Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.

Joint predisposition to malignant melanoma and nervous system tumors (NSTs) is a puzzle. Several melanoma susceptibility genes have been identified, including p16, a clustered tumor suppressor. However, the molecular bases of inherited proclivity to NSTs in the absence of a recognizable genetic syndrome are unknown. We analyzed two families with joint proneness to melanoma and NSTs in view of genetic linkage and identification of the causal molecular lesions. Highly informative linkage markers were used for segregation analyses of the predisposition alleles in the two pedigrees. Characterization of the molecular lesions required hemizygosity mapping based on microsatellite markers physically mapped to contigs of the 9p21 region and a Southern blot approach using several PCR-generated probes. Both families were found to be allelic and linked to p16 markers. In the family segregating the melanoma/NST syndrome, a large germ-line deletion ablated the whole p16, p19, and p15 gene cluster (or INK4 locus), whereas a more circumscribed molecular lesion disrupting p16 and p19 but leaving p15 unaltered segregated with the melanoma-astrocytoma syndrome (MIM 155755). Our results suggest that multiple cancer susceptibility in these two families ensues from contiguous tumor suppressor gene deletion. Indeed, known phenotypes associated with germ-line p16 mutations and an apparent correlation between the deletion span and tumor spectrum in the two families suggest a new model of cancer pathogenesis based on the inactivation of contiguous tumor suppressor genes, an alternative to the established pleiotropic effects of single-gene disruption.

[Congenital desproportion of various types of muscle fiber, with relative small size of type I fibers. Morphological documents on muscle biopsies in 3 members of the same family]. / Disproportion congénitale des différents types de fibre musculaire, avec petitesse relative des fibres de type I. Documents morphologiques concernant les biopsies musculaires prélevées chez trois membres d'une même famille

In two sisters with a neo-natal hypotonia, muscle biopsies demonstrated as main pathological feature a disproportion in size between the two types of muscle fibers defined according to their myofibrillar ATPase activity. Type I fiber mean diameter was at the lower limit of the normal values, and type II fibers were larger than normal. Their father's biopsy also showed an abnormal smallness of the type I fibers, with a bimodal distribution. By electron microscopy, the small type I fibers did not reveal any significant abnormality in children's biopsies. In father's biopsy, there was an abnormal degree of filamentary interchange between contiguous myofibrils and a few stacks of rods in the type I fibers. These three cases demonstrate the familiar character of the disorder. The relationship of this new entity with the other congenital myopathies is controversial, as a similar congenital fiber type disproportion, has been found in association with different ultrastructural changes. Several data favour an insufficient development of the type I fibers rather than an atrophying process. The mechanism of this "hypotrophy" remains unknown.

[Myasthenia and pregnancy: a clinical and immunologic study of 42 cases (21 neonatal myasthenia cases)]. / Myasthénie et grossesse: une étude clinique et immunologique de 42 cas (21 myasthénies néonatales).

Forty-two pregnancies in 39 myasthenic mothers were studied between 1978 and 1987. In 4 cases myasthenia gravis began during pregnancy and for 20 patients the clinical condition exacerbated in 15 cases, usually during the first 3 months, or during the postpartum. Except for 1 case, clinical exacerbation was controlled by anticholinesterase drug adjustment. Obstetrical problems were uncommon: abortion in 1 case and premature delivery in 4 cases. In 2 babies with severe fetal involvement polyhydramnios was present. Twenty-one babies had neonatal myasthenia gravis (NMG). In 17 cases, transient symptoms were present at delivery or shortly afterwards and full recovery occurred from a few days to 4 months. In 4 babies the clinical presentation was atypical: 1 showed a long evolution (15 months) and residual facial bilateral weakness, and three others presented fetal involvement (arthrogryposis). In these latter cases, presentation was severe with polyhydramnios, respiratory failure and long standing evolution in 2 cases (4 months and 1 year). Antiacetylcholine receptor antibodies (anti-AChR Ab) were found in all myasthenic babies and in 19 out of 20 asymptomatic babies. Maternal antibody titers were usually slightly higher than umbilical cord titers. There was a good correlation between maternal titer and onset or severity of disorder in baby. Among the 15 high titer mothers (greater than 60 nM), 13 had a myasthenic baby, 6 of them with serious disease. Conversely all low titer mothers (less than 10 nM) had a symptom-free baby. Therefore, anti-AChR Ab titration in the mother is predictive for NMG onset. Mother's myasthenia gravis severity and treatment were not correlated to the clinical condition of the newborns.

[Mitochondrial function and mitochondrial DNA in a series of 64 patients suspected of having mitochondrial myopathy]. / Etude de la fonction mitochondriale et de l'ADN mitochondrial sur une série de 64 patients suspects de myopathies mitochondriales.

