Treatment patterns from 647 patients with Gaucher disease: An analysis from the Gaucher Outcome Survey.

The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. For insight into how GD management varies among countries, we analyzed treatment patterns in GOS. As of October 30, 2015, data on GD-specific treatment (enzyme replacement therapy, substrate reduction therapy, or chemical chaperone therapy) received at any time were available for 647 patients. At analysis, velaglucerase alfa (316/573, 55.1%) and imiglucerase (184/573, 32.1%) were the treatments most widely used. Of the 647 treated patients, 446 (68.9%) had been treated for >5years and 368 (56.9%) had received only one GD-specific drug therapy. There were 377 patients who received velaglucerase alfa. Velaglucerase alfa was most widely used at 60U/kg every other week (134/492 dose entries, 27.2%), but there were differences in dosing between the three highest-enrolling countries (defined as >100 GOS patients enrolled in each), with most patients in Israel receiving <20U/kg, most patients in the United Kingdom receiving 20 to <40U/kg, and most in the United States receiving 60U/kg. This analysis provides a foundation upon which to examine real-life outcomes data from different treatment regimens globally.

A randomised, double-blind, placebo-controlled, crossover study to assess the efficacy and safety of three dosing schedules of agalsidase alfa enzyme replacement therapy for Fabry disease.

Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule.

Lysosomal delivery of therapeutic enzymes in cell models of Fabry disease.

The success of enzymatic replacement in Gaucher disease has stimulated development of targeted protein replacement for other lysosomal disorders, including Anderson-Fabry disease, which causes fatal cardiac, cerebrovascular and renal injury: deficiency of lysosomal α-Galactosidase A induces accumulation of glycosphingolipids. Endothelial cell storage was the primary endpoint in a clinical trial that led to market authorization. Two α-Galactosidase A preparations are licensed worldwide, but fatal outcomes persist, with storage remaining in many tissues. We compare mechanisms of uptake of α -Galactosidase A into cells relevant to Fabry disease, in order to investigate if the enzyme is targeted to the lysosomes in a mannose-6-phosphate receptor dependent fashion, as generally believed. α -Galactosidase A uptake was examined in fibroblasts, four different endothelial cell models, and hepatic cells in vitro. Uptake of europium-labeled human α -Galactosidase A was measured by time-resolved fluorescence. Ligand-specific uptake was quantified in inhibitor studies. Targeting to the lysosome was determined by precipitation and by confocal microscopy. The quantity and location of cation-independent mannose-6-phosphate receptors in the different cell models were investigated using confocal microscopy. Uptake and delivery of α -Galactosidase A to lysosomes in fibroblasts is mediated by the canonical mannose-6-phosphate receptor pathway, but in endothelial cells in vitro this mechanism does not operate. Moreover, this observation is supported by a striking paucity of expression of cation independent mannose-6-phosphate receptors on the plasma membrane of the four endothelial cell models and by little delivery of enzyme to lysosomes, when compared with fibroblasts. If these observations are confirmed in vivo, alternative mechanisms will be needed to explain the ready clearance of storage from endothelial cells in patients undergoing enzyme replacement therapy.

Quantifying the Erlenmeyer flask deformity.

OBJECTIVE: Erlenmeyer flask deformity is a common radiological finding in patients with Gaucher's disease; however, no definition of this deformity exists and the reported prevalence of the deformity varies widely. To devise an easily applied definition of this deformity, we investigated a cohort of knee radiographs in which there was consensus between three experienced radiologists as to the presence or absence of Erlenmeyer flask morphology. METHODS: Using the presence or absence of Erlenmeyer flask morphology as a benchmark, we measured the diameter of the femur at the level of the physeal scar and serially at defined intervals along the metadiaphysis. RESULTS: A measured ratio in excess of 0.57 between the diameter of the femoral shaft 4 cm from the physis to the diameter of the physeal baseline itself on a frontal radiograph of the knee predicted the Erlenmeyer flask deformity with 95.6% sensitivity and 100% specificity in our series of 43 independently diagnosed adults with Gaucher's disease. Application of this method to the distal femur detected the Erlenmeyer flask deformity reproducibly and was simple to carry out. CONCLUSION: Unlike diagnostic assignments based on subjective review, our simple procedure for identifying the modelling deformity is based on robust quantitative measurement: it should facilitate comparative studies between different groups of patients, and may allow more rigorous exploration of the pathogenesis of the complex osseous manifestations of Gaucher's disease to be undertaken.

