Unrecognized Cases Research Articles

Tau acts as an independent genetic risk factor in pathologically proven PD

MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.

A Case of Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS) is characterized by fever, skin rash, hematological abnormalities, and systemic involvement such as hepatitis. DRESS usually presents 2–6 weeks after drug initiation. DRESS should be suspected on clinical grounds in the setting of the introduction of new drug therapy and is most commonly described after the introduction of aromatic anticonvulsants, allopurinol, or antiretroviral therapies. We describe here a case of DRESS due to phenytoin exposure with complete resolution on drug discontinuation. Our patient developed DRESS with a skin rash, lymphadenopathy, and markedly abnormal liver enzymes, 4 weeks after drug initiation following drainage of a brain abscess. He was initially diagnosed as having a recurrence of the abscess or sepsis of another origin. It is important to recognise the possibility of DRESS in this setting, as a good outcome depends on the immediate withdrawal of the offending drug. A mortality rate of up to 10% has been described in unrecognised cases.

Challenges in the diagnosis and management of Lynch Syndrome in an Indigenous family living in a remote West Australian community

Lynch syndrome (LS), also referred to as hereditary non-polyposis colorectal cancer, is a familial cancer syndrome characterised by young age of onset of colorectal and other extra-colonic cancers. Most studies suggest that LS accounts for approximately 1% of all colorectal cancers (CRC). The identification of persons with a mutation for this syndrome is of major clinical importance because regular and life-long surveillance has been shown to improve their survival through early cancer detection. However, the identification of LS among CRC patients is a major challenge because there are no specific distinguishing clinical features. Clinical criteria based on family history of cancer and age of cancer diagnosis have been proposed. For various reasons, these are not well utilised and clinicians often fail to refer high-risk CRC patients for genetic assessment of LS. The low rate of referrals to the single, state-wide familial cancer program in Western Australia led to calls for a more sensitive and specific means of detecting LS cases. Virtually all tumours from LS patients are characterised by the molecular features of microsatellite instability (MSI) and loss of expression of mismatch repair proteins detected by immunohistochemistry (IHC). It was recently established that routine MSI and IHC testing in CRC patients aged under 60 years was an effective screening tool to identify previously unrecognized LS cases. This approach has now become routine practice in Western Australia and has led to the identification of more than 20 new LS families, including the Indigenous family described in this report. Population-based screening programs can identify individuals who may not be aware of their at-risk status, who may have little prior knowledge of their medical condition and who may have limited access to tertiary health services. This report describes some challenges met when following up a positive screening result for LS in an individual residing in a remote community more than 2000 km from the state's only Family Cancer Clinic. The challenges included finding the patient, arranging genetic counselling and testing, informing him of the result and providing advice regarding life-long surveillance. Also discussed are issues relating to management of the extended kindred in terms of cultural sensitivities, intra-familial communication and involvement of the local health providers, as well as the provision of genetic counselling, testing and surveillance services for patients living in remote regions. Prior to this study, there were no known Indigenous families with LS in Australia. The likelihood of finding hereditary cancer syndromes in Indigenous families living in remote communities is low. However, advances in modern diagnostic screening technologies will result in the identification of an increased number of at-risk individuals, some of whom will be from minority groups or from remote communities. Despite geographical isolation and cultural differences, hereditary cancer syndromes can be managed in individuals and families living in rural and remote areas. The key issues identified from this case are flexibility with standard clinical genetic protocols and the presence of a local medical practitioner who takes an active interest in delivery of the genetic testing and surveillance strategies.

Asymptomatic Paget’s bone disease in ethnic Thais: a series of four case reports and a review of the literature

Paget's bone disease is quite common in some parts of Europe and countries inhabited by European emigrants, but it is rare in Asia. There have been only 13 reported cases in Southeast Asia, including one reported case from Thailand. Half of the previously reported cases had bone symptoms and the other half were asymptomatic, but were incidentally discovered when patients were being investigated for other medical problems. Here are reported cases of four asymptomatic patients who presented elevation of serum alkaline phosphatase during routine annual medical checkups. All patients were of Chinese descent and all cases were proven by biopsy. Based on this experience, we are of the opinion that a substantial number of unrecognized cases of Paget's disease exist among ethnic Thais. We feel that they would be revealed if clinicians were alerted of its presence and if they included it as a possible diagnosis together with metastasis and osteoporosis when examining bone lesions or when results for elevated serum alkaline phosphatase are detected during routine checkups. We also anticipate that a higher prevalence of this disease may occur in future Thai generations due to the addition of offspring from Asian-European intermarriages to offspring of Chinese descent in the ethnic Thai population.

