Benign recurrent intrahepatic cholestasis with secondary renal impairment treated with extracorporeal albumin dialysis

Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive condition characterized by intermittent episodes of pruritis and jaundice that may last days to months. Treatment is often ineffective and symptoms, particularly pruritis, can be severe. Extracorporeal albumin dialysis (molecular adsorbent recycling system, MARS) is a novel treatment which removes albumin bound toxins including bilirubin and bile salts. We describe a case of a 34-year-old man with BRIC and secondary renal impairment who, having failed standard medical therapy, was treated with MARS. The treatment immediately improved his symptoms, renal and liver function tests and appeared to terminate the episode of cholestasis. We conclude that MARS is a safe and effective treatment for BRIC with associated renal impairment.

Mutation of the LUNATIC FRINGE gene in humans Causes spondylocostal dysostosis with a severe vertebral phenotype

The spondylocostal dysostoses (SCDs) are a heterogeneous group of vertebral malsegmentation disorders that arise during embryonic development by a disruption of somitogenesis. Previously, we had identified two genes that cause a subset of autosomal recessive forms of this disease: DLL3 (SCD1) and MESP2 (SCD2). These genes are important components of the Notch signaling pathway, which has multiple roles in development and disease. Here, we have used a candidate-gene approach to identify a mutation in a third Notch pathway gene, LUNATIC FRINGE (LFNG), in a family with autosomal recessive SCD. LFNG encodes a glycosyltransferase that modifies the Notch family of cell-surface receptors, a key step in the regulation of this signaling pathway. A missense mutation was identified in a highly conserved phenylalanine close to the active site of the enzyme. Functional analysis revealed that the mutant LFNG was not localized to the correct compartment of the cell, was unable to modulate Notch signaling in a cell-based assay, and was enzymatically inactive. This represents the first known mutation in the human LFNG gene and reinforces the hypothesis that proper regulation of the Notch signaling pathway is an absolute requirement for the correct patterning of the axial skeleton.

Two novel missense mutations in hairy-and-enhancer-of-split-7 in a family with spondylocostal dysostosis

Spondylocostal dysostosis (SCD) is an inherited disorder with abnormal vertebral segmentation that results in extensive hemivertebrae, truncal shortening and abnormally aligned ribs. It arises during embryonic development by a disruption of formation of somites (the precursor tissue of the vertebrae, ribs and associated tendons and muscles). Four genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), MESP2 (SCDO2: MIM 608681), LFNG (SCDO3: MIM609813) and HES7 (SCDO4). These genes are all essential components of the Notch signalling pathway, which has multiple roles in development and disease. Previously, only a single SCD-causative missense mutation was described in HES7. In this study, we have identified two new missense mutations in the HES7 gene in a single family, with only individuals carrying both mutant alleles being affected by SCD. In vitro functional analysis revealed that one of the mutant HES7 proteins was unable to repress gene expression by DNA binding or protein heterodimerization.

Mutated MESP2 causes spondylocostal dysostosis in humans

Spondylocostal dysostosis (SCD) is a term given to a heterogeneous group of disorders characterized by abnormal vertebral segmentation (AVS). We have previously identified mutations in the Delta-like 3 (DLL3) gene as a major cause of autosomal recessive spondylocostal dysostosis. DLL3 encodes a ligand for the Notch receptor and, when mutated, defective somitogenesis occurs resulting in a consistent and distinctive pattern of AVS affecting the entire spine. From our study cohort of cases of AVS, we have identified individuals and families with abnormal segmentation of the entire spine but no mutations in DLL3, and, in some of these, linkage to the DLL3 locus at 19q13.1 has been excluded. Within this group, the radiological phenotype differs mildly from that of DLL3 mutation–positive SCD and is variable, suggesting further heterogeneity. Using a genomewide scanning strategy in one consanguineous family with two affected children, we demonstrated linkage to 15q21.3-15q26.1 and furthermore identified a 4-bp duplication mutation in the human MESP2 gene that codes for a basic helix-loop-helix transcription factor. No MESP2 mutations were found in a further 7 patients with related radiological phenotypes in whom abnormal segmentation affected all vertebrae, nor in a further 12 patients with diverse phenotypes.

Intervenção dietoterápica em portadores de lipodistrofia generalizada congênita do Rio Grande do Norte

Congenital generalized lipodystrophy is a rare genetic disease with autosomal recessive inheritance characterized by the generalized absence of subcutaneous adipose tissue and insulin resistance. The aim of our study was to determine the profile of patients with congenital generalized lipodystrophy (Berardinelli-Seip syndrome) through their clinical history, eating habits, and socioeconomic and cultural aspects; assess food consumption and nutritional status of the study group; propose and evaluate a diet therapy model associated to oral supplementation with zinc to help in the control and prevention of metabolic complications associated to the pathology. Initial assessment of food consumption indicated a voracious appetite in all the patients studied. The introduction of zinc reduced appetite, contributing to patient adherence to the food plan proposed. It was also observed that the proposed diet contributed mainly to glycidic control, specifically with respect to HbA1c. The nutritional status of the patients investigated was adequate in terms of body mass index (BMI), arm muscle circumference (AMC), arm muscle area AMA, but triceps skinfold (TSF) indicated serious malnutrition. Our study is unique in the literature and provides important information to the field of nutrition and to individuals with this pathology. Furthermore, it contemplates the interdisciplinary and multidisciplinary requirements of the Postgraduate Program in Health Sciences of the Federal University of Rio Grande do Norte (UFRN), Natal, Brazil

