Diagnostics and management of sleep-related respiratory disturbances in children with skeletal dysplasia caused by FGFR3 mutations (achondroplasia and hypochondroplasia).

To evaluate the frequency of clinical indicators for sleep-related respiratory disturbances (SRD) and the polysomnographical manifestations of these disorders in children with skeletal dysplasia caused by FGFR3 mutations. From January 1990 to January 2009, 24 patients (22 achondroplasia, 2 hypochondroplasia; 13 boys, 11 girls; age 8 days to 15 years, median age 3.0 years) were examined, including a semi-structured interview, a clinical examination, and a polysomnographic sleep recording (65 polysomnographic sleep recordings (PSG) in 24 patients). We performed PSG in a subgroup of five patients before and after adenoidectomy (AT) and/or tonsilectomy (TE). Daytime symptoms suggestive of SRD (daytime somnolence, attention and concentration problems, behavioural problems, and pallor) were found in 4/24 patients (16.7%). Sleep-related symptoms (snoring, mouth breathing, cyanosis, observed apneas, excessive sweating, enuresis, problems of initiating and maintaining sleep) were present in 18/24 patients (75%). Prior to the first PSG, 11/24 patients (45.8%) had undergone AT, 1/24 (4.2%) TE, 2/24 (8.3%) adenotonsilectomy (ATE), 3/24 (12.5%) liquor drainage, and 6/24 (25%) a craniocervical decompression operation. Clinical examination prior to PSG revealed hypertrophied tonsils in 11/24 patients (45.8%), disturbed nasal breathing in 8/24 patients (33.3), and enlarged cervical lymph nodes as a sign of chronic tonsillitis in 5/24 patients (20.8%). PSG findings were abnormal in 19/24 patients (79.2%) with a nadir of oxygen saturation (pulse oximetry) below 90% and/or a nadir of transcutaneous partial pressure of oxygen below 45 mmHg. Pathologic PSG findings were found in 10/24 patients (41.7%): obstructive sleep apnea syndrome (OSAS) was diagnosed in 8/24 patients (33.3%), central sleep apnea syndrome in 1/24 patients (4.2%), and hypoventilation in 1/24 patients (4.2%). As a consequence, the following therapeutic interventions were performed: AT in 1/24 patients (4.2%), TE in 2/24 (8.3%), ATE in 2/24 (8.3%), and nasal continuous positive airway pressure (continuous positive airway pressure) and bilevel positive airway pressure therapy (bilevel positive airway pressure), respectively, in 3/24 patients(12.5%). SRD, especially OSAS, represent a complication of clinical and prognostic relevance in children with achondroplasia. We therefore think that not only those children with a history suggestive of SRD, but all achondroplastic children should be evaluated by PSG. At least in a part of these patients, the pathophysiological mechanisms of OSAS are connected with the etiology of achondroplasia. Achondroplastic children with OSAS, who do not benefit from AT and/or TE, should be treated with NCPAP therapy.

Hemodynamic responses to exercise in obese children and adolescents before and after overweight reduction.

OBJECTIVE: To determine the change of hemodynamic parameters in graded bicycle exercise testing in obese children before and after overweight reduction. METHODS: Forty-two obese children (mean age 11 years) and 40 healthy, lean children underwent graded bicycle exercise testing (1, 1.5, 2, 2.5 Watt/kg) recording the heart rate (HR) and blood pressure (BP) before exercise (T1), at maximum load (T2), and 6 min after ending the exercise (T3). Furthermore, the increase of the patient's heart rate within each ramp (I-HR) and the individual maximum load (Watt/kg) were recorded. After participating in an one-year outpatient intervention program for obese children, the study group underwent exercise testing again. Furthermore, we analyzed the lipid and insulin levels in the study group before and after overweight reduction and correlated the changes of the hemodynamic parameters to the changes of the insulin and lipid levels. RESULTS: The obese children had significantly (p<0.05) higher systolic blood pressure values at T1, T2, and T3 as compared to the lean children. The I-HR was significantly (p<0.05) higher in the study group. HR and BP at T1, T2, and T3, and the lipid and insulin values improved significantly in the study group after overweight reduction. The changes of HR and BP did not correlate to the changes of insulin and lipids. CONCLUSION: Compared to lean children, obese children demonstrated a significantly lower exercise capacity of the cardiovascular system, which improved after participating in an obesity intervention program. Overweight reduction influences the hemodynamic and metabolic changes of childhood obesity positively and thereby leads to an improvement of the cardiovascular risk factor profile.

