Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C.

Compound heterozygotes for a severe cystic fibrosis transmembrane conductance regulator (CFTR) mutation and the R117H or R117C mutation (R117H/C) have clinical presentations that vary from classic cystic fibrosis (CF) to an incidental genetic finding. The aim of this study was to assess the influence of the intron-8 polythvmidine sequence (IVS8) on the relationship between genotype and phenotype of individuals with R117H/C. All individuals with R117H/C known to CF clinics in Australia and New Zealand were retrospectively studied by collecting information on genotype, age, pancreatic status, sweat electrolytes, sputum microbiology and pulmonary function. Forty-one individuals (39 with R117H and two with R117C), 16 on an IVS8-5T background and 25 on an IVS8-7T background were identified. Twelve individuals presented clinically, four were siblings of known R117H/C compound heterozygotes and 25 were detected by newborn screening. Eleven of 14 of the IVS8-5T group (78%) with sweat chloride results available had sweat CI > 60 mmol x L(-1) compared to 5 (20%) of the R117H/7T group (Chi-squared=10.4, p=0.001). Two were pancreatic insufficient, both IVS8-5T. Two IVS8-5T individuals have recently died (aged 43 and 19) and of the 14 surviving IVS8-5T group, 11 (79%) are symptomatic compared to eight (32%) of the IVS8-7T individuals (Chi-squared=6.1, p=0.01). In conclusion, most individuals with R117H/C on a IVS8-5T background have an elevated sweat chloride and clinical cystic fibrosis, which in some cases is severe. Most individuals with R117H/C on an IVS8-7T background do not have clinical cystic fibrosis but should be followed for the development of clinical disease.

Pancreatic function and extended mutation analysis in DeltaF508 heterozygous infants with an elevated immunoreactive trypsinogen but normal sweat electrolyte levels.

BACKGROUND: Newborn screening for cystic fibrosis (CF) with immunoreactive trypsinogen (IRT) and DeltaF508 analysis followed by sweat testing misses some infants with CF and detects more DeltaF508 carriers than expected. Some of the apparent DeltaF508 carriers may be DeltaF508 compound heterozygotes with normal sweat electrolyte levels. METHODS: Infants identified by newborn screening with an elevated IRT level, one DeltaF508 allele, and a sweat chloride level <60 mmol/L underwent CF mutation analysis, pancreatic stimulation testing, and repeat IRT analysis followed by clinical review and repeat sweat test at 12 months. RESULTS: Over a 24-month period we identified 122 DeltaF508 heterozygotes and recruited 57; 4 had borderline sweat chloride levels (40 to 60 mmol/L), 5 (8.8%, 95% CI 1.4, 16.2) had a second CF mutation (R117H), and 11 (20%, 95% CI 10, 30) had the intron 8 5T allele. Three had clinical CF at 12 months (initial sweat chloride levels: 53, 51, and 32 mmol/L). Pancreatic electrolyte secretion in the subjects with a borderline sweat chloride level was similar to that in patients with known CF. CONCLUSION: The excess of DeltaF508 heterozygotes detected by IRT/DNA screening is associated with the presence of a second mutation or the 5T allele in some infants. Screened infants with borderline sweat chloride levels almost certainly have CF, but long-term follow-up of the infants with the genotype DeltaF508/R117H and DeltaF508/5T is required to determine their outcome. In the meantime, newborn screening should be confined to severe mutations associated with classic CF.

Long-term outcome of surgically treated acquired subglottic stenosis in infancy.

