Facial appearance in persistent hyperinsulinemic hypoglycemia

Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients.     

Prenatal diagnosis of sporadic Apert syndrome: a sequential diagnostic approach combining three-dimensional computed tomography and molecular biology

Apert syndrome is characterized by coronal craniosynostosis, midfacial hypoplasia, symmetrical syndactyly of the hands and feet described as 'mitten-like' with varying degrees of mental retardation. It results from a mutation of the fibroblast growth factor-2 (FGFR2) gene. In the absence of a family history, prenatal diagnosis may be difficult based on sonography alone. We report a case in which the prenatal diagnosis of Apert syndrome was suspected by ultrasonography, established by three-dimensional computed tomography scan (3DTS) and confirmed by the detection of a mutation on amniotic cells. This underscores the usefulness of a sequential diagnostic approach combining 3DTS and molecular biology in cases in which sonography alone is not con- clusive.     

Prenatal diagnosis of respiratory chain deficiency by direct mutation screening

Respiratory chain deficiency (RCD) is responsible for a clinically heterogeneous group of early-onset untreatable disorders. Enzymological prenatal diagnosis (PD) can only be offered to a fraction of families. Moreover, due to the two-fold genetic origin of the respiratory chain (nuclear and mitochondrial DNA) and owing to the large number of nuclear genes involved in the respiratory chain assembly, maintenance and functioning, the identification of the disease causing gene in a given family remains challenging. Here, we report on PD of RCD by direct screening of NDUFV1, SDH-Fp, SCO1 and SURF1 mutations in five unrelated families with complex I, II and IV deficiency, respectively. The identification of the disease-causing gene in a given family with RCD is a major issue to provide both adequate genetic counselling and early, reliable PD.     

Determination of enzyme activities for prenatal diagnosis of respiratory chain deficiency

Genetic counselling and prenatal diagnosis are major issues of mitochondrial respiratory chain deficiency, especially as these conditions are largely untreatable. In the absence of known mitochondrial or nuclear gene mutations, measurement of respiratory chain enzyme activities represents the only possibility to prevent recurrence of the disease in affected families. We carried out enzymatic prenatal diagnosis in 21 pregnancies from 10 unrelated couples using uncultured choriocytes and/or amniocytes. Twelve babies were born and are healthy, seven pregnancies were discontinued early on because of an enzyme deficiency detected prenatally. In two cases, a fetus which appeared normal after early and/or late prenatal diagnosis, turned out to be affected. We conclude that a deficient enzyme activity is indicative of recurrence, but a normal result at 10 weeks of gestation does not give conclusive evidence as to the outcome of the pregnancy. We therefore suggest the following procedure: (1) a choriocentesis or an amniocentesis in early pregnancy when the proband expresses the disease in cultured skin fibroblasts; (2) a second amniocentesis at 28 weeks' gestation should be offered to avoid false negative results due to a possible late expression of the disease, in combination with: (3) a careful and repeated ultrasound survey for detection of growth failure in the third trimester; (4) prenatal diagnosis should not be performed in case of late onset clinical symptoms in the proband; and (5) parents should be aware of the possibility of false negative results. Prenatal diagnosis should not be proposed for a complex I deficiency as this enzyme activity cannot be accurately measured in fetal cells.     

Evidence for a perilymphatic origin of the endolymph: application to the pathophysiology of Ménière's disease

The origin of the endolymph was elucidated by kinetic studies of the entry of water and electrolytes into endolymph and perilymph after intravenous administration of radioactive tracers in rats. The compartmental analysis of the data and the comparison of this study with the results of Konishi and associates (Acta Otolaryngol (Stockh) 86, 22-34 and 176-184, 1978), using perilymphatic perfusion of tracers, indicate that perilymph rather than plasma may be considered the precursor of endolymph. Since the cochlear epithelium was found to be freely permeable to water, an alteration of electrolyte transportation across the membranous labyrinth may be involved in the pathophysiology of Ménière's disease. Chloride transport across the cochlear epithelium was investigated using acetazolamide, a specific carbonic anhydrase inhibitor.     

Rib perichondrial grafts for the repair of full-thickness articular-cartilage defects. A morphological and biochemical study in rabbits

The purpose of this study was to investigate the use of perichondrial grafts in articular cartilage defects and to characterize the newly formed cartilage. In a rabbit model, rib perichondrium was used to repair full-thickness defects in the femoral condyle. The quality of repair was then evaluated histologically and biochemically at six and twelve weeks after grafting. Unacceptable results were obtained in 50 per cent of the rabbits. These failures were due to condylar fracture in 20 per cent, failure of graft attachment in 20 per cent, and infection in 10 per cent. The technique of grafting must be improved to increase the percentage of successful grafts in which neocartilage with a relatively normal chemical composition fills the articular cartilage defect. Successful grafts proliferate to fill the full-thickness defect with neocartilage, which has biochemical characteristics that are similar to those of hyaline cartilage.     

Two independent de novo mutations as a cause for neurofibromatosis type 1 and Noonan syndrome in a single family

Here we report on a family with two siblings born to unrelated healthy parents, one with neurofibromatosis type 1 (NF1) and the other with Noonan syndrome (NS). Molecular investigations performed on the NF1 and PTPN11 genes showed two independent de novo mutations as a cause for NF1 in the NF1 proband and NS in her affected brother. Both de novo mutations were potentially of paternal origin, given the advanced paternal age at the time of conception. ? 2012 Wiley Periodicals, Inc.