Clinical features of isolated noncompaction of the myocardium in children.

Isolated noncompaction of the myocardium, also known as "spongy myocardium", is a rare disease in children and adults. It is suggested that, during early development of the heart, the primary spongy structure persists due to an arrest of compaction. No other cardiac malformations are found, but there are familial occurences, relations to genetic disorders or syndromes such as Melnick-needles-syndrome or Xq28-linked cardiomyopathy, and reports of conduction disorders. We have now diagnosed isolated noncompaction in seven children aged between five weeks and 5.5 years. Three are doing well with anticongestive therapy, while transplantation of the heart was performed in one. Three of the children have died, but in only one case due to cardiac failure. Our experience emphasises the need rapidly to establish the diagnosis, to search for associated extracardiac abnormalities, and to consider transplantation at an early stage.

Treatment of neonatal thrombus formation with recombinant tissue plasminogen activator: six years experience and review of the literature.

BACKGROUND: Thrombosis is a relatively rare event in children. However, many conditions in the neonatal period result in an increased risk of thrombus formation. The major risk factor is the indwelling intravascular catheter. Numerous small studies have reported experience of thrombolytic treatment for neonatal thrombotic disease with a wide range of different thrombolytic agents in various forms of administration, dosage, and duration, but no conclusions on the most effective treatment for neonates has been reached. OBJECTIVE: To assess the efficacy and safety of thrombolytic treatment of neonatal catheter related thrombus (CRT) formation with recombinant tissue plasminogen activator (rt-PA). METHOD: Over a six year period, 14 neonates with CRT were treated with the same rt-PA protocol (an initial bolus of 0.7 mg/kg over 30-60 minutes followed by infusion of 0.2 mg/kg/h). RESULTS: Complete clot dissolution was documented in 11 patients, and partial clot lysis in two patients, leading to a patency rate of 94%. In two cases, local bleeding occurred, resulting in treatment failure in one case. Finally, antithrombin III substitution was required in one case. No other complications such as severe bleeding were recognised. CONCLUSION: With the use of close clinical and haematological monitoring on a neonatal intensive care unit combined with serial two dimensional colour echocardiography, the present rt-PA protocol was shown to be a safe and effective method of clot dissolution in neonates.

Rhythms and complexity of respiration during sleep in pre-term infants.

The aim of this study is to test rhythmic and complex properties of respiratory control in former ventilated, pre-term infants during quiet and active sleep. The children had a higher risk for sudden infant death due to bronchopulmonary dysplasia (BPD). Twelve infants suffering from BPD and 12 control infants, matched regarding their post-conceptional age, were examined polygraphically during quiet (QS) and active sleep (AS). The respiratory rate (RR), the ratio (LF/HF) between the low-frequency power (LF) and the high-frequency power (HF) of the spectra of the thoracic respiratory effort, and the frequency of the dominant peak within LF (LFF) and HF (HFF) were computed. The correlation dimension (D2) of the respiratory signal was calculated to determine the complexity of the respiratory control. The transcutaneous pO2 (tcpO2) and pCO2 and the oxygen saturation (sO2) were analysed. Infants with BPD had significantly higher RR and HFF during QS (median: BPD 48 breaths min-1; control 32 breaths min-1). tcpO2 and sO2 were significantly lower in the BPD group. No differences were found in LF/HF, LFF or D2 between groups, either in QS or in AS. D2 ranged between 1.8 and 3.8, showing significantly higher values during AS. LFF was found to be lower during active sleep (AS 0.04-0.05 Hz; QS about 0.06 Hz). We propose that in infants with BPD the lower lung compliance and the higher resistance, and possibly also the hypoxaemia, contribute to the acceleration of breathing. The behaviour of RR, spectral parameters and D2 indicates a specific, functional setting rather than a regulatory impairment in infants with BPD.

Magnetocardiography in the diagnosis of fetal arrhythmia.

