Association of congenital, diffuse electrical disease in children with normal heart: sick sinus syndrome, intraventricular conduction block, and monomorphic ventricular tachycardia.

INTRODUCTION Rhythm disturbances in children with structurally normal hearts are usually associated with abnormalities in cardiac ion channels. The phenotypic expression of these abnormalities ("channelopathies") includes: long and short QT syndromes, Brugada syndrome, congenital sick sinus syndrome, catecholaminergic polymorphic ventricular tachycardia, Lènegre-Lev disease, and/or different degrees of cardiac conduction disease. METHODS The study group consisted of three male patients with sick sinus syndrome, intraventricular conduction disease, and monomorphic sustained ventricular tachycardia. Clinical data and results of electrocardiography, Holter monitoring, electrophysiology, and echocardiography are described. RESULTS In all patients, the ECG during sinus rhythm showed right bundle branch block and long QT intervals. First-degree AV block was documented in two subjects, and J point elevation in one. A pacemaker was implanted in all cases due to symptomatic bradycardia (sick sinus syndrome). Atrial tachyarryhthmias were observed in two patients. The common characteristic ventricular arrhythmia was a monomorphic sustained ventricular tachycardia, inducible with ventricular stimulation and sensitive to lidocaine. In one patient, radiofrequency catheter ablation was successfully performed. No structural abnormalities were found in echocardiography in the study group. CONCLUSION Common clinical and ECG features suggest a common pathophysiology in this group of patients with congenital severe electrical disease.

Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse.

Leopard complex spotting is a group of white spotting patterns in horses caused by an incompletely dominant gene (LP) where homozygotes (LP/LP) are also affected with congenital stationary night blindness. Previous studies implicated Transient Receptor Potential Cation Channel, Subfamily M, Member 1 (TRPM1) as the best candidate gene for both CSNB and LP. RNA-Seq data pinpointed a 1378 bp insertion in intron 1 of TRPM1 as the potential cause. This insertion, a long terminal repeat (LTR) of an endogenous retrovirus, was completely associated with LP, testing 511 horses (χ(2)=1022.00, p<0.0005), and CSNB, testing 43 horses (χ(2)=43, p<0.0005). The LTR was shown to disrupt TRPM1 transcription by premature poly-adenylation. Furthermore, while deleterious transposable element insertions should be quickly selected against the identification of this insertion in three ancient DNA samples suggests it has been maintained in the horse gene pool for at least 17,000 years. This study represents the first description of an LTR insertion being associated with both a pigmentation phenotype and an eye disorder.

Ultrasonographic features of PMEL17 ( Silver ) mutant gene-associated multiple congenital ocular anomalies (MCOA) in Comtois and Rocky Mountain horses

OBJECTIVE: (1) To describe the ultrasonographic appearance of multiple congenital ocular anomalies (MCOA) in the eyes of horses with the PMEL17 (Silver) mutant gene. (2) To compare the accuracy of B-mode ocular ultrasound to conventional direct ophthalmoscopy. ANIMALS STUDIED: Sixty-seven Comtois and 18 Rocky Mountain horses were included in the study. PROCEDURES: Horses were classified as being carriers or noncarriers of the PMEL17 mutant allele based on coat color or genetic testing. Direct ophthalmoscopy followed by standardized ultrasonographic examination was performed in all horses. RESULTS: Seventy-five of 85 horses (88.24%) carried at least one copy of the Silver mutant allele. Cornea globosa, severe iridal hypoplasia, uveal cysts, cataracts, and retinal detachment could be appreciated with ultrasound. Carrier horses had statistically significantly increased anterior chamber depth and decreased thickness of anterior uvea compared with noncarriers (P < 0.05). Uveal cysts had a wide range of location and ultrasonographic appearances. In 51/73 (69.86%) carrier horses, ultrasound detected ciliary cysts that were missed with direct ophthalmoscopy. CONCLUSIONS: In this study, ultrasonography was useful to identify uveal cysts in PMEL17 mutant carriers and to assess anterior chamber depth.

