Rapid genome sequencing identifies novel variants in complement factor I.

Complement factor I deficiency (CFID; OMIM #610984) is a rare immunodeficiency caused by deficiencies in the serine protease complement factor I (CFI). CFID is characterized by predisposition to severe pneumococcal infection, often in infancy. We report a previously healthy adolescent male who presented with respiratory failure secondary to pneumococcal pneumonia and severe systemic inflammatory response. Rapid genome sequencing (rGS) identified compound heterozygous variants in CFI in the proband, with a novel maternally inherited likely pathogenic variant, a single nucleotide deletion resulting in premature stop (c.1646del; p.Asn549ThrfsTer25) and a paternally inherited novel likely pathogenic deletion (Chr 4:110685580-110692197del).

Concomitant diagnosis of immune deficiency and Pseudomonas sepsis in a 19 month old with ecthyma gangrenosum by host whole-genome sequencing.

X-linked agammaglobulinemia (XLA, OMIM#300300) is a rare monogenic primary immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. XLA is characterized by insufficient immunoglobulin levels and susceptibility to life-threatening bacterial infections. We report on a patient that presented with ecthyma gangrenosum and septicemia. Rapid trio whole-genome sequencing (rWGS) revealed an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15) in the BTK gene. Metagenomic analysis of rWGS sequences that did not align to the human genome revealed 770 aligned to the Pseudomonas aeruginosa PAO1 genome. The patient was diagnosed with XLA and pseudomonal sepsis.

Inherited cancer and the primary care physician. Barriers and strategies.

Difficulties faced by primary care physicians as they increase their responsibility for the diagnosis of inherited cancer risk include issues of cognitive strategy, the context of care, and cultural and institutional factors. Charateristics common to many genetic disorders--such as rarity, variability, implications for relatives, and temporal pattern--render our usual cognitive strategies less effective. Constraints of managed care, care teams, and high turnover of panels create a particularly difficult context for the care of people at risk for inherited cancer. Echoes of the eugenics movement, the implications of expanding genetic knowledge, and concerns about discrimination all complicate collaborative clinical decision making. Eight strategies are suggested to cope with these barriers to diagnosis. Primary care physicians also face challenges managing patients identified as at increased risk for inherited cancer. These include confidentiality, coordination and communication. Concerns for protecting the patient's confidentiality can inadvertently leave primary care physicians with partial information. Coordination is complicated when multiple organ systems and individuals are at risk, and knowledgable specialty centers may be distant. Communication requires sensitivity and skill in translating complex concepts from molecular biology and statistics into lay terms. Seven strategies are suggested to help with management.

Changing practice patterns for children with heart disease: a clinical pathway approach.

BACKGROUND: Pediatric cardiac care is costly and requires extensive resources. We studied the effect of clinical pathways on practice patterns and patient care outcomes in infants and children hospitalized for cardiac surgery. METHODS: In consecutive patients admitted for selected cardiac surgical procedures before (n = 69) and after (n = 173) implementation of clinical pathways, outcomes including hospital length of stay, days in the ICU, time to extubation, ordering of blood studies, costs, and readmissions were compared. Data were analyzed for each of five cardiac surgical procedures: repair of an atrial septal defect, repair of a ventricular septal defect, division of a patent ductus arteriosus, repair of tetralogy of Fallot, and neonatal arterial switch operation to correct transposition of the great arteries. RESULTS: A significant reduction in length of hospital stay, including days in the ICU (decreased 1 to 2 days per admission), was achieved after the clinical pathway was implemented. Reductions in average duration of mechanical ventilation ranged from 28% for repair of a ventricular septal defect to 63% for repair of tetralogy of Fallot. The number of blood studies ordered decreased 20% to 30%. A significant reduction in hospital costs for each procedure, ranging from 16% to 29%, was also achieved with no adverse effects on patients' outcomes. CONCLUSIONS: Use of clinical pathways with children hospitalized for cardiac surgery can shorten length of stay in the hospital, reduce use of resources, and improve cost-effectiveness with beneficial outcomes for patients.

Percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess in children.

