonstrate that correlations with breakpoint are possible. This implies that more correlations will become evident when the more precise molecularly based genotyping is completed. These correlations will identify critical regions on the chromosome in which genes responsible for specific abnormal phenotypes are located.

Cardiac malignant lymphoma: a case report.

A 76 year old man, who had undergone tonsillectomy for non Hodgkin's malignant lymphoma, died suddenly in rapidly evolving cardiogenic shock with electrocardiographic signs of acute lateral myocardial infarction. Post mortem examination showed three cardiac lesions, two in the left ventricle and one in the right atrium, corresponding to the "crista terminalis". Histologic examination of autopsy samples confirmed the presence of lymphoma in the heart, partially affecting the sino atrial node (NSA) but excluding other sites. There was no evidence of acute myocardial infarction in spite of the clinical signs and symptoms. An infarction-type electrocardiographic pattern associated with conduction disturbances in patients with lymphoma should suggest the possibility of cardiac localization of the disease.

Magnetic resonance imaging demonstrates incomplete myelination in 18q- syndrome: evidence for myelin basic protein haploinsufficiency.

Magnetic resonance imaging (MRI) and MRI relaxometry were used to investigate disturbed brain myelination in 18q- syndrome, a disorder characterized by mental retardation, dysmorphic features, and growth failure. T1-weighted and dual spin-echo T2-weighted MR images were obtained, and T1 and T2 parametric image maps were created for 20 patients and 12 controls. MRI demonstrated abnormal brain white matter in all patients. White matter T1 and T2 relaxation times were significantly prolonged in patients compared to controls at all ages studied, suggesting incomplete myelination. Chromosome analysis using fluorescence in situ hybridization techniques showed that all patients with abnormal MRI scans and prolonged white matter T1 and T2 relaxation times were missing one copy of the myelin basic protein (MBP) gene. The one patient with normal-appearing white matter and normal white matter T1 and T2 relaxation times possessed two copies of the MBP gene. MRI and molecular genetic data suggest that incomplete cerebral myelination in 18q- is associated with haploinsufficiency of the gene for MBP.

Growth hormone deficiency associated in the 18q deletion syndrome.

The 18q- syndrome is one of the commonest deletion syndromes. Clinical characteristics are variable but may include: hypotonia, tapered digits, "carp-like" mouth, mental retardation, and hearing impairment. Growth failure (GF; both weight and height < 3%) was reported in 80% of affected individuals. We evaluated growth hormone (GH) sufficiency in 5 18q- syndrome patients, 3 of whom had growth failure (< 3% weight and height); the remaining 2 had normal growth parameters. Laboratory evaluation of growth included measurement of IGF-1, IGFBP-3, bone ages and GH response to pituitary provocative agents. Three patients failed to produced adequate GH following stimulation testing. Of 3 patients with inadequate GH production, 1 had normal growth (above 3%). Only 1 of 5 patients had normal GH production and normal growth parameters. Our findings to date suggest that GH deficiency is common in individuals with the 18q- syndrome. The pathogenesis of this finding is unknown. We postulate that a gene(s) on 18q is involved in GH production.

Preferential loss of the paternal alleles in the 18q- syndrome.

Individuals with the 18q- syndrome have variable deletions from the long arm of chromosome 18. They also exhibit a highly variable phenotype. To correlate genotype with phenotype accurately, extensive molecular and phenotypic analyses are needed on each affected individual. As a part of this analysis, we have determined the parental origin of the deleted chromosome in 34 individuals with the 18q- syndrome. We have found that 85% of the de novo deletions are paternal in origin. The percentage of fathers of individuals with paternally derived deletions who were > 30 years old was (not significantly) greater than that of the general population. The mothers of individuals with maternally derived deletions were near an average age for childbearing compared to the general population. Individuals with maternally derived terminal deletions had breakpoints as varied as those with paternally derived deletions. These results are consistent with the hypothesis that the reduced incidence of maternally derived deletions is not due to reduced viability, since individuals with large maternally derived deletions of chromosome 18q were found. We hypothesize that the prevalence of paternally derived deletions is due to an increased frequency of chromosome breakage in male germ cells. These results are consistent with results observed in other segmental aneusomies in which there is a high incidence of paternally derived deletions.

Clinical and pathological features in hydrocarbon-induced parkinsonism.

A neuropathological examination was performed on a patient with parkinsonism induced by prolonged exposure to a mixture of aliphatic hydrocarbons, mainly n-hexane and halogenated compounds. The patient developed a rapid-course disease that progressed even after withdrawal from the toxic exposure. Pathological examination and immunohistochemical analysis of the brain revealed severe and widespread dopaminergic neuronal loss, associated with severe gliosis, in the substantia nigra, and almost complete loss of tyrosine hydroxylase immunostaining in the striatum. No Lewy bodies were detected. Neuronal loss was also observed in the periaqueductal gray matter, locus ceruleus, and pedunculopontine nucleus. These changes, combined with the moderate anemia due to marrow suppression, and the mild axonal neuropathy observed in vivo, are suggestive of a hydrocarbon toxic insult.

Short-limb dwarfism and hypertrophic cardiomyopathy in a patient with paternal isodisomy 14: 45,XY,idic(14)(p11).

