Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews.

BACKGROUND: The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. METHODS: Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. RESULTS: Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25-38.2) years, median (range). Sweat chloride was 106 ±â€¯13 meq/L, mean ±â€¯SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40-121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1-14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. CONCLUSION: In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.

Screening for pulmonary and cerebral arteriovenous malformations in children with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterised by vascular dysplasia complicated by visceral arteriovenous malformations (AVMs). To date, the diagnostic yield of screening procedures for pulmonary and cerebral AVMs in children with definite or potential HHT is not well defined. The aim of the present study was to prospectively evaluate the diagnostic yield of a screening protocol for pulmonary and cerebral AVMs in children with either a definite or potential HHT diagnosis. All children referred for evaluation for HHT between 1996 and 2008 were included in the present analysis. Screening tests for AVMs included chest computed tomography and brain magnetic resonance imaging. 61 children with a definite clinical and/or genetic diagnosis of HHT were asymptomatic for visceral AVMs at their first baseline assessment (mean+/-SD age 8.7+/-4.7 yrs; range 0-17.0 yrs). Of these, 15 (25%) had pulmonary and/or cerebral AVMs diagnosed on initial screening tests. Pulmonary AVMs predominated in paediatric HHT patients (14 out of 15 patients) and were found in eight children aged <10 yrs. 55 children had a potential HHT diagnosis as they fulfilled only one or two HHT clinical diagnostic criteria and did not have a confirmatory genetic diagnosis (age 10.9+/-4.8 yrs; range 0-17.9 yrs). None of these children had pulmonary or cerebral AVMs on initial screening tests. The present data suggest that children with a definite HHT diagnosis have a high frequency of pulmonary AVMs even when clinically asymptomatic. In contrast, no AVMs were observed in children not fulfilling HHT diagnostic criteria. Genetic testing appears to be useful in defining an at-risk group for pulmonary AVMs in childhood.

Microbial contamination of nebulizers in the home treatment of cystic fibrosis.

BACKGROUND: Home nebulizers are in widespread use in cystic fibrosis (CF) and other chronic pulmonary diseases. Bacterial contamination may be a source of respiratory tract colonization. OBJECTIVES: To investigate microbial contamination of home nebulizers in CF patients, compare with sputum cultures and relate to cleaning practices. METHODS: A total of 29 home nebulizers of CF patients were cultured. Families were interviewed regarding cleaning routines and patients had sputum cultures for bacteria and fungi. RESULTS: In total, 19/29 (65%) nebulizers were contaminated: 18 reservoir cups, 14 mouthpieces and five filters. Pseudomonas spp. were isolated from 10 nebulizers (35%) and all 10 had Pseudomonas aeruginosa airway infection although without genetic typing we could not be sure this was the same bacteria as that from their nebulizer unit. An additional 7/29 had Pseudomonas aeruginosa airway infection without a contaminated nebulizer (P=0.001). No nebulizers were contaminated with Aspergillus. Only 4/19 contaminated nebulizers (22%) had been cleaned after every use, compared with seven of the 10 (70%) uncontaminated nebulizers (P=0.017). Only 7/19 patients with contaminated nebulizers (37%) and 5/10 with clean nebulizers (50%) recalled receiving cleaning instructions (not significant). CONCLUSIONS: Home nebulizers are frequently contaminated, particularly when cleaning instructions are inadequate, and may be a source of airway infection or reinfection especially following contamination from a patient chronically colonized with P. aeruginosa. Simple oral and written cleaning instructions should be offered.

Computerised paediatric asthma quality of life questionnaires in routine care.

BACKGROUND: Asthma quality of life questionnaires are not readily incorporated into clinical care. We therefore computerised the Paediatric Asthma Quality of Life Questionnaire (standardised) (PAQLQ(S)) and the Paediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ), with a colour-coded printed graphical report. OBJECTIVES: To (a) assess the feasibility of the electronic questionnaires in clinical care and (b) compare the child's PAQLQ scores with the parent's score, physician's clinical score and spirometry. METHODS: Children with asthma were given a clinical severity score of 1-4 (increasing severity) and then completed the PAQLQ(S) electronically (scores 1-7 for increasing quality of life in emotional, symptoms and activity limitation domains) followed by spirometry and physician review. Parents completed the PACQLQ. Inclusion criteria required fluent Hebrew and reliable performance of spirometry. Children with additional chronic diseases were excluded. RESULTS: 147 children with asthma aged 7-17 years completed PAQLQs and 115 accompanying parents completed PACQLQs, taking 8.3 (4.3-15) and 4.4 (1.5-12.7) min, respectively (mean (range)). Graphical reports enabled physicians to address quality of life during even brief visits. Children's (PAQLQ) and parents' (PACQLQ) total scores correlated (r = 0.61, p<0.001), although the children's median emotional score of 6.3 was higher than their parents' 5.7 (p<0.001), whereas median activity limitation score was lower than their parents': 5.0 and 6.8, respectively (p<0.001). No correlation was found with physician's clinical score or spirometry. CONCLUSIONS: Electronic PAQLQs are easy to use, providing additional insight to spirometry and physician's assessment, in routine asthma care. Future studies must assess impact on asthma management.