Biochemical results concerning 64 patients suspected of mitochondrial myopathies are presented. Four clinical groups were studied including 21 encephalomyopathies, 42 ocular myopathies, 8 isolated myopathies and 3 cardiomyopathies. In 26 cases, the coexistence of a normal mitochondrial DNA and a mutated mitochondrial DNA (heteroplasmy) was found (19 simple deletions, 4 multiple deletions and 3 punctual mutations) and all cases presented with ocular disorders (excepted 2 cases with MERRF). Furthermore, 1 complex I deficiency (1 ocular myopathy), 1 complex IV deficiency (1 adult encephalomyopathy type Leigh), 3 complexes I + IV deficiencies (2 cases with a cardiomyopathy and 1 familial MELAS) and 2 pyruvate (1 adult from of Leigh's encephalomyopathy) dehydrogenase deficiencies (clinically and genetically different) did not show evidence of mitochondrial DNA mutation.

[Congenital muscular dystrophy with merosin deficiency: clinical, histopathological, immunocytochemical and genetic analysis]. / Dystrophie musculaire congénitale avec déficience en mérosine: analyse clinique, histopathologique, immunocytochimique et génétique.

A selective deficiency of a specific laminin isovariant, merosin made of M, B1 and B2 chains, was found in a series of 17 patients affected with congenital muscular dystrophy (CMD). The merosin deficiency was complete in 15 cases, and almost complete in two cases. An overexpression of the laminin A chain was seen in these biopsies, while B1 and B2 chains were normally expressed. Comparison of the clinical data with a series of 18 "merosin-non deficient" cases showed that the "merosin-deficient" cases were forming a more homogenous group than the "non-deficient" one. Hypotonia, contractures, motor development delay were generally more severe in the "merosin-deficient" series of cases. Moreover, white matter alterations were seen in most cases explored by MRI or scan imaging. A genetic linkage with a 6q2 locus, corresponding to the M chain gene localization, was found in a panel of informative families from French and Turkish origin with "merosin deficient" CMD. "Merosin non-deficient" families did not map on this locus. So, the "merosin-deficient" CMD can be considered as a peculiar entity within the group of Congenital Muscular Dystrophies.

[Contribution of the electromyogram in the diagnosis of infantile spinal muscular atrophy in the neonatal period]. / Apport de l'électromyogramme au diagnostic d'amyotrophie spinale infantile en période néonatale.

BACKGROUND: The acute form of Werdnig-Hoffman disease, infantile spinal muscular atrophy type I (SMA I), is characterized by severe paralytic hypotonia with neurogenic electromyographic (EMG) pattern and specific histologic features. PATIENTS: Four cases of very severe SMA I suffering from generalized muscle weakness at birth were included in the study. RESULTS: The neurogenic EMG pattern was observed at the first exam performed between D2 and D46. The muscular biopsy performed between D18 and D45 showed only a mild decrease of the muscle fiber size without grouping of fiber types. CONCLUSION: In those forms of SMA I with a neonatal clinical onset, the diagnosis is assessed by clinical and EMG findings while early muscular biopsy can be misleading. EMG is the relevant diagnostic test which confirms the anterior horn cell disease and can justify the DNA study.

[Acute basal ganglia necrosis with favorable course during Mycoplasma encepahlitis]. / Nécrose aiguë des noyaux gris d'évolution favorable lors d'une encéphalite à mycoplasme.

BACKGROUND: Acute bilateral striatal necrosis complicating the course of a post-infectious encephalitis is rare. CASE REPORT: A previously healthy 5-year-old boy presented with an atypical pneumonia; he rapidly developed, encephalitis revealed by a generalized status epilepticus. After transient improvement, he became confused and mutic, with dystonic postures of his limbs. Painful stimulation resulted in prolonged facial grimacing and doleful cry. CT scan and MRI showed abnormal signals in the whole basal ganglia, typical of bilateral striatal necrosis. Serologic tests for Mycoplasma pneumoniae were positive. The child recovered almost completely. CONCLUSION: A parainfectious process is probably responsible for the transient bilateral striatal necrosis seen in this patient who had Mycoplasma pneumoniae infection several days before the onset of neurologic symptoms. MRI seemed more reliable than CT-scan for the diagnosis of this condition.

[Clinical, cytogenetical, histological, immunological and hormonal studies in a case of true hermaphroditism (author's transl)]. / Etudes cliniques, cytogénétiques, histologiques, immunologiques et hormonales chez un hermaphrodite.

A true hermaphrodite with ambiguous genitalia and 46 XX caryotype was investigated during adolescence. At 13 years testosterone concentrations (ng/ml) were 6 and 390 respectively in peripheral and right ovotestis venous blood. After removal of the right gonad, large fluctuations of estradiol levels (40 to 220 pg/ml) were observed. But the testosterone secretion by the left ovotestis was low, although responsive to hCG. A significant LH surge was induced by ethinyl-estradiol load before removal of the left gonad. The 5 alpha-reductase activity was normal in the pubic skin and the levels of cytosolic receptors of testosterone and DHT were high in the left gonad. The presence of H-Y antigen was demonstrated on lymphocytes.

