Question in which the clinical picture must be recognized: cardiovascular anomalies - Tetralogy of Fallot -; thymic aplasia/hypoplasia - leading to primary T-cell immunodeficiency; parathyroid aplasia/hypoplasia - hence hypocalcemia -; palatal anomalies - nasal voice; psychomotor retardation. In my opinion, just with the words "thymic dysfunction", hypocalcemia and cardiopathy, we would have to go straight to DiGeorge syndrome. Indeed, the genetic defect is a 22q11.2 deletion (which if we know it, the better, but with the clinic it would be enough for us). The only option with which there could be doubt is Noonan syndrome, which can also be associated with cardiopathy, but above all it is characterized by short stature, cardiopathy and bone alterations; moreover, in most cases it is caused by an alteration in the PTPN11 gene, not in those mentioned in the question.

Question in which the clinical picture must be recognized: cardiovascular anomalies - Tetralogy of Fallot -; thymic aplasia/hypoplasia - leading to primary T-cell immunodeficiency; parathyroid aplasia/hypoplasia - hence hypocalcemia -; palatal anomalies - nasal voice; psychomotor retardation. In my opinion, just with the words "thymic dysfunction", hypocalcemia and cardiopathy, we would have to go straight to DiGeorge syndrome. [HIDDEN] The only option with which there could be doubt is Noonan syndrome, which can also be associated with cardiopathy, but above all it is characterized by short stature, cardiopathy and bone alterations; moreover, in most cases it is caused by an alteration in the PTPN11 gene, not in those mentioned in the question.

Amalia is a 3-year-old girl who has undergone surgery for tetralogy of Fallot. She also presented thymic dysfunction in the neonatal period and hypocalcemia as well as a nasal voice and psychomotor retardation. Which genetic test do you consider most appropriate to reach an etiological diagnosis?

22q11 deletion study (Di George or Velo-cardio-facial syndrome).

Study of FMR1 gene expansion, responsible for Fragile X syndrome.

Sequencing of genes related to HRAS (Noonan syndrome).

Genetic study of Williams Beuren syndrome.

[Congenital cardiopathies and syndromes in adults].

Among congenital defects the most common are the congenital heart defects, which constitute a heterogeneous group with a multifactor etiology. A single gene mutation has been identified in some of them, such as in of Williams's syndrome, or they can be due to teratogenic agents. The advance in diagnosis and treatment of congenital heart defects has become very important because mortality has diminished and patients live longer and better, reaching adult hood. Molecular biology offers now opportunities understand the cause of many genetic diseases thanks to molecular studies of chromosomes. Conotruncal malformations are known to be caused by a microdeletion in chromosome 22(22q11), this mutation is also responsible for the DiGeorge and cardiovelofacial syndromes, the most relevant aspects are: congenital heart disease, which is present in 75% of the cases, the leading disorder is Fallot's tetralogy with pulmonary atresia, in second place is interruption of the aortic arch type B, followed by common truncus arteriosus. These patients have other phenotypic features, such as high palate, speech problems, malimplantation of ears, and protuberant nose tip, among others. Diagnosis is made with the FISH (fluorescent in situ hybridization) test that shows a microdeletion in chromosome 22 at the 11.2 region. Another syndrome that has received great attention is the Williams-Beuren syndrome, which courses with mental retardation, hypercalcemia, characteristic facies, and supravalvular aortic and pulmonary stenosis. To day, it is known that its cause is a deletion in chromosome 7(7q11.23), which affects elastin region, in consequence, affecting the vessels.

[Improvement of genetic diagnostic strategy in velo-cardio-facial syndrome].

Velo-Cardio-Facial Syndrome (VCFS) is characterized by congenital heart defects (CHD), palatal abnormalities, facial dysmorphism, neonatal hypocalcemia, immune deficit, speech and learning disabilities. SVCF is caused by microdeletion 22q11.2. Microdeletion is detected by fluorescence in situ hybridization (FISH). The highly variable phenotype makes diagnosis and selection for FISH more difficult. To retrospectively analyze and compare the phenotype of children with a clinical diagnosis of VCFS with/without 22q11 deletion; to verify the validity of literature guidelines and to describe combinations of clinical features that should lead to molecular analysis. The present study was performed in 21 patients with a clinical diagnosis of VCFS. Methaphase chromosome spreads were prepared from phytohaemagglutinin stimulated lymphocyte culture by standard methods before FISH. The patients were divided into two groups according to FISH test: positive and negative. The features commonly noticed in FISH positive patients were: palatal abnormalities/hypernasal speech, learning disabilities, facial dysmorphism, tapered fingers (6/6), CHD (5/6) and recurrent infections (2/6). In FISH negative patients the following were found: learning disabilities, CHD (12/15); facial dysmorphism (10/15), family history of CHD (7/15), short stature (6/15), hypocalcemia, tapered fingers (5/15), recurrent infections (3/15) and palatal cleft (2/15). In both groups, Tobias and McDonald-McGinn guidelines were positive. VCFS has a highly variable phenotype. Our study suggests that 22q11.2 deletion analysis by FISH should be performed in patients who have at least 2 (newborn)/3 (child, adult) specific criteria: CHD, hypocalcemia, palatal abnormalities, facial dysmorphism, learning disabilities, digital anomalies, and immune deficit.

Williams-Beuren's Syndrome: A Case Report.

Williams-Beuren syndrome is a rare familial multisystem disorder occurring in 1 per 20,000 live births. It is characterized by congenital heart defects (CHD), skeletal and renal anomalies, cognitive disorder, social personality disorder and dysmorphic facies. We present a case of Williams syndrome that presented to us with heart murmur and cognitive problem. A 5-year-old girl referred to pediatric cardiologist because of heart murmurs. She had a systolic murmur (2-3/6) in right upper sternal border with radiation to right cervical region. She also had a bulge forehead. Angiography showed mild supra valvular aortic stenosis and mild multiple peripheral pulmonary stenosis. Fluorescent in situ hybridization (FISH) was performed and the result was: 46.XX, ish del (7q11.2) (ELN X1) (7q22 X2) ELN deletion compatible with Williams syndrome. Peripheral pulmonary artery stenosis is associated with Noonan syndrome, Alagille syndrome, Cutis laxa, Ehler-Danlos syndrome, and Silver-Russel syndrome. The patient had peripheral pulmonary artery stenosis, but no other signs of these syndromes were present, and also she had a supravalvular aortic stenosis which was not seen in other syndromes except Williams syndrome. Conclusion. According to primary symptoms, paraclinical and clinical finding such as dysmorphic facies, cognitive disorder and congenital heart defect, Williams syndrome was the first diagnosis. We suggest a more attention for evaluating heart murmur in childhood period, especially when the patient has abnormal facial features or mental problem.

[22q11.2 chromosome deletion and velo-cardio-facial syndrome in a   patient with tetralogy of Fallot].

Velo-cardio-facial syndrome includes the following clinical features: congenital heart anomaly, velo-pharyngeal malformations and dysmorphic facial features. In 80% of the patients microdeletion of the long arm of chromosome 22 can be detected. Many patients with DiGeorge syndrome have the same underlying chromosomal etiology, however the same deletion results in severe dysmorphic features, immune defect, hypocalcaemia and in severe mental retardation. In isolated heart defects deletion can be detected in about 15% of the patients. We report the detection of the microdeletion in a patient with tetralogy of Fallot, minimal dysmorphic facial features and normal psychomotor development. Early diagnosis of 22q11.2 chromosomal deletion is important for genetic counseling and further rehabilitation. We emphasize the importance of genetic screening in patients with isolated congenital heart defects.

[Clinical characterization, molecular and FISH studies in 80 patients with clinical suspicion of Williams-Beuren syndrome].

Williams-Beuren syndrome is a developmental disorder affecting vascular and connective tissues and central nervous system. The syndrome is caused by a submicroscopic deletion in the chromosome 7 implicating the 7q11.23 region. Fluorescence in situ hybridization (FISH) and molecular studies allow us to confirm the clinical suspicion of this syndrome. We report clinical evaluation, FISH using Elastin Williams/D7S427 probe and molecular study with markers: D7S672, D7S653, D7S489B, D7S2476, D7S1870 and D7S489A, in 80 patients referred to test for Williams-Beuren syndrome. We found hemizygosity for the critical region in 36 patients. From 69 cases studied by FISH, 28 showed the deletion. Molecular studies in 78 cases showed loss of heterozygosity (LOH) in 26 patients. The patients presented the deletion from the paternal or maternal chromosome at equal frequency. Clinical evaluation of mental retardation, facial features, esotopia dental, malocclusion, hoarse voice, supravalvular aortic stenosis (SVAS), hernias, join limitation, WBS personality and mental retardation from positive and negative patients showed estatistical significant differences for all items except mental retardation and joint limitation. The most significant item was the presence of SVAS. This study confirms the usefulness of genetic studies as a diagnostic tool for William-Beuren Syndrome.

