A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome.

Although deficiency of complex I of the mitochondrial respiratory chain is a frequent cause of encephalopathy in children, only a few mutations have been reported in each of its subunits. In the absence of families large enough for conclusive segregation analysis and of robust functional testing, it is difficult to unequivocally show the causality of the observed mutations and to delineate genotype-phenotype correlations, making additional observations necessary. We observed two consanguineous siblings with an early-onset encephalopathy, medulla, brainstem and mesencephalon lesions on brain magnetic resonance imaging and death before 8 months of age, caused by a complex I deficiency. We used a homozygosity mapping approach and identified a missense mutation in the NDUFV1 gene. The mutation, p.Arg386His, affects a highly conserved residue, contiguous to a cysteine residue known to coordinate an Fe ion. This observation adds to our understanding of complex I deficiency disease. It validates the important role of Arg386 and therefore supports the current molecular model of iron-sulfur clusters in NDUFV1.

Decrease of telomere length in thyroid adenomas without telomerase activity.

In somatic cells, telomeres shorten with population doubling, thus limiting their capacity to divide. Telomerase, which synthesizes telomeric repeats, can compensate for such shortening. Telomerase activity is known to be absent from most somatic differentiated cells but is present in germline cells, immortal cell lines, or a large majority of malignant tumors. Autonomous thyroid adenomas are benign tumors composed of highly differentiated cells characterized by TSH-independent function and growth. Telomere length and telomerase activity were measured in autonomous and hypofunctioning adenomas and their surrounding tissues. A significant decrease of 3.8+/-1.0 kilobases (kb) was observed in the length of the terminal restriction fragments (TRF) in 12 autonomous adenomas (8.6+/-1.1 kb), compared with the TRF length of their surrounding tissues (12.4+/-1.6 kb). The same kind of decrease, 3.5+/-1.2 kb, was also observed in 16 hypofunctioning adenomas (12.3+/-1.7 kb in surrounding tissue and 8.8+/-1.6 kb in the adenomas). No telomerase activity was detected either in the 12 autonomous adenomas studied or in most of the quiescent tissues (10 of 12). Most of the hypofunctioning adenomas tested (15 of 16) did not display telomerase activity. These results suggest that the cells have undergone a higher number of cell divisions in the adenomas than in the surrounding tissue. Moreover, there is a larger spread of the TRF length distribution in autonomous adenomas than in the collateral tissue. This could reflect the heterogeneity in proliferation status of the cells in the nodule, some of which have reached the end of their life span, whereas others are still proliferating (but with no malignant potential for the autonomous adenomas). In conclusion, benign adenomas exhibit a shorter and more variable telomere length than the normal collateral quiescent tissue, with no telomerase activity to compensate this loss in telomere length.

Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.

Congenital hypothyroidism (CH) is a relatively frequent and potentially severe disease. It is classically subdivided into: 1) thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to hypoplastic, ectopic, or absent thyroid gland; or 2) thyroid dyshormonogenesis, a defect in one of the biochemical mechanisms responsible for thyroid hormone synthesis. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, several genes have been implicated in a small proportion of TD, but, in the majority of the cases, the etiology remains unknown. PAX8 is a transcription factor involved in thyroid development. So far, three loss-of-function mutations of PAX8 have been described, two in sporadic cases and one in familial thyroid hypoplasia. Here, we describe a novel mutation of PAX8 causing autosomal dominant transmission of CH with thyroid hypoplasia. The mutation consists of the substitution of a tyrosine for cysteine 57 in the paired domain of PAX8. When tested in cotransfection experiments with a thyroid peroxidasse promoter construct, the mutant allele was unable to exert its normal transactivation effect on transcription. Our results give further evidence that, contrary to the situation in knockout mice, haplo-insufficiency of PAX8 is a cause of CH in humans.

Structural and functional analysis of spontaneous anti-nitrophenyl antibodies in three cyprinid fish species: carp (Cyrinus carpio), goldfish (Carassius auratus) and tench (Tinca tinca).

