EEC syndrome: report on 20 new patients, clinical and genetic considerations

We report on 20 Brazilian patients (11 sporadic and 9 familial cases) with the ectrodactyly, ectodermal dysplasia, clefting syndrome (EEC syndrome). Genetic aspects, clinical manifestations, and differential diagnosis of the syndromes involving ectodermal dysplasia/limb anomalies and cleft lip/palate are discussed.     

Assessing semantic comprehension: Methodological considerations,and a new clinical test

Abstract

Most tests designed to assess semantic comprehension involve confronting the patient with an array of pictures including a target and a set of semanticallyrelated items, and asking him to select the one which matches a spoken word. These tests are defective on several counts. First, they do not give the patient the opportunity to make errors other than semantic errors, so that a patient who makes errors because of auditory perceptual problems, or because of nonlinguistic factors such as reluctance to scan the full array, will appear to have a “semantic” disorder. Second, many of the semantic distractors used in such tests are visually similar to the target (e.g., knife and spoon, sheep and goat), so that errors might arise for perceptual rather than linguistic reasons. The test materials described here have proved useful in distinguishing receptive semantic problems from perceptual deficits.     

Von Recklinghausen neurofibromatosis and genetic linkage studies: clinical considerations.

For genetic linkage purposes, a subject at risk for Von Recklinghausen neurofibromatosis (VRNF) is one who has a first degree relative with independently documented VRNF. The presence of one or more of the designated criteria establishes the phenotypic diagnosis of VRNF in a subject at risk regardless of age. The absence of all of these criteria excludes the phenotypic diagnosis for all at risk subjects over five years of age. The absence of all the criteria in subjects at risk below five years of age or the presence of equivocal or merely suggestive findings neither excludes nor substantiates the phenotypic diagnosis of VRNF; rather, that subject should be removed from the preliminary scoring and analyses of the data.     

Neuronal ceroid lipofuscinosis: an ultrastructural, genetic, and clinical study report

The term "neuronal ceroid lipofuscinosis" (NCL) describes a complex of inherited neurodegenerative conditions associated with storage of lipopigments in brain tissue. In 1989 Dyken proposed a classification of NCL based on the age, clinical symptoms, and ultrastructural aspects of the lipopigments. At the ultrastructural level it is possible to distinguish 5 different patterns of osmiophilic lipopigments: usual lipofuscin, fingerprint deposits, granular profiles, curvilinear bodies, and microtubular aggregates. The concept that each ultrastructural pattern was the counterpart of a specific clinical type has been proved not to be true. Advances in molecular genetic techniques have allowed the identification of defective genes and their protein products in several NCL clinical forms. Ceroid lipofuscin deposits may be ultrastructurally observed not only in neuronal cells, but also in several other sites, such as trophoblastic cells, thus permitting prenatal diagnosis. In spite of recent advances in immunohistochemical identification of biochemical markers, the ultrastructural identification of lipofuscinic pigments remains the gold standard to identify NCL, together with clinical aspects and respective gene defects. This study describes the ultrastructural aspects observed in 8 cases of NCL syndromes (3 juvenile, 3 infantile, 1 late infantile, and 1 congenital clinical form). In these patients, genetic analysis was also performed.     

Wolman disease: morphological, clinical and genetic studies on the first Scandinavian cases

On the Aland Islands, a 1-month-old girl was diagnosed as having Wolman disease. The diagnosis was confirmed neurochemically; a decreased activity of acid lipase was noted in the proband and her parents had typical carrier values. This is the first Scandinavian case reported. The skin biopsy revealed cytoplasmic accumulations identical to those noted in two sibs who highly probably had Wolman disease during the 1950s. Both these sibs died at the age of about 3 months and presented a heavy accumulation of lipid material in lymph nodes, spleen, adrenal glands, liver, gut, and also some pathological alterations in other organs. Electron microscopic findings from deparaffinized samples showed cytoplasmic accumulation of lipid material similar to that noted in Wolman disease. Genealogical analyses revealed that the index families had ancestors from the same restricted area and also common ancestors during the 17th century. The parents of the two affected sibs were born on a small island and were related in many different ways. On the basis of genealogical studies and other genetic investigations performed, the importance of founder and drift effect for manifestations of rare hereditary disorder in isolates is stressed.     