Williams syndrome

If a physician suspects a case of WS, the diagnosis is confirmed using one of two possible genetic tests: Micro-array analysis or the fluorescent in situ hybridization test, which examines chromosome 7 and probes for the existence of two copies of the elastin gene. Since 98-99% of individuals with WS lack half of the 7q11.23 region of chromosome 7, where the elastin gene is located, the presence of only one copy of the gene is a strong sign of WS. This confirmatory genetic test has been validated in epidemiological studies and has been demonstrated to be a more effective method of identifying WS than previous methods, which often relied on the presence of cardiovascular problems and facial features (which, while common, are not always present).

Neurodevelopmental disorder

Less commonly known genetically determined neurodevelopmental disorders include Fragile X syndrome. Fragile X syndrome was first described in 1943 by Martin and Bell, studying persons with family history of sex-linked "mental defects". Rett syndrome, another X-linked disorder, produces severe functional limitations. Williams syndrome is caused by small deletions of genetic material from chromosome 7. The most common recurrent Copy Number Variannt disorder is 22q11.2 deletion syndrome (formerly DiGeorge or velocardiofacial syndrome), followed by Prader-Willi syndrome and Angelman syndrome. Immune dysfunction

Ryan Dempster

In early June 2009, Dempster released a statement explaining that his daughter, Riley Dempster, had DiGeorge Syndrome, also known as Velo-cardio-facial syndrome (VCFS), 22q11.2 deletion syndrome, and Shprintzen syndrome (after Dr. Robert Shprintzen who identified it in 1978). About 1 baby in 1800 is born with this genetic deletion which ubiquitously affects swallowing, breathing, and speech. Dempster did this because he wanted to help raise awareness of this genetic disease. When asked if she would lead a normal life, he replied, "Yeah, she will. There can be (problems), but so far all the signs are good. There's a lot of work to do. They say there are 186 symptoms you can have. You just check off ones as you go along." After roughly 2 months in the hospital, Riley was able to go home in early June.

Fryns-Aftimos syndrome

Fryns-Aftimos syndrome (also known as Baraitser-Winter Syndrome 1, or BWS1) is a rare chromosomal condition and is associated with pachygyria, severe mental retardation, epilepsy and characteristic facial features. This syndrome is a malformation syndrome, characterized by numerous facial dysmorphias not limited to hypertelorism, iris or retinal coloboma, cleft lip, and congenital heart defects. This syndrome has been seen in 30 unrelated people. Characterized by a de novo mutation located on chromosome 7p22, there is typically no family history prior to onset. The severity of the disorder can be determined by the size of the deletion on 7p22, enveloping the ACTB gene and surrounding genes, which is consistent with a contiguous gene deletion syndrome. Confirming a diagnosis of Fryns-Aftimos syndrome typically consists of serial single-gene testing or multigene panel of genes of interest or exome sequencing.

[22q11 deletion in conotruncal anomalies].

22q11 deletions in conotruncal anomalies. Two children are reported in whom conotruncal anomalies (truncus arteriosus communis, tetralogy of Fallot) were associated with chromosome 22q11 deletion. In both cases, which represent the first published cases in Hungary according to the knowledge of the author, deletions were suspected on the basis of phenotype termed Di George syndrome. Nowadays the role of molecular genetics is growing in the etiology of congenital heart defects and the chromosome 22q11 deletions constitute one of the most frequent genetic mutations associated with congenital heart defects. The author emphasizes that clinicians must know about this disease, and in case of suspicion they should request for molecular genetic investigation. 22q11 deletions have an important roles in the prognosis of congenital heart disease, in counseling and in the prenatal diagnosis as well.

Floating–Harbor syndrome

Diagnosis Until recently, doctors have diagnosed patients with FHS based on clinical observations and how well they fit the disease description, usually occurring in early childhood. Molecular genetic testing is also used now to test for genetic mutations. By performing a sequence analysis test of select exons, mutations can be detected in exon 34 of the SRCAP gene. This mutation has been observed in 19 patients to date. In most cases, if the patient shows classic facial features of FHS, the molecular testing will show a mutation on the SRCAP gene. Differential diagnosis FHS shares some common features with Rubinstein–Taybi (due to overlapping effects of mutations on SRCAP), however cranial and hand anomalies are distinctive: broad thumbs, narrow palate, and microcephaly are absent in Floating-Harbor Syndrome. One child in the UK has a diagnosis of microcephaly alongside Floating–Harbor syndrome.

Fragile X syndrome

This disorder and finding of Fragile X syndrome has an X-linked dominant inheritance. It is typically caused by an expansion of the CGG triplet repeat within the FMR1 (fragile X mental retardation 1) gene on the X chromosome. This results in silencing (methylation) of this part of the gene and a deficiency of the resultant protein (FMRP), which is required for the normal development of connections between neurons. Diagnosis requires genetic testing to determine the number of CGG repeats in the FMR1 gene. Normally, there are between 5 and 40 repeats; fragile X syndrome occurs with more than 200. A premutation is said to be present when the gene has between 40 and 200 repeats; women with a premutation have an increased risk of having an affected child. Testing for premutation carriers may allow for genetic counseling.

[Microdeletion 22q11: apropos of case of schizophrenia in an adolescent].

Deletion of chromosome 22q11 concerns nearly 1/5.000 births, and is the most frequent interstitial microdeletion. The deletion generates various phenotypes which were initially regarded as distinct syndromes. 1) Di George syndrome was described in 1962 by immunologists, and associates thymic and parathyroid hypoplasia, cardiac malformation, and dysmorphic face; the prognosis is severe, as Di George syndrome is a life-threatening condition. 2) The velocardiofacial syndrome was described in 1978 by stomatologists, and associates palate abnormalities, cardiac malformations, dysmorphic faces, and learning disabilities. 3) The Takao syndrome was described in the late seventies by cardiologists as a clinical condition associating cardiac abnormalities and dysmorphic faces. During the nineties, a common molecular etiology was identified, and a new name proposed: CATCH 22, an acronyme for Cardiac abnormalities, Abnormal face, Thymic hypoplasia, Cleft palate, Hypocalcemia, deleted chromosome 22. Furthermore, new phenotypes have been recently recognized, most of them belonging to the psychiatric spectrum. Descriptive studies of large samples of children with 22q11 deletion, conducted, both in the United States and european countries, have shown the following pattern of associated symptoms:--abnormal face (100%), which expression varies with age, and can be discrete;--cardiac abnormalities (84%), including cardiac malformations of conotroncal types;--mouth abnormalities (49%), including cleft palate (14%), and velar dysfunction (20%);--urinary tract abnormalities (36%), including ureteric reflux, lung dysplasia;--transitory hypocalcemia (60%) mostly during infancy, and due to transitory hypoparathyroid dysfunction;--seizures (21%), which are usually a consequence of hypocalcemia;--immunodeficiency (1%), which worsens the prognosis. Deletion of chromosome 22q11 has been also associated with various psychiatric phenotypes, which can be classified into two groups, developmental abnormalities and psychiatric conditions. The great majority of patients with the deletion exhibit impairment of language and motor development, mild mental retardation, persistent coordination deficits, and poor academic performance. The deletion of chromosome 22q11 is also associated with high frequency of behavioral disorder with attention deficit during childhood, and with high frequency of psychotic disorder (bipolar disorder, and schizophrenia) during adolescence and young adulthood. The link between the 22q11 deletion and schizophrenia has been also supported by recent studies showing that the rate of 22q11 deletion in adults with schizophrenia (2%) is higher than it is in the general population. The rate may even be higher (6%) in subjects with childhood onset schizophrenia. The present work reviews the psychiatric literature associated with 22q11 deletion. We also report a case of 22q11 deletion in a 17-year-old girl that was initially diagnosed as paranoid schizophrenia. We will discuss the diagnostic, prognostic, and therapeutic consequences that such a genetic diagnosis implies. In the case reported here, transitory hypocalcemia induced: 1) dystonic symptoms that was believed to be catatonic symptoms or neuroleptic secondary effects, by clinicians; 2) a poor response to neuroleptic medication.

FISH analysis in both classical and atypical cases of Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder, characterized by distinct facial changes, growth deficiency, mental retardation, supravalvular aortic stenosis (SVAS)/peripheral pulmonary stenosis, and associated at times with infantile hypercalcemia. A pilot study has been carried out to assess the reliability of the detection of hemizygosity at the elastin locus by fluorescence in situ hybridization (FISH) analysis as a diagnostic test in both classical and atypical WBS. Eight subjects with classical WBS and four others in whom a diagnosis could not be confirmed on clinical criteria alone were enrolled. In the classical WBS group, five (5/8) had a visible interstitial 7q11.22-11.23 deletion detected by high-resolution banding, and all (8/8) had a submicroscopic deletion of the elastin locus on chromosome 7 by FISH analysis. In the atypical WBS group, only one (1/4) had elastin deletion. The other three, with isolated SVAS, had normal development and minimal signs of WBS. Furthermore, the patients with microscopic 7q11.22-11.23 deletion have more associated features of WBS than those without visible interstitial deletions by high-resolution banding. These results, therefore, emphasize the importance of a combined high-resolution and molecular cytogenetic (i.e., FISH) approach to diagnosis and suggest that the degree to which microscopic/submicroscopic deletions of chromosome 7 extending in beyond the elastin locus may explain some of the phenotypical variability found in WBS.