Respiratory Illness in Households of School-Dismissed Students during Pandemic (H1N1) 2009

Respiratory Illness in Households of School-Dismissed Students during Pandemic (H1N1) 2009

“Glandular intoxication” following emergent tracheotomy during transsphenoidal surgery for acromegaly: Cushing’s 1910 unrecognized case of thyroid storm?

Harvey Cushing's monograph The Pituitary Body and Its Disorders describes Case XXXVIII, H. M. B., a 33 year-old man who presented with acromegaly in 1910. The detailed operative note reports an emergency tracheotomy performed following induction of anesthesia, and immediately prior to a naso-labial approach to a suspected sellar lesion. Cushing's post-operative notes document a significant increase in temperature prior to the patient's death. Cushing offered an explanation for the patient's symptoms immediately pre-mortem, which is largely unsatisfying. Following institutional review board approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical records from the Johns Hopkins Hospital, 1896-1912, were reviewed. A review of the original surgical file revealed a more extensive description of the emergent tracheotomy required following induction of anesthesia, and provided additional information regarding the patient's symptoms in the immediate pre-mortem period. Namely, the urgent tracheotomy transected the thyroid gland, and post-operatively the patient experienced significant tachycardia and hyperthermia, consistent with thyroid storm. The new information regarding the hospital course of H. M. B. offers insight into the previously incompletely described circumstances surrounding his emergent tracheotomy, and subsequent death. Additionally, the case underscores the clinical importance of recognizing and appropriately treating thyroid storm.

Giant Cell Arteritis: Clinical Features of Patients Visiting a Headache Clinic in Japan

The first symptom of giant cell arteritis (GCA) is usually a headache. Japan has a low prevalence of GCA, and clinical features of this disorder have not been fully investigated. We conducted a retrospective evaluation of clinical features in patients with giant cell arteritis who visited a headache clinic in Japan. Clinical and demographic data were obtained from clinical examinations, face-to-face interviews, and hospital records. Subjects comprised 19 patients (9 men, 10 women). Mean age at disease onset was 78.1 ± 4.8 years (range, 71-86 years). Seventeen of 19 patients (89.5%) had consulted other medical institutions before consulting our hospital, but only 2 of those patients had been diagnosed with GCA at these medical institutions. Manifestations at disease onset included headache (89.5%), ear pain (5.3%), and jaw pain (5.3%). Ocular manifestations were reported in 2 patients (10.5%). No loss of vision occurred. One patient showed trigeminal nerve palsy involving the third division of the nerve. Jaw claudication was observed in 3 patients (15.8%). Concomitant polymyalgia rheumatica was seen in 3 patients (15.8%). No patient showed upper respiratory tract symptoms, arm claudication, or aortic aneurysms. Although most patients had consulted other medical institutions before consulting our hospital, they were not diagnosed with GCA at these institutions. Infrequent clinical findings of GCA and lack of symptoms other than headache may contribute to the high rate of unrecognized and misdiagnosed cases of GCA.

Hypopituitarism in the tropics

Hypopituitarism in the tropics

Cytogenetic Predictors of Response to Lenalidomide In Myeloid Malignancies without Del(5q)