Cystic fibrosis mutations with widely variable phenotype: the D1152H example.

D1152H is a type IV cystic fibrosis transmembrane regulator (CFTR) mutation associated with abnormal chloride gating. Although comprising 5-6% of mutations on genetic screening, clinical reports of cystic fibrosis (CF) are rare, suggesting that the disease is mild, atypical, or even absent. We describe our experience, which contrasts with this assumption, in a retrospective case series encompassing 91 CF patients (74 Jewish) aged 8 months to 56 years, from 2000-2005. Nine patients of varied Jewish ethnic origins were homozygous (2 patients) or compound heterozygous for D1152H with 11 of 182 potential alleles (6%). Five were diagnosed at age 33-49 years. Of 4 infants, 1 was diagnosed by prenatal screening, 1 had a prenatal dilated bowel, and 1 had pulmonary symptoms. Sweat chloride was 28-120 meq/l. Three adults had chronic mucoid Pseudomonas aeruginosa in sputum, and a forced expired volume in 1 sec (FEV1) of 20-55%. One was on bilevel positive airway pressure (BIPAP) ventilation. The infants had pulmonary symptoms that responded well to therapy. All 9 patients had good nutrition, 6 were pancreatic-sufficient, and 3 adults had subclinical pancreatic insufficiency. Three adults had recurrent pancreatitis. None had a bowel obstruction. Two of 3 adult males were fertile. Although asymptomatic at times, the D1152H mutation is associated with a broad clinical spectrum. This information is crucial for genetic counseling. Lung disease may be evident from infancy, and is severe in some adults, although all have outlived the median life expectancy of CF. Hopefully, with early diagnosis and therapy, prognosis can be good. A multicenter study of this mutation is warranted.

The prevalence and clinical characteristics of cystic fibrosis in South Asian Canadian immigrants.

BACKGROUND: Cystic fibrosis (CF) is considered to be rare among individuals from the Indian subcontinent. Furthermore, affected individuals are reported to experience a more severe clinical course. AIMS: It was hypothesised that CF is under diagnosed in people of South Asian origin and therefore the prevalence may be higher than previously estimated. METHODS: The prevalence of CF in the South Asian and in the general population living in the same geographic region (Metropolitan Toronto) were compared between 1996 and 2001. Population data were obtained from the Canadian census survey. CF phenotype and genotype data were obtained from the Toronto CF database. RESULTS: Among 381 patients with CF, 15 were of South Asian descent. The age related prevalence of CF among the South Asian and general populations was: 0-14 years, 1:9200 versus 1:6600; 15-24 years, 1:13,200 versus 1:7600; older than 25 years, 1:56,600 versus 1:12,400. Age at diagnosis, duration and severity of symptoms at diagnosis, current nutritional status, and FEV(1) were similar in the two groups. While not significant, FEV1 tended to be lower (48% versus 57% predicted) among adult South Asians, compared to the general CF population. Also, the percentage with pancreatic sufficiency was higher (27% versus 16%) and the frequency of DeltaF508 allele was lower (50% versus 65.1%). CONCLUSIONS: These data suggest that the prevalence and natural history of CF in South Asians is similar to that among individuals of European origin. The relatively lower prevalence among older South Asians may reflect an improving recognition of CF in this ethnic subgroup.

Cystic fibrosis presenting as kwashiorkor in a Sri Lankan infant.

Growth failure is a common presentation of patients with pancreatic insufficient cystic fibrosis. However, full blown kwashiorkor is extremely rare. Cystic fibrosis is also considered to be rare in the South Asian population. This report describes a Sri Lankan infant with cystic fibrosis who presented with clinical features of severe kwashiorkor.

Bochdalek diaphragmatic hernia: not only a neonatal disease.

AIMS: To characterise the clinical manifestations of late presenting Bochdalek diaphragmatic hernia (DH), the incidence of misdiagnosis, and prognosis; and to explore the sequence of events that leads to this clinical picture. METHODS: Retrospective chart review. All children with Bochdalek DH were identified. Children 1 month of age and older at the time of diagnosis were included. RESULTS: Twenty two children with Bochdalek DH met the inclusion criteria. Three clinical presentations could be defined. Fourteen children presented with acute onset of symptoms, predominantly vomiting and respiratory distress. Four had chronic non-specific gastrointestinal or respiratory symptoms, and in four the DH was found incidentally. Although five children were initially misdiagnosed, in 20 children (91%) the correct diagnosis was made on x ray examination. One child experienced a complicated course when the x ray picture was misinterpreted as pneumothorax. All children had favourable outcome. Two children had previously normal chest imaging, suggesting acquired herniation. A large pleural effusion without DH in a 9.5 year old girl with an abdominal infection prior to presenting with herniation suggests a pre-existing defect in the diaphragm. CONCLUSIONS: Late presenting Bochdalek DH can present with acute or chronic gastrointestinal, or less frequently, respiratory symptoms. It can also be found incidentally. Misdiagnosis can result in significant morbidity. Favourable outcome is expected when the correct diagnosis is made. The sequence of events is probably herniation of abdominal viscera through a pre-existing diaphragmatic defect. Although rare, DH should be considered in any child presenting with respiratory distress or with symptoms suggestive of gastrointestinal obstruction.