Oculocerebrocutaneous syndrome: report of three additional cases and aetiological considerations

The oculocerebrocutaneous (OCC) syndrome is characterized by the presence of orbital cysts and microphthalmia/anophthalmia, focal hypo-and aplastic skin defects, skin appendages and cerebral malformations. Most of the patients suffer from psychomotor retardation and seizures. To date, 23 patients in total have been reported. We report on three additional cases which illustrate the broad clinical spectrum of this disorder. In one case, the differentiation between OCC syndrome and encephalocraniocutaneous lipomatosis was difficult. A brief review of the clinical features of OCC syndrome is given. Possible aetiological hypotheses are discussed, namely survival of a lethal mutation by mosaicism, an autosomal dominant mutation and external causal factors. Disruption of the anterior neuroectodermal plate seems to be the most probable pathogenic mechanism.     

Fryns syndrome: report on 8 new cases

The name Fryns syndrome was given to a new variable multiple congenital anomaly syndrome, almost always lethal, described in 1978, and now known to be autosomal recessive. Since that date, 20 patients have been reported in the literature. We describe 8 new cases, 6 of which were diagnosed in a series of 112,276 consecutive births (livebirths and perinatal deaths). The prevalence of this syndrome can be estimated to be around 0.7 per 10,000 births. These new cases confirm that the most frequent anomalies are diaphragmatic defects, lung hypoplasia, cleft lip and palate (often bilateral), cardiac defects (septal defects and aortic arch anomalies), renal cysts (type II, III or IV), urinary tract malformations, and distal limb hypoplasia. Most patients also have hypoplastic external genitalia and anomalies of internal genitalia (bifid or hypoplastic uterus, immature testes). The digestive tract is also often abnormal: duodenal atresia, pyloric hyperplasia, malrotation and common mesentery are present in half of the patients. When the brain was examined, more than half were abnormal (Dandy-Walker anomaly and agenesis of corpus callosum). A few patients demonstrated cloudy cornea. We examined the eyes of three patients histologically: two of them showed retinal dysplasia with rosettes and gliosis of the retina, thickness of posterior capsula of lens and irregularities of the Bowman membrane. Four of our cases were diagnosed prenatally between 24 and 27 weeks. It is to be expected that prenatal diagnosis will be made often and earlier in the future, as the spectrum of anomalies of the Fryns syndrome can easily be evidenced by sonography.     

Annular pancreas: A review of its molecular embryology,genetic basis and clinical considerations

The annular pancreas remains an intriguing congenital anomaly. Many theories have sought to explain its embryological basis; however, no consensus has yet been reached regarding the exact mechanism of aberration. More recently, molecular investigations have shed light on some of these theories, confirming the origination of annular tissue from the ventral pancreatic bud. These studies highlight the role of the hedgehog signaling pathway in the development of this anomaly. Overexpression of the ventral-specific gene transmembrane 4 superfamily member 3 (tm4sf3) has also been associated with annular formation. Moreover, isolated case reports of familial annular pancreas have also been documented, suggesting a genetic basis for the development of this anomaly. Annular pancreas can initially present in childhood or adulthood with symptoms of duodenal obstruction and is diagnosed using a variety of imaging modalities. Treatment usually involves surgical correction, with bypass procedures (e.g. duodenoduodenostomy, gastrojejunostomy or duodenojejunostomy) currently favored over annular resection due to complications associated with the latter approach.     

猝死37例死因分析

目的 分析不明原因死亡患者的疾病分布及尸检病理学特点。方法 收集不明原因死亡尸体107例，解剖结果显示37例为猝死，占35％，对其进行组织病理学检查。结果 37例猝死的疾病分布以心血管最常见，共16例，占43．2％，其次为呼吸系统、神经系统、消化系统疾病。结论 通过尸体解剖和病理学检查，为解决医疗纠纷和明确猝死死因提供科学的鉴定依据，对提高医疗质量起到积极的作用。     

Ectopic hamartomatous thymoma: clinicopathologic, immunohistochemical, and histogenetic considerations in four new cases.