Age adjusting severity scores for Anderson-Fabry disease.

Anderson-Fabry Disease (AFD) is a life-threatening X-linked lysosomal storage disorder, caused by a deficiency of alpha galactosidase A. The disease affects males and females, and may present in childhood or adulthood. In the absence of a biomarker of disease burden or therapeutic response, scoring systems based on clinical manifestations, have been developed. Such global scores e.g. the Mainz Severity Score Index (MSSI) are confounded by the natural history of disease that deteriorates with age, making comparisons across age groups invalid. In this study the baseline MSSI, as adapted for data collected in the Fabry Outcome Survey (FOS) database (FOS-MSSI), was calculated for 655 females and 617 males with confirmed AFD. Using an ANCOVA model, equations for the predicted FOS-MSSI based on age were derived for males and females from data where patients from the UK or outside Europe were excluded. The initially excluded patients were used for validation. The predicted severity scores of UK and non-Europe-cohorts of adult and paediatric patients were found to follow the model produced for the European cohort thereby providing validation of the methodology. Deviation of the actual FOS-MSSI from the predicted was calculated and termed the age-adjusted score. Examples of the use of the age-adjusted score in individual patients, in comparison of mutations and in investigation of early factors which may impact on later severity of Fabry disease are given. This validated age and gender adjusted scoring system allows the comparison of disease severity in different subgroups such as genotypes without age or sex as confounding factors.

Does geographical location influence the phenotype of Fabry disease in women in Europe?

This study examines the relationship between phenotype and geographical location of patients with Fabry disease in Europe. Data were taken from patients enrolled in the Fabry Outcome Survey (FOS), as of October 2007. A modified version of the Mainz Severity Score Index (FOS-MSSI) was used to classify patients according to the severity of disease. European patients were grouped depending on country of residence (northern or southern European countries). Results are presented from 762 patients enrolled in FOS in Europe (357 men and 405 women); 66% lived in northern and 34% in southern countries. Median age at onset of symptoms of Fabry disease was similar in both sexes. No differences in disease severity were seen among men, according to place of residence; however, women living in northern countries had higher severity scores (p < 0.001) than those in southern countries. In men and women, FOS-MSSI scores increased with age, irrespective of place of residence. The results suggest that expression of different phenotypic features in Fabry disease in women living in Europe may be influenced by extra-genetic or epigenetic factors. These factors might be related to dietary or environmental influences that differ according to the patient's country of residence.

Depression in adults with Fabry disease: a common and under-diagnosed problem.

BACKGROUND: Anderson-Fabry disease (AFD), an X-linked lysosomal storage disorder, leads to multi-organ dysfunction and premature mortality. Depression in adults with AFD has been reported, but no large study has been done. We have examined the adult Fabry population in the United Kingdom to describe the prevalence, associated factors and frequency of diagnosis of depression. METHODS: Postal questionnaires were sent from four adult clinics to 296 AFD patients. A response rate of 62% (n = 184; 74 male, 110 female) formed the data set. Questionnaires collected demographic and Fabry-specific information. Depression status was assessed using the Centre for Epidemiological Studies depression scale (CES-D). RESULTS: Responders were aged between 18 and 76 years (mean 44). The prevalence of depression was 46%, of which 28% were consistent with 'severe clinical depression'. Unlike the normal population, males with AFD report a higher prevalence of severe depression than females (36% males; 22% females). Interference of AFD symptoms with individuals' lives (particularly acroparaesthesiae or anhidrosis) showed the largest odds of association with depression. Relationship and financial status proved strong predictors of depression: 88% of those with mild-moderate depression and 72% with severe depression were undiagnosed. CONCLUSION: Depression is common and under-diagnosed in AFD. Proper assessment of and treatment for depression could improve the quality of life of these patients.