[Hurst-type acute leukoencephalitis with complete recovery in a child]. / Leucoencéphalite aiguë type Hurst avec guérison complète chez un enfant.

A case of acute haemorrhagic leukoencephalitis in an 11-year old girl demonstrates the usefulness of computerized tomography which shows large, asymmetric hypodense areas in the white matter and diffuse oedema. The causative role of a Mycoplasma pneumoniae infection is suggested by positive serology and by a high level of cold anti-l agglutinins. Treatment with corticosteroids in massive doses combined with a tetracycline resulted in complete cure without sequelae.

[Assay of anti-acetylcholine receptor antibodies in myasthenic syndromes of newborn infants]. / Dosage des anticorps antirécepteur de l'acétylcholine dans les syndromes myasthéniques du nouveau-né.

Eighteen neonates were investigated for antibodies directed against acetylcholine receptors. No antibody was detected in 3 cases of congenital myasthenic syndrome, whereas positive results (3.5 to 250 nM) were obtained in 7 cases of transitory neonatal myasthenia and in 7 of 8 asymptomatic infants born to myasthenic mothers. The neonatal antibodies are fully cleared within 1 to 6 months (half-life: 9 days to 2 and a half months). The prognostic value of the maternal and infantile antibody titers is limited: maternal titer at the end of pregnancy, though usually higher in the mothers of myasthenic children, do not predict or preclude the occurrence of transitory myasthenia, and there is no clear correlation between the severity and duration of the myasthenia and the initial titer or the level of the child's antibodies. The assay which measures antibodies against acetylcholine receptors is useful in that it confirms the diagnosis of transitory myasthenia and excludes congenital myasthenic syndromes.

[Familial Mediterranean fever in childhood (author's transl)]. / La maladie périodique chez l'enfant.

Most cases of familial mediterranean fever (periodic disease) begin in childhood. However reports of this disorder in the pediatric literature are rare. This diagnosis is too often missed in pediatric practice. His symptomatology is the same as in adulthood with some particularities. Familial history is often the corner-stone of the diagnosis. Assessment of C'4 fraction of complement seems of good help for the diagnosis. The frequent occurrence of premonitory symptoms heralding the attacks allows us in many cases to start an intermittent colchicine therapy. Long term colchicine therapy should be used very cautiously in children and should be restricted to those children whose activities are disrupted by crisis occurring without alarm or to cases associated with amyloidosis.

[Neonatal hypotonias with congenital disproportion of various types of muscular fiber, especially type I fibers. Demonstration of the familial character of this new entity]. / Hypotonies neon-natales avec disproportion congenitale des differents types de fibre musculaire, et petitesse relative des fibres de type I Demonstration du caractere familial de cette nouvelle entite

Two sisters presenting with benign congenital hypotonia are reported. In both cases the muscle biopsies demonstrated the same pathological pattern, consisting in an abnormal size disproportion between the two main cytoenzymological types of muscle fibers. Their father, exhibiting a slight and diffuse muscle weakness, showed a closely related histological aspect. These three cases bring the first evidence of a familial transmission of this new entity. Its relationship with the other types of "congenital myopathies" is discussed.

Sudden infant death syndrome and inherited disorders of fatty acid beta-oxidation.

Evidence that inherited disorders of mitochondrial fatty acid beta-oxidation can cause sudden infant death syndrome (SIDS) comes from case reports, systematic autopsy studies, and family studies. Family studies are important when no pediatric autopsy has been done, which is still frequent. After reviewing the fatty acid beta-oxidation, and its pathophysiology, we present the results of our metabolic study on 189 siblings of SIDS victims, and on 84 'near-miss' infants. We have found evidence for a disorder of fat oxidation in 28 (15%) infants in the first group, and in 14 (17%) infants in the second group. Diagnosing and treating such disorders early in infancy may prevent some cases of SIDS to occur.

Multiple acyl-CoA dehydrogenase deficiency occurring in pregnancy and caused by a defect in riboflavin metabolism in the mother. Study of a kindred with seven deaths in infancy: Value of riboflavin therapy in preventing this syndrome.

Seven infants in one kindred died: one was stillborn; the others, who were floppy at birth and were breast-fed, developed a disorder with the odor of sweaty feet and died in early infancy. In two further pregnancies, 3-hydroxvisovaleric, glutaric, and C6-C10-dicarboxylic acids were demonstrated in the mother's urine during the seventh month. Riboflavin therapy in the last trimester of pregnancy and a riboflavin-rich diet given the infants prevented this syndrome. The presence of abnormal erythrocyte glutathione-reductase activity in the mother while she excreted normal amounts of riboflavin in her urine indicates a probable disorder of riboflavin metabolism resulting in multiple acyl-CoA dehydrogenase deficiency.