Convulsions and retinal haemorrhage: should we look further?

BACKGROUND AND AIMS: The prevalence of retinal haemorrhages after convulsions is not well established. As these haemorrhages are considered characteristic of child abuse, we investigated their occurrence after convulsive episodes to see whether the finding of haemorrhage should prompt further investigation. METHODS: Prospective study of 153 children (aged 2 months to 2 years), seen in the emergency department after a convulsive episode. After a thorough history and physical examination, a retinal examination was performed by an ophthalmologist. If findings were positive, further investigation was undertaken to rule out systemic disorder or child abuse. RESULTS: One child was found with unilateral retinal haemorrhages following an episode of a simple febrile convulsion. A thorough investigation uncovered no other reason for this finding. CONCLUSION: Retinal haemorrhages following a convulsive episode are rare. Such a finding should trigger an extensive search for other reasons, including child abuse.

Ambulatory blood pressure monitoring in children with a solitary kidney - a comparison between unilateral renal agenesis and uninephrectomy.

BACKGROUND: In experimental animals, a reduction in renal mass leads to glomerulosclerosis of the residual parenchyma and eventual renal failure. In humans, however, data on the influence of nephrectomy or agenesis on future functional parameters and hypertension are as yet controversial. OBJECTIVE: To evaluate blood-pressure patterns in children with a solitary kidney as a result of either unilateral renal agenesis (URA) or uninephrectomy (UNX) and correlate them to the increase in size of the remaining kidney. METHODS: Twenty-eight children with a solitary kidney were divided into two groups: the URA group, with 18 subjects (13 male and five female, with a mean age of 9.6 +/- 3.9 years), and the UNX group, which contained 10 subjects (four male and six female, with a mean age of 14.0 +/- 2.7 years). The mean time since nephrectomy was 8.7 years. Each study group was assigned an age-, weight- and height-matched control group. In all subjects, ambulatory blood pressure monitoring was performed using the SpaceLabs model no. 90207. Daytime and night-time were defined as 0800-2200 h and 2200-0800 h, respectively. Urinalysis, serum creatinine and urea results were recorded for all the study group participants. The size of the remaining kidney was determined by ultrasound examination. The percentage increase in kidney size, as calculated from standard kidney-length-against-age nomograms was correlated to the percentage deviation from normal blood pressure values. RESULTS: The mean 24 h, daytime and night-time systolic blood pressure (SBP) readings were significantly higher in children in the URA group than in those in the corresponding control group (111.4 +/- 7.5 mmHg versus 106.9 +/- 6.7 mmHg, P < 0.004; 115.2 +/- 3.1 mmHg versus 110.7 +/- 3.4 mmHg, P < 0.004; and 105.2 +/- 2.6 mmHg versus 101.2 +/- 1.8 mmHg, P < 0.002, respectively). Daytime heart rate was found to be significantly reduced (84.4 +/- 5.2 versus 87.8 +/- 8.2 beats/min, P < 0.04). In the UNX group, 24 h mean, systolic and diastolic blood pressure (DBP), as well as heart rate, did not differ from control values. Daytime systolic and diastolic blood pressures were higher than those of the controls (119.8 +/- 4.0 mmHg versus 115.5 +/- 3.8 mmHg, P < 0.02; and 72.7 +/- 4.0 mmHg versus 70.0 +/- 11.0 mmHg, P < 0.02, respectively). Nocturnal dipping was present in all groups and was of equal magnitude in the corresponding control groups. The mean 24 h diastolic blood pressure load was significantly greater in URA patients than in controls (19.6 versus 10.8%, respectively, P < 0.01). In the UNX group, the blood pressure loads were similar to those of controls. The percentage increase in length of the remaining kidney was found to correlate positively with the percentage delta increase in both systolic and diastolic blood pressure. CONCLUSIONS: Compared with the age-, height- and weight-matched controls, the children with a solitary kidney caused by URA had an elevated mean 24 h SBP. In contrast, those with UNX had mean 24 h blood pressure values similar to those of their controls. A rise in SBP was, however, seen in both groups during the daytime hours. Thus, the presence of a solitary kidney, for whatever reason, may be pathogenetically linked to a raised blood pressure, and this linkage may be more pronounced in URA. The delta increase in size of the remaining kidney may serve as a prognostic indicator of blood pressure elevation.