Robert M. Greenstein

Screening for Fetal Down's Syndrome in Pregnancy by Measuring Maternal Serum Alpha-Fetoprotein Levels

Although the risk of Downs syndrome increases with maternal age, women under 35 bear about 80 percent of the infants born with this condition. We prospectively investigated the utility of measuring maternal serum alpha-fetoprotein during the second trimester in women under 35 in order to identify pregnancies in which the fetus was affected with Downs syndrome. Over a two-year period, 34,354 women in this age group were screened. Amniocentesis was offered when the risk of Downs syndrome, calculated as a function of maternal age and maternal serum alpha-fetoprotein concentration adjusted for maternal weight and race, was 1:270 or higher, the risk for a 35-year-old woman. This threshold was exceeded in 1451 women in whom gestational age was confirmed by ultrasound; 9 women in this group had a fetus with the syndrome. In three women whose fetuses had trisomy 18 and one whose fetus had trisomy 13, the calculated risk of Downs syndrome was 1:270 or higher. Thus, among women in whom the risk exceeded our cutoff point, 1 in 161 were found to have a pregnancy in which the fetus was affected with Downs syndrome; the figure was 1 in 112 for all autosomal trisomies. Eighteen pregnancies involving Downs syndrome, three involving trisomy 18, and two involving trisomy 13 were not associated with a calculated risk above the cutoff point. The available data indicate that in our population, using a cutoff for risk at which 5 percent of women under 35 are offered amniocentesis, we will detect one quarter to one third of pregnancies in which the fetus has Downs syndrome.

Neurofibromatosis Type 1: Magnetic Resonance Imaging Findings

The purpose of this study was to determine the locations and characterize the types of brain abnormalities noted on brain magnetic resonance imaging in patients with probable and definite neurofibromatosis type 1. Patients with definite neurofibromatosis type 1 (n = 17) were studied when clinically indicated, and patients with probable neurofibromatosis type 1 (n = 9) were studied to evaluate for asymptomatic optic pathway glioma. Of the 26 patients evaluated, 14 (53%) had high-intensity signal abnormalities and 11 (42%) had significant structural abnormalities. Subsequent clinical follow-up has confirmed conversion to a definite neurofibromatosis type 1 diagnosis in three of the four cases of probable neurofibromatosis type 1 who had high-intensity signal abnormalities. The most common locations of high-intensity signal lesions were in the globus pallidus of the basal ganglia and cerebellar white matter. Tortuous or thickened optic nerves and/or optic chiasm were seen in eight cases. Brain magnetic resonance imaging scans frequently reveal high-intensity signal lesions and structural abnormalities in selected patients with both probable and definite neurofibromatosis type 1. These findings may allow for a definitive diagnosis in clinically probable cases. (J Child Neurol 1993;8:32-39).

Behavioral correlates in the happy puppet syndrome: A characteristic profile?

Nine children with the ‘happy puppet’ syndrome are presented here and 19 previously reported cases are reviewed. A characteristic psychological profile is suggested by the childrens ‘unfocused’ activities and inconsistent responsiveness to their surroundings. Behavioral characteristics are atypical for mental age and do not appear to represent unusual seizure equivalents. Recognition of such non‐adaptive behavior may be of importance n selecting specific treatment and management techniques to modify the characteristics of this syndrome at an early age.

Clinical course of sly syndrome (mucopolysaccharidosis type VII)

Background Mucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients’ phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data. Methods We have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease. Results We collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS. Conclusions MPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.

Improved pulmonary and growth outcomes in cystic fibrosis by newborn screening

Newborn screening for cystic fibrosis (CF) is effective in improving long‐term growth outcomes. However, there is conflicting evidence that early diagnosis maintains normal pulmonary function. Our goal was to determine if newborn screening results in improved longitudinal growth and maintenance of normal pulmonary function.

Motion analysis of a child with Niemann-Pick disease type C treated with miglustat.

Niemann–Pick disease type C (NPC) is a progressive neurodegenerative disorder for which there is no effective treatment other than supportive therapy. Recently, the oral medication miglustat has been offered as a possible therapy aimed at reducing pathological substrate accumulation. This article describes the use of computerized three‐dimensional motion analysis to evaluate a 3‐year‐old child with NPC treated with miglustat for 12 months. Motion analysis provided quantitative data on the patients gait. However, dementia and motor dysfunction progressed despite the treatment, and the patient lost the ability to walk between 9 and 12 months of the study. Motion analysis should be considered among the tools for measuring functional outcomes in future therapeutical trials of patients with neurodegenerative diseases. It is not possible to draw conclusions about miglustat therapy in NPC from a single patient experience.