Congenital heart defect

which includes electrical conduction defects and abnormalities of the upper limb. The Wnt signaling co-factors BCL9, BCL9L and PYGO might be part of this molecular pathways, as when their genes are mutated, this causes phenotypes similar to the features present in Holt-Oram syndrome. Another T-box gene, TBX1, is involved in velo-cardio-facial syndrome DiGeorge syndrome, the most common deletion which has extensive symptoms including defects of the cardiac outflow tract including tetralogy of Fallot.

Williams-Beuren Syndrome: A Clinical Study of 55 Brazilian Patients and the Diagnostic Use of MLPA.

Williams-Beuren syndrome (WBS) is a genetic disease caused by a microdeletion in the 7q11.23 region. It is characterized by congenital heart disease, mainly supravalvular aortic stenosis, mental retardation, mild short stature, facial dysmorphisms, and variable abnormalities in different systems. Objectives. To report the clinical findings of 55 Brazilian patients confirmed by multiplex ligation-dependent probe amplification (MLPA). Methods. Patients were followed up for 4 years at the Genetics Unit of the Instituto da Criança of the Hospital das Clínicas, FMUSP, Brazil. A kit specific for WBS was used to detect the 7q11.23 microdeletion. Results. Two patients with negative FISH results had positive MLPA results for WBS. The characteristics of the patients with the deletion were as follows: typical WBS facies (98.2%), neuropsychomotor delay (98.2%), hypersocial behavior (94.5%), hyperacusis (94.5%), and congenital heart disease (81.8%). Conclusions. MLPA was effective in detecting the microdeletion in the 7q11.23 region to confirm the diagnosis of WBS. MLPA was also able to confirm the diagnosis of WBS in two patients with typical clinical characteristics but negative FISH results. Thus, MLPA is a promising method in the diagnostic investigation of WBS. WBS is a multisystemic disorder and therefore requires multidisciplinary care and specific follow-up to prevent complications.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder most frequently seen in male premutation carriers of Fragile X syndrome (FXS) over the age of 50. The main clinical features of FXTAS include problems of movement with cerebellar gait ataxia and action tremor. Associated features include parkinsonism, cognitive decline, and dysfunction of the autonomic nervous system. FXTAS is found in Fragile X "premutation" carriers, which is defined as a trinucleotide repeat expansion of 55-200 CGG repeats in the Fragile X mental retardation-1 (FMR1) gene. 4-40 CGG repeats in this gene is considered normal, while individual with >200 repeats have full Fragile X Syndrome.

22q11.2 deletion detected by <i>in situ</i> hybridization in Mexican patients with velocardiofacial syndrome-like features.

Deletion 22q11.2 occurs in 1:4,000-1:6,000 live births while 10p13p14 deletion is found in 1:200,000 newborns. Both deletions have similar clinical features such as congenital heart disease and immunological anomalies. We looked for a 22q11.2 deletion in Mexican patients with craniofacial dysmorphisms suggestive of DiGeorge or velocardiofacial syndromes and at least one major phenotypic feature (cardiac anomaly, immune deficiency, palatal defects or development delay). A prospective study of 39 patients recruited in 2012-2015 at the Instituto Mexicano del Seguro Social at Guadalajara, Mexico. The patients with velocardiofacial syndrome-like features or a confirmed tetralogy of Fallot (TOF) or complex cardiopathy were studied by G-banding and fluorescence <iin situ</i hybridization (FISH) with a dual TUPLE1(HIRA)/ARSA or TUPLE1(22q11)/22q13(SHANK3) probe, six patients without the 22q11.2 deletion (arbitrarily selected) were tested with the dual DiGeorge II (10p14)/D10Z1 probe. Twenty-two patients (7 males and 15 females) had the 22q11.2 deletion and 17/39 did not have it; no patient had a 10p loss. Among the 22 deleted patients, 19 had congenital heart disease (mostly TOF). Twelve patients without deletion had heart defects such as TOF (4/12), isolate ventricular septal defect (2/12) or other disorders (6/12). In our small sample about ~56% of the patients, regardless of the clinical diagnosis, had the expected 22q11.2 deletion. We remark the importance of early cytogenetic diagnosis in order to achieve a proper integral management of the patients and their families.

Tetralogy of Fallot

NOTCH1 is involved in the vascularization of tissues and is the most common site of genetic variations involved with TOF, accounting for 7% of all TOF cases. TBX1 expresses progenitors involved with the development of the right ventricle. Chromosome 22q11 deletions also deleting TBX1 gene have been seen in 17% TOF cases. FLT4 gene expression leads to Vascular endothelial growth factor receptor 3 (VEGFR-3) which helps vascularization. Mutations of this gene have been associated with TOF, accounting for 2.4% of all cases. FOXC2 is another gene involved in embryonic development of the cardiac system. Mutations of this gene have been shown to result in dysfunctional lymphatic syndrome and TOF. GATA4 aids in cardiac development by helping increase the production of cardiomyocytes. Mutations of this gene have been seen in various familial TOF cases often lasting 2-3 generations.

[Detection of a Williams Beuren syndrome case by MLPA].

Williams-Beuren syndrome (WBS) is a rare developmental disorder characterized by distinctive facial, neurobehavioral, and cardiovascular features. WBS is caused by a heterozygous contiguous gene microdeletion of the WBS crítical region on chromosome 7q11.23. Confirmation of clinical suspicion is essential for clinical monitoring of the patient and genetic counseling of the family. Fluorescence in situ hybridization (FISH) is considered the gold standard technique for detecting WBS. Multiplex ligation-dependent probe amplification (MLPA) has been introduced into DNA diagnostic laboratories for the detection of copy number variations in several diseases including WBS. The objective of this study was to confirm, by MLPA, the clinical diagnosis of WBS in a pediatric patient. This technique allowed to detect the deletion of CYLN2, FZD9, STX1A, ELN, LIMK1 and RFC2 genes. In geographic regions were the detection by FISH is not available for this disease, the MLPA methodology allowed to confirm the clinic diagnostic of WBS. To our knowledge this is the first report demonstrating the confirmation of WBS by MLPA in Argentina.

Nagwa Abdel Meguid

Meguid developed a simple molecular screening method to detect premutation carriers of fragile X syndrome. A premutation carrier is an individual who has between 55-200 CGG repeats in the Fragile X (FMR1) gene. The full mutation has over 200 CGG repeats. The procedure included a rapid modified polymerase chain reaction (PCR)-based screening tool for expanded Fragile X Mental Retardation 1 (FMR1) alleles. The results showed that 16 males out of 53 males had the CGG abnormal repeats characteristic of Fragile X gene. 10 of their mothers and 4 of their sisters also had the FMR1 premutation. 66.6% consanguineous marriages were present in the families studied. It was concluded that fragile X syndrome was ruled out of families with consanguineous parents. Instead, fragile X syndrome could be contributed to earlier carrier detection, which may reduce the number of affected children. By isolating the mutation early, the effects of the disease could be reduced in children and in their

Williams-Beuren syndrome: diagnosis by polymorphic markers.

Williams-Beuren syndrome (WBS) is caused by a 1-2 Mb microdeletion in the region 7q11.23. The clinical presentation may vary and most of the connective tissue abnormalities can be explained by the haploinsufficiency of the ELN gene in this region. The purpose of this study was to determine the value of a polymerase chain reaction assay that uses three polymorphic markers to detect the microdeletion and compare the clinical features. Thirty-two patients with WBS were ascertained accordingly to clinical diagnostic criteria. The markers D7S1870, ELN 17/exon 18, and Hei 1.3/1.4 were designed to detect the heterozygosity in the region 7q11.23. The three markers were informative in 78% and uninformative in 22% of the cases. The most informative marker (69%) was D7S1870, followed by Hei (55%) and ELN 17/exon 18 (44%). The microdeletion was present in 56% and absent in 22% of patients. The craniofacial and cardiovascular abnormalities did not have significant statistical differences in the cases with and without microdeletion. Two of the syndrome characteristics (an overfriendly personality and hyperacusis) were more frequent in the microdeletion group and these differences were statistically significant (p = 0.006 and p = 0.02, respectively). Polymorphic markers might be a good alternative for the molecular diagnosis of WBS in centers where fluorescence in situ hybridization analysis is not available.

