Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause.

We describe 8 patients affected with Costello syndrome including an affected sib pair and review the literature on 29 previously reported cases. We emphasize an association with advanced parental age, which is consistent with autosomal dominant inheritance with germline mosaicism. The pathogenesis appears to involve metabolic dysfunction, with growth disturbance, storage disorder appearance, acanthosis nigricans, hypertrophic cardiomyopathy, and occasional abnormalities of glucose metabolism. Although the cause is currently unknown, Costello syndrome is interesting because of a potential genetic-metabolic etiology.

Differentiation of homozygous hemoglobin E from compound heterozygous hemoglobin E-beta O-thalassemia by hemoglobin E mutation analysis.

OBJECTIVES: To facilitate the differential diagnosis of hemoglobin FE in newborn infants (homozygous hemoglobin E vs hemoglobin E-beta O-thalassemia). METHODS: The beta-globin gene in DNA from infants found to have hemoglobin FE in the California newborn screening program was amplified by the polymerase chain reaction, and the product was digested with Mnl I, which fails to cut the product when the hemoglobin E mutation is present. When both amplified alleles fail to be cut, homozygous EE is diagnosed. If only one allele is cut, a beta-globin allele without the E mutation is present (non-E), which is most likely a gene with a beta O-thalassemia mutation. RESULTS: Samples from 18 infants revealed an EE genotype, and from two samples a non-E/E genotype was determined. Clinical examination of these two patients confirmed a diagnosis of hemoglobin E-beta O-thalassemia. An independent clinical diagnosis agreed with DNA analysis for all 17 of the 20 infants for whom follow-up and family studies were available. The DNA results were obtained within a week, but the clinical diagnoses often could not be resolved unequivocally for months. CONCLUSIONS: The direct analysis of patient DNA samples for the hemoglobin E mutation allowed rapid and accurate diagnosis in this sample of infants with hemoglobin FE on the newborn screen. This rapid discriminatory test should reduce cost and simplify the diagnostic approach for these patients, which currently consists of expensive and lengthy follow-up until clinical data and family studies result in a diagnosis.

Communication of information about therapeutic alternatives: end-stage renal disease model.

We analyzed data from questionnaires obtained from 59 patients with end-stage renal disease and nine nephrologists and transplant surgeons to determine outcome of transplantation and dialysis (probability estimates) and the relative advantages of these two treatments (attitudinal responses). Data from national and local studies were available for comparison with the probability estimates. Results indicate that although personal experience with transplantation can bias a patient's estimate of treatment outcome, neither physicians nor patients had a bias toward optimism. Attitudinal responses were similar for patients and physicians, suggesting that physicians communicate personal views more easily than information. Results suggest that shortcomings in information processing need not make informed consent procedures invalid.

Femoral hypoplasia-unusual facies syndrome in infants of diabetic mothers.

Three children with the femoral hypoplasia-unusual facies syndrome are described. Two had the characteristic facial pattern of upslanted palpebral fissures, long philtrum with thin upper lip, micrognathia, and hypoplastic alae nasi. The other, an infant girl who died within 24 hours after birth, had a cleft lip, which distorted some of the other features. She also had a cleft palate, as did one of the two older boys. All three children had ear defects, upper limb involvement, and rib, vertebral, lower extremity, and genitourinary tract abnormalities. The infant girl died of lung hypoplasia associated with dysplastic kidneys and widely patent ductus arteriosus. All three were infants of diabetic mothers, one mother having developed overt diabetes in the first trimester of pregnancy. A literature review of 36 reported cases of FH/UFS revealed 12 individuals who were IDMs, establishing a strong relationship of the syndrome with maternal diabetes. A multifactorial inheritance model fits with the reported patients, with the relationship to diabetes, and with the similarity of FH/UFS to caudal regression, another condition related to maternal diabetes.