Haploinsufficiency of NSD1 causes Sotos syndrome.

We isolated NSD1 from the 5q35 breakpoint in an individual with Sotos syndrome harboring a chromosomal translocation. We identified 1 nonsense, 3 frameshift and 20 submicroscopic deletion mutations of NSD1 among 42 individuals with sporadic cases of Sotos syndrome. The results indicate that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.

[Pediatric pneumonia, pleural effusion, and pericarditis following cat scratch disease and serological cross-reactions among Bartonella henselae and Rickettsia japonica determined by indirect fluorescence antibodies].

Cat scratch disease is associated with a variety of systemic manifestations. We report a pediatric case associated with pneumonia, pleural effusion, and pericarditis. A 3-year-old boy developed prolonged fever unresponsive to antibiotic treatment, including azithromycin and minocycline. Although the fever resolved with corticosteroid treatment, Bartonella henselae IgG titer was positive in indirect fluorescence antibodies, as was Rickettsia japonica IgG titer. Both titers were significantly reduced by serum absorption with B. henselae antigens, and we observed a serological cross-reaction between B. henselae and R. japonica.

Screening for partial deletions in the CREBBP gene in Rubinstein-Taybi syndrome patients using multiplex PCR/liquid chromatography.

Rubinstein-Taybi syndrome (RTS, MIM 180849) is a multiple malformation syndrome characterized by growth retardation, developmental delay, and dysmorphic features, including down-slanting palpebral fissures, a beaked nose, broad thumbs, and halluces. Mutations in the gene encoding the CREB-binding protein gene (CREBBP, also known as CBP) on chromosome 16p13.3 were identified in 1995. Recently, we developed a mutation analysis protocol using denaturing high-performance liquid chromatography (DHPLC) and identified heterozygous CREBBP mutations in 12 of 21 RTS patients. To test whether exonic deletions represent a common pathogenic mechanism, we assessed the copy number of all the coding exons using a recently developed method, the multiplex PCR/liquid chromatography assay (MP/LC). By using MP/LC, we performed screening for CREBBP exonic deletions among 25 RTS patients in whom no point mutations or small insertions/deletions were identified by DHPLC screening. We identified four classic RTS patients with deletions encompassing multiple exons (14-16, 5-31, 1-16, and 4-26). We conclude that large deletions including several exons are a relatively frequent cause of RTS, and that MP/LC is an effective method for detecting these deletions.

A case of cat scratch disease neuroretinitis confirmed by polymerase chain reaction.

BACKGROUND: Cat scratch disease neuroretinitis is caused by infection by Bartonella henselae. To demonstrate B. henselae infection, serologic examination is commonly used, but sometimes serologic examination is not adequate for correct diagnosis. Here we present a case of cat scratch disease neuroretinitis confirmed by polymerase chain reaction in addition to serologic examination. CASE: A 55-year-old woman, presenting with headache and high fever, had noticed visual disturbance. The best-corrected visual acuity in her right eye was 0.01. Meningitis, optic neuritis and retinitis were observed and she was treated with oral prednisolone. After repeated questioning, the patient remembered being scratched by a cat. Systemic examination focusing on B. henselae infection was conducted and B. henselae-specific immunoglobulin (Ig) G, but not IgM, was detected in both serum and cerebrospinal fluid. To confirm B. henselae infection, polymerase chain reaction (PCR) analysis using cerebrospinal fluid was performed and the presence of B. henselae-specific DNA was demonstrated. From these results, we diagnosed cat scratch disease neuroretinitis and treated the patient with minocycline hydrochloride together with prednisolone. Following this treatment regimen, the patient's condition improved, and the best-corrected visual acuity in her right eye increased to 0.6 five months after the onset. CONCLUSION: The PCR technique is useful to correctly diagnose cat scratch disease neuroretinitis, if patients exhibit marginal data on B. henselae-specific antibody titer.

[Evaluation of isolation media for the detection of Bartonella henselae--isolation of Bartonella henselae from domestic cats].

Bartonella henselae is a causative agent of cat scratch disease. We preliminarily tested four media for the bacterial growth, including agar plates with sheep, horse or rabbit blood, and chocolate agar. Of these media, rabbit blood and chocolate agar plate were found to be more excellent for the growth than the medium with sheep or horse blood. Blood samples from 60 domestic cats in Yamaguchi Prefecture were then cultured using 7% rabbit blood agar plates and BACTEC9050 (BD), automated blood culture microbial detection system. B. henselae was isolated from six of the 60 (10%) blood samples. Tiny colonies of B. henselae were visible on the agar medium after one week of culture at 35 degrees C in the 5% CO2 atmosphere. BACTEC 9050 detected B. henselae in one of the 10 blood samples and it took two weeks to detect the bacteria automatically, though gram stain failed to show organisms in the blood culture bottle. In conclusion, rabbit blood or chocolate agar and incubation of agar media more than one week and of BACTEC more than two weeks are recommended for the detection of B. henselae.