There is little information about the long-term outcome of infants with acquired severe subglottic stenosis (SGS) who require surgical intervention. We retrospectively identified infants with acquired subglottic stenosis who required anterior cricoid split (ACS) or tracheostomy for primary airway management; some of these children later required laryngotracheoplasty (LTP). All children were treated at our hospital from 1989-1997. During follow-up, we assessed patients for persistent symptoms (stridor at rest, exercise limitation, difficulty with respiratory tract infections, recurrent croup, and voice alteration), and we measured lung function when possible. We identified 34 infants with acquired SGS: 13 treated primarily with tracheostomy, and 21 with ACS. Nine patients could not be extubated following ACS and required tracheostomy, while the 12 who were extubated were followed up at a mean time of 76 months postoperatively; 3 had moderate stridor at rest, 1 moderate exercise limitation, and none had recurrent croup. Four of 5 who had lung function measured had moderately severe extrathoracic airflow limitation. From the tracheostomy group (n = 13) and the failed ACS group (n = 9), 2 patients were decannulated without further surgery, 17 underwent LTP, and 2 have LTP planned. Fifteen of the 17 patients who had LTP have been decannulated. Follow-up, at a mean time of 58 months postoperatively, showed none with stridor at rest, 3 with moderate exercise limitation, none with recurrent croup, and 2 with moderate voice alteration. All 5 patients who had lung function measured had airflow limitation, 1 being severe. In conclusion, ACS facilitates extubation in selected patients with severe, acquired SGS of infancy, and the long-term outcome of patients successfully extubated is excellent. Failure of ACS invariably means tracheostomy, and subglottic repair by LTP is associated with a good long-term outcome.

Newborn screening for cystic fibrosis in Victoria: 10 years' experience (1989-1998).

OBJECTIVE: To review the effectiveness of statewide newborn screening for cystic fibrosis (CF) in Victoria over the first 10 years of the program (1989-1998). DESIGN: Population study involving screening of newborns by immunoreactive trypsinogen (IRT) testing on Day 3-5, followed by either repeat IRT testing (1989-1990) or delta F508 mutation analysis (1991-1998). PATIENTS AND SETTING: All babies screened for CF in a newborn screening program in Victoria in 1989-1998. MAIN OUTCOME MEASURE: The diagnosis of CF. RESULTS: Of 635,157 babies born in Victoria in the 10 years, 191 were diagnosed with CF. A further 30 cases were detected antenatally, giving an incidence of 1/2874 (95% CI, 1/2519-1/3294). CF was detected early in 182 babies (95.3% of affected babies in the screened cohort)--136 by screening, 35 because they had meconium ileus, and 11 because they were siblings of older children with CF. Nine cases of CF were missed by screening. Of these nine babies, four did not have an elevated neonatal IRT level, one had a normal IRT level at repeat testing at 4-6 weeks (1989-1990), three did not have a delta F508 mutation (1991-1998), and one had a false negative sweat test result. Six of the nine missed babies (67%) were diagnosed within four months of birth. CONCLUSION: Newborn screening for CF in Victoria has proven effective in detecting most babies with CF in the newborn period. However, a sweat test should be requested when the clinical features suggest the diagnosis of CF, even if the child has been screened.

The musculoskeletal complications of cystic fibrosis.

OBJECTIVE: To determine the spectrum of musculoskeletal complications of cystic fibrosis (CF) in a paediatric population in Australia. METHOD: Clinical assessment followed by serology and bone scan on patients attending a specialized CF clinic. RESULTS: Of 125 patients studied, 21 had musculoskeletal complications, 17 attributable to CF. Eleven had joint involvement (six hypertrophic pulmonary osteoarthropathy (HPOA)), one CF arthropathy, two ciprofloxacin induced arthralgia, one joint contracture following long-line placement, one chest infection associated arthralgia), four kyphosis (two also with HPOA) and two thoracic deformity. HPOA was associated with older age, lower average pulmonary function and lower average Shwachman score. Three patients with HPOA died within 12 months of reporting symptoms. Kyphosis was also associated with older age and lower pulmonary function. CONCLUSION: Increasing age with deteriorating clinical and pulmonary function were associated with a higher incidence of musculoskeletal involvement. The development of symptomatic HPOA is a marker of poor prognosis.

Pneumocystis carinii pneumonia: pitfalls of prophylaxis.