Four new cases of ectopic hamartomatous thymoma are presented. The tumor occurred either superficially or deep in the area of the sternoclavicular joint and consisted of solid islands of squamous epithelium which blended with spindled cells. Cysts lined by squamous epithelium, small glands, and fat also occurred in variable amounts. Both the spindled and epithelial regions of the tumor expressed keratin and muscle actin, but neither desmin nor S100 protein. The tumor probably originates from thymic anlage associated with the third pharyngeal pouch (thymus III), although origin from other structures such as thymus IV and the cervical sinus of His are discussed. Our experience indicates that the large size and extreme cellularity of the spindled portion of some tumors may result in the mistaken diagnosis of sarcoma.     

Monosomy 6q: report on four new cases

We report on four patients with partial monosomy of the long arm of chromosome 6: two children presenting with an interstitial deletion del(6)(q14q16), the two others presenting with a terminal deletion del(6)(q25qter). These patients are compared with previous reports in the literature: 16 cases of terminal deletion and 17 cases of interstitial deletion. The deletions most often occur de novo. Mental retardation is always described. Dysmorphic facial features range between minor and major. There may be associated visceral abnormalities. After comparing the size and the localisation of the deletions with clinical data, we are now able to suggest a clinical localisation on chromosome 6.     

The clinical spectrum of the Fraser syndrome: report of three new cases and review.

Three new cases of the Fraser syndrome are presented and 68 published cases are reviewed. A quantitative estimate of the frequency of clinical manifestations is given. Craniofacial abnormalities were reported in all patients, cryptophthalmos in 93%, and syndactyly in 54%. Abnormalities of the ears, nose, genitalia, and urinary system were reported in 44%, 37%, 49%, and 37% of cases respectively. This variability should be taken into account when attempting prenatal diagnosis; a combination of ultrasound and fetoscopy should provide the best approach. Of the reported cases 26% were stillborn and 19% died in the first year of life. Renal and pulmonary malformations were associated with early death.     

Tibial tubercle transfer on a medial periosteal pedicle--a report of a new technique

Tibial tubercle transfer is still probably the most widely used procedure of the numerous operative procedures described to realign the patella and extensor mechanism and to prevent a recurrent dislocation. Although this procedure most likely disturbs the blood supply to the tibial tubercle and thus may lead to a delayed union. Tibial tubercle transfer is also considered to play a role in the incidence of a tibial tubercle delayed union. Furthermore, a fracture of the tibial metaphysis has been reported to occur in some cases. We therefore devised a new procedure in which the periosteum of the medial side of the proximal portion of the tibia was left intact when tibial tubercle transfer is performed. The current paper describes the results of new technique in 25 knees with patellar maltracking. Eighty-four percent of the patients had good or excellent results at a mean follow-up time of 49 months. All of the patients achieved complete healing radiographically within 2 months after the operation. Serious complications such as compartment syndrome, infection and skin slough were also completely avoided in all cases. This new procedure that the use of a protective maneuver for the periosteum of the medial side of the tibia may thus reduce the incidence of a delayed union and thereby promote early postoperative rehabilitation after tibial tubercle transfer.     

第四脑室肿瘤显微外科治疗37例临床分析

目的 探讨第四脑室肿瘤行显微外科治疗的手术技巧及临床效果。方法 回顾性分析2010年9月—2015年11月郑州大学附属肿瘤医院神经外科收治的37例第四脑室肿瘤患者的临床资料。37例患者中,男22例、女15例,年龄3～72(29.64±5.27)岁。肿瘤位于第四脑室外侧区8例,位于第四脑室底近中线下半部分24例,第四脑室顶部和侧壁5例。患者均行显微外科手术治疗。术后观察患者恢复情况及并发症发生情况,术后3、6个月采用卡氏功能状态标准(KPS)评估患者的恢复情况。结果 37例患者均顺利完成手术,肿瘤全切除34例(91.89%),次全切除3例(8.11%)。术后患者头晕、呕吐等临床症状均得到明显改善。术后并发颅内感染4例,呛咳1例,颅内积气1例,皮下积液1例,均经相应处理后治愈。37例患者均获随访6~20个月。随访期间,31例生活正常,6例原位复发,后者中2例死亡。术后3、6个月KPS评分60、70、80、90、100分的患者分别有4、17、11、5、0例和1、7、20、7、2例,3、6个月功能状态正常率分别为43.24%(16/37)和78.38(29/37)。结论 选择适宜的手术入路、运用良好的手术技巧、正确处理并发症,可增强第四脑室肿瘤显微手术治疗的效果,有利于患者的术后恢复。     