[A case of cat scratch disease with encephalopathy].

We report an atypical case of cat scratch disease (CSD), accompanied with encephalopathy that is a rare complication of CSD. A 17-year old man consulted a doctor for his right axillary lymphadenopathy. The history of his contact with cats and the sign of lymphnode swelling and fever suggested a suspect of cat scratch disease. Administration of ampicillin improved his clinical symptoms, but a few days later he suddenly fell into coma after an episode of convulsion. The CT scan of the brain and laboratory tests showed no significant findings except the slightly elevated cell counts and concentration of protein in his cerebrospinal fluid. He was referred to our hospital on the next day for further examinations and treatments for his coma of unknown cause. The physical examination on admission revealed slight neck stiffening and hypertonicity of his right lower limb, but radiological and laboratory tests showed no significant findings. He gradually recovered from his coma without apparent sequelae in three weeks. Indirect fluorescence antibody titers for CSD in his serum showed a significant elevation to 1:160 of IgM and 1:512 of IgG, and his clinical features were compatible to these of CSD with complications of the central nervous system.

Molecular typing of Bartonella henselae DNA extracted from human clinical specimens and cat isolates in Japan.

Bartonella henselae is the causative agent of cat scratch disease (CSD). To clarify the population structure and relationship between human and cat strains of B. henselae, 55 specimens isolated in Japan, including 24 B. henselae DNA-positive clinical samples from CSD patients and 31 B. henselae isolates from domestic cats, were characterized by multilocus sequence typing (MLST) and the 16S-23S tRNA-Ala/tRNA-Ile intergenic spacer (S1) sequence, which were used previously for strain typing of B. henselae. Three different sequence types (STs) were identified by MLST, one of which was novel. Fifty-two strains (94.5%), including all strains detected in CSD patients, were assigned to ST-1. Eight S1 genotypes were observed, three of which were novel. The 52 ST-1 strains were classified into seven S1 genotypes, two of which were predominant in both human and cat strains. In addition, 5.5% of the strains (3/55) contained two different intergenic spacer S1 copies. These results indicate that the predominant B. henselae MLST ST-1 in Japan is a significantly genetically diverse population on the basis of the sequence diversity of intergenic spacer S1, and that highly prevalent S1 genotypes among cats are often involved in human infections.

Analysis of data in 30 patients with cat scratch disease without lymphadenopathy.

The prominent clinical manifestation of cat scratch disease is regional lymphadenopathy at the site of the cat scratch or bite, associated with fever or general symptoms. A serological study of 540 patients with either lymphadenopathy, persistent fever, or pet ownership disclosed that 30 (16.1%) of the 186 patients with a serological diagnosis of cat scratch disease had no regional lymphadenopathy, and in these 30 patients, the absence of lymphadenopathy was closely related to the presence of persistent fever, fever of unknown origin, or systemic complications. Physicians should be alert to cat scratch disease that is not associated with lymphadenopathy to enable prompt diagnosis and treatment.

R352Q mutation of the DHCR7 gene is common among Japanese Smith-Lemli-Opitz syndrome patients.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by microcephaly, syndactyly of toes, ambiguous genitalia, and mental retardation. The underlying DHCR7 gene has been identified and a wide variety of distinct mutations were reported in USA and European SLOS patients. A significant difference has been suggested in the frequency of SLOS among different ethnic populations. Here, we report mutational analysis of seven Japanese SLOS patients. Five mutations, R352Q, R242H, G303R, X476Q, and S192F, were identified, and R352Q appeared most frequent, since nine out of the 13 mutations of Japanese origin were the same R352Q. These results suggest that R352Q is a predominant founder mutation in Japanese SLOS patients.

Evaluation of indirect fluorescence antibody assay for detection of Bartonella clarridgeiae and Seroprevalence of B. clarridgeiae among patients with suspected cat scratch disease.

The possibility of Bartonella clarridgeiae being a causative agent of cat scratch disease (CSD) was investigated by using indirect fluorescence antibody assays with 288 suspected CSD patients. Immunoglobulin G antibody to noncocultivated B. clarridgeiae was suitable only for detection of B. clarridgeiae antibody. Significant cross-reactivity between Bartonella henselae and B. clarridgeiae was noted, and no CSD case caused by B. clarridgeiae was detected.

Genetic education in baccalaureate and associate degree nursing programs in Japan.