ARVCF

Function Armadillo repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) is a member of the catenin family which play an important role in the formation of adherens junction complexes, which are thought to facilitate communication between the inside and outside environments of a cell. ARVCF gene was isolated in the search for the genetic defect responsible for the autosomal dominant Velo-Cardio-Facial syndrome (VCFS) a relatively common human disorder with phenotypic features including cleft palate, conotruncal heart defects and facial dysmorphology. ARVCF gene encodes a protein containing two motifs, a coiled coil domain in the N-terminus and a 10 armadillo repeat sequence in the midregion. Since these sequences can facilitate protein-protein interactions ARVCF is thought to function in a protein complex. In addition, ARVCF contains a predicted nuclear-targeting sequence suggesting that it may have a function as a nuclear protein.

Stephen Warren (geneticist)

Research and work His doctoral dissertation was entitled "Bloom syndrome as a human mutator mutation". He published 12 manuscripts during his doctoral training. Warren's postdoctoral studies were focused on human molecular genetics and he first began his studies on fragile X syndrome. He made somatic cell hybrids isolating the human fragile X chromosome in rodent cells and devised a strategy to molecular clone the DNA responsible for the syndrome. He began his molecular experiments to implement this strategy in 1985 when he established his own laboratory at Emory University. Using his somatic cells hybrids, Warren led an international group, including his longtime collaborator David L. Nelson at Baylor College of Medicine, that isolated the FMR1 gene responsible for fragile X syndrome in 1991. The cloning of this locus also uncovered, for the first time, a trinucleotide repeat expansion mutation, a mechanism now known to be responsible for dozens of genetic diseases.

Williams-Beuren Syndrome: Experience of 43 Patients and a Report of an Atypical Case from a Tertiary Care Center in India.

Williams-Beuren syndrome (WBS) or Williams syndrome (OMIM 194050) is a multisystem disorder manifested by neurodevelopmental delay and is caused by a hemizygous deletion of ∼ 1.5-1.8 Mb in the 7q11.23 region. Clinical features include cardiovascular anomalies (mainly supravalvular aortic stenosis), peripheral pulmonary stenosis, distinctive facies, intellectual disability (usually mild), unique personality characteristics, and growth and endocrine abnormalities. Clinical diagnostic criteria are available for WBS; however, the mainstay of diagnosis is the detection of the contiguous gene deletion. Although FISH remains the most widely used laboratory test, the diagnosis can also be established by means of qPCR, MLPA, microsatellite marker analysis, and chromosomal microarray (CMA). We evaluated the utility of MLPA to detect deletion/duplication in the 7q11.23 region in 43 patients suspected to have WBS using MLPA kits for microdeletion syndromes. A hemizygous deletion in the 7q11.23 region was found in 41 (95.3%) patients using MLPA. One patient had an atypical deletion detected by CMA. During the initial period of this study, the results of 12 patients tested by MLPA were also confirmed by FISH. Compared to FISH and CMA, MLPA is a cheaper, high-throughput, less labor-intensive and less time-consuming technique for the diagnosis of WBS. Although CMA is expensive and labor-intensive, its effectiveness is demonstrated to detect an atypical deletion and to delineate the breakpoints.

Ying-Hui Fu

Neurodegeneration Trinucleotide repeat expansions and neurological diseases When Fu did her post-doctoral work in Baylor College, she was part of the team that was positional cloning the Fragile-X syndrome gene. There, she studied the trinucleotide repeat sequence expansions, the mutations responsible for the Fragile-X Syndrome, and their correlation with disease severity and age of onset. This work led to the discovery of underlying molecular mechanism for genetic anticipation. Following this work, she cloned the gene responsible for Myotonic dystrophy based on the hypothesis that genetic anticipation in Myotonic dystrophy is also caused by trinucleotide repeat expansion on patient DNA. This mutational mechanism is now known to cause not only Fragile X syndrome and Myotonic dystrophy, but also Huntington's disease and many of the spinocerebellar ataxias. Thus, it is a common mutational mechanism in inherited neurological diseases.

FMR1

Fewer than 1% of all cases of fragile X syndrome are caused by mutations that delete part or all of the FMR1 gene, or change a base pair, leading to a change in one of the amino acids in the gene. These mutations disrupt the 3-dimensional shape of FMRP or prevent the protein from being synthesized, leading to the signs and symptoms of fragile X syndrome. A CGG sequence in the FMR1 gene that is repeated between 55 and 200 times is described as a premutation. Although most individuals with the premutation are intellectually normal, some of these individuals have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience mental health problems such as anxiety or depression. Fragile X-associated tremor/ataxia syndrome

[Genetic diagnosis and noninvasive prenatal testing of a family with Williams-Beuren syndrome].

To explore the genetic basis of a fetus with ventricular septal defect (VSD) by using modified noninvasive prenatal testing (NIPT) for the detection of microdeletion syndromes. Chromosomal karyotypes of the fetus and its parents were analyzed by G-banding technique. Next generation sequencing (NGS) was used to detect genomic copy number variations (CNVs) in cell-free fetal DNA. The results were verified by fluorescence in situ hybridization (FISH). The fetus and its parents all had a normal karyotype at 320-400 band level. NGS revealed a deletion of 1.30 Mb at 7q11.23 in the fetus, with a 93% overlap with that of Williams-Beuren syndrome (WBS). The father also had a deletion of 1.42 Mb at 7q11.23, with a 99% overlap with that of WBS. Modified NIPT also detected the 1.30 Mb deletion at 7q11.23 in the fetus. The result of FISH has confirmed the above results. It is necessary to carry out genetic testing on fetuses with VSD. NGS can detect fetal microdeletion syndromes and help to trace their parental origin. The modified NIPT for fetal chromosomal microdeletions/microduplication syndromes is highly accurate.

1q21.1 deletion syndrome

GJA5 has been identified as the gene that is responsible for the phenotypes observed with congenital heart diseases on the 1q21.1 location. In case of a duplication of GJA5 tetralogy of Fallot is more common. In case of a deletion other congenital heart diseases than tetralogy of Fallot are more common. References Further reading Genetics of Mental Retardation, Karger. Knight S. (ed) Chapter One: 'A Parent's' Perspective' contains description and photos of female with 1q21.1 microdeletion External links 1q21.1 deletion, GeneReviews NCBI Bookshelf Orpha.net Hematology Congenital disorders Syndromes affecting the nervous system Animal developmental biology Syndromes affecting the heart

Accuracy in identification of patients with 22q11.2 deletion by likely care providers using facial photographs.

Numerous facial characteristics are associated with velocardiofacial syndrome. Care providers may use these facial characteristics to identify patients who may benefit from fluorescence in situ hybridization genetic testing to determine the presence of the 22q11.2 deletion. The purpose of this study was to test the hypothesis that experienced care providers were able to correctly diagnose the 22q11.2 deletion on the basis of studying frontal facial photographs. After approval was obtained from the human studies committee, patients who had undergone fluorescence in situ hybridization genetics testing for the presence of a 22q11.2 deletion were asked to submit two frontal photographs: one at infancy and one beyond the second birthday. These photographs were randomized, made anonymous, and then placed on a secure Web site. Specialists in the fields of plastic surgery, otolaryngology, genetics, and speech pathology were asked to evaluate their experience and confidence levels in diagnosing a 22q11.2 deletion and were then asked to rate the photographs by likelihood of deletion using a five-point Likert scale. Thirty-two specialists (10 surgeons, nine geneticists, and 13 speech pathologists) participated in the study. On the basis of clear responses, respondents predicted the presence (sensitivity) and absence (specificity) of the 22q11.2 deletion at chance levels. Of the remaining responses, 20 to 25 percent were unsure and 20 to 25 percent were clearly wrong. When an unsure response was treated as a weak positive, the results favored sensitivity slightly, with a sensitivity of 70 percent and a specificity of 50 percent. Sensitivity improved somewhat with experience, as measured by the number of patients seen per year. The prediction of the presence or absence of the 22q11.2 deletion at chance levels suggests that the ability to diagnose on the basis of appearance alone is not a sufficient diagnostic tool. Although the ability does increase with experience, it is of statistical but not clinical significance.

Fragile X syndrome

FMRP is a chromatin-binding protein that functions in the DNA damage response. FMRP also occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis. Causes Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1.

Using a combination of MLPA kits to detect chromosomal imbalances in patients with multiple congenital anomalies and mental retardation is a valuable choice for developing countries.