Late-onset central hypoventilation syndrome: a family genetic study.

Congenital central hypoventilation syndrome is a rare disorder characterised by chronic alveolar hypoventilation, which becomes more pronounced during sleep and may be associated with neurocristopathies, such as Hirchsprung's disease. A mutation in the PHOX2B gene has recently been identified. In a family of both parents and five offspring, detailed clinical assessment, pulmonary function testing, overnight sleep studies and ventilatory responsiveness to progressive hypercapnia (V'(R,CO(2))) were performed, in addition to analysis of known genetic loci for this condition. The father and four of the offspring demonstrated features of central hypoventilation with nonapnoeic oxygen desaturation during sleep and diminished V'(R,CO(2)), despite normal pulmonary function. The lowest sleep saturation was median (range) 79% (67-83%) and V'(R,CO(2)) was 2.1 (0.03-4.3) L x min(-1) x kPa(-1). The normal values for the authors' centre (St Vincent's University Hospital, Dublin, Ireland) are 15-40 L x min(-1) x kPa(-1). An in-frame five amino acid polyalanine expansion of the PHOX2B gene was found in all affected subjects, while the mother and fifth child, who did not have features of central hypoventilation, had a normal PHOX2B gene. Magnetic resonance imaging of the brainstem in one severely affected child was normal. The present study of a unique family confirms that transmission of late-onset congenital central hypoventilation syndrome is autosomal dominant in nature.

Natural history of Fabry disease in females in the Fabry Outcome Survey.

BACKGROUND: Fabry disease is a rare X linked lysosomal storage disorder resulting from deficiency of alpha-galactosidase A activity. Although the severity of clinical features in male patients is well described, only recently have studies reported the high prevalence of disabling clinical features in heterozygous females. AIMS: This study sets out to examine the clinical features and natural history of Fabry disease in further detail in a large group of female patients. METHODS: Data were obtained from 303 females enrolled in the Fabry Outcome Survey. Pain was assessed using the Brief Pain Inventory, and health related quality of life (HRQoL) was assessed using the European Quality of Life Questionnaire. A modified version of the Mainz Severity Score Index was also applied. Data on left ventricular mass (LVM) index, mean ventricular wall thickness, and glomerular filtration rate (GFR) were used to assess cardiac and renal involvement. RESULTS: The most commonly reported clinical features in females were neurological (77%) and cardiac (59%). A history of renal involvement was recorded in 40% of cases. Neurological features were the earliest to develop (mean age: 16 years), whereas cardiac (mean age: 33.5 years) and renal (mean age: 37.3 years) features developed later. LVM index increased exponentially with age. In addition, age was negatively correlated with estimated GFR and HRQoL. CONCLUSIONS: Females with Fabry disease report important age related clinical features and clinical investigation demonstrates evidence of disease progression. This study highlights the importance of careful and longitudinal assessment of female heterozygote patients with Fabry disease.

Clinical evaluation of biomarkers in Gaucher disease.

UNLABELLED: Novel or candidate biomarkers require thorough evaluation to establish their utility in a clinical setting. This paper describes an evaluation of several established enzyme markers of Gaucher disease and a newly-described chemokine, pulmonary and activation-regulated chemokine (PARC). The ability of the biomarkers to rank patients with Gaucher disease in order of disease severity and organ bulk, and to reflect changes in key clinical parameters in response to enzyme replacement therapy were evaluated. PARC concentrations were found to be reliably correlated with visceral disease and with key clinical responses to enzyme replacement in an unbiased manner. Unlike chitotriosidase and serum angiotensin-converting enzyme activity, genetic variation in serum PARC did not appear to influence its utility as a biomarker. CONCLUSION: For each new candidate biomarker of lysosomal storage diseases, a similar clinical evaluation will be required, though the approach will need to be modified according to the clinical features and natural history of each disorder.

