Craniosynostosis in Pycnodysostosis: Broadening the Spectrum of the Cranial Flat Bone Abnormalities

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia caused by the absence of active cathepsin K, which is a lysosomal cysteine protease that plays a role in degrading the organic matrix of bones, acting in bone resorption and bone remodeling. The disease is primarily characterized by osteosclerosis, bone fragility, short stature, acro-osteolysis, and delayed closure of the cranial sutures. A differing feature, cranial synostosis, has occasionally been described in this disorder. We reviewed six unrelated patients with pycnodysostosis (mean age of 10 years and 4 months) in order to evaluate the presence of craniosynostosis. In addition to the typical findings of the condition, they all presented premature fusion of the corona! suture. Although none of them showed signs of cranial hypertension, one patient had had the craniosynostosis surgically corrected previously. These data suggest that the cranial sutures in pycnodysostosis can display contradictory features: wide cranial sutures, which are commonly described, and craniosynostosis. The clinical impact of this latter finding still remains to be elucidated. Further studies are necessary to address more precisely the role of cathepsin K in suture patency. (C) 2010 Wiley-Liss, Inc.

Spastic Paraplegia, Optic Atrophy, and Neuropathy: New Observations, Locus Refinement, and Exclusion of Candidate Genes

SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty-one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homozygotes for D11S1889 at 11q13. This enabled us to reduce the critical region for the SPOAN gene from 4.8 to 2.3 Mb, with a maximum two point lod score of 33.2 (with marker D11S987) and of 27.0 (with marker D11S1889). Three genes located in this newly defined critical region were sequenced, but no pathogenic mutation was detected. The gene responsible for SPOAN remains elusive.

Screening of ARHSP-TCC Patients Expands the Spectrum of SPG11 Mutations and Includes a Large Scale Gene Deletion

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing. (C) 2008 Wiley-Liss, Inc.

Structure, Dynamics, and RNA Interaction Analysis of the Human SBDS Protein

Shwachman-Bodian-Diamond syndrome is an autosomal recessive genetic syndrome with pleiotropic phenotypes, including pancreatic deficiencies, bone marrow dysfunctions with increased risk of myelodysplasia or leukemia, and skeletal abnormalities. This syndrome has been associated with mutations in the SBDS gene, which encodes a conserved protein showing orthologs in Archaea and eukaryotes. The Shwachman-Bodian-Diamond syndrome pleiotropic phenotypes may be an indication of different cell type requirements for a fully functional SBDS protein. RNA-binding activity has been predicted for archaeal and yeast SBDS orthologs, with the latter also being implicated in ribosome biogenesis. However, full-length SBDS orthologs function in a species-specific manner, indicating that the knowledge obtained from model systems may be of limited use in understanding major unresolved issues regarding SBDS function, namely, the effect of mutations in human SBDS on its biochemical function and the specificity of RNA interaction. We determined the solution structure and backbone dynamics of the human SBDS protein and describe its RNA binding site using NMR spectroscopy. Similarly to the crystal structures of Archaea, the overall structure of human SBDS comprises three well-folded domains. However, significant conformational exchange was observed in NMR dynamics experiments for the flexible linker between the N-terminal domain and the central domain, and these experiments also reflect the relative motions of the domains. RNA titrations monitored by heteronuclear correlation experiments and chemical shift mapping analysis identified a classic RNA binding site at the N-terminal FYSH (fungal, Yhr087wp, Shwachman) domain that concentrates most of the mutations described for the human SBDS. (C) 2010 Elsevier Ltd. All rights reserved.

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.