Ectopia lentis phenotypes and the FBN1 gene

Mutations of the fibrillin-1 (FBN1) gene on chromosome 15 have been described in patients with classical Marfan syndrome (MFS), neonatal MFS, the "MASS" phenotype, autosomal dominant ascending aortic aneurysms, autosomal dominant ectopia lentis (EL), Marfanoid skeletal features [Milewicz et al., 1995: J Clin Invest 95:2373-2378], familial arachnodactyly, Shprintzen-Goldberg syndrome [Hayward et al., 1994: Mol Cell Probes 8:325-327; Furthmayr and Francke, 1997: Semin Thorac Cardiovasc Surg 9:191-205], and severe progressive kyphoscoliosis [Adès et al., 2002: Am J Med Genet 109:261-270]. We report the use of denaturing high performance liquid chromatography (DHPLC) to facilitate the characterization of a previously elusive FBN1 mutation in the large autosomal dominant EL kindred described by Edwards et al. [1994: Am J Med Genet 53:65-71]. This isolated EL kindred remains the largest for which detailed clinical data is available. Nine years on, we present an update of the clinical status of the family. We report a recurrent FBN1 mutation, R240C, in the kindred. This mutation has been reported three times before, once in a family with classic MFS [Loeys et al., 2001: Arch Intern Med 161:2447-2454], once in one member of a multi-generation EL kindred, [K?rkk? et al., 2002: J Med Genet 39:34-41], and once in an adult from a familial EL kindred who had EL, and involvement of the integument, without cardiovascular involvement [Comeglio et al., 2002: Br J Ophthalmol 86:1359-1362]. This is the second report of the R240C mutation in association with isolated EL, and supports the existing evidence that the R240C mutation can result in two quite distinct, yet related, phenotypes. It also raises the possibility that R240C may prove to be a relative mutational "hot-spot" for isolated EL. We review the current literature regarding EL (isolated and other) and FBN1 mutations.     

Ectopia lentis and aortic root dilatation in congenital contractural arachnodactyly.

Congenital contractural arachnodactyly (CCA) was described by Beals and Hecht as an autosomal dominant disorder distinct from Marfan syndrome and comprising joint contractures, arachnodactyly, scoliosis, and a distinct "crumpled ear" deformity. While the disorder is similar to Marfan syndrome, it was split from it due to the distinct physical appearance of the patients and, more importantly, the lack of heart and eye findings. Since the original report, several CCA patients have been found to have mitral valve prolapse, structural cardiac anomalies, and occasionally aortic root dilatations similar to those seen in Marfan syndrome. We report on a patient with CCA with bilateral ectopia lentis and aortic root dilatation. Our review of the literature of CCA showed that serial echocardiography and careful eye examinations have not become a standard of medical practice in this condition. Partly this may be due to a lack of documented cases of CCA having severe ectopia lentis and cardiac complications. This patient underscores the need for periodic eye and echocardiographic evaluations of all CCA patients.     

Ectopia lentis as the presenting and primary feature in Marfan syndrome

Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5' portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.     

Ectopia lentis and aortic root dilatation in congenital contractural arachnodactyly

Congenital contractural arachnodactyly (CCA) was described by Beals and Hecht as an autosomal dominant disorder distinct from Marfan syndrome and comprising joint contractures, arachnodactyly, scoliosis, and a distinct “crumpled ear” deformity. While the disorder is similar to Marfan syndrome, it was split from it due to the distinct physical appearance of the patients and, more importantly, the lack of heart and eye findings. Since the original report, several CCA patients have been found to have mitral valve prolapse, structural cardiac anomalies, and occasionally aortic root dilatations similar to those seen in Marfan syndrome. We report on a patient with CCA with bilateral ectopia lentis and aortic root dilatation. Our review of the literature of CCA showed that serial echo-cardiography and careful eye examinations have not become a standard of medical practice in this condition. Partly this may be due to a lack of documented cases of CCA having severe ectopia lentis and cardiac complications. This patient underscores the need for periodic eye and echocardiographic evaluations of all CCA patients.     

Gestational trophoblastic diseases: recent advances in histopathologic diagnosis and related genetic aspects

Gestational trophoblastic disease refers to a spectrum of proliferative disorders of the placental trophoblast, with a wide range of histologic appearances and clinical behaviors. This review discusses the more recent developments in the diagnosis of these entities. Changes in criteria for the histologic diagnosis of these lesions due to earlier clinical diagnosis are reviewed, and the ability to make more accurate diagnoses due to the introduction of newer antibodies such as p57 is highlighted. A discussion of epithelioid trophoblastic tumor, a newly introduced tumor subtype, with its differential diagnosis from placental-site trophoblastic tumor and squamous cell carcinoma is also presented. Last, a brief discussion on the role of genetic studies and the future direction of research in elucidating the nature of this intriguing group of lesions is presented.     

Hodgkin's disease: classification and differential diagnosis.

During the past decade, there have been many advances in our understanding of Hodgkin's disease. Among the most important is the discovery that the Reed-Sternberg cell is a lymphoid cell, in most cases a B cell, and that it is clonal. Hodgkin's disease is thus a true lymphoma, deserving of a name change to Hodgkin's lymphoma (HL). On the basis of a combination of immunophenotype and morphologic features, the Revised European-American classification system recognizes two main types of HL: classical types (nodular sclerosis, mixed cellularity, lymphocyte-rich classical HL, and lymphocyte depletion) and nodular lymphocyte-predominant type. These two types probably are distinct biologic entities. The immunophenotype and genetic features of the classical HL and the nodular lymphocyte-predominant type have been defined. These are useful in the subclassification of HL and in distinguishing HL from two recently described, aggressive lymphomas that were in the past often diagnosed as HL, i.e., anaplastic large-cell lymphoma, T-cell type, and T-cell/histiocyte-rich large B-cell lymphoma. Epstein-Barr virus has been detected in approximately 40% of the cases of classical HL, and it is clonal; this suggests that this virus might play a role in the pathogenesis of at least some types of HL. Alternatively, its presence might simply reflect the prevalence of Epstein-Barr virus-infected B cells in the individual. Despite the advances of the past 10 years, many questions remain to be answered; these will provide the challenges of the next decade.     