High spontaneous anti-trinitrophenyl (TNP) activities were found in three Cyprinid fish species: Carp (Cyprinus carpio), Goldfish (Carassius auratus) and Tench (Tinca tinca). The molecules involved, isolated by affinity chromatography on dinitrophenyl-lysine Sepharose (DNP-lysine-Sepharose), had the main characteristics of a high molecular weight immunoglobulin (IgM-like). Affinity measurements were performed on natural anti-DNP/TNP antibodies isolated from nine individual tench sera, using the inhibition of DNP-T4 bacteriophage inactivation technique. The antibodies analysed were more specific for TNP than for DNP. No activity was found against paranitrophenyl hapten. Affinities were all very low, even for TNP. In the three species, natural anti-DNP/TNP antibodies constitute as much as 11 to 16% of the total immunoglobulin concentration. This high level of nitrophenyl-binding serum immunoglobulins either suggests the existence of a particular regulatory mechanism in fish or reflects a generally low antibody diversity in these species.

Sporadic case of trichorhinophalangeal syndrome type III in a European patient.

Trichorhinophalangeal syndrome type III (TRP III) shares common traits with TRP I and II, including sparse hair, a "pear-shaped" nose, osteodysplasia with cone-shaped epiphyses, and autosomal dominant inheritance, but is distinguished by the presence of severe brachydactyly. TRP III was first described in 1984 in Japanese patients, one sporadic case [Sugio and Kajii, 1984: Am. J. Med. Genet. 19:741-753,1984] and two families [Niikawa and Kamei, 1986: Am. J. Med. Genet. 24:759-760; Nagaï et al., 1994: Am. J. Med. Genet. 49:278-280], and more recently in a Turkish family [Itin et al., 1996: Dermatology 193:349-352]. We report an additional observation in a patient of European descent, who presented with short stature, cone-shaped epiphyses, sparse hair, a pear-shaped nose, normal intelligence and severe brachydactyly. Neither parent had manifestations of TRP and there was no other reported case in the family, indicating a presumably fresh mutation. Our observation refines the clinical spectrum of TRP III in another ethnic background and may be of help in identifying the gene or genes for TRP syndromes.

Neuroimaging fails to identify asymptomatic carriers of familial porencephaly.

Familial porencephaly is a rare condition usually transmitted as an autosomal dominant trait with incomplete penetrance. We describe a new family in which six members across four generations had congenital hemiplegia. Cerebral imaging was performed in three patients and showed porencephaly in all cases. In order to provide effective genetic counseling, three asymptomatic carriers were investigated by cerebral computerized tomography (three patients) and cerebral magnetic resonance imaging (one patient). These investigations failed to show any congenital abnormalities. We conclude that cerebral imaging is unreliable to detect obligate carriers of familial porencephaly.

Characteristics of chronic venous insufficiency in 895 patients followed in general practice.

BACKGROUND: This study was designed to describe the main semiological and etiological characteristics of chronic venous insufficiency (CVI) and to determine if there was a relationship between the extent of objective signs, severity of symptoms and aetiology. MATERIALS AND METHODS: 895 outpatients presenting CVI of the lower limbs over a period of at least one year, irrespective of grade of severity or aetiology, were included in this retrospective study. They were treated with 2 different pharmaceutical forms of the same venoactive medication (1000 mg of micronised flavonoid fraction) for 2 months. Organic CVI (OCVI) was classified, in stages of increasing severity, according to the Widmer and Porter classification. In the absence of anatomical lesions of the main veins or their valvular system, CVI was termed functional (FCVI). RESULTS: Analysis indicated that CVI was more frequent in women than in men (sex ratio 10:1). 26% were FCVI and 91% of OCVI were of varicose origin. The mean progression time of the disease was 13+/-11 years. Disease began earlier in women than in men (34+/-14 vs 41+/-14 years). Oedema was the first objective sign in 68% of patients and the only one in 20% of FCVI. Heaviness was more frequent in FCVI and its intensity was not related to the severity of CVI. Trophic complications were more frequent in the advanced stages. CONCLUSIONS: In order to avoid progression to more severe forms which are disabling or expensive to treat, a rational approach to the management of early CVI is essential.