OBJECTIVE: To examine the possible use of magnetocardiography in the diagnosis of fetal arrhythmias. DESIGN: Investigation of routinely examined pregnant women, as well as women referred because of arrhythmias or other reasons. PARTICIPANTS: Sixty-three women between the 13th and 42nd week of pregnancy. METHODS: Recording of 189 fetal magnetocardiograms, of which 173 traces (92%) demonstrated sufficient fetal signal strength to permit evaluation. After digital subtraction of the maternal artefact, all fetal complexes were identified and the recording was examined for arrhythmic events. RESULTS: Short bradycardic episodes, not associated with any pathological condition, were found in 26% of all recordings, usually in mid-pregnancy. In 12 cases, isolated extrasystoles of no clinical importance could be identified. There were nine traces which revealed multiple arrhythmias including ventricular and supraventricular ectopic beats, bigeminy and trigeminy, sino-atrial block and atrio-ventricular conduction disturbances. Furthermore, two cases with tachycardia were found. CONCLUSION: Magnetocardiography offers a simple noninvasive method for examination of the fetal cardiac electrophysiological signal. It may thus be useful in the identification and classification of clinically relevant arrhythmia and aid in decisions concerning treatment.

[Isolated abnormality ("noncompaction") of the myocardium in 3 children]. / Isolierte Fehlentwicklung ("Noncompaction") des Myokards bei drei Kindern.

UNLABELLED: In three asymptomatic children an isolated myocardial noncompaction was detected by echocardiography at age 11 months, 5 weeks and 5.5 years. In the first male infant both ventricles and septum were severely affected and myocardial function was depressed. Nevertheless, during a follow up of 16 months he remained asymptomatic on anticongestive therapy. In the other two children apex and lateral wall of the left ventricle were affected and myocardial function was still normal. The second boy had also an infantile epilepsy-encephalopathy syndrome and the third child (a girl) had a Wolff-Parkinson-White syndrome; an association of either syndromes with myocardial noncompaction has not been reported earlier. DISCUSSION: Myocardial noncompaction (spongy myocardium) is a rare maldevelopment, which occurs either associated with certain congenital heart defects or, even more rarely, isolated, as the two cases reported here. Myocardial failure, severe arrhythmias or thromboembolism may occur at any age and determine the outcome. Clinical course, therapy and prognosis are similar to dilatative cardiomyopathy, which represents an important differential diagnosis.

Pulmonary veno-occlusive disease, antiphospholipid antibody and pulmonary hypertension in an adolescent.

UNLABELLED: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension (PH); Antiphospholipid antibody (APL) is another known cause of pulmonary hypertension, due to recurrent pulmonary thromboembolism. The coincidence of both causes, PVOD and APL, without thromboembolism, in PH has not been reported previously in children. A 12.5-year-old boy presented with a one year history of fatigue. Pulmonary hypertension was diagnosed by echocardiography. Pulmonary function tests revealed a moderate restrictive pattern and elevated granulocytes were detected in bronchoalveolar lavage. An isolated high-titer APL was detected. Open lung biopsy established the diagnosis of PVOD, with no evidence of pulmonary thrombosis, but with accompanying interstitial and alveolar cellular infiltration. We speculate that APL may have played a role in the pathogenesis of PVOD. Prednisone++ improved the symptoms of the interstitial pneumonitis and was stopped; on follow up of 30 months, the patient ist in stable condition on therapy with nifedipin, phenprocoumon and digoxin. CONCLUSIONS: PVOD and APL may be present simultaneously as a rare cause of PH. Interstitial pneumonitis may accompany PVOD and produce the leading symptoms. Open lung biopsy is essential for early establishment of the diagnosis.

[Interstitial lung diseases with pulmonary hypertension associated with epidermolysis bullosa in an infant]. / Interstitielle Lungenerkrankung mit pulmonaler Hypertension assoziiert mit Epidermolysis bullosa bei einem Säugling.

Interstitial lung diseases, with or without pulmonary hypertension and epidermolysis bullosa are rare in infancy. Pathogenetic correlations between these disease are not known and their coincidence has not been reported, yet. We report on a seven weeks old boy of consanguine parents with typical skin efflorescences of epidermolysis bullosa, tachydyspnoea and cyanosis. Echocardiography and cardiac catheterisation revealed pulmonary hypertension, which persisted under therapy with oxygen and nifedipin. Lung biopsy showed interstitial and peribronchiolar increased lymphocytes and lymphfollicels, a mild intraalveolar desquamation and a media hypertrophy of the arteries. A combined therapy of prednisone and nifedipine normalised the pulmonary hypertension and the oxygen saturation. The activity of the epidermolysis bullosa showed no correlation with the interstitial lung disease or with the therapy. A connection between both diseases is discussed.