Toxoplasma gondii Infection in Kyrgyzstan: Seroprevalence, Risk Factor Analysis, and Estimate of Congenital and AIDS-Related Toxoplasmosis

Background HIV-prevalence, as well as incidence of zoonotic parasitic diseases like cystic echinococcosis, has increased in the Kyrgyz Republic due to fundamental socio-economic changes after the breakdown of the Soviet Union. The possible impact on morbidity and mortality caused by Toxoplasma gondii infection in congenital toxoplasmosis or as an opportunistic infection in the emerging AIDS pandemic has not been reported from Kyrgyzstan. Methodology/Principal Findings We screened 1,061 rural and 899 urban people to determine the seroprevalence of T. gondii infection in 2 representative but epidemiologically distinct populations in Kyrgyzstan. The rural population was from a typical agricultural district where sheep husbandry is a major occupation. The urban population was selected in collaboration with several diagnostic laboratories in Bishkek, the largest city in Kyrgyzstan. We designed a questionnaire that was used on all rural subjects so a risk-factor analysis could be undertaken. The samples from the urban population were anonymous and only data with regard to age and gender was available. Estimates of putative cases of congenital and AIDS-related toxoplasmosis in the whole country were made from the results of the serology. Specific antibodies (IgG) against Triton X-100 extracted antigens of T. gondii tachyzoites from in vitro cultures were determined by ELISA. Overall seroprevalence of infection with T. gondii in people living in rural vs. urban areas was 6.2% (95%CI: 4.8–7.8) (adjusted seroprevalence based on census figures 5.1%, 95% CI 3.9–6.5), and 19.0% (95%CI: 16.5–21.7) (adjusted 16.4%, 95% CI 14.1–19.3), respectively, without significant gender-specific differences. The seroprevalence increased with age. Independently low social status increased the risk of Toxoplasma seropositivity while increasing numbers of sheep owned decreased the risk of seropositivity. Water supply, consumption of unpasteurized milk products or undercooked meat, as well as cat ownership, had no significant influence on the risk for seropositivity. Conclusions We present a first seroprevalence analysis for human T. gondii infection in the Kyrgyz Republic. Based on these data we estimate that 173 (95% CI 136–216) Kyrgyz children will be born annually to mothers who seroconverted to toxoplasmosis during pregnancy. In addition, between 350 and 1,000 HIV-infected persons are currently estimated to be seropositive for toxoplasmosis. Taken together, this suggests a substantial impact of congenital and AIDS-related symptomatic toxoplasmosis on morbidity and mortality in Kyrgyzstan.

Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort

BACKGROUND & AIMS Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry

Hereditary thrombotic thrombocytopenic purpura, Upshaw-Schulman syndrome, ADAMTS13 Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is a rare recessively inherited disease. Underlying is a severe constitutional deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, due to compound heterozygous or homozygous mutations in the ADAMTS13 gene. The clinical picture is variable and more and more patients with an adult-onset are diagnosed. In the majority of countries the only available treatment is plasma, which when administered regularly can efficiently prevent acute disease bouts. The decision to initiate regular prophylaxis is often not easy, as evidence based guidelines and long term outcome data are lacking. Through the hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov identifier: NCT01257269), which was initiated in 2006 and is open to all patients diagnosed with Upshaw-Schulman syndrome and their family members, we aim to gain further information and insights into this rare disease, which eventually will help to improve clinical management of affected patients.

Congenital factor XIII deficiency in Pakistan: characterization of seven families and identification of four novel mutations

Deficiency of coagulation factor XIII (FXIII) belongs to the rare bleeding disorders and its incidence is higher in populations with consanguineous marriages. The aims of this study were to characterize patients and relatives from seven families with suspected FXIII deficiency from Pakistan and to identify the underlying mutations. As a first indicator of FXIII deficiency, a 5M urea clot solubility test was used. Plasma FXIII A- and B-subunit antigen levels were determined by ELISA. FXIII activity was measured with an incorporation assay. Sequencing of all exons and intron/exon boundaries of F13A was performed, and a novel splice site defect was confirmed by RT-PCR analysis. Genetic analysis revealed six different mutations in the F13A gene. Two splice site mutations were detected, a novel c.1460+1G>A mutation in the first nucleotide of intron 11 and a previously reported c.2045G>A mutation in the last nucleotide of exon 14. Neither of them was expressed at protein level. A novel nonsense mutation in exon 4, c.567T>A, p.Cys188X, was identified, leading in homozygous form to severe FXIII deficiency. Two novel missense mutations were found in exons 8 and 9, c.1040C>A, p.Ala346Asp and c.1126T>C, p.Trp375Arg, and a previously reported missense mutation in exon 10, c.1241C>T, p.Ser413Leu. All patients homozygous for these missense mutations presented with severe FXIII deficiency. We have analysed a cohort of 27 individuals and reported four novel mutations leading to congenital FXIII deficiency.

The temporal impulse response function in infantile nystagmus.