The purpose of the present study was to ascertain the amount and type of genetic content in basic nursing education programs in Japan baccalaureate degree (BSN) and associate degree (ADN), and to describe the qualifications of faculty members teaching the genetics content. A questionnaire was used to examine these. The sample was derived from 66 basic nursing preparatory programs. Faculty members from 34 out of 75 (44.7%) of the BSN programs and 32 out of 52 (61.5%) of the ADN programs returned completed surveys, providing a total response rate of 52%. As a result of the analysis of the survey data, the researchers recommend increasing the amount of genetic content, related to nursing practice, in the curriculum of Japanese baccalaureate and associate degree nursing programs. In addition, the researchers recommend increasing the number of nursing faculty specialising in genetics. Japanese nursing education must incorporate genetic knowledge into the curricula to produce professionals who are prepared to practise in the current and future genetic health care arena.

Genetic content in Japanese language nursing textbooks.

The purpose of this study was to assess the amount of genetic content included in Japanese language nursing textbooks. A total of 222 Japanese nursing textbooks for registered nurses, public health nurses, and nurse midwives published by five publishers in 2001 were evaluated for genetic content. The textbooks were reviewed for content in fundamental knowledge of genetics, genetic diseases, genetic counseling, and nursing care for patients with genetic problems. Results from the review indicated that although information about genetics was found in more than half of the textbooks, descriptions of the roles of nurses in genetic counseling and nursing interventions related mostly to single gene disorders. These findings suggest that not all Japanese nursing textbooks contain genetic content and that they do not include the latest knowledge concerning common diseases and genetic nursing interventions. Although the study did not review other educational methods, based on these findings, nursing educators in Japan should introduce textbooks with genetic information that will prepare registered nurses, public health nurses, and nurse midwives to remain current in genetic concepts and to apply these concepts to their nursing roles through genetic counseling and patient care.

Clinical implication of prolonged fever in children with cat scratch disease.

Cat scratch disease, caused by Bartonella henselae, typically presents with a localized lymphadenopathy with a brief period of fever and general symptoms. However, there are atypical cases with a wide spectrum of clinical manifestations including prolonged fever (> or =37.5 degrees C, for more than 7 days), or with systemic complication, or without lymphadenopathy. We analyzed relationships among those manifestations in children with cat scratch disease. A total of 127 patients were serologically diagnosed as having Bartonella infection between 1997 and 2003. Relationships among clinical manifestations were analyzed by use of multiple regression and multiple logistic regression analyses. Of the 127 seropositive cases, 75 (59.1%) had typical cat scratch disease and 52 (40.9%) had an atypical one. As atypical manifestations, 46 (36.2%) had prolonged fever, 23 (18.1%) had no lymphadenopathy, and 21 (16.5%) had complications: hepatic/splenic abscesses or low-echoic lesions, hepatic granuloma, and central nervous system involvements. Prolonged fever was observed in 20 (87%) of the 23 cases without lymphadenopathy and 16 (76.2%) of the 21 cases with complications. By multiple regression analysis, the duration of fever was significantly associated with both the absence of lymphadenopathy and the presence of complications. The child suffering from cat scratch disease without lymphadenopathy or with complication tends to have prolonged fever. Conversely, when a child has a prolonged fever of unknown origin, possibility of cat scratch disease should be considered, and a search for underlying systemic complications is recommended for prompt diagnosis and appropriate treatment.

Cat scratch disease: analysis of 130 seropositive cases.

To clarify the clinical manifestations of cat scratch disease (CSD), we evaluated a total of 130 seropositive patients with CSD. The patients' ages ranged from 1 to 68 years; 103 (79.2%) were under 18 years of age. CSD occurred predominantly in the fall and winter months. Regional lymphadenopathy was noted in 110 (84.6%) of the cases, and the most common sites were the neck (33%), axillary (27%), and inguinal (18%) regions. One hundred of the patients (77%) had general symptoms, such as fever, headache, and malaise. The clinical manifestations of CSD showed a wide spectrum from typical or classical CSD, with regional lymphadenopathy, to atypical or systemic CSD. Of the 130 cases, 103 (79.2%) were typical CSD and 27 (20.8%) were atypical CSD. Atypical cases of CSD were commonly reported as fever of unknown origin (37.0%), neuroretinitis (22.2%), encephalopathy (14.8%), hepatosplenic granuloma (11.1%), and Parinaud's oculoglandular syndrome (7.4%). Fever of unknown origin or prolonged fever lasting more than 14 days was evident in 27 (20.8%) of the 130 cases in this study. Eleven of the 27 cases lacked lymphadenopathy. Our findings suggest that CSD is not a rare disease in Japan. The indirect fluorescent antibody (IFA) test to detect Bartonella species may provide a prompt diagnosis of CSD and facilitate appropriate therapy.

Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome.

Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically.