Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1.

Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 -a condition known as neurofibromatosis-Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.

Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders.

BACKGROUND: Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFC) are related disorders associated with disrupted RAS/RAF/MEK/ERK signalling. NS, characterised by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2. METHODS: A comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11 is presented. RESULTS: Mutations were identified in seven patients with CFC (two in BRAF, one in KRAS, one in MEK1, two in MEK2 and one in SOS1). Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed with CFC, has previously been reported in patients with NS. In one patient with NS, we also identified a mutation, BRAF K499E, that has previously been reported in patients with CFC. We thus suggest involvement of BRAF in the pathogenesis of NS also. CONCLUSIONS: Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS-PTPN11-associated or CFC-BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.

Body composition of children with myelomeningocele, determined by 40K, urinary creatinine and anthropometric measures.

OBJECTIVE: The purpose of this study was to develop a method to prevent obesity in myelomeningocele (MM) children by determining the effects of growth, calories and physical activity on body composition and to apply this data to clinical practice, specifically, to correlate lean body mass (LBM) with calorie needs and to correlate body fatness with anthropometry measures. METHODS: The body compositions of 14 children (four males and ten females) with MM were estimated from potassium content (40K), urinary creatinine and anthropometry measurements at the beginning and end of a six-month period. Three subjects who did not have MM were also evaluated as controls. Dietary and physical activity and dietary-goals estimates were taken from records kept by the patients after initial discussion of physical activity and dietary goals with the families. RESULTS: The study showed potassium content (40K), or LBM, in children with MM to be approximately 50% of the potassium content (40K) of children without MM. The percentage of LBM correlated with physical activity, but not with the location of neurological lesion. Lean body mass and creatinine excretion also were significantly correlated, indicating that creatinine excretion is a good measure of lean body tissue in these children. Thorax and abdominal skinfolds, as well as total circumferential measurements (waist being highest), showed significant correlations with the percent of body fat. The caloric intake requirement to maintain the growth of a child with MM was found to be approximately 50% of the recommended daily allowance (RDA) for a child without MM of the same age. Changes in LBM were observed in children with MM who increased physical activity over a six-month interval and were greater than in those who reduced calories alone, however not significantly, presumably due to the short duration of the study. CONCLUSION: To prevent obesity, physical activity should begin in infancy; this will increase LBM and thereby calorie needs. Skinfolds and circumferences (abdominal and thorax skinfolds and waist circumference) which significantly correlated with body fat should be used clinically. Calorie needs according to LBM should be reduced to 50% of the RDA or approximately nine cal/cm height for maintenance or seven cal/cm height for weight loss in MM children after age six (possibly at three to four years of age if nonambulatory).

Extension of health and nutrition services via advanced telecommunications.

The present and future technology of telecommunications will revolutionize the promotion and dissemination of health and nutrition services. Telecommunications can extend health and nutrition services because of its communicating and tracking capability. The University Affiliated Cincinnati Center for Developmental Disorders' Federal Project and other selected projects and programs using telecommunications technology illustrate the promotion and dissemination of nutrition and health services and the economic and efficient aspects of teleconferencing, electronic mail, and video imaging. This technology must be incorporated into the field of nutrition and health to meet the changing advances in the world and to improve the nutrition and health of individuals--particularly those who are at high risk, such as children with developmental disorders and chronic diseases.

Linear growth measurement: a comparison of single arm-lengths and arm-span.

An investigation was done to determine whether the arm-lengths of 44 children with myelomeningocele differed from those of 96 control children; whether the level of the meningocele lesion has any effect on arm-length; and to compare the relationship between arm-length and both stature and age. Mean total arm-lengths did not differ significantly between the two groups of children. However, the mean arm-spans of children with high myelomeningocele lesions differed significantly from those of control children. Within the myelomeningocele group, the height of the lesion had no significant effect on any of the arm-length variables. Very high positive correlations were found between upper-arm and total arm-lengths and stature, and between arm-span and stature in the control children. These results suggest that arm-length may be used as an alternative measure of linear growth in children, and that a single arm-length will be the most accurate indicator of growth of children with myelomeningocele.