Despite rapid to-and-fro motion of the retinal image that results from their incessant involuntary eye movements, persons with infantile nystagmus (IN) rarely report the perception of motion smear. We performed two experiments to determine if the reduction of perceived motion smear in persons with IN is associated with an increase in the speed of the temporal impulse response. In Experiment 1, increment thresholds were determined for pairs of successively presented flashes of a long horizontal line, presented on a 65-cd/m2 background field. The stimulus-onset asynchrony (SOA) between the first and second flash varied from 5.9 to 234 ms. In experiment 2, temporal contrast sensitivity functions were determined for a 3-cpd horizontal square-wave grating that underwent counterphase flicker at temporal frequencies between 1 and 40 Hz. Data were obtained for 2 subjects with predominantly pendular IN and 8 normal observers in Experiment 1 and for 3 subjects with IN and 4 normal observers in Experiment 2. Temporal impulse response functions (TIRFs) were estimated as the impulse response of a linear second-order system that provided the best fit to the increment threshold data in Experiment 1 and to the temporal contrast sensitivity functions in Experiment 2. Estimated TIRFs of the subjects with pendular IN have natural temporal frequencies that are significantly faster than those of normal observers (ca. 13 vs. 9 Hz), indicating an accelerated temporal response to visual stimuli. This increase in response speed is too small to account by itself for the virtual absence of perceived motion smear in subjects with IN, and additional neural mechanisms are considered.

A study of the cost and effect of newborn screening for Congenital Adrenal Hyperplasia in Texas

Congenital Adrenal Hyperplasia (CAH), due to 21-Hydroxylase deficiency, has an estimated incidence of 1:15,000 births and can result in death, salt-wasting crisis or impaired growth. It has been proposed that early diagnosis and treatment of infants detected from newborn screening for CAH will decrease the incidence of mortality and morbidity in the affected population. The Texas Department of Health (TDH) began mandatory screening for CAH in June, 1989 and Texas is one of fourteen states to provide neonatal screening for the disorder.^ The purpose of this study was to describe the cost and effect of screening for CAH in Texas during 1994 and to compare cases first detected by screen and first detected clinically between January 1, 1990 and December 31, 1994. This study used a longitudinal descriptive research design. The data was secondary and previously collected by the Texas Department of Health. Along with the descriptive study, an economic analysis was done. The cost of the program was defined, measured and valued for four phases of screening: specimen collection, specimen testing, follow-up and diagnostic evaluation.^ There were 103 infants with Classical CAH diagnosed during the study and 71 of the cases had the more serious Salt-Wasting form of the disease. Of the infants diagnosed with Classical CAH, 60% of the cases were first detected by screen and 40% were first detected because of clinical findings before the screening results were returned. The base case cost of adding newborn screening to an existing program (excluding the cost of specimen collection) was $357,989 for 100,000 infants. The cost per case of Classical CAH diagnosed, based on the number of infants first detected by screen in 1994, was \$126,892. There were 42 infants diagnosed with the more benign Nonclassical form of the disease. When these cases were included in the total, the cost per infant to diagnose Congenital Adrenal/Hyperplasia was $87,848. ^

Patterns of care and outcomes for pregnant inmates and their infants in Texas state prisons: Epidemiologic and ethnographic analyses

Female inmates make up the fastest growing segment in our criminal justice system today. The rapidly increasing trend for female prisoners calls for enhanced efforts to strategically plan the correctional facilities that address the needs of this growing population, and to work with communities to prevent crime in women. The incarcerated women in the U.S. have an estimated 145,000 minor children who are predisposed to unique psychosocial problems as a result of parental incarceration.^ This study examined the patterns of care and outcomes for pregnant inmates and their infants in Texas state prisons between 1994 and 1996. The study population consists of 202 pregnant inmates who delivered in a 2-year period, and a randomly sampled comparison cohort of 804 women from general Texas population, matched on race and educational levels. Both quantitative and qualitative data were used to elucidate the inmates' risk-factor profile, delivery/birth outcomes, and the patterns of care during pregnancy. The continuity-of-care issues for this population were also explored.^ Epidemiologic data were derived from multiple record systems to establish the comparison between two cohorts. A significantly great proportion of the inmates have prior lifestyle risk-factors (smoking, alcohol, and illicit drug abuse), poorer health status, and worse medical history. However, most of these existing risk-factors seem to show little manifestation in their current pregnancy. On the basis of maternal labor/delivery outcome and a number of neonatal indicators, this study found some evidence of a better pregnancy outcome for the inmate cohort when compared to the comparison group. Some possible explanations of this paradox were discussed. Seventeen percent of inmates gave birth to infants with suspected congenital syphilis. The placement patterns for the infants' care immediately after birth were elucidated.^ In addition to the quantitative data, an ethnographic approach was used to collect qualitative data from a subset of the inmate cohort (n = 20) and 12 care providers. The qualitative data were analyzed for their contents and themes, giving rise to a detailed description of the inmates' pregnancy experience. Eleven themes emerged from the study's thematic analysis, which provides the context for interpreting the epidemiologic data.^ Meaningful findings in this study were presented in a three-dimensional matrix to shed light on the apparent relationship between outcome indicators and their potential determinants. The suspected "linkages" between the outcome and their determinants can be used to generate hypotheses for future studies. ^