Conventional karyotyping detects anomalies in 3-15% of patients with multiple congenital anomalies and mental retardation (MCA/MR). Whole-genome array screening (WGAS) has been consistently suggested as the first choice diagnostic test for this group of patients, but it is very costly for large-scale use in developing countries. We evaluated the use of a combination of Multiplex Ligation-dependent Probe Amplification (MLPA) kits to increase the detection rate of chromosomal abnormalities in MCA/MR patients. We screened 261 MCA/MR patients with two subtelomeric and one microdeletion kits. This would theoretically detect up to 70% of all submicroscopic abnormalities. Additionally we scored the de Vries score for 209 patients in an effort to find a suitable cut-off for MLPA screening. Our results reveal that chromosomal abnormalities were present in 87 (33.3%) patients, but only 57 (21.8%) were considered causative. Karyotyping detected 15 abnormalities (6.9%), while MLPA identified 54 (20.7%). Our combined MLPA screening raised the total detection number of pathogenic imbalances more than three times when compared to conventional karyotyping. We also show that using the de Vries score as a cut-off for this screening would only be suitable under financial restrictions. A decision analytic model was constructed with three possible strategies: karyotype, karyotype + MLPA and karyotype + WGAS. Karyotype + MLPA strategy detected anomalies in 19.8% of cases which account for 76.45% of the expected yield for karyotype + WGAS. Incremental Cost Effectiveness Ratio (ICER) of MLPA is three times lower than that of WGAS, which means that, for the same costs, we have three additional diagnoses with MLPA but only one with WGAS. We list all causative alterations found, including rare findings, such as reciprocal duplications of regions deleted in Sotos and Williams-Beuren syndromes. We also describe imbalances that were considered polymorphisms or rare variants, such as the new SNP that confounded the analysis of the 22q13.3 deletion syndrome.


Given this clinical picture and without having complementary tests available, the most likely diagnosis is reactive arthritis. The only problem is that the statement speaks of joint pain and not arthritis... Reiter's syndrome (triad of conjunctivitis, urethritis and arthritis) is one of the forms in which reactive arthritis can present. In Behçet's disease oral and genital aphthous ulcers may occur but urethritis is not a feature. And the characteristic ocular condition is uveitis.

A 40-year-old patient who comes to the emergency room with aphthous stomatitis, conjunctivitis, urethritis, balanitis and joint pain. Which of the following diagnoses is the most likely?

Reactive arthritis

Ocular involvement (mild bilateral conjunctivitis) occurs in about 50% of men with urogenital reactive arthritis syndrome and about 75% of men with enteric reactive arthritis syndrome. Conjunctivitis and uveitis can include redness of the eyes, eye pain and irritation, or blurred vision. Eye involvement typically occurs early in the course of reactive arthritis, and symptoms may come and go. Dactylitis, or "sausage digit", a diffuse swelling of a solitary finger or toe, is a distinctive feature of reactive arthritis and other peripheral spondylarthritides but can also be seen in polyarticular gout and sarcoidosis. Mucocutaneous lesions can be present. Common findings include oral ulcers that come and go. In some cases, these ulcers are painless and go unnoticed. In the oral cavity, the patients may suffer from recurrent aphthous stomatitis, geographic tongue and migratory stomatitis in higher prevalence than the general population.

Increased prevalence of joint manifestations in patients with recurrent aphthous stomatitis (RAS)

To characterize the systemic manifestations and joint disease in patents with recurrent aphthous stomatitis (RAS). The presence and features of extra-oral manifestations were determined by a rheumatologist, who examined and interviewed 64 patients, referred during 1993 to the oral medicine clinic for treatment of RAS. Controls were 65 medical staff members of a military clinic associated with the hospital. Based on the rheumatologist's findings and published criteria, the patients were diagnosed as suffering from RAS alone (24 patients), Reiter's syndrome (8), Behçet disease (8), familial Mediterranean fever (1), or RAS with undiagnosable extra oral manifestations (23). Thirteen patients in the last group had joint disease (p < 0.01 compared to the controls), characterized by recurrent mono- or oligoarthritis/arthralgia of short duration, affecting mostly the large joints. Conjunctivitis, pustular rash, lower back pain and urethritis/cervicitis were also common in RAS patients, but only the latter was significantly more frequent in RAS patients than in controls (p < 0.02). These findings suggest that patients with RAS have an increased frequency of a palindromic type joint disease.

[Behçet's disease in childhood].

To make Pediatricians aware of the fact that they must investigate Behçet's disease while performing differential diagnosis of recurrent aphthous stomatitis, even though it is a vasculitis of rare occurrence in early life. Between June 1996 and December 2000, we retrospectively evaluated seven patients of our Pediatric Rheumatology Unit. Demographic, clinical, and laboratory data as well as data regarding treatment and follow-up were presented. Five out of seven patients were female (71.4%), four were non-Caucasian (57.1%), the mean age at onset was 8 years and 11 months (variation of 6 months to 13 years and 8 months), the mean period until diagnosis was 2 years and 3 months (variation of 2 months to 8 years) and the mean follow-up period was 4 years and 2 months (three patients without follow-up). The major criteria of diagnosis were: oral ulcers in seven patients (100%), genital ulcers in three patients (42.8%), ophthalmic alterations in four patients (57.1%) cutaneous vasculitis in one patient (14.2%) and positive pathology test in one patient (14.2%). The minor criteria were: arthralgia/arthritis in five patients (71.4%), family history in two patients (28.5%), and sagittal sinus thrombosis in one patient (14.2%). The initial symptoms included recurrent aphthous stomatitis (more than three painful aphthous ulcers episodes in the period of 1 year), genital ulcers, arthralgia, fever and weight loss. The laboratory findings were: mild anemia in 1/6 patients, ESR>25 in 3/6 patients, increased serum gammaglobulin level in 2/4 patients, B5 histocompatibility antigen in 2/7 patients. The treatment included corticosteroids for 5/7 patients (4 oral, 1 intravenous and one local use), thalidomide for 4/7 patients, colchicine for 2/7 patients and dapsone for 1/7 patient. The outcome was favorable in 4/6, and 3/6 patients presented relapse. Our results confirm the importance of considering the diagnosis of Behçet's disease in patients with recurrent oral and genital ulcers.

[A case of Reiter's disease with severe skin manifestations successfully treated with oral etretinate].

A case of Reiter's syndrome with severe keratoderma being successfully treated with oral Etretinate is reported. A 38 year-old man was referred to our hospital in December, 1985 for treatment of refractory skin eruptions and polyarthralgia. He previously experienced urethritis in December, 1983 with subsequent development of high fever, balanitis, skin eruptions and polyarthritis. Treatments with antibiotics, anti-inflammatory drugs and glucocorticoids were ineffective at that time. The patient was diagnosed as Reiter's syndrome based on his clinical symptoms and the presence of HLA-B27. He was treated in our clinic with oral administration of Etretinate, aromatic retinoids, at the initial doses of 40 mg/day with subsequent increase up to 75 mg/day in 2 weeks. This maintenance dose was continued for two months, resulted in improvements of joint pain, skin eruptions and the laboratory abnormalities. The doses of Etretinate was gradually decreased and then was discontinued after 4 months, when approximately 90% of the skin lesion disappeared. No noticeable side-effect was observed except slight stomatitis. The remission continued for about 2 and half years after cessation of Etretinate without any medication. However, evidence of relapse with the same skin lesions and arthralgia was observed in March, 1989. A repeated treatment with oral Etretinate was attempted with similar but slightly delayed effects.

The clinical features and HLA associations of reactive arthritis associated with non-gonococcal urethritis.

Fifty-seven patients with arthritis associated with non-gonococcal genital infection have been studied. Synovitis characteristically affected one or a few joints, expecially the knee, ankle or metatarsophalangeal joints and was accompanied by tenosynovitis and enthesopathies--each in about one third of the patients. A quarter of the patients had ocular, cutaneous, or mucous membrane lesions (Reiter's syndrome). Although six patients developed a chronic or relapsing course, average duration of the acute episode in the majority was three to five months. Available evidence strongly suggests that infection following sexual intercourse, usually but not always with a new partner, was instrumental in the initiation of the disease. We have suggested the term 'sexually acquired reactive arthritis (SARA)' to emphasize the mode of acquisition of the disease, and note that similar syndromes are seen associated with gut infection. We consider that usage of the term Reiter's syndrome is correctly applied to only those cases which exhibited the characteristic triad of urethritis, arthritis and conjunctivitis with or without other cutaneous and mucous membrane lesions. Thirty-six of the 54 patients who were HLA typed (67 per cent) possessed the antigen HLA-B27. Of 30 who presented directly to a rheumatology unit 25 (82 per cent) were HLA-B27 positive. The other 24 patients initially attended a venereology clinic and only 11 (46 per cent) of these bore the antigen. This appears to reflect disease severity, HLA-B27 positive patients having a significantly longer duration of disease symptoms and a higher frequency of extra-articular manifestations, than those lacking this antigen.

Aphthous stomatitis

Behçet's disease is a triad of mouth ulcers, genital ulcers and anterior uveitis. The main feature of Behçet's disease is aphthous-like ulceration, but this is usually more severe than seen in aphthous stomatitis without a systemic cause, and typically resembles major or herpetiforme ulceration or both. Aphthous-like ulceration is the first sign of the disease in 25–75% of cases. Behçet's is more common in individuals whose ethnic origin is from regions along the Silk Road (between the Mediterranean and the Far East). It tends to be rare in other countries such as the United States and the United Kingdom. MAGIC syndrome is a possible variant of Behçet's disease, and is associated with aphthous-like ulceration. The name stands for "mouth and genital ulcers with inflamed cartilage" (relapsing polychondritis).