Pneumocystis carinii pneumonia (PCP) occurs commonly in immunocompromised patients. Sulfamethoxazole-trimethoprim (SMX-TMP) is effective prophylaxis, although PCP may still occur despite apparently adequate use. We report three cases of PCP which highlight some of the pitfalls of prophylaxis.

A review of open biopsy for mediastinal masses.

OBJECTIVE: To review the recent experience with biopsied mediastinal lesions in children and to assess the impact of recent advances in imaging and surgical techniques on diagnosis. METHODOLOGY: The clinical and radiological features of 55 patients who had mediastinal biopsies at The Royal Alexandra Hospital For Children (RAHC) over 15 years were reviewed. RESULTS: Fifty-five patients presented to RAHC between 1978 and 1993 with lesions of the mediastinum requiring biopsy of that site. Thirty-one of the 55 (56%) lesions were malignant. Neurogenic tumours were the most common (40%). In order of frequency the following lesions were found: neuroblastoma (15), teratoma (eight), non-Hodgkin's lymphoma (NHL; eight), enteric cyst/duplication (five), ganglioneuroma (five), bronchogenic cyst (three), ganglioneuroblastoma (two), lymphangioma (two), abscess (two), Hodgkin's lymphoma (HL; two), oesophageal granuloma (one), Langerhan's cell histiocytosis (one), congenital fibromatosis (one). Eighty-two per cent of neurogenic tumours were located in the posterior mediastinum, while 75% of teratomas and 100% lymphoid tumours were located anteriorly. Symptoms were generally unhelpful in establishing a specific diagnosis and in 27% of cases the lesions were discovered incidentally. Physical signs, such as thoracic inlet obstruction and neurological findings, were helpful clinically in localizing lesions within the mediastinum. Chest radiography enabled lesions to be subdivided within the mediastinum. This localization, in combination with the age at presentation, predicted the tissue diagnosis. Computerized tomography (CT) and magnetic resonance imaging (MRI) further defined the lesion and demonstrated involvement of adjacent structures. Histology, however, was essential to distinguish benign from malignant lesions. CONCLUSIONS: The clinical presentation of mediastinal masses is often non-specific or incidental. Despite recent advances in imaging technology and biopsy techniques, full histological examination is required to exclude malignancy.

The economic aspects of drug delivery in asthma.

The need for cost-effective asthma therapy is driven by the high prevalence of asthma as well as the high cost of both medical care and lost productivity through illness. Limited healthcare resources demand proven therapies that maintain sustained disease control. Optimal disease control is the essence of cost effectiveness, but this in turn is dependent on correct drug selection and appropriate drug delivery. Successful treatment depends on delivery of medication to the site of action in the airways. Although there is a substantial number of aerosol delivery systems available, there is considerable confusion as to the most suitable method in different clinical settings, and across different age groups. Optimal drug delivery can be achieved without adding substantially to the overall cost of therapy. Both drugs and delivery systems need to be individualised to the needs of the patients. The early introduction of oral corticosteroids for acute exacerbations has resulted in reduced hospitalisation and shortened illness, providing substantial cost savings. A reduction in the reliance on nebuliser therapy in both the acute and chronic setting will further optimise therapy and reduce costs. We have reviewed the current literature to determine the most cost-effective methods of drug delivery in asthma.

Intracranial choriocarcinoma causing precocious puberty and cured with combined modality therapy.

Precocious puberty can be caused by hormonally active tumours, which may arise intracranially. Treatment of these intracranial lesions traditionally involves biopsy and radiotherapy. Chemotherapy has been used recently, although radiotherapy has been given irrespective of the response to chemotherapy. We report a case of precocious puberty in an 8 year old boy due to a malignant intracranial germ cell tumour. Although one could speculate that he was cured by such combined modality therapy, the patient was left with several long-term problems. Radiotherapy was a major cause of these complications. Radiotherapy is now thought unnecessary for most extracranial germ cell tumours, as chemotherapy alone is curative in most patients. Therefore it seems appropriate to consider the elimination of radiotherapy for patients with intracranial disease.