Linear and nonlinear properties of heart rate control in infants at risk.

The aim of this study was to test whether the heart rate (HR) control in infants at risk differs in comparison with healthy infants. Twelve former preterm infants suffering from bronchopulmonary dysplasia and 18 control infants, matched for their postconceptional age, were examined polygraphically during quiet and active sleep. HR, low-frequency (LF) power, high-frequency (HF) power, total power, and the ratio of LF to HF power (LF/HF) of the instantaneous HR spectra were calculated for linear analysis. The largest Lyapunov exponent (LLE) of the R-R interval time series was calculated to determine a nonlinear property of HR. Infants at risk had significantly lower LF power (median: 0.51 x 10(-3) vs. 1.16 x 10(-3) Hz2) and lower LF/HF (median: 1.05 vs. 1.94) during quiet sleep. LLE was positive, revealing low-dimensional chaotic behavior of HR control, and did not differ between both groups (median: quiet sleep, 0.05 bit/s vs. 0.06 bit/s; active sleep, 0.16 bit/s vs. 0.15 bit/s). Sleep state-related changes in spectral parameters and LLE were similar in both groups. In infants at risk, the lower LF/HF during quiet sleep can be interpreted in terms of changes in the rhythmic components of the sympathovagal balance of the autonomic system, which is an expression of linear properties of HR control. Conversely, the lack of differences in LLE between both groups indicates similar nonlinear properties of the control system.

Respiratory control in children with Prader-Willi syndrome.

UNLABELLED: Physiological parameters of infants and children with Prader-Willi syndrome were examined in order to clarify whether there were indicators of disturbed respiratory control mechanisms in the pre-obesity stage of the syndrome. From January 1993 to March 1995 in eight patients with Prader-Willi syndrome (five boys, three girls, aged 6 weeks-12.5 years), polysomnography was performed and compared with 28 children matched for gestational age, sex, birth weight and age at sleep study. The recordings included thoracic and abdominal breathing movements, nasal airflow, tcPO2, tcPCO2, oxygen saturation, EEG, EOG and ECG. Respiratory responses to hypercapnia during quiet sleep were obtained from five Prader-Willi patients and ten peers. The Prader-Willi group showed an increased number of apnoeas per hour of sleep, a decreased nadir of oxygen saturation, increased maximum of the instantaneous heart rate and decreased respiratory responses to hypercapnia during quiet sleep. CONCLUSION: These findings indicate a primary disturbance of central respiratory control in patients with Prader-Willi syndrome which may be worsened by the development of obesity.

[Apnea characteristics of children who later died: comparison of sudden infant death with other causes of death]. / Apnoekennwerte bei später verstorbenen Kindern: Vergleich von plötzlichem Säuglingstod mit anderen Todesursachen.

Apnea characteristics of infants, who were destined to die, were compared with control infants, matched for gestational age, sex, birth weight and age at sleep study. From 1989 to 1994 polygraphic recordings were performed in 4268 infants. In this population 7 cases of sudden infant death (SID) and 13 deaths from other causes (non-SID) occurred. Concerning all forms of apneas a higher frequency and maximal duration was found in the SID group. The number of infants with obstructive apneas and the number of obstructive apneas per infant were higher in future SID victims, as was the frequency, mean and maximal duration of central apneas of 3 to 10 s. The recordings of non-SID-infants were not different from their controls. As a group, future SID victims showed apnea characteristics different from control infants. Together with epidemiologic risk factors these polygraphic factors contribute to an identification of infants at risk for SID.

Polygraphic findings in young infants with Joubert's syndrome.

In three young infants with Joubert's syndrome polygraphic recordings were carried out in the awake state and during REM and NREM sleep in order to characterize the respiratory disorder associated with this condition. In all three states disturbed respiration parameters were found in variable amounts. The highest breath rate occurred in the awake state followed by REM and NREM sleep. The highest incidence of apnoea and periodic breathing was observed in NREM sleep, followed by REM sleep and the awake state.

Polysomnographic recordings of respiratory disturbances in Rett syndrome.