OBJECTIVE: To describe the use of percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess in children. DESIGN: Retrospective case series. SETTING: A 24-bed pediatric intensive care unit. PATIENTS: Patients with tension pneumatocele, secondarily infected pneumatocele, or lung abscess. Tension pneumatocele was defined as an expanding intraparenchymal cyst compressing adjacent areas of the lung. Infected pneumatocele and lung abscess were defined, respectively, as intraparenchymal thin-walled cyst or thick-walled cavity containing an air-fluid level and purulent fluid. INTERVENTIONS: Seven pneumatoceles/lung abscesses were percutaneously drained in five patients. After computed tomography of the chest was obtained to localize the optimum site for drainage, a modified Seldinger technique was used to insert an 8.5-Fr soft catheter percutaneously into the cyst/cavity. The catheter was left in place until drainage (fluid and air) stopped. MEASUREMENTS AND MAIN RESULTS: All patients had clinical and radiologic improvement and were afebrile within 24 hrs after drainage. Bacterial culture grew aerobic bacteria from three cysts/cavities, anaerobic bacteria from one, and mixed bacteria from three. One patient had three secondarily infected pneumatoceles. Four of five secondarily infected pneumatoceles were under tension in two patients receiving mechanical ventilation. In both patients, the trachea was extubated within 24 hrs of drainage after prolonged mechanical ventilation. The number of days the catheter was in place ranged from 1 to 20 days. CONCLUSIONS: Percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess can be performed safely and effectively in children. Early drainage is helpful, both as a diagnostic and therapeutic procedure. Drainage of tension pneumatocele may assist in weaning from mechanical ventilation. Computed tomography of the chest is helpful in determining the optimum site for percutaneous drainage.

Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism.

The Institution's experience with hypoglycemia in different types of organic acidemias, branched chain amino acidemia (MSUD), and disorders of fructose metabolism was reviewed retrospectively. The charts of 144 patients who were followed for 1-5 years were studied for the severity and frequency of hypoglycemia. The patients were mainly Saudi; however, 10-25% were from neighboring countries. Therefore, the observations pertain to the genetic groups in the Arabian peninsula. Organic acidemias which primarily manifest with neurologic signs, such as 4-hydroxybutyric aciduria, infantile onset 3-methylglutaconic aciduria, and glutaric aciduria type 1 never showed hypoglycemia. Patients with beta-ketothiolase deficiency, biotinidase deficiency, or intermittent or intermediate MSUD, also did not have hypoglycemia during metabolic crisis. Hypoglycemia was rare and mild among neonates with classic MSUD, ethylmalonic aciduria, and isovaleric acidemia. Less than 50% of the patients with MSUD older than 8 months, pyruvate carboxylase deficiency, methylmalonic acidemia, or propionic acidemia had hypoglycemia during metabolic crisis. On the other hand, patients with 3-hydroxy-3-methyl glutaryl-CoA lyase deficiency, holocarboxylase synthetase deficiency, medium or long-chain acyl-CoA dehydrogenase deficiency, neonatal onset 3-methylglutaconic aciduria, glutaric aciduria type 2, and disorders of fructose metabolism invariably had moderate-to-severe hypoglycemia associated with metabolic crisis. The purpose of this report is to provide the pediatrician, particularly in the Middle East, with a diagnostic guideline to the identification and management of different types of organic acidemias, based on co-existing hypoglycemia.

Glutaric aciduria yype 1: First reported cases in three Saudi patients.

The clinical and biochemical findings in three patients with glutaric aciduri Type 1 (GAT1) are presented. They had a normal postnatal period of three to 14 months. They developed sudden and severe encephalopathy following an infection or trauma (patient 3) that gradually progressed to severe dystonia, choreathetosis, spastic quadriplegia and mental retardation. Neuroradiologic studies of the brain revealed while matter disease and frontotemporal lobe hypoplasia. The urine findings by gas chromatography/mass spectrometry (GC)/(MS) were characteristic of GAT1. Since GAT1 is an organic acidemia without intermittent acidotic attacks, but primarily manifests with progressive encephalopathy, it is important to recognize the potential of its existence among handicapped children in chronic care facilities. The good clinical response in two of the patients urges early diagnosis in subsequent newborn siblings of the families with the disease. The diagnosis of three patients in less than two years indicate the need for neonatal screening for the recognition of this disease, among other treatable metabolic diseases, in Saudi Arabia.

Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel.

Mutations in the skeletal muscle sodium channel gene (SCN4A) have been described in paramyotonia congenita (PMC) and hyperkalaemic periodic paralysis (HPP). We have found two mutations in SCN4A which affect regions of the sodium channel not previously associated with a disease phenotype. Furthermore, affected family members display an unusual mixture of clinical features reminiscent of PMC, HPP and of a third disorder, myotonia congenita (MC). The highly variable individual expression of these symptoms, including in some cases apparent non-penetrance, implies the existence of modifying factors. Mutations in SCN4A can produce a broad range of phenotypes in muscle diseases characterized by episodic abnormalities of membrane excitability.

Measurement of free amino acid levels in ultrafiltrates of blood plasma by high-performance liquid chromatography with automatic pre-column derivatization.

Although there are many techniques available for the analysis of amino acids, deproteinization is still one of the major problems in the analysis of amino acids in physiological fluids. The method used to prepare the plasma and to remove the plasma protein has a marked effect on the final results. The most widely used method of deproteinization is precipitation with 5-sulphosalicyclic acid followed by centrifugation to remove the precipitated protein. We have not had success in using this deproteinization agent for the analysis of plasma amino acids by a high-performance liquid chromatographic method with automatic pre-column o-phthaldialdehyde-3-mercaptopropionic acid and 9-fluorenylmethyl chloroformate derivatization because of the adverse effect of the sulphosalicyclic acid supernatant on the quantitation and separation. Ultrafiltration was used as an alternative method for the preparation of plasma samples in this experiment. The results were satisfactory for the analysis of plasma amino acids in 1500 samples during a period of four years. Some factors that might influence the results of the ultrafiltration were investigated.

Dinucleotide repeat polymorphisms at the SCN4A locus suggest allelic heterogeneity of hyperkalemic periodic paralysis and paramyotonia congenita.

Two polymorphic dinucleotide repeats--one (dGdA)n and one (dGdT)n--have been identified at the SCN4A locus, encoding the alpha-subunit of the adult skeletal muscle sodium channel. When typed using PCR, the dinucleotide repeats display 4 and 10 alleles, respectively, with a predicted heterozygosity of .81 for the combined haplotype. We have applied these polymorphisms to the investigation of hyperkalemic periodic paralysis and paramyotonia congenita, distinct neuromuscular disorders both of which are thought to involve mutation at SCN4A. Our data confirm the genetic linkage of both disorders with SCN4A. Haplotype analysis also indicates the strong likelihood of allelic heterogeneity in both disorders.

Gastrostomy and Nissen fundoplication in neurologically impaired children.

We report our experience with 90 neurologically impaired children treated with gastrostomy and Nissen fundoplication. Malnutrition was the main problem, followed by aspiration, recurrent pneumonia, and vomiting. The symptomatology was caused by swallowing incoordination and gastroesophageal reflux. The diagnosis of gastroesophageal reflux was confirmed by upper gastrointestinal series and pH probe. Nissen fundoplication was performed following a standard technique with preservation of the vagus nerves and its branches, repair of the diaphragmatic crura, reconstruction of the angle of His, and a 360 degree wrap. A gastrostomy and pyloroplasty or pyloric dilatation were part of the operative procedure. There were no deaths and few complications related to the surgical procedure. Marked nutritional improvement was seen in most cases with an average weight gain of 3.2 kg/patient 3 months following surgery. There was also improvement in milestones and seizure control. The majority of parents were very satisfied and would recommend the procedure to other parents with similar problems.

Anaesthesia for children with junctional epidermolysis bullosa (letalis).

The anaesthetic management of two children with junctional epidermolysis bullosa, formerly called the letalis form, is described. Anaesthesia for children with this disease has not been described previously. Special precautions were taken to avoid mucosal injury and some customary monitoring devices were omitted. The previous anaesthetic literature, which discusses related but distinct forms of bullous skin diseases, is reviewed. The special concerns which relate to airway management in this disease are discussed.

Slipped capital femoral epiphysis associated with hyperparathyroidism.