AbstractAbstract 4016Lenalidomide (LEN) is effective in patients with myelodysplastic syndromes (MDS) and the del(5q) cytogenetic abnormality, and has activity in a proportion of patients without this chromosomal defect. To date, no clinically actionable biomarkers, other than the presence of del(5q) detected by metaphase cytogenetics, have been identified to predict response to LEN. The diagnostic yield of metaphase cytogenetics can be enhanced by application of fluorescence in situ hybridization (FISH) for targeted chromosomal lesions including del(5q), as this technique is more sensitive. Similarly, single nucleotide polymorphism array (SNP-A)-based karyotyping, due to its superb resolution, allows for detection of previously cryptic unbalanced chromosomal defects. Both techniques can be preformed on interphase cells and thereby do not require cell division. We hypothesized that application of these technologies may allow for better identification of putative responders to LEN in patients with MDS without del(5q); we stipulated that i) we may detect previously unrecognized cases of del(5q) and that ii) more precise analysis of the karyotypes may allow for recognition of other chromosomal markers of response or refractoriness to LEN. In patients with MDS (N=82), MDS/myeloproliferative neoplasm (MPN) (N=13), acute myeloid leukemia (AML) (N=23), and MPN (N=4), the detection rate of del(5q) increased only marginally with use of additional techniques, from 24% (metaphase cytogenetics (MC) + FISH), to 25% (MC + SNP-A), 25% (FISH + SNP-A) and 26% (all 3 methods). Within this cohort, we then analyzed by FISH and SNP-A karyotype a subset of 42 patients with myeloid malignancies without del(5q) by MC who received LEN. This cohort included 33 MDS (RA, N=5; RARS, N=12; RARS-T, N=1; RCMD, N=1; RAEB1, N=4; RAEB2, N=6; MDS-U, N=4), 6 MDS/MPN and MPN patients (CMML1, N=1; CMML2, N=3, IMF; N=2) and 3 secondary AML. By MC, 32 (76%) showed normal karyotype, 1 (2.4%) no growth and 9 (21%) abnormal karyotype other than del(5q). The overall response rate (ORR) (2006 International Working Group criteria) was 44%, including 3 CR, 3 PR and 8 HI. Previously cryptic del(5q) was detected in an additional 1/18 patient by both SNP-A and FISH (secondary AML with normal metaphase cytogenetics), but this case was refractory to LEN. Del(5q) was also revealed by FISH in 1 patient with unsuccessful MC, but, due to the small size of the clone (8%), SNP-A did not detect this lesion. This patient had a sustained PR with transfusion independence. In 28 patients who received LEN for more than 3 months, the ORR to LEN in patients with normal metaphase cytogenetics was 62%, and 17% for those with chromosomal aberrations (p=.08); the addition of SNP-A did not improve the predictive value of normal cytogenetics. We also analyzed 10 patients without del(5q) by MC who received combination therapy with azacitidine (AZA) and LEN, for whom the ORR was 80% (7 CR, 1 PR). By metaphase cytogenetics, 7/10 patients had a normal karyogram and a response of 86%, compared to 3 patients with chromosomal lesions, 1 of whom responded. Similar to the results in LEN alone, inclusion of defects detected by SNP-A or FISH did not allow for better separation of responders based on normal cytogenetics by MC. Six out of 38 LEN-treated patients had a gain of chromosome 8 material by FISH or SNP-A. 4 out of 6 patients had CR (all of them received combination therapy of AZA and LEN), 1 out of 6 had HI, and 1 with complex karyotype had NR (ORR was 83%), while ORR in patients with other chromosomal abnormalities by FISH or SNP-A was 18%. In conclusion, FISH and SNP-A, when added to routine metaphase cytogenetics, marginally increased the diagnostic yield leading to detection of only 2/42 additional cases with del(5q). In our cohort, the non-del(5q) patients with normal karyotype and those with trisomy 8 or microduplication on chromosome 8 were associated with a favorable response to LEN. Disclosures:Sekeres:Celgene: Consultancy, Honoraria, Research Funding. List:Celgene: Research Funding. Maciejewski:Celgene: Research Funding.

Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children

Background Primary mediastinal large B-cell lymphoma is a rare lymphoma accounting for no more than 3% of all B-cell lymphomas in children and adolescents. However, patients in this young age group with this lymphoma have the shortest event-free survival of patients with any B-cell lymphoma under current standard chemotherapy protocols. Lymphomas with features intermediate between primary mediastinal large B-cell lymphoma and classical Hodgkin's lymphoma (mediastinal gray zone lymphomas) have been acknowledged in the latest World Health Organization classification. Recent studies suggest that mediastinal gray zone lymphomas have an aggressive clinical course whereas patients, at least adult ones, with primary mediastinal large B-cell lymphoma might respond very well to chemotherapy in combination with anti-CD20 antibody. We aimed to evaluate whether biological differences or so far unrecognized admixed mediastinal gray zone lymphomas might explain the relatively poor outcome of pediatric patients with apparent primary mediastinal large B-cell lymphoma. We, therefore, performed a retrospective histopathological, immunohistochemical and interphase cytogenetic analysis of 52 pediatric lymphomas. The childhood primary mediastinal large B-cell lymphomas (n=44) showed a similar pattern of histology, immunophenotype and gains at 9p (59%) and 2p (41%) as adult cases, as determined from published data. We identified only four so far unrecognized cases of mediastinal gray zone lymphoma among 52 lymphomas registered in previous trials. Conclusions Mediastinal gray zone lymphoma is very rare in children and adolescents. It does, therefore, seem unlikely that these lymphomas account for the unsatisfactory clinical results with current therapy protocols in pediatric patients. These data have major implications for the design of future treatment protocols for mediastinal lymphomas in children and adolescents.

A 2009 Varicella Outbreak in a Connecticut Residential Facility for Adults with Intellectual Disability

We investigated a varicella outbreak in a residential facility for adults with intellectual disabilities. A case of varicella was defined as a generalized maculopapular rash that developed in a facility resident or employee. Immunoglobulin M testing was conducted on serologic samples, and polymerase chain reaction testing was performed on environmental and skin lesion samples. Eleven cases were identified among 70 residents and 2 among ∼145 staff. An unrecognized case of herpes zoster was the likely source. Case patients first entered any residential facility at a younger age than non-case residents (9.5 vs 15.0 years; P < .01). Varicella zoster virus DNA was detected 2 months after the outbreak in environmental samples obtained from case patients' residences. This outbreak exemplifies the potential for at-risk pockets of varicella-susceptible adults, especially among those who have lived in residential facilities from a young age. Evidence of immunity should be verified for all adults and healthcare staff in similar residential settings.

The Cost of Detecting Lynch Syndrome by Microsatellite Instability Testing in Community Practice

Purpose: Background: Microsatellite instability (MSI) DNA analysis identifies increased length variations of repetitive sequences in the genome that suggest failure of mismatch repair genes and help identify patients with Lynch syndrome. Aim: To calculate the cost to diagnose one case of Lynch syndrome using automatic MSI testing on colonic adenocarcinomas that fulfill one of the first three revised Bethesda criteria. Methods: From April 2007 through July 2009, MSI testing was performed on patients undergoing colon cancer resection who met the first 3 Bethesda Criteria. 898 colorectal adenocarcinomas were diagnosed and 98 (11%) patients met 1 of the first 3 Bethesda criteria and underwent MSI testing. Costs were calculated by determining the total cost of screening strategy using the real costs of procedures and interventions divided by the number of new cases of Lynch syndrome identified. Results: The median age of the study population was 47.1 years, there were 49 males and 49 females; 83% Caucasian. 67 MSI DNA tests were done on individuals < 50 years of age, 16 had synchronous or metachronous tumors and 43 were less than 60 years of age with high-risk histology. Of the 98 colorectal adenocarcinomas analyzed with MSI testing, 22 had a high level of microsatellite instability (MSI-H) defined as 2 or more of the 5 microsatellite loci being unstable. Of the 22 with MSI-H testing, 15 met with a genetic counselor, 3 were not referred, and 4 refused for personal reasons. Immunohistochemistry was performed on 7 of the MSI-H patient samples. There was a loss of expression of MLH1 and PMS2 in 5 patients, MSH2 and MSH6 in 1 patient, and PMS2 alone in 1 patient. 14 of the MSI-H patients underwent germline genetic testing. Ten of the 14 genetic tests were positive for a mutation: 5 patients with MLH1 mutations, 4 with MSH2 mutations, and 1 with a PMS2 mutation. Twelve of the 22 MSI-H patients evaluated met the Amsterdam criteria which included the 10 patients with confirmed germline genetic mutations, one individual refused to meet with a genetic counselor for personal reasons, and one refused genetic testing for financial reasons. The average cost per case detected was $8492. Conclusion: 1. Selective MSI testing can detect previously unrecognized cases of Lynch syndrome. 2. Although all detected cases met the Amsterdam criteria, many patients became aware of their family history only when MSI testing prompted a careful assessment of family history by the genetic counselor. 3. Downstream reductions in cost and premature mortality in relatives of index cases may justify the cost 4. Measures to enhance adherence with genetic counseling and genetic testing are necessary.