Polygraphic recordings in the awake state and during sleep were performed in two girls with Rett syndrome, aged 9 y and 17 y, in order to characterize the clinically manifest breathing disorder of these patients. Primary hyperventilation was detected, leading to hypocapnia and compensatory apnoea. Hypoxaemia occurred as the consequence of prolonged apnoea. In the younger patient these disturbances were observed only in the awake state, whereas in the older patient they were found in the awake state and during sleep.

[Obstructive apnea and periodic respiration in premature infants]. / Obstruktive Apnoen und periodische Atmung bei Frühgeborenen.

BACKGROUND: Disturbances of cardiorespiratory function are common clinical problems in preterm infants. Polygraphic recordings during sleep were performed in order to determine frequency and severity of idiopathic apnea of prematurity. METHOD: In 137 preterm infants at the corrected age of < +/- 0 weeks, 0-12 weeks, 13-24 weeks and > or = 25 weeks respectively central and obstructive apnea and periodic breathing were recorded by polysomnography including nasal airflow and thoracic and abdominal breathing movements and compared with 50 normal full-term infants. RESULTS: Apnea frequency was inversely correlated to gestational age in premature and term infants. Whereas no differences were found concerning central apnea and periodic breathing, obstructive apnea occurred more frequently in premature than in term infants during the first weeks of life. CONCLUSIONS: Conclusively, in early infancy premature infants have an inclination to upper airway obstruction.

[Sleep apnea in hyperplasia of the pharyngeal lymphatic tissue. Polysomnographic studies in children]. / Schlafapnoen bei Hyperplasie des lymphatischen Rachenrings. Polysomnographische Untersuchungen an Kindern.

BACKGROUND: Hyperplasia of tonsils and adenoids is a common finding in early childhood. Breathing difficulties caused by hyperplastic lymphatic tissue represent an indication for adenoidectomy and tonsillectomy. It was examined, whether a polysomnographic recording is a useful tool to assess the severity of obstructive sleep apnea in children with hyperplasia of tonsils and adenoids. METHODS: In 15 patients (10 boys, 5 girls), 1.0 to 6.6 years of age, with a history of breathing difficulties during sleep a thorough clinical evaluation was performed. Additionally, a polysomnographic recording was carried out, including thoracic and abdominal breathing movements, nasal and buccal thermistor, ECG and transcutaneous blood gases. RESULTS: Before therapy, severe obstructive apnea was demonstrated by polysomnography in all patients. This finding disappeared almost completely after surgery. Hyperplasia of adenoids was diagnosed in 3 patients, hyperplasia of tonsils in 3 patients, hyperplasia of tonsils and adenoids in 8 patients, and other kind of lymphatic hyperplasia in 1 patient. CONCLUSION: Hyperplasia of tonsils and adenoids contributes to the development of sleep-apnea-syndrome in childhood. A polysomnographic recording seems to be a useful tool to describe the severity of obstructive sleep apnea in children with hyperplasia of tonsils and adenoids.

Echocardiographic proof of pulmonary hypertension with irreversible increased resistance in the pulmonary circulation as a complication after placement of a ventriculo-atrial shunt for internal hydrocephalus.

Increased resistance in the pulmonary vessels in children with ventriculo-atrial shunts is a rare and often unrecognized permanent complication. We report 2 children in whom this diagnosis was detected by two-dimensional echocardiography. The first patient received a ventriculo-atrial shunt at age 9 days for congenital internal hydrocephalus. At 17 months it had to be replaced because of infection of the efferent catheter limb. At 22 months at a routine follow-up the echocardiographic diagnosis of pulmonary hypertension was made. Invasive studies confirmed the presence of irreversible increased resistance in the pulmonary circulation. The second patient received a ventriculo-atrial shunt at age 13 months because of a cerebral cyst. After repeated catheter infections, at 28 months a ventriculo-peritoneal shunt was placed. At age 4 years the diagnosis of pulmonary hypertension was made by routine echocardiography. This finding was confirmed by invasive studies. The left pulmonary artery was completely occluded. Both patients had developed microemboli, caused or aggravated by catheter sepsis, in the second case probably through contiguous clot growth up to complete occlusion of the left pulmonary artery. Therapeutic measures seemed not to be indicated. Two-dimensional echocardiography proved to be a reliable method for diagnosing increased resistance and pulmonary hypertension. We recommend routine echocardiography for follow-up in all children with ventriculo-atrial shunts.