Uniparental disomy (UPD) has been shown to result in specific disorders either due to imprinting and/or homozygosity of mutant alleles. Here we present the findings in a child with paternal UPD14. Ultrasound evaluation was performed at 30 weeks of gestation because of abnormally large uterine size. Pertinent ultrasound findings included polyhydramnios, short limbs, abnormal position of hands, small thorax, and nonvisualization of the fetal stomach. Post-natally the infant was found to have a low birth weight, short birth length, contractures, short limbs, and a small thorax with upslanting ribs. Assisted ventilation and gastrostomy were required. At age 6 months, the infant required hospitalization for hypertrophic cardiomyopathy which responded to Atenolol. Initial cytogenetic studies demonstrated an apparently balanced de novo Robertsonian translocation involving chromosomes 14 and a karyotype designation of 45,XY,t(14q14q). No indication of mosaicism for trisomy 14 was observed in metaphase spreads prepared from peripheral blood lymphocytes or skin-derived fibroblasts. C-band and fluorescence in situ hybridization results demonstrated that the chromosome was dicentric. DNA analyses showed paternal uniparental isodisomy for chromosome 14. Based on the cytogenetic and DNA results a final karyotype designation of 45,XY,idic(14)(p11) was assigned to this infant with paternal isodisomy of chromosome 14.

Autoptic findings in HIV-1 positive children.

The growing incidence of AIDS in children and newborns has been related to increasing incidence of AIDS in women. Case records were composed by 14 children with death occurring at different ages--from 1 hour to 12 years--and 1 female fetus, all with serological confirmation of AIDS. Brain and internal organs samples were collected at autopsy for morphological, immunohistochemical and "in situ" hybridization's technical examination. The prevailing extracerebral pathology observed at autopsy consisted of opportunistic infections. The cerebral findings were HIV-encephalopathy; cytomegalovirus encephalitis; vascular alterations such as necrosis and hemorrhage; calcifications and edema. Neurologic symptoms were reported in 3 children of intravenous drug-abuser mothers as drug withdrawal syndrome. HIV positivity in one or both the intravenous drug-abuser parents is the main risk factor of congenital AIDS. This factor means lack of care during the gestational stage and may determine relevant differences in the course of disease. The cerebral changes due to opportunistic infection must be differentiated from HIV-specific lesions; it has to be stressed that "diffuse" leukoencephalopathy is not AIDS-specific but can be found in every chronic encephalitis/encephalopathy especially in newborns and children. Chronologically, HIV encephalopathy appears as late manifestation of the disease, due to an infiltration of CNS of HIV-infected macrophages and not to an impairment of neuronal or glial cells infected by HIV in the early stages of the disease.

Autopsy findings in three patients with von Willebrand disease type IIB and type III: presence of atherosclerotic lesions without occlusive arterial thrombi.

It has been reported that pigs with severe von Willebrand disease (vWd) are protected from spontaneous and diet-induced atherosclerosis, but there are very few studies in human patients. Autopsies were carried out on three patients with vWd (one case with the type IIB variant and two cases with type III, a variant similar to that protecting pigs from atherosclerosis), aged 73, 44 and 52 years at the time of death. Hemorrhagic diathesis was an important cause of death for these patients. Atherosclerosis lesions were found in all patients, though of different extent and localization: severe lesions in all vascular areas in the patient with type IIB, few and slighter in all areas in the two patients with type III, except that in one of them there were moderately severe lesions in the coronary arteries. There was no clinical or pathologic evidence of thrombosis in the coronary arteries or other arteries. These data indicate that severe vWd did not protect completely against the development of atherosclerosis, although it is possible that intensive lifelong treatment with plasma concentrates had a modifying influence in these patients.

Hepatitis C virus infection in liver allograft recipients.

The impact of HCV infection after liver transplantation remains a topic of discussion. The aims of this study were to define the prevalence of anti-HCV antibodies in liver donors; the risk of acquired HCV infection and HCV re-infection according to the pre-transplant anti-HCV status; the prevalence of HCV infection in post-transplant chronic hepatitis. Sera from 42 recipients with follow up longer than 6 months and their donors were tested for anti-HCV. By results at pre-transplant time patients were classified as follows: donor (D) negative and recipient (R) negative (D-/R-) 31; D-/R+ 9; D+/R- 1; D+/R+ 1. Twenty-one patients with sustained hepatic dysfunction underwent liver biopsy. In group D-/R-, 5 patients showed anti-HCV positivity and 3 (9.7%) of them had acquired HCV hepatitis. In group D-/R+, 6 patients showed persistent anti-HCV positivity and 4 (44.4%) of them had recurrent HCV hepatitis; of these 2 died due to liver failure. The 2 patients of groups D+/R- and D+/R+ had normal liver function. Anti-HCV negative hepatitis was found in 2 patients. The prevalence of anti-HCV positivity in liver donors appeared low (3.2%). Acquired HCV infection rate was 9.7%. Pre-transplant HCV infection led to a high incidence of recurrence (44.4%). HCV was the major etiological agent in post-transplant chronic hepatitis (77.8%).

[Arrhythmogenic Takayasu disease]. / Malattia di Takayasu ad impronta aritmogena.

The Authors report a case of Takayasu disease in a woman who died at the age of forty-six, in whom the histological examination of the cardio-vascular system revealed giant cells granulomatous arteritis localized in the aortic arch and collateral arteries; endocarditis and granulomatous coronaritis. The bases of arrhythmogenic alterations, in this study, take into account the thrombosis of the conduction system arteriolar vessels and the phlogosis extending to the cardiac plexus.

Histopathological findings in a case of systemic lupus erythematosus-associated anti-phospholipid syndrome.

The vessel anatomopathological lesions in a patient with systemic lupus erythematosus associated anti-phospholipid syndrome are described. Vasculitic lesions were nearly absent but small vessels showed hyalin thrombosis or substenosis due to subendothelial deposition of amorphous PAS-positive material in different anatomical districts. These findings can be related to the patient's clinical manifestations, particularly the central nervous system involvement and can be discussed regarding the possible pathogenetic mechanisms.