Behcet's disease: Diagnosed as isolated recurrent oral aphthae; a case report.

Behçet's disease is a multisystem autoimmune disorder of unknown origin, characterized by frequent oral and genital ulcerations, ocular and cutaneous lesions, arthritis, and it may also involve the gastrointestinal, and central nervous system. In this paper we discuss a case of Behcet syndrome presenting with isolated oral aphthous initially and spotlight on the clinical features and treatment. A case of a 32-year-old male with repetitive oral aphthous on the tongue and the inner cheeks for four days with a history of frequent recurrence. The patient responded to topical triamcinolone acetonide and 5-10 mg/day prednisone. Three weeks later, there was a recurrence of oral aphthous, genitalia lesions, and blurred vision with left eye redness. A uveitis diagnosis was made, and the patient was placed on 75mg (1mg/kg) prednisone with a resultant response. There was another recurrence with all the previous symptoms, so the decision with Dopson treatment was made. The patient was placed on Dapsone, resulting in complete resolution of the lesions with no reproduction within and after six months of several recall visits. The diagnosis of Bechet syndrome was made. Aphthous ulcers may be seen in a variety of disorders, while recurrent and persistent >6 weeks, individual non-healing ulcers require a review of the diagnosis. Behcet disease usually appears 2-3 years after oral and genital ulcers, but oral aphthae may be its first manifestation in 10-20% of cases. AS oral ulcers are among the common complaints of the polyclinics-patients, it is recommended to educate the health professionals to diagnose these unusual cases in the first instance, thus avoiding underdiagnosed and the time management to reduce complications and improve the quality of life in these patients. A case of Behçet's disease in a 32-year-old male who presented initially with oral mucosa and later caused uveitis and genitalia aphthae.

[A case of intestinal Behçet's disease with abnormal ossification complicated by myelodysplastic syndrome, symptoms revealed after the perforation of ileum ulcer].

A 39-year-old man, who had been treated with Etretinate for common wart since he was 29 years old, was admitted to Taga General Hospital complaining of gradually deteriorating lumbago and bilateral hip joints pain in September, 1996. His lower vertebrae and bilateral hip joints showed abnormal ossification on X-ray. The bone scintigraphy indicated the existence of sacroiliitis. His platelet counts were fluctuating between 8 x 10(4) and 9 x 10(4)/mm3. During the follow-up in our out-patient clinic, he was suddenly suffered from severe abdominal pain in August, 1997 and admitted to our hospital. An emergency operation revealed multiple ulcers of his ileum with several perforations. Histological findings of the specimen of the ileum showed simple ulcer. After the operation, he had oral and genital ulcers. He did not have any signs or symptoms of ocular involvement. He was diagnosed as intestinal Behçet's disease. Because he showed gradually pancytopenia for several months after the operation, bone marrow aspiration was performed and a diagnosis of refractory anemia, a type of myelodysplastic syndrome (MDS), with trisomy of chromosome 8 was made. Abnormal ossification of his vertebrae and hip joints were considered to be related to Behçet's disease because an coexistence with sacroiliitis. On the other hand, there is no denying the effects of orally Etretinate administration. Several cases have been reported the association of MDS with Behçet's disease. In this case, the existence of MDS or various symptoms in Behçet's disease became apparent after the perforation of ileum ulcer. This paper discusses possible etiology of the relation between Behçet's disease and MDS, or the characteristic clinical course in this case.

Aphthous stomatitis

Other examples of systemic conditions associated with aphthous-like ulceration include reactive arthritis, and recurrent erythema multiforme. Diagnosis Diagnosis is mostly based on the clinical appearance and the medical history. The most important diagnostic feature is a history of recurrent, self healing ulcers at fairly regular intervals. Although there are many causes of oral ulceration, recurrent oral ulceration has relatively few causes, most commonly aphthous stomatitis, but rarely Behçet's disease, erythema multiforme, ulceration associated with gastrointestinal disease, and recurrent intra-oral herpes simplex infection. A systemic cause is more likely in adults who suddenly develop recurrent oral ulceration with no prior history.

Oral manifestations of systemic disease

Oral manifestations of systematic disease are signs and symptoms of disease occurring elsewhere in the body detected in the oral cavity and oral secretions. High blood sugar can be detected by sampling saliva. Saliva sampling may be a non-invasive way to detect changes in the gut microbiome and changes in systemic disease. Another example is tertiary syphilis, where changes to teeth can occur. Syphilis infection can be associated with longitudinal furrows of the tongue. Mineral and vitamin deficiencies can cause the tongue to appear beefy red and feel sore. Those deficiencies are iron, folate, and vitamin B12. A hairy tongue may be an indication of Epstein Barr virus infection and is usually seen in those infected with human immunodeficiency virus. Other systemic diseases that can cause the tongue to form aphthous ulcers are: Crohn's disease and ulcerative colitis, Behcet's Syndrome, pemphigus vulgaris, herpes simplex, histoplasmosis, and reactive arthritis.

[Recurrent aphthous stomatitis: treatment with colchicine. An open trial of 54 cases].

Colchicine is a treatment used for aphthous stomatitis but its efficacy has never been proved. We report the results of an open trial of 54 patients treated with colchicine for aphthous stomatitis. The aim of our study was to assess the long and short term efficacy and tolerance of this molecule in this disease. The case reports of 64 patients presenting with severe, recurrent aphthous stomatitis treated with colchicine between 1986 and 2000 were analyzed retrospectively. Only immunocompetent patients exhibiting idiopathic aphthous stomatitis or Behçet's disease were included. Ten patients were excluded: 4 cases of Behçet's disease treated with colchicine and systemic corticosteroids, 4 cases of aphthous stomatitis secondary to a hematological cause and 2 patients who were lost to follow-up after 3 month's treatment. Colchicine was prescribed at a dose of 1 to 1.5 mg/d for at least 3 months. All the patients were assessed after 3 month's treatment and all were contacted by phone in May 2000. Our end-point criteria were: the frequency and duration of the episodes, intensity of pain and impact on the quality of life of the patients. Fifty-four patients were included: 39 women (mean age=44 +/- 16.8) and 15 men (mean age=49 +/- 13.5). The disease had progressed for a mean of 11.6 +/- 13.5 years. After 3 month's treatment, 12 patients (22 p. 100) no longer had aphta and were in complete remission, 22 patients (41 p. 100) were significantly improved, since the frequency and duration of the lesions had decreased by at least 50 p. 100 and the latter were no longer painful. Treatment failed or tolerance was poor in 20 patients (37 p. 100). Patients were monitored and assessed for a mean of 4.7 years (range: 6 months to 13 years). Six patients were lost to follow-up. Three patients (6 p. 100) were considered as cured, since they were still in complete remission after suspension of colchicine respectively 6, 24 and 72 months later. Fifteen patients (31 p. 100) had still improved. Among the latter, 10 continued colchicine for a mean of 27 months, and 5 patients stopped treatment, which they considered tedious, after a mean of 16 months. These 15 patients noted a significant reduction in the frequency and duration of the lesions. Moreover, the subjective end-point criteria had improved significantly for them not to wish to change treatment. Thirty patients (63 p. 100) were not improved by the treatment. Some benign adverse events were noted in 10 patients (18.5 p. 100) and led to suspension of treatment in 4 cases. This study, which is the first in size (n=54) and duration of follow-up (4.7 years), showed that colchicine is an efficient preventive treatment of severe aphthous stomatitis for 63 p. 100 of patients after 3 month's treatment and that this improvement was lasting in 37 p. 100 of them. Colchicine should therefore be proposed in first intention in severe recurrent aphthous stomatitis, since it is effective, well tolerated and easy to use.

Case Study: 24-Year-Old Male Presenting With Polyarthralgias -- Differential Diagnosis

The differential diagnosis for a young male (before fourth decade) with polyarthralgia is more inclined towards rheumatologic conditions like SLE, sarcoid arthritis, scleroderma, or gout. If associated with signs and symptoms of infection, gonococcal joint infection is high on the differential. Rheumatoid arthritis and polymyalgia rheumatica usually affect the older population (after the fourth decade). Based on the distribution of the joints, duration of symptoms, and association with other organ systems the classification of polyarthralgia is very broad and makes for a very challenging diagnosis. The most common differentials for a patient presenting with polyarthralgia are Rheumatoid arthritis, Lupus, Lyme, Septic arthritis, Gonorrheal joint arthritis, or Gout.