Characterization of axolotl heavy and light immunoglobulin chains by monoclonal antibodies.

Axolotl specific antibodies to 2,4-dinitrophenyl (DNP) were purified by affinity chromatography from the sera of animals immunized with 2,4,6-trinitrophenylated sheep red blood cells (TNP-SRBC). The purified anti-TNP/DNP antibodies, when analyzed by SDS-PAGE, were constituted of high molecular weight molecules, which in reducing conditions, were separated into heavy 72-88 kD and light 27-30 kD polypeptides. The axolotl heavy antibody chains strongly bound Concanavalin-A and migrate faster in SDS-PAGE after endoglycosidase-F (Endo-F) treatment. Using the same techniques, no carbohydrate components were detected onto light chains. Monoclonal antibodies (MAbs) were obtained against these purified axolotl immunoglobulins (Ig) and their specificities were studied by immunoblotting. MAbs 33.45.1 and 33.101.2 respectively recognized heavy and light chains determinants of the Ig molecule. These determinants were resistant to Endo-F digestion, suggesting that the two MAbs were not directed to polypeptide-associated N-linked high mannose or complex oligosaccharides. MAbs 33.45.1 and 33.101.2 were compared to 11.5.2, an anti-axolotl thymocytes MAb which was reactive for both axolotl leucocytes and soluble Ig. MAb 11.5.2 reacted in immunoblotting against several high molecular weight axolotl serum proteins, including heavy Ig chains. Light chains were not recognized. However, 11.5.2 did not further recognize Endo-F treated Ig, suggesting its specificity for a carbohydrate determinant of the heavy chain, and link to a large diversity of soluble or membrane glycoproteins.

[Castleman disease localized in the mesentery]. / Maladie de Castleman localisée au mésentère.

We report a case of Castleman disease in the mesentery localized to a 58 year-old man. The mass is hypervascular on CT, which can suggest the diagnostic before surgery.

[Aortic-pulmonary chemodectoma (non-chromaffin paraganglioma). Apropos of a case which followed an adrenal pheochromocytoma]. / Chémodectomes (paragangliomes non chromaffines) aortico-pulmonaires. A propos d'un cas faisant suite à un phéochromocytome surrénalien.

The authors present the 61st published case of an aorticopulmonary chemodectoma diagnosed in patient of 59 years who had been operated on 7 years previously for a right sided adrenal pheochromocytoma. The diagnosis was provided by the histological examination of the operative specimen, since computerised tomography had predicted that this large hypervascular tumour of the anterior mediastinum would be totally resectable.

[Chronic relapsing polychondritis. Clinical characteristics]. / Polychondrite chronique atrophiante. Particularitiés cliniques.

Some imperfectly known clinical aspects of polychondritis chronica atrophicans (relapsing polychondritis), as extracted from a series of 12 cases, are presented. The osteoarticular lesions are sometimes unusual, involving the temporomandibular or cervical articulations, and the renal lesions may be severe. Pericarditis seems to be more frequent than usually mentioned in the literature. Pulmonary complications are not always those which are classically associated with lesions of the tracheo-bronchial cartilages. Haematological manifestations are not uncommon and must be taken into account when evaluating the prognosis of the disease.

[Use of very low doses of intravenous immunoglobulins for the treatment of bullous pemphigoid]. / Utilisation de très faibles doses d'immunoglobulines intraveineuses pour le traitement des pemphigoïdes bulleuses.

High dose intravenous immunoglobulins have proved effective immunosuppressants in various autoimmune diseases, including bullous pemphigoid. However, their specific point of impact remains undetermined and no study supports the need for high doses. We treated elderly patients with proven and corticosteroid-resistant bullous pemphigoid, using a therapeutic regimen consisting of continuous oral corticosteroid therapy and continuous infusion of immunoglobulins in very low doses by means of an electric syringe. Clinical improvement was observed in every case without any characteristic change in immunological parameters (anti-basal membrane antibody, cutaneous immune deposits), which suggests that immunoglobulins administered in that way act on immune response regulatory mechanisms. The therapeutic effect observed potentiates that of corticosteroids which can thus be given in lower doses in bullous pemphigoid.

