Noonan syndrome: a cryptic condition in early gestation

Noonan syndrome is one of the most common of genetic syndromes and manifests at birth, yet it is usually diagnosed during childhood. Although prenatal diagnosis of Noonan syndrome is usually not possible, in a few cases the ultrasonographic findings suggested the diagnosis in utero. Reported sonographic clues include septated cystic hygroma, hydrothorax, polyhydramnios, and cardiac defects, such as pulmonic stenosis and hypertrophic cardiomyopathy. During a 6-year period, 46,224 live-born infants were delivered at the Chaim Sheba Medical Center. Seven newborn infants and four fetuses were found to have Noonan syndrome. One fetus showed transient nuchal translucency of 4 mm and bilateral neck cysts at the 13th gestational week. Both findings resolved spontaneously by the 18th gestational week, but during the third trimester this fetus developed hydrothorax, skin edema, and polyhydramnios. In the three other fetuses, first- and second-trimester ultrasonographic findings were normal, and the diagnosis of Noonan syndrome was suggested only during the third trimester. All three fetuses had polyhydramnios and skin edema. A cardiac malformation, hydrothorax, and a large head were present in one fetus. Sonographic facial findings were investigated. In all four fetuses posteriorly angulated, apparently low-set ears and depressed nasal bridge were identified. Wide nasal base was seen in two fetuses. In two fetuses, persistent opening of the fetal mouth was interpreted as fetal hypotonia. One fetus developed progressive postnatal hypertrophic cardiomyopathy and in one case, pulmonic stenosis became apparent at age 6 months. This small series suggests that Noonan syndrome has an evolving phenotype during in utero and postnatal life. Amelioration of early nuchal region findings and late onset of the more "typical" ultrasonographic changes may limit early prenatal detectability.     

Measurement of circulating Clq precipitable immune complexes by a nephelometric type assay after polyethylene glycol extraction in model system

Clq precipitins were assayed in a model system by absorption nephelometry. Polyethylene glycol was used to extract immune complexes so that sufficient sensitivity with minimal interference could be achieved. Using a double beam spectrophotometer, we found that the reaction of immune complexes with Clq occurred rapidly and plateaued between 5-20 minutes. The optimal concentration of sodium in the reaction mixture was between 0.155-0.165 M, while chloride and EDTA did not affect the reaction significantly. Standard curves generated from heated aggregated gamma globulin showed a high degree of linearity, between 12.5-400 mg/L. Need for conductivity meters, radioisotopes, and other special equipment was eliminated because highly purified Clq is not required for nephelometric assay, and all necessary parameters can be monitored by flame photometry and electrophoresis, which are available in most clinical laboratories. Day to day reproducibility showed CVs of 5.4, 9.5, and 11.4% at control levels of 210, 160, and 70 mg/ L of immune complexes, respectively. Twelve patients with elevated levels of immune complexes by other methods were differentiated from normals by the present method. Nephelometry may offer a simplified approach for testing immune complexes and may become more widespread in clinical laboratories.     

Phenotypic switching of Cryptococcus neoformans can produce variants that elicit increased intracranial pressure in a rat model of cryptococcal meningoencephalitis

Increased intracranial pressure (ICP) plays an important role in the morbidity and mortality of cryptococcal meningoencephalitis. The microbial and host factors that contribute to the development of increased ICP are poorly understood. We found that phenotypic switch variants of Cryptococcus neoformans (smooth and mucoid) differed in their abilities to promote increased ICP in a rat model of cryptococcal meningitis. Rats infected with the mucoid variant developed increased ICP, whereas rats infected with the smooth parent did not. This trend correlated with a shorter survival time and a higher cerebrospinal fluid (CSF) fungal burden for mucoid variant-infected rats, although brain fungal burdens were comparable between mucoid variant- and smooth parent-infected rats. Magnetic resonance imaging revealed enhanced T2 signal intensity over the surfaces of the brains of mucoid variant-infected rats. In addition, more polysaccharide accumulated in the CSF and brains of mucoid variant-infected rats. The accumulation of glucorunoxylomannan was associated with elevated levels of MCP-1 (CCL2) and, accordingly, a more pronounced but ineffective monocytic inflammatory response in the meninges of mucoid variant-infected rats. In summary, these findings suggest that strain-specific characteristics can influence the development of increased ICP and indicate a manner in which phenotypic switching could influence the outcome of a central nervous system infection.     

Clinical and cytogenetic aspects of X-chromosome deletions

Karyotype/phenotype correlations in six non-mosaic patients with dysgenetic ovaries and partial deletions of the X-chromosome (three patients with short arm, and three with long arm deletions) are presented and the pertinent literature is analysed. It would appear that functioning ovarian tissue is present more often in patients with a short arm deletion than in those with a deleted long arm. This may represent a difference in the strength of two sets of controlling factors, but it can also be related to break point position. This in turn may be misinterpreted due to the difficulty in distinguishing between terminal and interstitial deletions in the long arm. Stature may be a heterochromatic effect, but if specific genetic factors influencing stature exist, then they would appear to be situated mostly on the short arm of the X-chromosome, although some 'statural determinants' occur also on the long arm and could be located rather close to the centromere. Deletions of the short arm of the X-chromosome were almost always associated with some features of the Turner phenotype, and could possibly be related to a gene dosage effect.     