Eosinophilic Cholangiopathy (EOC): An Extremely Rare Mimicker of Cholangiocarcinoma

Purpose: EOC is one of the least recognized entities in the growing concept of eosinophilic gastrointestinal disorders and only case reports have been so far published. Its diagnosis remains difficult as it shares many clinical and radiological aspects of primary sclerosing cholangitis and biliary tract cancer. This report illustrates the first case seen in Michigan that we know about. Patient: A 65 year-old male presented with epigastric discomfort, vomiting, a 10-lb weight loss, and right upper quadrant pain radiating to the back. He was icteric and had tenderness in the upper abdomen with a negative Murphy's. The total bilirubin was 10.5, Alk Phos 376, ALT 314, with normal amylase and lipase. WBC count was normal with eosinophilia of 26.50%. CT scan of the abdomen and MRCP revealed intrahepatic biliary ductal dilation and concentric thickening of the proximal aspect of the CBD. ERCP revealed dilatation of the intrahepatic ducts. The CBD was narrow with no choledocholithiasis. CBD brushings were negative for malignant cells. Other tests included a CEA of 5.2, while alpha-fetoprotein, CA 19-9, and serum IgG4 were normal. With the presumptive diagnosis of cholangiocarcinoma, the patient underwent a CBD resection with cholecystectomy, right hepatectomy, and Roux-en-Y hepaticojejunostomy with retroperitoneal lymph node dissection. Histology demonstrated severe cholangitis and cholecystitis, with an extensive inflammatory infiltrate composed almost entirely of eosinophilis forming scattered abscesses in the gallbladder, cystic duct, right hepatic duct, common hepatic duct, and common bile duct. The patient is maintained on prednisone and has remained asymptomatic and with normal LFTs for over four months. Recent EGD and colonoscopy with biopsies were normal. Discussion: EOC is a form of secondary sclerosing cholangitis where there is diffuse infiltration of the biliary tract with eosinophils. Review of the literature reveals about 30 cases. Many were reported as eosinophilic cholecystitis, with limited case reports of concomitant cholangitis or isolated cholangitis. Eosinophilic cholangitis has also been associated with PSC, hypereosinophilic syndrome, eosinophilic gastritis and urerteritis, IgG4-related cholangitis, and hydatid disease. This condition can exist with or without peripheral eosinophilia. Prednisone has been used effectively, as well as Hydroxyurea and Ursodeoxycholic acid in steroid refractory cases. Surgery has been successful in previously unrecognized cases. Conclusion: EOC remains a difficult diagnosis to make. As our ability to diagnose EOC improves, patients may avert unnecessary surgery and may obtain prompt and effective medical therapy.

Unrevealed In clinical practice, acute form of ischemic heart disease: frequency, Laws, impact on Epidemiology

To analyse the frequency of unrecognized and/or unregistered fatal and nonfatal cases of acute coronary heart disease (CHD) and to estimate the unrecognized / unregistered cases influence on the acute CHD morbidity and mortality rate. Materials and methods. The unrecognized in medical documents acute CHD cases were actively revealed among 285 736 population according to the Study Design. Results. The portion of unrecognized cases in qualified acute CHD morbidity rate was 20.78% among males and 24.48% - among females, and 89.43% unrecognized cases had fatal outcome. In the issue of unrecognized cases revealing the acute CHD morbidity rate was increased by 26.24% among males and by 32.41% - among females, and the acute CHD mortality rate was increased in 2.13 and 2.28 times accordingly. Conclusion. The study results indicated the low acute CHD detectability in clinical practice and underestimate of acute CHD as cause of death.