Variability of dietary assessment values among nutrition students.

The effect of the interviewer's recording and evaluation of responses and calculation of nutrient data on the variability of dietary assessment results was studied. Thirty-seven dietary history interviews were examined for significant differences between the results calculated by a University Affiliated Cincinnati Center for Developmental Disorders (UACCDD) staff nutritionist and by a group of student observers. A significant difference using a paired t-test (p less than .05) for the calculated magnesium intake and the Food Frequency Summary Score for the meat group was found. The mean results for all graduate students on each variable were also compared with the undergraduate means using a group t-test. Significant differences were found in the calculation of calcium and vitamin D intake and in estimated daily caloric output. These findings agree in general with the reports of other investigators, i.e., that few significant differences of less than 10% are attributable to variability among interviewers when the mean results from large samples are examined. Since large variations between the individual results reported by different students observing the same interview were found, there is a need for extensive training and experience with interviewing, interpretation of food intake data, and familiarity with the use of a variety of food composition tables and computer data bases.

The effect of supplemental ascorbic acid on serum vitamin B12 levels in myelomeningocele patients.

Serum levels of ascorbic acid and vitamin B12 were analyzed in 40 myelomeningocele children to study the effect of supplemental ascorbic acid on serum vitamin B12 levels. The experimental group was composed of 20 children receiving ascorbic acid for urinary acidification: 10 received an average of 1.8 g daily, 10 received an average of 1.5 g daily (the amount depending on the requirement needs for urinary acidification) half of each group received ascorbic acid for less than 3 yr (an average of 2.1 yr) and half received ascorbic acid for more than 3 yr (an average of 4.3 yr). The control group consisted of 20 myelomeningocele children not receiving supplemental ascorbic acid. Both groups were matched for age, sex, race, and physical activity. Dietary levels of ascorbic acid and B12 were calculated to rule out their influence on serum levels. Results showed that the experimental group with supplemental ascorbic acid produced significantly higher ascorbic acid values than the control group. The serum B12 levels of the experimental group were not significantly different than those of the control groups and these children showed neither a deficient serum levels of B12, anemia, nor elevated mean corpuscular volume. Hemoglobin levels were slightly higher for the experimental group. Dietary calculations of B12 and ascorbic acid were not significantly greater than the Recommended Daily Allowance ruling out any influence of diet on serum levels. No evidence of vitamin B12 deficiency developed in 20 myelomeningocele children receiving daily mean doses of 1.65 g of supplemental ascorbic acid. In view of our findings, it is highly improbable that megadoses of supplemental ascorbic acid would induce vitamin B12 deficiency in man.

The effect of supplemental vitamin E on vitamin A serum levels in cystic fibrosis.

Effects of the ingestion of vitamin E with vitamin A on the serum levels of these vitamins and the urinary creatine to creatinine ratios of 18 children with cystic fibrosis disease of the pancreas (CF) was studied. After the daily ingestion for two months of a specially prepared capsule containing 5000 IU vitamin A palmitate and 100 mg d alpha-tocopherol acetate in aqueous dispersible form there was a significant increase in vitamin A as well as vitamin E levels of serum taken 3 1/2 hr postprandially. Creatine to creatinine ratios in single voiding of urine decreased.

Diets of handicapped children: physical, psychological, and socioeconomic correlations.

Diets of patients at the University Affiliated Cincinnati Center for Developmental Disorders were evaluated in order to identify relationships between nutritional deficiencies and selected physical, psychological, and socioeconomic factors. Results showed primary nutritional and feeding problems to be: low ascorbic acid and iron intakes, lack of a daily source of fluorid, protein intake of borderline biological quality, and mechanical and postnatal feeding difficulties. Nutritional and feeding problems were correlated with various hematological, psychological, anatomical, and social factors.