Idiopathic chylothorax and lymphedema in 2 whippet littermates.

Idiopathic chylothorax and limb edema was diagnosed in two 2-year-old male whippet siblings. The fact that the 2 related animals developed similar clinical signs at a young age may suggest a congenital or hereditary etiology.

Congenital Hepatic Fibrosis in the Franches-Montagnes Horse Is Associated with the Polycystic Kidney and Hepatic Disease 1 (PKHD1) Gene

Congenital hepatic fibrosis has been described as a lethal disease with monogenic autosomal recessive inheritance in the Swiss Franches-Montagnes horse breed. We performed a genome-wide association study with 5 cases and 12 controls and detected an association on chromosome 20. Subsequent homozygosity mapping defined a critical interval of 952 kb harboring 10 annotated genes and loci including the polycystic kidney and hepatic disease 1 (autosomal recessive) gene (PKHD1). PKHD1 represents an excellent functional candidate as variants in this gene were identified in human patients with autosomal recessive polycystic kidney and hepatic disease (ARPKD) as well as several mouse and rat mutants. Whereas most pathogenic PKHD1 variants lead to polycystic defects in kidney and liver, a small subset of the human ARPKD patients have only liver symptoms, similar to our horses with congenital hepatic fibrosis. The PKHD1 gene is one of the largest genes in the genome with multiple alternative transcripts that have not yet been fully characterized. We sequenced the genomes of an affected foal and 46 control horses to establish a comprehensive list of variants in the critical interval. We identified two missense variants in the PKHD1 gene which were strongly, but not perfectly associated with congenital hepatic fibrosis. We speculate that reduced penetrance and/or potential epistatic interactions with hypothetical modifier genes may explain the imperfect association of the detected PKHD1 variants. Our data thus indicate that horses with congenital hepatic fibrosis represent an interesting large animal model for the liver-restricted subtype of human ARPKD.

Diseases of the Tendons and Tendon Sheaths

Contracted flexor tendon leading to flexural deformity is a common congenital defect in cattle. Arthrogryposis is a congenital syndrome of persistent joint contracture that occurs frequently in Europe as a consequence of Schmallenberg virus infection of the dam. Spastic paresis has a hereditary component, and affected cattle should not be used for breeding purposes. The most common tendon avulsion involves the deep digital flexor tendon. Tendon disruptions may be successfully managed by tenorrhaphy and external coaptation or by external coaptation alone. Medical management alone is unlikely to be effective for purulent tenosynovitis.

Congenital nasolacrimal duct fistula in Brown Swiss cattle

BACKGROUND An increased incidence of nasolacrimal duct fistula in the offspring of dam J and three of her sons (bulls A, B and C) prompted a study to investigate the prevalence and clinical manifestation of this anomaly. The dam J, bull B, 255 direct offspring of bulls A, B, and C and eight other direct and indirect offspring of cow J were examined. The periocular region of each animal was examined for unilateral or bilateral nasolacrimal duct fistula and the location, appearance and size of the lesions. RESULTS Of 265 cattle examined, 54 had unilateral (n = 24) or bilateral fistula (n = 30). The prevalence of affected offspring differed significantly among the three bulls. The fistulae were located medial to the medial canthus of the eye and were 1 to 10 mm (median, 1 mm) in height and 1 to 12 mm (median, 2 mm) in length. The shape of the opening was circular in 58, oval in 23 and slit-like in three. One other animal had a large opening with an atypical shape and another had an abnormal medial canthus with several fistulous openings. Seventy openings were pigmented and 52 were hairless. The fistulae were clinically significant in 12 animals. CONCLUSIONS The findings suggest a hereditary cause of nasolacrimal duct fistula in Brown Swiss cattle.

Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura.

UNLABELLED We report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. DIAGNOSIS In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. CONCLUSION Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.