Trichophyton Rubrum with the ‘raubitschekii’ Morphotype: The First Report from Turkey

In modern taxonomy, Trichophyton rubrum with the 'raubitschekii' morphotype differs from the common strains of T. rubrum morphologically, physiologically, and clinically, despite genetic homogeneity. In this paper, we report the first autochthonous Turkish cases in a 24-year-old woman and her 26-year-old fiancé with tinea cruris and tinea manuum, respectively. The isolates were proven to be T. rubrum with the 'raubitschekii' morphotype by their morphological and physiological characteristics including the following: (1) granular colony surface, (2) profuse macroconidia and microconidia, (3) strongly positive urease activity after 3days, (4) non-perforating hair, (5) restricted growth and producing no alkaline reaction on bromocresol purple-milk solids-glucose agar, and (6) restricted growth and producing no conidia on 3-9% NaCl-supplemented Sabouraud agar. The internal transcribed spacer (ITS) regions of both isolates were sequenced, and the assembled DNA sequences were examined using the Basic BLAST (nucleotide-nucleotide) software of the National Center for Biotechnology Information web database. Actually, the lack of epidemiological data on this variety is notable, and the actual prevalence is unknown. Otherwise, routine methods misidentified the strains as T. rubrum or unrecognized cases were underreported.

Commentary

Commentary

Pediatric brain tumors: a histologic and genetic update on commonly encountered entities

As our understanding of pediatric brain neoplasia flourishes, so does the development of diagnostic, prognostic, and predictive biomarkers. The neuropathologist uniquely stands at the crossroads between pathology and molecular genetics, often overseeing the creation, development, implementation, delivery, and reporting of the newest bioassays. This review serves to highlight the key microscopic and genetic features of the most common pediatric brain tumors. For example, INI-1 immunohistochemistry has assisted in identifying several previously unrecognized cases of rhabdoid cell-poor atypical teratoid rhabdoid tumor (ATRT). The latest discovery involving the tandem duplication and fusion BRAF-KIAA1549 on chromosome 7q34 in pilocytic astrocytoma has drawn attention to the MAPK-ERK pathway and its potential chemotherapeutic manipulation. The newly identified IDH1 mutation, which appears characteristic of "secondary astrocytomas," has yet to be studied in the pediatric population, but some researchers have extolled concomitant BRAF-KIAA1549/IDH1 analysis in the neuropathologic workup of many astrocytomas. Through these and other advances, our understanding of pediatric brain tumors will continue to expand exponentially, and as such will set the stage for truly effectual future treatments.

Bone and joint diseases in children. Skeletal dysplasia in children--unrecognized cases in daily practice

Skeletal dysplasia is a group of diseases caused by aberration of growth, development and differentiation of skeletal tissues including bone and cartilage. Most of the diseases that belong to skeletal dysplasia are monogenic diseases. Diagnosis of skeletal dysplasia during childhood is easier than those in other period of life ; usually we can diagnose them clinically by their characteristic radiographic features and confirm the diagnosis by genetic test when the disease genes are known. However, some skeletal dysplasias may escape from detection because of their mild phenotypes and lack of diagnostic complications, and may be diagnosed as common orthopedic diseases. Here, we present several cases of such skeletal dysplasia that we experienced in our daily practice and highlight diagnostic problems. For correct diagnosis of skeletal dysplasia, it is important to consider its possibility always in the clinical practice and to collect clinical information appropriately, including those regarding family history. The collect diagnosis would lead to better treatment and care for patients and families.

Liddle's syndrome caused by a novel mutation of the gamma-subunit of epithelial sodium channel gene SCNN1G in Chinese

To screen the mutation of the beta and gamma subunits of epithelial sodium channel gene SCNN1 in two families with Liddle's syndrome. Two patients clinically diagnosed as Liddle's syndrome and their family members were enrolled. Peripheral blood samples were collected and total genomic DNA was prepared. Polymerase chain reaction (PCR) was used to amplify the exon 13 of the SCNN1B and SCNN1G gene. PCR products were purified and subjected to direct DNA sequencing. A heterozygous nonsense mutation at codon 564 of the SCNN1B gene from CGA(Arg) to stop codon(TGA) was detector in the proband of family 1. More importantly, a novel heterozygous nonsense mutation of CAG(Gln) to stop codon TAG at codon 567 of the SCNN1G gene was detected in the proband and another two members of family 2. Screening for specific mutations of the SCNN1 gene in relatives of patients with Liddle's syndrome can be used to identify the previously unrecognized cases within the family. A new nonsense mutation(Q567X) of the SCNN1G gene is likely the cause of Liddle's syndrome in family 2.

Isolated fever in horses: a new case of equine anaplasmosis in France

Anaplasma phagocytophilum is an obligate intracellular bacterium that invades neutrophils, creating intravacuolar aggregates called morulae. It is transmitted to humans and horses through Ixodes tick bites and induces a febrile disease. This research note describes the second equine case confirmed in France. A 14-year-old French saddle horse from an area where Ixodes ricinus ticks are endemic (Ecole Polytechnique, Paris) was referred in May 2007 to the military veterinary clinic for fever and depression. The horse was presented after having received a single-dose penicillin treatment 24 h before because of hyperthermia. The horse underwent thorough clinical examination and blood was collected for analysis, haematology and PCR. Blood was stained with Hemacolor 61650 (Merck, Darmstadt, Germany). DNA was extracted using the QIAamp Tissue Kit and amplified and sequenced by PCR using primers targeting the citrate synthase (gltA) gene and 16S rRNA gene [1]. Clinical signs included fever (39.5 C), depression, anorexia, lethargy, mild icterus and reluctance to move. No limb oedema was noted. The blood count revealed a lymphopenia (745 ⁄mm), an anaemia and a thrombocytopenia (67000 ⁄mm). The horse received prior to other examinations and analyses a single intramuscular dose of 1.2 g of imidocarb dipropionate. An attentive examination of the blood smears showed later basophilic morulae inclusions in the neutrophils, which was suggestive of Anaplasma phagocytophilum infection (Fig. 1). The PCR on blood was positive for both genes and sequencing analysis identified A. phagocytophilum (similarity 100%). The horse recovered within 5 days without any treatment and fever disappeared within 48 h. The first case of European equine anaplasmosis was confirmed in 1998, by PCR and sequencing, in a 12-year-old Arabian mare from an area where ticks were endemic in Switzerland. The first case of Ehrlichia equi infection in an adult horse in France was reported in 2002 [2]. The diagnosis was confirmed by PCR of a blood product and serology (IFA). In France, many cases of fever of unknown origin (FUO) in horses are treated successfully with tetracycline by veterinary practitioners. This led to the hypothesis that A. phagocytophilum incidence might be underestimated and responsible for a part of these cases as suggested by previous epidemiological and molecular studies [3]. The diagnosis of equine anaplasmosis is a challenge if limb oedema and ataxia are lacking, as other clinical signs are not specific. Consequently, this diagnosis should be investigated systematically when facing ‘fever of unknown origin’, which is a frequent syndrome in horses. Horses, indeed, are not well protected from tick bites by ectoparasiticides because of their weak remanency due to equine sudation. This may explain the sporadic cases of ‘subclinical babesiosis’ and even unrecognised cases of mild anaplasmosis. In a case series of horses with FUO, 43% had a well-defined infectious disease, 22% had neoplasia, 6.5% had immune-mediated disease, 19% had miscellaneous causes, and in 9.5% the cause was not determined [4]. Consequently, diagnosis by both PCR and serology appears to be the most appropriate method to confirm a case. In an experimental infection of six horses in Sweden, PCR signal was consistently detected 2–3 days before appearance of clinical signs and persisted 4–9 days after the clinical signs cleared. Antibody response appeared 12–16 days after inoculation and rapidly increased within 3–7 days of clinical illness [5]. For an isolated fever in horses in endemic Corresponding author and reprint requests: P. Brouqui, URMITE, CNRS-IRD UMR 6236, Faculte de medecine et de pharmacie, Universite de la Mediterranee, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France E-mail: philippe.brouqui@medecine.univ-mrs.fr