Recurrent Aphthous Stomatitis -- Evaluation

Recurrent aphthous stomatitis is a clinical diagnosis. [3] However, excluding other causes of recurrent aphthous ulcers in the mouth is necessary, like Behçet disease, nutritional deficiencies, or inflammatory bowel disease, particularly when RAS develops suddenly in an adult patient. [14] Some RAS patients have anemia, hematinic, or dietary deficiencies; it is common practice to evaluate the complete blood count, red cell folate, and ferritin and vitamin B12 serum levels, which may also reveal gastrointestinal disorders. [3]

Urban legends: recurrent aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) is the most common idiopathic intraoral ulcerative disease in the USA. Aphthae typically occur in apparently healthy individuals, although an association with certain systemic diseases has been reported. Despite the unclear etiopathogenesis, new drug trials are continuously conducted in an attempt to reduce pain and dysfunction. We investigated four controversial topics: (1) Is complex aphthosis a mild form of Behçet's disease (BD)? (2) Is periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome a distinct medical entity? (3) Is RAS associated with other systemic diseases [e.g., celiac disease (CD) and B12 deficiency]? (4) Are there any new RAS treatments? Results from extensive literature searches, including a systematic review of RAS trials, suggested the following: (1) Complex aphthosis is not a mild form of BD in North America or Western Europe; (2) Diagnostic criteria for PFAPA have low specificity and the characteristics of the oral ulcers warrant further studies; (3) Oral ulcers may be associated with CD; however, these ulcers may not be RAS; RAS is rarely associated with B12 deficiency; nevertheless, B12 treatment may be beneficial, via mechanisms that warrant further study; (4) Thirty-three controlled trials published in the past 6 years reported some effectiveness, although potential for bias was high.

Juvenile onset Reiter's syndrome. A retrospective study of 26 patients.

Clinical, laboratory and radiological findings were evaluated in 26 children with Reiter's syndrome, all of whom met the 1982 diagnostic criteria of A. Calin. Twenty-two of the patients (85%) were male and 4 were female (15%); the mean age at onset was 10.5 years (range 4-15.5 yrs). Mean follow-up time was 28.6 months. Diarrhea prior to onset was observed in 18 cases (69%), but there was no report of venereal disease. The full classic triad was initially observed in only 9 patients (35%), urethritis alone in 6 (23%) and conjunctivitis alone in 4 (15%). Arthritis was present in all patients, with the lower limb joints involved in 25 cases (96%); the pattern was pauciarticular in 18 (69%), polyarticular in 7 (27%) and monoarticular in one (4%). There was complete remission in 15 out of the 26 patients (58%), while a sustained and fluctuating course was seen in 7 (27%) and 3 (11.5%) patients, respectively; a single patient showed a remitting course. Balanitis was present in 11 out of the 22 male (50%) cases. Twelve out of 18 patients tested (67%) proved to be HLA B27 positive and there was radiological evidence of sacroiliitis in 5 out of 24 patients (21%). Reiter's syndrome should be included in the differential diagnosis of the arthritic child. As a rule, the course of joint involvement is remittent and sequelae affecting functional capacity are indeed exceptional.

Aphthous stomatitis

RAS type ulceration Recurrent oral ulceration associated with systemic conditions is termed "RAS-type ulceration", "RAS-like ulceration", or "aphthous-like ulcers". Aphthous stomatitis occurs in individuals with no associated systemic disease. Persons with certain systemic diseases may be prone to oral ulceration, but this is secondary to the underlying medical condition (see the systemic disease section). This kind of ulceration is considered by some to be separate from true aphthous stomatitis. However, this definition is not strictly applied. For example, many sources refer to oral ulceration caused by anemia and/or nutritional deficiencies as aphthous stomatitis, and some also consider Behçet's disease to be a variant. Treatment

First_Aid_Step2

Arthritis, conjunctivitis, and urethritis in young men. Associated organisms? A 55-year-old man has sudden, excruciating first MTP joint pain after a night of drinking red wine. Diagnosis, workup, and chronic treatment? Spinal stenosis. MCP and PIP joints; DIP joints are spared. Osteoarthritis. Osteogenesis imperfecta. Suspect ankylosing spondylitis. Check HLA-B27. Reactive (Reiter’s) arthritis. Associated with Campylobacter, Shigella, Salmonella, Chlamydia, and Ureaplasma. Gout. Needle-shaped, negatively birefringent crystals are seen on joint ﬂuid aspirate. Chronic treatment with allopurinol or probenecid. Rhomboid-shaped, positively birefringent crystals on joint ﬂ uid aspirate. An elderly woman presents with pain and stiffness of the shoulders and hips; she cannot lift her arms above her head. Labs show anemia and ↑ ESR.

Recurrent Aphthous Stomatitis -- Etiology -- Systemic

Aphthous-like ulcerations may occur in various systemic diseases, including Behçet disease, nutritional deficiencies, gastrointestinal disorders, and primary and secondary immunodeficiencies, including HIV. [3]

Mouth ulcer

Other causes A wide range of other diseases may cause mouth ulcers. Hematological causes include anemia, hematinic deficiencies, neutropenia, hypereosinophilic syndrome, leukemia, myelodysplastic syndromes, other white cell dyscrasias, and gammopathies. Gastrointestinal causes include celiac disease, Crohn's disease (orofacial granulomatosis), and ulcerative colitis. Dermatological causes include chronic ulcerative stomatitis, erythema multiforme (Stevens-Johnson syndrome), angina bullosa haemorrhagica and lichen planus. Other examples of systemic disease capable of causing mouth ulcers include lupus erythematosus, Sweet syndrome, reactive arthritis, Behçet syndrome, granulomatosis with polyangiitis, periarteritis nodosa, giant cell arteritis, diabetes, glucagonoma, sarcoidosis and periodic fever, aphthous stomatitis, pharyngitis and adenitis. The conditions eosinophilic ulcer and necrotizing sialometaplasia may present as oral ulceration.

Exacerbation of soft tissue rheumatism by excess vitamin A: case reviews with clinical vignette.

In certain situations, health problems can arise if physicians are not aware of over-the-counter medications and vitamins a patient may be taking in addition to their regular prescriptions. Since many people do not consider OTC drugs to be medications, they often do not relay this information while discussing their medical histories. This article describes how the symptoms of soft tissue rheumatism can become worse if patients ingest an excess amount of vitamin A.

[Adult-onset Still's disease. Differential diagnosis in recurrent pharyngitis, fever of unknown original and excessive hyperferritinemia].

Six weeks before admission a 43-year old previously healthy woman got right-sided pharyngitis, accompanied with Herpes labialis and oral candidiasis. Two weeks later she travelled to a holiday in the Caribbean. During the first week of holiday she developed pharyngitis again, this time accompanied with fever and arthralgies. Therapeutic trial with antibiotics, antimalaric drugs and antiamoebics, given at the holiday resort, did not reduce fever. Immediately after return to Germany a therapeutic trial with imipenem was was attempted, without any apparent improvement. At admission, the patient was febrile, had pinky patchy exanthema and arthralgias. At admission, abnormal findings included anaemia (Hb 8.8 mg/dl), severe leukocytosis (35.3/nl), increased ESR (43/89 mm), CRP (24.2 mg/dl) and ferritin (5751 micrograms/l). Ultrasound examination revealed mild splenomegaly. Computed tomography of the abdomen and chest were without apparent abnormalities. Infection, autoimmune diseases and neoplasia were ruled out. The diagnosis of adult onset Still's disease was established on the basis of a typical triad of symptoms (fever, exanthema, arthritis). Treatment with 100 mg/d prednisolon (started intravenously) was beneficial for fever and arthralgia, and resulted in the normalisation of laboratory findings. After gradual reduction in the corticosteroid dosage, maintenance treatment with 20 mg/d prednisolon was continued over following months. Recurrent prodromal pharyngitis and excessive hyperferritinaemia are, in addition to the triad fever-exanthema-arthritis, further important diagnostic criteria of adult onset Still's disease.

Autoinflammatory diseases

Clinical classification 1. Episodic and multisystemic AIDs (NLRP12-associated disease, Mevalonate kinase deficiency, PFAPA (Periodic fever syndrome, aphthous stomatitis, pharyngitis, and cervical adenitis) or TRAPS (tumor necrosis factor (TNF) receptor–associated periodic fever syndrome)) 2. Episodic, affecting the joints (Gout) 3. Episodic, affecting bone (Chronic recurrent multifocal osteomyelitis (CRMO)) 4. Persistent and multisystemic (Schnitzler syndrome, Crohn's disease or DIRA) 5. Persistent, affecting the skin (Interleukin-36-receptor antagonist deficiency (DITRA), Sweet syndrome or Neutrophilic panniculitis) Molecular mechanism of the origin 1. Inflammasome activation (Mevalonate kinase deficiency or Muckle–Wells syndrome) 2. NFκB activation (NLRP12-associated disease, Crohn's disease or Blau syndrome) 3. IL‑1β pathway dysregulation (PFAPA, Schnitzler syndrome, DIRA or DITRA)

[Clinical observation of Behçet's disease in a 33-year-old woman].

The paper describes a clinical case of Behçet's disease accompanied by oral aphthous elements and external genital sores. The disease occurred after an infectious and inflammatory process in the oropharynx; chronic erythema nodosum and arthritides were successively diagnosed. A set of anamnestic data and clinical and laboratory examinations could establish a correct diagnosis.