Attitudes Toward Direct-to-Consumer Advertisements and Online Genetic Testing Among High-Risk Women Participating in a Hereditary Cancer Clinic

Genetic testing for the breast cancer genes 1/2 (BRCA 1/2) has helped women determine their risk of developing breast and ovarian cancer. As interest in genetic testing has grown, companies have created strategies to disseminate information about testing, including direct-to-consumer advertising (DTCA) and online genetic testing. This study examined attitudes toward DTCA and online testing for BRCA among 84 women at a high-risk clinic as well as additional factors that may be associated with these attitudes, such as personal and familial cancer history, cancer worry and risk perception, and history with genetic testing/counseling. Results showed that the majority of the women held favorable attitudes toward DTCA for BRCA testing but did not support online testing. Factors such as familial ovarian cancer, cancer worry, and satisfaction with genetic counseling/testing were associated with positive attitudes toward DTCA, whereas personal breast cancer history was related to negative attitudes. The findings suggest that women may view DTCA as informational but rely on physicians for help in their decision to undergo testing, and also suggest that cancer history may affect womens acceptance of DTCA and genetic testing.

Newborn screening compared to clinical identification of biochemical genetic disorders

A group of 28 patients with inherited metabolic disease (homocystinuria galactosaemia, maple syrup urine disease and biotinidase deficiency) diagnosed by screening were compared with a group of 17 similar patients identified clinically. The rate of hospitalization was similar for the two groups. The patients diagnosed clinically showed a higher incidence of mental retardation and their parents experienced greater stress and found greater difficulty in meeting their childs needs.

New England Consortium: a model for medical evaluation of expanded newborn screening with tandem mass spectrometry.

Newborn screening by tandem mass spectrometry (MS-MS), enabling presymptomatic identi¢cation of more than 20 inborn errors of metabolism, is used in several screening programmes throughout the world (Levy and Albers 2000).Most disorders identi¢ed by this technology are still incompletely understood. Consequently, there is a need to gather information about the bene¢ts of presymptomatic identi¢cation of these disorders and to develop a comprehensive system of management for this new group of identi¢ed newborns. In New England, it was felt that these objectives could best be realized through a consortium of those involved in screening and those who provide metabolic management. A consortium would also offer the unique opportunity to compare the outcome between infants detected presymptomatically and those diagnosed clinically, an opportunity presented because, in New England, only the state of Massachusetts has yet fully integrated MS-MS into newborn screening. The state of Maine also allows this technology for expanded screening, but only for medium-chain acyl-CoA dehydrogenase de¢ciency (MCADD). The main goal of the New England Consortium is the integration of newborn screening, metabolic evaluation, primary care and research into a comprehensive and e¤cient system for management of metabolic patients (Figure 1). The primary care physician, considered the medical home, occupies an active role in the general care of the child in this proposed system. Following newborn screening detection and con¢rmation of a metabolic disorder, the Consortium provides this physician with the most recent information about the disorder and recommendations for emergency care as well as general paediatric follow-up. The management of the child is then coordinated among the metabolic centre, the primary care physician and the family. The primary care physician is invited to join the Consortium, which also includes representatives from other metabolic centres, the New England Newborn Screening Program and parent groups. Exchange of information is facilitated by awebsite that contains information on the metabolic diseases identi¢able by MS-MS, on social support programmes and on advances in research ( ). Consortium members meet anually to exchange experiences and report on recent developments. J. Inherit. Metab. Dis. 24 (2001) 303^304 # SSIEM and Kluwer Academic Publishers. Printed in the Netherlands.

ANALYSIS OF SKULL ANTHROPOMETRIC MEASUREMENTS IN PATIENTS WITH NEUROFIBROMATOSIS TYPE-1

RATIONALE AND OBJECTIVES.The authors studied selected anthropometric measurements of plain postero-anterior and lateral skull roentgenograms to ascertain whether these were useful in distinguishing patients with clinically probable neurofibromatosis type-1 from controls. METHODS.A retrospective review of medical records of patients for whom skull roentgenograms were available was conducted. Patients were assigned to one of three groups: definite neurofibromatosis type-1 (DNF), probable neurofibromatosis type-1 (PNF), and controls. A blinded analysis of 29 measurements, 9 qualitative assessments, and 3 area/volume calculations was performed. RESULTS.There were 58 patients (29 controls, 14 DNF, and 15 PNF). The majority (75%) of all predetermined landmarks could be ascertained in 43 of these subjects. After age and gender were held constant, analysis of covariance showed that both DNF and PNF subjects could be distinguished from controls, but not from each other when comparing the mean: sella turcica height (P < .001), sella turcica depth (P< .005), skull width (P< .0001), skull length (P < .002), skull height (P <,003), and skull volume (P < .0001). CONCLUSIONS.Anthropometric analysis of skull roentgenograms coupled with results of clinical examination improves the ability to distinguish between patients with DNF and PNF from controls.