Clinical features of hepatic artery thrombosis after pediatric liver transplantation

Thrombosis of the hepatic artery (HAT) is a severe complication of liver transplantation, and most cases need regrafting. The aim of this study was to review our experience with this complication. From January 1986 through January 1992, 76 liver transplants were performed in 59 pediatric patients at the Children's Hospital La Paz, Madrid. The diagnosis of HAT was made in 12 cases (15.7%). The common patterns of clinical presentation were: fulminant liver necrosis (5), bile leak due to necrosis of the bile duct (4), and relapsing bacteremia (3). Clinical symptoms of fulminant liver necrosis started within the first 2 weeks after transplantation, with rapid deterioration and steep rises in SGOT and SGPT levels. All these patients were retransplanted on an urgent basis, but only 1 is alive 4 years later. Four patients developed bile leaks 13 to 60 days after transplantation; SGOT, SGPT, and total bilirubin were only slightly increased. Three children were retransplanted electively and are alive with a mean follow-up of 3 years. One exceptional patient had a Roux-en-Y jejunostomy and is doing well 30 months later with his original graft. The 3 remaining children had episodes of septicemia with hepatic abscess, liver infarction, and pleural effusion. Liver function tests were normal, with bilirubin levels below 2 mg/dl. All patients were retransplanted, but only 1 is alive and well 13 months later. In the present series, we found that early HAT produces fulminant clinical deterioration requiring an urgent regraft. Late HAT presenting with either infection or bile leak allows time for treatment by elective retransplantation. The best survival was obtained in the latter group. Correspondence to: J. Vázquez     

Factors affecting the surgical management of infective endocarditis

Congestive heart failure and septic embolism complicate the clinical course of patients with infective endocarditis (IE). This study reviews the clinical records of patients with systemic disease secondary to IE and stratifies their disease severity according to individual risk factors and medical, and surgical interventions. The hospital records of all patients presenting to our institution from 1992 through 1997 with heart valve destruction secondary to IE were reviewed. Ten patients with hemodynamically significant valve lesions were included in this study: seven with aortic valve disease and two with mitral valve disease, and one with combined aortic and mitral valve lesions. All were diagnosed by echocardiogram. All ten patients experienced systemic septic arterial emboli: four intracranial lesions, four visceral lesions, and three extremity arterial occlusive events. Two patients required peripheral arterial repair. Cultures revealed infection secondary to Staphylococcus aureus in five, Streptococcus species in three, Coxiella species in one, and an unidentified organism in one patient. Seven patients underwent valve replacement. Three patients died from their disease processes. Statistical significance was established by Wilcoxon rank analysis with a two-tailed P < 0.05. Patients with IE secondary to staphylococcal infections suffered a more acute and virulent disease process (P = 0.04), with a 40 per cent mortality rate in the first 48 hours. There was no increased incidence of embolization associated with longer duration of symptoms (P = 0.32). Surgical repair conferred improved clinical outcome as compared with no surgical intervention (P = 0.03). Improved patient outcome was associated with nonstaphylococcal infection (P = 0.02), and a successful initial antibiotic regimen (P = 0.03). Peripheral arterial repair was successful in both cases.     

Symptom correlates of global measures of severity in schizophrenia

There is an increasing need for practical instruments that can rapidly and accurately assess the effectiveness of treatments for mental illness in clinical settings. Symptom rating scales used in clinical research are too complex and time-consuming to be useful in these settings. In contrast, single-item global measures of severity such as the Clinical Global Impression-severity scale (CGI) and the Global Assessment of Function scale (GAF) are brief and easy to complete, but little is known about their relationship with the specific symptoms of severe mental illnesses. In this study, we examine the extent to which CGI and GAF scores reflect the severity and the change in severity of positive, negative, depressive, and agitation symptoms in a sample of 102 schizophrenia inpatients at the University of Michigan Medical Center. At admission, positive symptoms were the strongest correlates of both CGI and GAF scores, followed by negative symptoms, and agitation. Depressive symptoms did not correlate significantly with either global measure. The three symptom scores together explained 58% of the variation in CGI and 39% of the variation in GAF. A similar pattern of association was found for the scores measured at discharge and for the relationships between the change in global measures and change in specific symptom clusters. Thus, by demonstrating that single-item global measures, particularly the CGI, can be reasonably good indicators of psychopathology, this study suggests that these measures may be practical tools for routine monitoring of the effectiveness of treatments for severe mental illness in community settings.