Monitoring enzyme replacement therapy in Fabry disease--role of urine globotriaosylceramide.

Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb(3) concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant alpha-galactosidase A. The marked decline in urine Gb(3) on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment.

Reversible hypertension following coeliac disease treatment: the role of moderate hyperhomocysteinaemia and vascular endothelial dysfunction.

The vascular endothelium maintains a relatively vasodilated state via the release of nitric oxide (NO), a process that could be disrupted by hyperhomocysteinaemia. Since endothelial dysfunction is associated with increased systemic vascular resistance that is the hallmark of sustained arterial hypertension, we hypothesised that in patients with both hypertension and coeliac disease with hyperhomocysteinaemia (via malabsorption of essential cofactors), treatment of the latter disease could improve blood pressure (BP) control. A single patient with proven sustained hypertension and newly-diagnosed coeliac disease had baseline and post-treatment BP and endothelial function assessed by ambulatory BP monitoring (ABPM) and brachial artery forearm occlusion plethysmography respectively. This 49 year-old woman had uncomplicated sustained hypertension proven on repeated ABPM carried out 6 weeks apart (daytime mean 151/92 mm Hg and 155/95 mm Hg), and sub-clinical coeliac disease (gluten-sensitive enteropathy). Initial assessments revealed raised homocysteine levels with low normal vitamin B(12) level. It was likely that she had impaired absorption of essential cofactors for normal homocysteine metabolism. She adhered to a gluten-free diet and was give oral iron, folate and B(6) supplementations as well as B(12) injections for 3 months. Her BP had improved by 6 months and normalised by 15 months (daytime ABPM mean 128/80 mm Hg). There was parallel restoration of normal endothelial function with normalisation of her homocysteine levels. These observations suggest that sub-clinical coeliac disease related hyperhomocysteinaemia might cause endothelial dysfunction, potentially giving rise to a reversible form of hypertension. In addition, this case study supports the notion that irrespective of aetiology, endothelial dysfunction may be the precursor of hypertension. This highlights the need to resolve co-existing vascular risk factors in patients with hypertension.

Prognostic value of troponin T in hemodialysis patients is independent of comorbidity.

BACKGROUND: Patients on long-term hemodialysis have a high mortality. Various clinical and biochemical markers are of prognostic value. Cardiac troponin T (cTnT) is a sensitive and specific marker for myocardial damage. Asymptomatic dialysis patients have a high prevalence of cTnT concentrations above the diagnostic threshold for myocardial damage. There is controversy over whether this represents a false positive cTnT or an underlying pathology with a poor outcome. It is not known whether cTnT reflects comorbidity in these patients. METHODS: A cohort of 73 long-term hospital hemodialysis patients had cTnT estimated once prior to a mid-week dialysis. Samples were analyzed using the second-generation cTnT assay from Boehringer Mannheim on an Elecsys 1010 analyzer. The standard diagnostic threshold for myocardial damage of 0.1 ng/mL was used. A commonly employed measure of comorbidity (Khan) was applied at the time cTnT was measured. Patients were followed for 15 months. Mortality was used as the clinical end point. Kaplan-Meier survival analysis was employed and differences between groups were assessed using the Cox-Mantel log-rank test. RESULTS: Of the 73 patients, 20 were positive for cTnT and 53 were negative, at the cut-off of 0.1 ng/mL. At fifteen months, 65% of the positive patients were dead, whereas only 15% of the negative patients were dead. Survival analysis confirmed that this difference was statistically significant (P < 0.00001), and that the effect of cTnT on survival was independent of comorbidity. CONCLUSIONS: There is a high prevalence of positive cTnT in stable hemodialysis patients. A single estimation of cTnT in this group has significant prognostic value, independent of comorbidity.

Reducing waiting times for sleep apnoea hypopnoea syndrome and snoring using a questionnaire and home oximetry: results of a second audit cycle.