Reactive arthritis

The manifestations of reactive arthritis include the following triad of symptoms: an inflammatory arthritis of large joints, inflammation of the eyes in the form of conjunctivitis or uveitis, and urethritis in men or cervicitis in women. Arthritis occurring alone following sexual exposure or enteric infection is also known as reactive arthritis. Patients can also present with mucocutaneous lesions, as well as psoriasis-like skin lesions such as circinate balanitis, and keratoderma blennorrhagicum. Enthesitis can involve the Achilles tendon resulting in heel pain. Not all affected persons have all the manifestations. The clinical pattern of reactive arthritis commonly consists of an inflammation of fewer than five joints which often includes the knee or sacroiliac joint. The arthritis may be "additive" (more joints become inflamed in addition to the primarily affected one) or "migratory" (new joints become inflamed after the initially inflamed site has already improved).

[Nosological diagnosis and outcomes of arthritis associated with streptococcal infection].

To specify the course and outcomes of arthritides associated with streptococcal infection (AASI). The trial comprised 60 patients with arthritis (mean age 26.8 +/- 14.0). The patients met the following criteria: arthritis, elevated (< 500 U) titers of antistreptolisin-0 in the absence of heart disorders detected at Doppler-echocardiography (2D-echoCG), urogenital infection, Yersinia infection, psoriasis. In addition to routine clinical tests, the following investigations were made: tests for alloantigen of B-lymphocytes D8/17 and antigen HLA-B27, antibodies to polysaccharide of streptococcus of group A, bacteriological test of laryngeal smears for streptococcal infection, prospective follow-up (mean 31.2 +/- 19.6 mon) with 2D-echoCG. Rheumatic arthritis was rejected in 33.3% patients. Other diseases were diagnosed: early rheumatoid arthritis (10%), seronegative spondylarthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Still's disease, Konig's disease, sarcoidosis, gout, arthritis on the background of streptococcal nodular erythema. Acute rheumatoid fever (ARF) was diagnosed in 56.7% patients, poststreptococcal arthritis (PSA) in 10%. PSA differed from ARF by onset at the age of 36.0 +/- 10.2 years, short latent period (11.2 +/- 1.3 days), a significantly longer course of arthritis (95.0 +/- 3.9 days), recurrences. Alloantigen of B-lymphocytes was detected in 52.8% AASI patients (the difference from the control is highly significant (p < 0.001). Arthritis development was not associated with carriage of HLA-B27 carriage. In examination of AASI patients for diagnosis of ARV and PSA it is necessary to reject other diseases among which early RA (10%) is most frequent. It is recommended to make diagnosis of ARF in AASI patients with definition of risk factors (age 7-15 years, family history of rheumatic fever, carriage of alloantigen d8/17), 2.5-year and longer follow-up with 2D-echoCG. Diagnosis of PSA is made in rejection of ARF and in the presence of the following characteristics: development of the disease at the age 30-40 years, a short latent period of the infection, long-term persistent course of arthritis, insufficient effect of nonsteroid anti-inflammatory drugs, frequent affection of sacroiliac joints, recurrence, entezopathy.

Aphthous stomatitis

Gastrointestinal disorders are sometimes associated with aphthous-like stomatitis, e.g. most commonly celiac disease, but also inflammatory bowel disease such as Crohn's disease or ulcerative colitis. The link between gastrointestinal disorders and aphthous stomatitis is probably related to nutritional deficiencies caused by malabsorption. Less than 5% of people with RAS have celiac disease, which usually presents with severe malnutrition, anemia, abdominal pain, diarrhea and glossitis (inflammation of the tongue). Sometimes aphthous-like ulcerations can be the only sign of celiac disease. Despite this association, a gluten-free diet does not usually improve the oral ulceration. Other examples of systemic conditions associated with aphthous-like ulceration include reactive arthritis, and recurrent erythema multiforme. Diagnosis

Acute venereal arthritis. Comparative study of acute Reiter syndrome and acute gonococcal arthritis.

Acute venereal arthritis, a syndrome of fever and inflammatory arthritis following recent sexual intercourse, is a frequently misdiagnosed arthritic presentation. Nearly half of 39 patients admitted with a diagnosis of acute gonococcal arthritis were subsequently recognized as having acute Reiter syndrome. A retrospective study of both diseases revealed differentiating features that, when prospectively applied to 21 consecutive patients, permitted a correct and prompt bedside diagnosis. Acute Reiter syndrome could be differentiated by characteristic mucucutaneous lesions, arthritis/tenosynovitis confined to lower extremities, massive recurrent knee effusions, low back pain, conjunctivitis, and genitourinary inflammation. Gonococcal arthritis could be differentiated by migratory arthralgias, high fevers, arthritis/tenosynovitis initially confined to upper extremities, typical cutaneous lesions, and dramatic defervescence to penicillin therapy. Laboratory data provided support for each diagnosis.

First_Aid_Step2

Typical onset is in the late teens and early 20s. Presents with fatigue, intermittent hip pain, and LBP that worsens with inactivity and in the mornings. ■↓ spine ﬂ exion ( Schober test), loss of lumbar lordosis, hip pain and stiffness, and ↓ chest expansion are seen as the disease progresses. Anterior uveitis and heart block may occur. Other forms of seronegative spondyloarthropathy must be ruled out, including the following: Reactive arthritis (formerly known as Reiter’s syndrome): A disease of young men. The characteristic arthritis, uveitis, conjunctivitis, and urethritis usually follow an infection with Campylobacter, Shigella, Salmonella, Chlamydia, or Ureaplasma. Psoriatic arthritis: An oligoarthritis that can include the DIP joints. TABLE 2.9-3. Gout vs. Pseudogout Associated with psoriatic skin changes and sausage-shaped digits (dactylitis).

Recurrent Aphthous Stomatitis -- Differential Diagnosis

Behçet disease: patients also have recurrent ulcerations in the genitalia, skin disorders (usually erythema nodosum or papulopustular lesions), ocular disease (usually posterior uveitis), and a variety of neurological, gastrointestinal, renal, hematological, or joint disorders.

[Wxanthema and acute polyarthritis in a young patient].

A young woman developed acute polysynovitis and vasculitis-like changes to the skin. Her blood cultures were positive for Neisseria meningitidis, enabling us to diagnose chronic meningococcemia. This finding was a surprise; in retrospect this diagnosis would not have been expected in light of the fact that there was no meningism, the patient's general condition was only slightly diminished and the temperatures were subfebrile. Besides an episode of vasculitis, the primary differential diagnosis of acute polysynovitis in young women should include a bacterial infection, for example with Neisseria. Usually, Neisseria gonorrhoeae (gonococci) are involved and, as in the case described, only very rarely Neisseria meningitidis (meningococci). The present case report is given to illustrate new clinical aspects of known, but rare disease, to remind clinicians to consider the differential diagnosis of acute polyarthritis and to generate discussion about the clinical signs and pathogenesis of reactive arthritides, in particular, Neisseria.

Reactive arthritis

Because common systems involved include the eye, the urinary system, and the hands and feet, one clinical mnemonic in reactive arthritis is "Can't see, can't pee, can't climb a tree." The classic triad consists of: Conjunctivitis Nongonococcal urethritis Asymmetric oligoarthritis Symptoms generally appear within 1–3 weeks but can range from 4 to 35 days from the onset of the inciting episode of the disease. The classical presentation of the syndrome starts with urinary symptoms such as burning pain on urination (dysuria) or an increased frequency of urination. Other urogenital problems may arise such as prostatitis in men and cervicitis, salpingitis and/or vulvovaginitis in women. It presents with monoarthritis affecting the large joints such as the knees and sacroiliac spine causing pain and swelling. An asymmetrical inflammatory arthritis of interphalangeal joints may be present but with relative sparing of small joints such as the wrist and hand.

[Sweet's syndrome: a study of 16 cases].

We performed a retrospective analysis of the records of 16 patients diagnosed in our dermatology service as Sweet's syndrome (SS), with the aim of describing their clinical findings and associations, and comparing our results with previous ones. The mean age was 51, and 82% were female. A previous infection was recorded in 5 cases (31%) (gastroenteritis, primary pulmonary tuberculosis, upper airways infection, wound infection, and streptococcal pharyngitis). Two patients (12%) suffered from a malignant neoplasia (acute myeloid leukemia and prostatic neoplasia), another patient had a coincident bout of acute ulcerative colitis with pyoderma gangrenosum, and a third one referred previous ingestion of diclofenac and intense sun exposure. Most patients had their lesions localized on the upper extremities (75%), fever was present in 8 cases (50%), arthralgia in six (37%), and erythema nodosum in five (31%). The most frequent laboratory finding was an elevated sedimentation rate (93% had values over 20 mm/h), and only 44% of patients had leukocyte counts over 10 x 10(9)/l. Urinanalysis was abnormal in one third of the patients, and chest roentgenograms, performed in ten patients, were all normal. Most of the patients were treated with low doses of oral prednisone (30 mg/day) with good results. The disease recurred in 25% of the patients.