Diagnosis of Smith-Lemli-Opitz syndrome by ultraviolet spectrophotometry

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder due to an inborn error of cholesterol metabolism, characterized by congenital malformations, dysmorphism of multiple organs, mental retardation and delayed neuropsychomotor development resulting from cholesterol biosynthesis deficiency. A defect in 3ß-hydroxysteroid-delta7-reductase (delta7-sterol-reductase), responsible for the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, causes an increase in 7-DHC and frequently reduces plasma cholesterol levels. The clinical diagnosis of SLOS cannot always be conclusive because of the remarkable variability of clinical expression of the disorder. Thus, confirmation by the measurement of plasma 7-DHC levels is needed. In the present study, we used a simple, fast, and selective method based on ultraviolet spectrophotometry to measure 7-DHC in order to diagnose SLOS. 7-DHC was extracted serially from 200 µl plasma with ethanol and n-hexane and the absorbance at 234 and 282 nm was determined. The method was applied to negative control plasma samples from 23 normal individuals and from 6 cases of suspected SLOS. The method was adequate and reliable and 2 SLOS cases were diagnosed.

Estratégia anestesiológica para cesariana em paciente portadora de deficiência de fator XI: relato de caso

JUSTIFICATIVA E OBJETIVOS: A deficiência do fator XI é uma doença hematológica rara na população. A hemofilia C (deficiência do fator XI) ocorre em ambos os sexos e normalmente não apresenta qualquer sintomatologia, podendo manifestar-se apenas como hemorragia pós-cirúrgica. É uma doença autossômica recessiva, homozigótica ou heterozigótica, e sua gravidade depende dos níveis de fator XI. O objetivo desse relato foi apresentar a estratégia anestésica em paciente portadora de hemofilia C. RELATO do CASO: Paciente com 32 anos, gesta I/para 0, 39 semanas de gestação programada para cesariana eletiva. Paciente portadora de deficiência de fator XI. Exame clínico e laboratorial sem alterações. Conforme orientação do hematologista, no dia da cesárea a paciente usou prometazina 25 mg; hidrocortisona 500 mg, devido a reações transfusionais prévias, e plasma 10 mL-1.kg-1 num total de 700 mL. Após 2 horas foi submetida ao bloqueio subaracnóideo sob monitorização de rotina. Hidratação com RL 2000 mL. Procedimento anestésico-cirúrgico sem intercorrências. A paciente evoluiu no pós-operatório sem intercorrências, sendo que no 3º DPO fez uso de plasma fresco congelado (PFC) 10.mL-1.kg-1 com o objetivo de evitar sangramento pós cirúrgico tardio. CONCLUSÕES: O objetivo do caso foi apresentar o protocolo anestésico para pacientes portadores de hemofilia C e alertar para a necessidade de investigação em caso de antecedente de sangramento pós-operatório, quando um estudo da coagulação deve ser realizado antes de qualquer procedimento invasivo e, se um TTPA prolongado for encontrado, torna-se imperativo pesquisar a deficiência desse fator.

Você conhece esta síndrome?

A síndrome de Rothmund-Thomson é distúrbio autossômico recessivo de expressividade variável associado a mutações do gene RecQL4. Caracteriza-se por poiquilodermia, alopecia, defeitos de crescimento e desenvolvimento, catarata juvenil, alterações dentárias e esqueléticas e predisposição ao câncer cutâneo e ao osteossarcoma. Relata-se caso de paciente de 29 anos de idade com lesões cutâneas desde a infância, catarata bilateral antes dos 20 anos e carcinoma espinocelular aos 26 anos de idade.

A nonsense mutation in the tyrosinase gene causes albinism in water buffalo

Background: Oculocutaneous albinism (OCA) is an autosomal recessive hereditary pigmentation disorder affecting humans and several other animal species. Oculocutaneous albinism was studied in a herd of Murrah buffalo to determine the clinical presentation and genetic basis of albinism in this species.Results: Clinical examinations and pedigree analysis were performed in an affected herd, and wild-type and OCA tyrosinase mRNA sequences were obtained. The main clinical findings were photophobia and a lack of pigmentation of the hair, skin, horns, hooves, mucosa, and iris. The results of segregation analysis suggest that this disease is acquired through recessive inheritance. In the OCA buffalo, a single-base substitution was detected at nucleotide 1,431 (G to A), which leads to the conversion of tryptophan into a stop codon at residue 477.Conclusion: This premature stop codon produces an inactive protein, which is responsible for the OCA buffalo phenotype. These findings will be useful for future studies of albinism in buffalo and as a possible model to study diseases caused by a premature stop codon.

Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene

Acheiropodia is an autosomal recessive developmental disorder presenting with bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet. This severely handicapping condition appears to affect only the extremities, with no other systemic manifestations reported. Recently, a locus for acheiropodia was mapped on chromosome 7q36. Herein we report the narrowing of the critical region for the acheiropodia gene and the subsequent identification of a common mutation in C7orf2-the human orthologue of the mouse Lmbr1 gene-that is responsible for the disease. Analysis of five families with acheiropodia, by means of 15 polymorphic markers, narrowed the critical region to 1.3 cM, on the basis of identity by descent, and to <0.5 Mb, on the basis of physical mapping. Analysis of C7orf2, the human orthologue of the mouse Lmbr1 gene, identified a deletion in all five families, thus identifying a common acheiropodia mutation. The deletion was identified at both the genomic-DNA and mRNA level. It leads to the production of a C7orf2 transcript lacking exon 4 and introduces a premature stop codon downstream of exon 3. Given the nature of the acheiropodia phenotype, it appears likely that the Lmbr1 gene plays an important role in limb development.

Identity by descent and candidate gene mapping of Richieri-Costa and Pereira syndrome

The Richieri-Costa-Pereira syndrome is a rare autosomal recessive disorder characterized by short stature, Robin sequence, cleft mandible, pre/postaxial anomalies and clubfoot. of 15 families reported with this disorder 14 are from Brazil suggesting a founder effect. We studied 15 families using identity-by-descent as a hypothesis to attempt gene localization We have examined through linkage analysis 497 polymorphicmarkers and also performed direct sequencing of exons for 10 candidate genes selected on the basis of their expression in the developing mandible and limb. No evidence for allele sharing at any locus tested or mutations in candidate genes was found. Additional higher resolution mapping, new families and other candidate genes might improve future chances of gene identification. (C) 2003 Wiley-Liss, Inc.

Hereditary equine regional dermal asthenia in three related Quarter horses in Brazil

Hereditary equine regional dermal asthenia belongs to a group of inherited, congenital connective tissue dysplasias usually described as hyperelastosis cutis, cutaneous asthenia, dermatosparaxis, or Ehlers-Danlos-like syndrome. This report presents the clinical and histological features of three related Quarter horses affected with regional dermal asthenia. These horses had bilateral asymmetric lesions of the trunk and lumbar regions, where the skin was hyperextensible. Handling of the skin elicited a painful response and superficial trauma led to skin wounds. The skin was thinner than normal in the affected areas, with thickened borders and harder fibrotic masses (pseudotumours). The histopathological findings included thinner and smaller collagen fibrils, and a loose arrangement of collagen fibres in the middle, adventitial and deep dermis. Masson's trichrome and Calleja stains did not reveal any abnormality of collagen and elastic fibres. Electron microscopy showed no abnormalities. As in human patients, pseudotumour histopathological findings included fibroplasia and neovascularization. The pedigree chart of these animals supports an autosomal recessive type of inheritance, which has been suggested by other studies. This is the first report of this disease in Brazil. Its clinical and histological features resemble those described in horses affected with this condition in the United States.

Spondylothoracic dysplasia in two siblings

The spondylothoracic dysplasia syndrome is characterized by congenital malformations of vertebrae and ribs. As a consequence of the anomalous development of the vertebral column, the neck and thorax are short, and the normal head looks as if emerging from the shoulders. The thorax is short and asymmetric with an increased anteroposterior diameter. Dorsolumbar lordosis and a protuberant abdomen are present. The extremities though normal in length appear long relative to the shortened trunk. Short stature results from the vertebral abnormalities. The syndrome was seen in 2 siblings of nonconsanguineous parents.

Naso-orbicular tissue necrosis by Streptococcus parasanguis in a patient with Fanconi anemia: Clinical and laboratory aspects

Fanconi anemia (FA) is a rare autosomal recessive disorder, characterized by pancytopenia and progressive hypoplasia of the bone marrow. A 23-year-old woman with FA showed severe pancytopenia and developed an abscess on the infraorbicular region on the right side of the face that progressed to phlegmon and caused tissue necrosis of the nostrils, nasal septum, nasal fossa, and posterior orbital region. Laboratory examination showed Streptococcus parasanguis as the etiologic agent of the phlegmon. Supportive treatment was recommended due to donor incompatibility for bone marrow transplant. The intraoral examination showed spontaneous gingival bleeding, edema of the interdental papillae, hematomas on the superior and inferior lips, bacterial and fungal infections, and adequate oral hygiene. The patient was treated with the administration of an antibiotic (imipenem), an antifungal (amphotericin B), and mouth washing with antiseptic solutions. Periodontal prophylaxis and orientation to and control of oral hygiene and diet were also used during the remission period. For functional and esthetic rehabilitation of the alar regions and nasal dorsum, an acrylic resin nasal prosthesis was made, supported by a spectacle frame.