Paragangliomas: Update on differential diagnostic considerations,composite tumors,and recent genetic developments

Recent developments in molecular genetics have expanded the spectrum of disorders associated with pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGLs) and have increased the roles of pathologists in helping to guide patient care. At least 30% of these tumors are now known to be hereditary, and germline mutations of at least 10 genes are known to cause the tumors to develop. Genotype–phenotype correlations have been identified, including differences in tumor distribution, catecholamine production, and risk of metastasis, and types of tumors not previously associated with PCC/PGL are now considered in the spectrum of hereditary disease. Important new findings are that mutations of succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 (collectively “SDHx”) are responsible for a large percentage of hereditary PCC/PGL and that SDHB mutations are strongly correlated with extra-adrenal tumor location, metastasis, and poor prognosis. Further, gastrointestinal stromal tumors and renal tumors are now associated with SDHx mutations. A PCC or PGL caused by any of the hereditary susceptibility genes can present as a solitary, apparently sporadic, tumor, and substantial numbers of patients presenting with apparently sporadic tumors harbor occult germline mutations of susceptibility genes. Current roles of pathologists are differential diagnosis of primary tumors and metastases, identification of clues to occult hereditary disease, and triaging of patients for optimal genetic testing by immunohistochemical staining of tumor tissue for the loss of SDHB and SDHA protein. Diagnostic pitfalls are posed by morphological variants of PCC/PGL, unusual anatomic sites of occurrence, and coexisting neuroendocrine tumors of other types in some hereditary syndromes. These pitfalls can be avoided by judicious use of appropriate immunohistochemical stains. Aside from loss of staining for SDHB, criteria for predicting risk of metastasis are still controversial, and “malignancy” is diagnosed only after metastases have occurred. All PCCs/PGLs are considered to pose some risk of metastasis, and long-term follow-up is advised.     

Ethical and clinical practice considerations for genetic counselors related to direct-to-consumer marketing of genetic tests

Several companies utilize direct-to-consumer (DTC) advertising for genetic tests and some, but not all, bypass clinician involvement by offering DTC purchase of the tests. This article examines how DTC marketing strategies may affect genetic counselors, using available cardiovascular disease susceptibility tests as an illustration. The interpretation of these tests is complex and includes consideration of clinical validity and utility, and the further complications of gene-environment interactions and pleiotropy. Although it is unclear to what extent genetic counselors will encounter clients who have been exposed to DTC marketing strategies, these strategies may influence genetic counseling interactions if they produce directed interest in specific tests and unrealistic expectations for the tests' capacity to predict disease. Often, a client's concern about risk for cardiovascular diseases is best addressed by established clinical tests and a family history assessment. Ethical dilemmas may arise for genetic counselors who consider whether to accept clients who request test interpretation or to order DTC-advertised tests that require a clinician's authorization. Genetic counselors' obligations to care for clients extend to interpreting DTC tests, although this obligation may be fulfilled by referral or consultation with specialists. Genetic counselors do not have an obligation to order DTC-advertised tests that have minimal clinical validity and utility at a client's request. This can be a justified restriction on autonomy based on consideration of risks to the client, the costs, and the implications for society.     

Brief clinical report: A genetic association between microcephaly and lymphedema

We discuss a family in which microcephaly and lymphedema are co-segregating as an apparently autosomal or X-linked dominant trait. A review of each malformation is presented with reference to the known genetic patterns of each. This combination of microcephaly and lymphedema may be a unique syndrome, previously undescribed because of subtleties of expression in affected individuals.