Slippage of the upper femoral epiphysis can occur in association with multiple endocrine imbalances. This report documents the second case of primary parathyroid adenoma with hyperparathyroidism and symptomatic concomitant slipped capital femoral epiphyses. In the evaluation of children with slipped capital femoral epiphysis, care must be taken to eliminate other treatable disease states that are known to be associated with this phenomenon. The capital femoral physes in this child with hyperparathyroidism promptly closed following removal of the parathyroid adenoma.

Response to pneumococcal vaccination in children with nephrotic syndrome.

Serologic responses to a 14-valent pneumococcal vaccine were measured in 20 children with steroid-responsive idiopathic nephrotic syndrome. All patients were free of proteinuria and receiving either daily (five patients) or alternate-day (15 patients) prednisone in a dosage of 1-2 mg/kg/day at the time of vaccination. Patients on alternate-day steroids received the vaccine on a day prednisone was not given. The mean fold rise in antibody titer was found to be normal in these children when antibody levels measured 3-6 wk post-vaccination were compared to prevaccination levels. This serologic response has correlated well with a 3-yr follow-up of the patients, none of whom has developed peritonitis secondary to any pneumococcal types in the vaccine. Also described are three patients who developed pneumococcal peritonitis during this period despite prior vaccination; in two of these patients, the pneumococcal type was not included in the vaccine (types 6b and 10a) and in one patient the organism was not typed. It is concluded that in children with nephrotic syndrome pneumococcal vaccination confers good protection against types included in the vaccine despite the concomitant administration of steroids. However, the patients who developed peritonitis secondary to other pneumococcal types remind us that pneumococcus must still be considered as an etiologic agent for peritonitis in nephrotic children who have been vaccinated.

Renal failure during the first year of life.

All cases of persistent renal failure in infants less than 1 year of age were reviewed to determine whether the prognosis has improved equally for infants as for adults. During a ten-year period, 52 infants were treated by applying uniform therapy; 28, more than half, were less than 4 weeks old. All cases were separated into two groups; 19 infants without and 33 infants with congenital renal or urinary tract anomalies. In 20 patients of the latter group, additional serious anomalies of other organs were present. The age distribution was strikingly different: in 18 of 21 infants, renal anomalies were present, as diagnosed on the first day of life. In contrast, only 3 of 11 infants, 4 to 12 months old, had urinary tract anomalies. In infants without renal anomalies, renal failure was caused by hypotension or shock in 10 of 19 cases, by pyelonephritis or sepsis un 6 of 19. Of this group, eight infants (42%) recovered completely, nine (47%) died. Death occurred within one to two days of hospitalization in all but three cases, caused by shock or sepsis. In this group medical problems that are amenable to therapy have caused either renal failure or contributed to the infant's death. In infants with renal or urinary tract anomalies, renal failure was caused by renal dysplasia or agenesis in 16 of 33 infants, by urinary tract obstruction in 12 of 33. Only three patients (9%) recovered, all older than 4 months, 20 (61%) died, and 10 are living with signs of chronic renal failure. Death usually occurred within one week of hospitalization and, in 16 of 20, it was caused by renal failure and multiple additional anomalies. The multiplicity and complexity of the congenital anomalies in most instances precluded effective, lifesaving therapy. Renal failure in infants is still a serious disease accompained by a high mortality rate in which therapeutic possibilities are limited. No improvement in prognosis can be expected in the near future. Pediatrics, 59:987-994, 1977, RENAL FAILURE, CONGENITAL RENAL ANOMALIES, INFANT, ISCHEMIC RENAL DAMAGE.

The occurrence of hepatoma in the chronic form of hereditary tyrosinemia.

A 5 1/2-year-old child with hepatocarcinoma complicating hereditary tyrosinemia is presented. A review of the literature and an attempted follow-up of previously reported patients with the chronic form of hereditary tyrosinemia have disclosed 16 cases of hepatocarcinoma occurring in 43 patients surviving beyond 2 years of age (37%). This incidence is considerably higher than that generally given for the occurrence of hepatoma in adults with macronodular cirrhosis. Females and males are equally at risk. Additional factors beyond the development of cirrhosis are likely operative in the induction of hepatocarcinoma in patients with this metabolic disorder; those surviving beyond infancy are at considerable risk for the development of fatal hepatic neoplasms.