As a result of a previous audit on the management of sleep apnoea hypopnoea syndrome (SAHS) which showed long waiting times that were primarily due to unnecessary interspecialty referrals, a change in practice was adopted. All referrals are now sent a questionnaire about symptoms suggestive of SAHS, the Epworth Sleepiness Scale score and their body mass index (BMI) which when returned are categorized into having a high, intermediate or low risk of SAHS. Those patients with a high probability have home overnight oximetry and those with intermediate probability have video oximetry. Those with a low probability are referred directly to ENT. We audited the first 100 patients referred. All were General Practitioner referrals to either ENT or respiratory medicine. Only two patients had a low probability score and were seen directly in ENT. Following sleep study analysis, 10 patients were referred directly to ENT with no respiratory medicine follow-up and nine were discharged back to the General Practitioner with no apnoea or snoring. Eighty-one patients were followed up by respiratory medicine. Of these, 49 received a trial of nasal continuous positive airway pressure (nCPAP) and six were referred to ENT. Therefore the majority justified an investigation to exclude SAHS in the first instance and an unnecessary initial ENT appointment was avoided. We have reduced the average waiting times to sleep study by approximately 90 days and to nCPAP trial by 32 days, mostly due to decreased delays in interspeciality referrrals. We have also demonstrated a greater than 50 per cent reduction in ENT clinic visits, a small increase in the number of sleep studies but no increase in respiratory clinic workload.

Prospective audit of a respiratory sleep disorders service at District General Hospital level.

This study was designed to examine the organisation and outcomes of a District General Hospital respiratory sleep service, since data are lacking on the management of sleep-disordered breathing at this level. Questionnaires and case-notes review were used to assess the management of 119 consecutive patients referred with suspected sleep-disordered breathing. Patients diagnosed with sleep-disordered breathing were assigned nasal continuous positive airway pressure (nCPAP), ear/nose/throat (ENT) surgery or simple measures (e.g., weight loss). There were six non-attenders. At 12 months follow-up, 33 patients had been assigned to nCPAP, 25 to ENT surgery, and 37 to simple measures. Of the remainder, nine had alternative diagnoses, two were still being assessed and seven were lost to follow-up. Patients prescribed nCPAP (81% compliance) had significant symptomatic improvements with low dissatisfaction rates (20%); patients on simple measures did not improve (33% dissatisfied); only half assigned surgery had it performed, with 42% awaiting surgery and dissatisfied. Interspecialty referral resulted in major delays (mean 16 weeks). Referral letters were generally unhelpful in deciding on the appropriateness of initial referral (respiratory physician vs ENT). nCPAP was generally effective in improving symptoms, with a high level of patient satisfaction, while simple measures did not improve symptoms and were associated with lower satisfaction levels. Waiting times to ENT surgery can be long and patients express significant dissatisfaction. Referral letters are not useful in directing initial referral. Services should be co-ordinated between respiratory and ENT specialties to reduce waiting times and improve patient satisfaction.

Association between low-density lipoprotein composition and its metabolism in non-insulin-dependent diabetes mellitus.

Atheroma is related to low-density lipoprotein (LDL) composition. LDL in diabetic patients-a group with increased risk of severe atheroma-has been shown by our group and others to have various compositional alterations that are potentially atherogenic. Little is known about the relationship between LDL turnover and composition. This study examined the relationship between LDL composition and turnover in non-insulin-dependent diabetes mellitus (NIDDM) patients. Twenty-two NIDDM patients with a mean plasma cholesterol of 6.6+/-1.5 mmol/L were studied. Twelve subjects were hypercholesterolemic (mean cholesterol, 7.7+/-0.8 mmol/L), and eight of these agreed to be studied a second time after 4 weeks of treatment with simvastatin. LDL was isolated by density gradient ultracentrifugation, iodinated, and reinjected into the patient. LDL turnover was determined by measuring the clearance of [125I]-LDL from plasma over a 10-day period. The LDL residence time, determined using a biexponential model, correlated negatively with the body mass index (BMI) (r = -.73, P<.001) and serum triglycerides (r = - .57, P<.01). There was a significant inverse correlation between LDL residence time and the LDL esterified to free cholesterol ratio in hypercholesterolemic subjects (r = -.94, P<.001). There was a significant inverse relationship between LDL residence time and both hemoglobin A1c (HbA1c) and fasting blood glucose in these subjects before treatment (P<.005). After simvastatin therapy, the relationships were no longer significant. Simvastatin treatment was associated with a shorter LDL residence time (P<.01) and a decrease in LDL glycation (P<.001) with virtually no change in diabetic control (HbA1c, 6.0%+/-3.1% v. 6.3%+/-3.3%, NS). This study suggests that a decrease in residence time by upregulation of the LDL receptor with simvastatin alters LDL composition in a way that is likely to render the particle less atherogenic.