Facioscapulohumeral muscular dystrophy: aspects of genetic counselling, acceptance of preclinical diagnosis, and fitness.

A questionnaire about the interest in and demand for preclinical diagnosis for facioscapulohumeral muscular dystrophy (FSH) was sent to 46 patients. Most stated that they would have liked to have known their diagnosis earlier in order to seek more efficient help, to avoid strenuous activities, to prepare themselves emotionally, or to choose an appropriate profession. Similar arguments were used to explain their interest in preclinical diagnosis for their children. Most patients also favoured prenatal diagnosis although only two stated they would abort a pregnancy in the case of an affected fetus. Genetic counselling had apparently little influence on family planning. According to this study, FSH does not seem to reduce reproductive performance in our population.     

Calcifying solitary bone cyst: morphological aspects and differential diagnosis of sclerotic bone tumours

Fourteen solitary bone cysts (SBC) with large areas of calcification (7 in the femur, 4 in the humerus, and 1 each in the pelvis, the tibia and the scapula) and 402 SBC from the Hamburg Bone Tumour Registry were reviewed in a retrospective study. The analysis was done with emphasis on the clinical, radiological and histological appearances. SBC are well known lesions, but calcifying SBC (CSBC) or extensive extragnathic cement-like bone productions are rare. The clinical and radiological differential diagnosis includes fibrous dysplasia, chondroma, low-grade chondrosarcoma and osteosarcoma. Bits of this cement-like matrix are detectable within the wall of approximately 70% (278 of 402) of SBC from the registry. CSBC are changed SBC. The intraoperative confirmation of the diagnosis on a frozen section by the bone pathologist leads to curettage which is currently the most common therapy in this benign lesion.     

Prenatal diagnosis of isolated femoral bent bone skeletal dysplasia: problems in differential diagnosis and genetic counseling

Severe localized and symmetric bowing of the femora, in the absence of other significant skeletal or nonskeletal abnormalities, is a rare prenatal ultrasound finding. A 38-year-old woman was referred at 19 weeks gestation and ultrasound of the fetus showed severe shortening, and marked symmetric bowing of the femora. A provisional diagnosis of kyphomelic dysplasia (KD) was made. The patient elected termination of pregnancy and post mortem assessments were most consistent with kyphomelic dysplasia. KD is bent-bone skeletal dysplasia that, in contrast to campomelic dysplasia, involves principally the femora with relative sparing of the remainder of the skeleton. KD can be difficult to distinguish, particularly from symmetric cases of femoral hypoplasia unusual facies syndrome (FH-UFS), and few prenatal diagnoses have been reported. Because KD is thought to an be autosomal recessive disorder, the possibility that definitive diagnosis may not be possible prenatally, and even by postmortem assessment in cases choosing to abort, is an important counseling consideration.     

Histiocytic sarcoma: diagnosis and differential diagnosis

Two cases of clinical diagnosis of tumour of the trachea and tumour of the stomach are described in a 42- and 52-year-old males. Immunohistochemical and ultrastructural methods were used to prove the histiocytic nature of the tumour cells which were morphologically similar to poorly differentiated carcinoma and large cell lymphosarcoma.     

传染性单核细胞增生症淋巴结病病理诊断与鉴别诊断

目的 探讨传染性单核细胞增生症淋巴结病的病理形态学特点及诊断与鉴别诊断要点.方法 收集3例传染性单核细胞增生症淋巴结病(均为会诊病例:1例原单位诊断为间变性大细胞淋巴瘤,1例诊断为经典型霍奇金淋巴瘤,另1例未能定性),观察和分析其临床、病理组织学和免疫表型,并对病变淋巴结做EB病毒原位杂交检测.结果 3例患者中男性2例,女性1例,平均年龄15岁,平均病程16天;3例患者均表现为颈部淋巴结肿大,1例伴有低热及咽部疼痛.术后均未予特殊治疗,随访时间分别为5、9、18个月,无1例复发.镜检、免疫表型及EBV检测:淋巴结基本结构不同程度破坏,滤泡外免疫母细胞样大细胞增生,其大多数CD3、CD45RO、CD43、CD30均(+),CD15、EMA和ALK1(-),3例EBER均(+).结论 传染性单核细胞增生症淋巴结病的副皮质区有较多免疫母细胞增生,易过诊,但其临床特征、病理特点和免疫表型与大细胞淋巴瘤不同;结合EBV检测有助于其诊断.     

Psychological aspects of dialysis: a semantic differential study.

As a consequence of technological advances over the last 15 years, patients suffering from terminal renal failure are now being kept alive for considerable periods of time, either by renal haemodialysis or, where appropriate and possible, by renal transplantation. The former necessarily imposes restrictions on the patients' lives which may be manifest at various levels. The basic aim of the study to be reported was to conduct an exploratory investigation of the psychological impact of dialysis on such patients, together with some of the factors that may influence their reactions to it. Using a Semantic Differential technique, 21 patients on dialysis were compared with a group of 21 healthy control subjects in terms of the personal meaning of selected concepts. Both groups were then subdivided on the basis of age, sex and, in the case of the patients, in terms of length of time on dialysis. Subgroup comparisons were then conducted. The findings suggest various hypotheses which have both theoretical and clinical implications.