[Raynaud's phenomenon after chemotherapy. Apropos of 3 cases]. / Phénomène de Raynaud après chimiothérapie. A propos de 3 observations.

Raynaud's phenomenon is studied in three patients after cancer chemotherapy. In these cases, Raynaud's phenomenon occurs as: a true coincidence, a secondary complication of which neoplastic biological signs are thrombocythemia, hyperfibrinemia, immune complexes, cryoglobulinemia..., a therapeutic implication. The rate of therapeutic implication is difficult to precise. Raynaud's phenomenon is a little symptom over a severe illness. Several drugs are responsible for this fact. A literature review mentions Vincristine, Bleomycin, Cisplatin... For our three patients as in the literature review the tumoral nature is less important than the drug type. For us Bleomycin alone as in association is able to induce Raynaud's phenomenon. The occurrence of single Raynaud's phenomenon may be a systemic scleroderma is first sign. However it is important to affirm the true single Raynaud's phenomenon. In this case there is a lack of signs: scleroderma may be paraneoplastic, drugs may be pulmonary toxic, anticentromere antibodies may be positive during antineoplastic treatment. The pathogenesis for Raynaud phenomenon drug induction is unknown. For Bleomycin action the role of skin concentration, fibroblastic lesion, and vascular disturbance is discussed.

[A rare tumor of the mediastinum: benign hemangioma]. / Une tumeur rare du médiastin: l'hémangiome bénin.

Mediastinal hemangiomas are rare tumours occurring more often in children and young adults. A new case is reported in a 21 years old male who had an anterior mediastinal mass detected on a routine chest roentgenogram. Pre-operative investigations including CT, venous digital angiography, MRI did not aid in the right diagnosis. The mass was totally removed surgically although involving extensively adjacent structures. Histologic examination of the tumour showed it to be a benign venous hemangioma. Clinical, radiological, pathologic features of mediastinal hemangiomas are reviewed and discussed.

[Prevalence of hypothyroidism and hyperthyroidism in temporal arteritis and rhizomelic pseudopolyarthritis. A controlled study of 104 cases]. / Prevalence de l'hypothyroidie et de l'hyperthyroidie dans la maladie de Horton et la pseudopolyarthrite rhizomélique. Etude contrôlée portant sur 104 cas.

The aim of this study was to assess the prevalence of hyperthyroidism and hypothyroidism in giant cell arteritis and polymyalgia rheumatica. The prevalence of thyroid dysfunction in giant cell arteritis and polymyalgia rheumatica patients was determined retrospectively from 1976 through 1984 and prospectively from 1984 through 1991. A control group was composed of patients over 55 years of age consecutively admitted to the same hospital department for another condition. Patients were screened for thyroid dysfunction using a thyrotropin assay. Abnormal results were evaluated by T3 and T4 assays and, if needed, a TRH test. Among the 68 giant cell arteritis patients (mean age 72.6 +/- 7 years), of which 41 were included in the prospective arm of the study, 6 had hypothyroidism and 3 had hyperthyroidism. Corresponding figures were 4 and 4 among the 36 patients with polymyalgia rheumatica (mean age 71.7 +/- 8.3 years), of which 18 were evaluated prospectively. Among the 305 controls (mean age 71.6 +/- 9.4 years), 16 had hypothyroidism and 10 had hyperthyroidism. Prevalences of hypothyroidism, hyperthyroidism, and antithyroid antibodies were not significantly different in the control and case groups. Data fail to support previous suggestions that giant cell arteritis or polymyalgia rheumatica patients may be an increased risk for hypothyroidism or hyperthyroidism. They lend no indirect support to the hypothesis that giant cell arteritis and polymyalgia rheumatica may be autoimmune disorders.

IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign.

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.