Tamar Stricker

Vaginal foreign bodies

Objective:  To evaluate the clinical features and outcome in girls with a vaginal foreign body.

Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium

The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the National Institutes of Health to study rare diseases. This paper reviews the UCDCs accomplishments over the first 6years, including how the Consortium was developed and organized, clinical research studies initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foundations and biotech and pharmaceutical companies.

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial.

Mastitis in early infancy

Aim: To evaluate the clinical features and microbiological findings in young infants with mastitis. Methods: Retrospective review of medical records of 18 infants with breast inflammation during the first 3 mo of life seen in the paediatric emergency department between 1992 and 2002. Results: All were full‐term infants with female–male ratio of 3.5∶1. The age ranged from 12 to 45 d, with a peak in the 4th and 5th weeks of life. Only five patients had systemic manifestations, and five were pretreated with oral antibiotics (amoxicillin‐clavulanic acid). The latter as well as seven additional cases required incision and drainage due to abscess formation. Bacterial cultures grew Staphylococcus aureus in 10 cases including all pretreated infants. In four of these cases, Gram stain showed the pathogen. After antimicrobial treatment, no recurrence was observed in any of the patients.

Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders

Sodium phenylbutyrate (NaPBA) is a commonly used medication for the treatment of patients with urea cycle disorders (UCDs). Previous reports involving small numbers of patients with UCDs have shown that NaPBA treatment can result in lower plasma levels of the branched-chain amino acids (BCAA) but this has not been studied systematically. From a large cohort of patients (n=553) with UCDs enrolled in the Longitudinal Study of Urea Cycle Disorders, a collaborative multicenter study of the Urea Cycle Disorders Consortium, we evaluated whether treatment with NaPBA leads to a decrease in plasma BCAA levels. Our analysis shows that NaPBA use independently affects the plasma BCAA levels even after accounting for multiple confounding covariates. Moreover, NaPBA use increases the risk for BCAA deficiency. This effect of NaPBA seems specific to plasma BCAA levels, as levels of other essential amino acids are not altered by its use. Our study, in an unselected population of UCD subjects, is the largest to analyze the effects of NaPBA on BCAA metabolism and potentially has significant clinical implications. Our results indicate that plasma BCAA levels should to be monitored in patients treated with NaPBA since patients taking the medication are at increased risk for BCAA deficiency. On a broader scale, these findings could open avenues to explore NaPBA as a therapy in maple syrup urine disease and other common complex disorders with dysregulation of BCAA metabolism.

Oral bleeding: Child abuse alert

Abstract:  Physicians must be aware of histories, behaviours and physical findings of maltreated children. We report two cases of physical child abuse in which the initial symptom was oral bleeding. In both cases, the diagnosis was delayed and was made only after severe injuries were inflicted. Injuries to the oral cavity and oral bleeding of uncertain origin in infants should be considered seriously and should be carefully assessed in relation to adequacy of history to explain the mechanism of injury. When an infant has been injured and no adequate explanation is available to account for the mechanism, inflicted injury must be suspected and evaluated, so that in cases of child maltreatment, diagnosis and protection of the child from further injury can take place as early as possible.

Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder

Purpose:The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.Methods:The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.Results:Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), 0.5 to <1.0 ULN, and ≥1.0 ULN, the probability of a normal average daily ammonia value was 87, 60, and 39%, respectively, and 10.3, 14.1, and 37.0% of these patients, respectively, experienced ≥1 hyperammonemic crisis over 12 months. Time to first hyperammonemic crisis was shorter (P = 0.008) and relative risk (4.5×; P = 0.011) and rate (~5×, P = 0.006) of hyperammonemic crises were higher in patients with fasting ammonia ≥1.0 ULN vs. <0.5ULN; relative risk was even greater (20×; P = 0.009) in patients ≥6 years old. A 10- or 25-µmol/l increase in ammonia exposure increased the relative risk of a hyperammonemic crisis by 50 and >200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis.Conclusion:Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.Genet Med 17 7, 561–568.

Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD).

Background Acute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known. Aim To evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis. Results More than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%. Conclusion In conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.

Complex febrile seizures associated with influenza A

To the Editors: We have read with interest the October 2003 Supplement to The Pediatric Infectious Disease Journal, Influenza in Children: The Unrecognized Burden. A commercial rapid immunochromatographic membrane test (Binax NOW) for identification of influenza A and B antigens in nasopharyngeal secretion specimens has recently been introduced for clinical use in our children’s hospital. Within 3 weeks (in January) we observed three pediatric patients with complex febrile seizures in whom the test was positive for influenza A. Patient 1 was a 1-year 8-month-old boy with a fever of 40°C and three episodes of generalized tonic-clonic seizures within 5 h, each lasting 5 min. He then developed nasal congestion and rhinitis. An electroencephalogram was normal. Patient 2, who was 1 year, 9 months old, had rhinitis and cough for 2 days and developed a fever of 40.7°C and a short generalized seizure followed by a second episode 30 min later. The third patient was 1 year, 7 months old and had cough and rhinitis that was followed by a fever of 39°C. His convulsion was focal and lasted for 25 min. Patients presenting with complex febrile seizures often undergo evaluation for possible source of the fever, especially meningitis, and for abnormality in electroencephalogram results and cranial imaging. A rapid diagnostic test that discloses the source of the fever and the cause of the complicated convulsion is of significant advantage in the clinical setting. Influenza A was an important cause of febrile seizures, especially complex. With the availability of rapid diagnostic tests for influenza A and B, the management of children with complex febrile seizures, even in the absence of respiratory symptoms, can be made cost-effective, straightforward and less invasive in selected cases. We suggest that in children with febrile seizures, especially complex, during the influenza season, nasopharyngeal secretions be obtained for rapid diagnostic test for identification of influenza A or B antigens.

Hypoglossal nerve palsy associated with deep cervical lymphadenopathy

Results. Family 1 gave a positive logarithm of odds (LOD) score of 0.85. The typical homozygous haplotype of our HIBM patients6 was present in both patients of this family, whereas other sibs were heterozygous. Family 2 gave a lower LOD, score but the patient presented the same haplotype. Analysis in Family 4, assuming dominant transmission, excluded linkage to the HIBM locus on chromosome 9 (LOD score = -5.4). Our observations suggest that facial involvement may be a part of the recessive and dominant HIBM clinical spectrum. Such involvement, not reported before, may mimic fascioscapulo-humeral dystrophy, although scapular winging was absent: Rimmed vacuoles are found in numerous other distal myopathies but without facial weakness. Desmin storage myopathies may involve cranial muscle, but this was excluded in Families 2 and 4. HIBM should be included in the differential diagnosis of familial myopathies with facial weakness. Molecular genetic analysis definitely excludes the chromosome 9pl-ql locus as the site of the dominant form of HIBM with facial involvement. Both families with recessively inherited HIBM and facial weakness could be linked to chromosome 9pl-ql, as could other forms of HIBM.? However, because the size of these families is small, the linkage statistics are not definite at this stage.