How do general practitioners respond to reports of abnormal chest X-rays?

General practitioners (GPs) in the UK have long had direct access to hospital radiological services, which in theory shortens investigation time and improves the quality of service. Chest X-rays (CXRs) account for a substantial proportion of requests, and we investigated what happened when an abnormality was detected. In one year, 204 GPs in the Nottingham area requested CXRs in 605 patients. 362 were reported normal, 165 abnormal but hospital follow-up not indicated and 71 abnormal with radiological follow-up or hospital referral indicated (mass lesion suspicious of tumours 27, infective shadowing 35, other 9). 64 of the 71 were seen in hospital within three months, and in those with suspected cancer the median time to follow-up was 20 days. These results show that GPs do act on the results of abnormal CXRs, but only 37% of those with a mass suspicious of cancer were seen in hospital within two weeks as recommended by the British Thoracic Society. Time might be saved if GPs agreed to direct referral from the radiology department to respiratory physicians.

Reducing waiting times in lung cancer.

BACKGROUND: Concern exists over delays in the management of lung cancer patients. Maximum waiting times and a multidisciplinary team (MDT) approach have been recommended in several recent national reports. OBJECTIVE: Having implemented a MDT approach, we wished to assess whether national recommendations were achievable and to identify the major factors causing delays. METHODS: Prospective survey over five months of all new referrals with suspected lung cancer, documenting waiting times at all stages from referral to definitive treatment. RESULTS: Of the total of 92 patients, 57 were outpatients (67% seen within one week, 89% within two weeks of receipt of referral) and 35 were inpatients (all seen within two working days). Patient age did not influence waiting times to first being seen or to investigation. The result of the initial diagnostic test was received within two weeks of first being seen in 86% of patients. All patients received definitive treatment within recommended times from diagnosis. Delays in the early part of the care pathway were largely due to potentially remediable service factors, but unavoidable patient related factors were important in some prolonged diagnostic delays. CONCLUSIONS: National recommendations on waiting times are achievable in a high proportion of cases. The probable importance of the MDT approach is discussed.

Resolution of obstructive sleep apnoea with growth in the Robin sequence.

A 12 year old female with the Robin sequence presented with a one year history of snoring, witnessed apnoeas and daytime sleepiness. Surgery in early childhood had consisted of cleft palate repair, tonsillectomy and adenoidectomy and, later, revision palatoplasty. Overnight polysomnography (PSG) demonstrated severe obstructive sleep apnoea syndrome with an apnoea/hypopnoea index (AHI) of 49 events x h(-1), and repetitive oxygen desaturations below 50%. Nasal continuous positive airway pressure (nCPAP) effectively controlled her sleep abnormalities. After 3 yrs of nCPAP therapy, she requested discontinuation and was fully reassessed. PSG without nCPAP revealed an AHI <5 events x h(-1) with no desaturations below 90% and normal sleep quality. A repeat lateral cephalometrogram showed increased mandibular length and posterior airway space and reduced soft palate length. The patient remains asymptomatic 9 months following nCPAP discontinuation. This case indicates that nasal continuous positive airway pressure is an effective nonsurgical therapy in children with obstructive sleep apnoea syndrome and the Robin sequence. It is likely that mandibular growth, increase in mandibular length and enlargement of the posterior airway space was responsible for the resolution of obstructive sleep apnoea syndrome in this case.