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.

Two-dimensional echocardiographic evaluation of right ventricular size and function in newborns with severe right ventricular outflow tract obstruction.

Critical pulmonary stenosis or atresia with intact ventricular septum represents a congenital cardiac lesion for which the long-term prognosis appears to depend partly on the size of the right ventricle. Thus, the capability of noninvasive assessment of right ventricular size to predict operative outcome was examined in 15 infants (aged 1 to 30 days, mean 5.6) with severe right ventricular outflow tract obstruction (either critical pulmonary stenosis [7 patients] or pulmonary atresia with intact ventricular septum [8 patients]). Using echocardiography in two orthogonal subxiphoid views, right ventricular volume, wall thickness, area change fraction, ejection fraction and tricuspid anulus dimension were measured. All patients with a normalized right ventricular enddiastolic volume of less than 5 ml/m2 and a normalized tricuspid anulus dimension of less than 1.0 cm/m2/3 required a shunt operation. Only one patient with a volume of more than 6 ml/m2 and a normalized tricuspid anulus dimension of more than 1.4 cm/m2/3 required more than relief of right ventricular outflow tract obstruction. In this patient, residual severe pulmonary stenosis necessitated the shunt procedure. One patient with a volume of more than 6 ml/m2 had an anulus diameter of less than 1.4 cm/m2/3 and one patient with an anulus diameter of more than 1.4 cm/m2/3 had a volume of less than 6 ml/m2; both required shunt procedures. It therefore appears that if either the ventricular volume or tricuspid anulus size is excessively small, a shunt procedure is necessary. Wall thickness, area change fraction and ejection fraction measurements were not significantly correlated with right ventricular volume or postoperative outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Two-dimensional echocardiographic findings in double orifice mitral valve.

Between December 1981 and April 1984, five children ranging in age from 1 month to 5 1/2 years examined by two-dimensional echocardiography appeared to have a double orifice mitral valve. The diagnosis was verified in one patient at surgery, one patient by angiography and one patient by necropsy. Associated malformations included mitral stenosis and regurgitation, coarctation of the aorta, ostium primum and secundum atrial septal defect, ventricular septal defect and hypoplastic left heart syndrome. Three varieties of double orifice mitral valve were observed: an incomplete bridge type (one patient), in which a small strand of tissue connected the anterior and posterior leaflets at the leaflet edge level; a complete bridge type (three patients), in which a fibrous bridge divided the atrioventricular orifice completely into equal or unequal parts and a hole type (one patient), in which an additional orifice with subvalvular apparatus occurred in the posterior commissure of the mitral valve. These three types could be distinguished by sweeping the transducer in cross-sectional view from the apex toward the base of the heart. Both orifices could be seen throughout the scan in the complete bridge type while in the incomplete bridge type the two orifices could be seen only at the level of the papillary muscles. In the hole type, the second orifice was seen at about midleaflet level. In all three types, the chordae surrounding each orifice attached to only one papillary muscle. Congenital mitral stenosis or regurgitation was evident in three patients. The type of the double orifice mitral valve did not predict the presence or severity of symptoms.

Two-dimensional echocardiographic estimation of right ventricular area change and ejection fraction in infants with systemic right ventricle (transposition of the great arteries or hypoplastic left heart syndrome).

A reproducible, noninvasive method for estimating right ventricular (RV) function would greatly facilitate evaluation of infants in whom the RV supplies the systemic circulation. Therefore, 2-dimensional echocardiographically derived parameters, RV area-change fraction and RV ejection fraction (EF), were evaluated in 19 preoperative infants (age 1 to 30 days, mean 7 days), 12 with hypoplastic left heart syndrome and 7 with transposition of the great arteries. The area enclosed by the RV was measured in both a subxiphoid long-axis (coronal plane) and short-axis (parasagittal plane) view. From these measurements end-systolic and end-diastolic volumes were derived using Simpson's rule and the EF was calculated. The total area change fraction was calculated as the average of the long and the short-axis area change fraction. Similar measurements were made independently from biplane cineangiograms obtained within 3 days of the echocardiogram. The echocardiographically derived EF and area-change fraction were compared with the angiographic EF using linear regression analysis. The echocardiographic EF (mean 49 +/- 11) correlated well with the angiographic EF (mean 51 +/- 12, r = 0.84). The echocardiographic area-change fraction was somewhat less closely correlated with the angiographic EF (r = 0.79). Comparing short- and long-axis area-change fraction to echocardiographic EF, the short-axis measurements were better correlated than long-axis measurements (r = 0.86 and 0.75, respectively). (ABSTRACT TRUNCATED AT 250 WORDS)

Double-orifice mitral valve: a study of 27 postmortem cases with developmental, diagnostic and surgical considerations.

What is double-orifice mitral valve anatomically and embryologically? In 27 postmortem cases, an anomaly of the tensor apparatus was always found. These malformations may be summarized as: (1) chordal ring; (2) accessory papillary muscle or muscles; (3) subdividing muscular ridge; (4) fused papillary muscles (parachute mitral valve); (5) crossing chordae tendineae; and (6) central fibrous subdivision. More than 1 of these anomalies often coexisted per case. Double-orifice mitral valve almost always consisted of abnormal holes in essentially normal leaflets, rather than of abnormal fibrous bridges or adhesions between normal leaflets. Since these fibrous "bridges" between the smaller accessory orifice and the larger main orifice are composed of mitral leaflet tissue and chordae, not fibrous adhesions, these bridges should not be transected surgically, to avoid iatrogenic mitral regurgitation. The accessory (smaller) orifice was at the anterolateral commissure in 11 cases (41%), at the posteromedial commissure in 12 (44%) and there was a central fibrous subdivision with approximately equal-sized orifices in 4 (15%). The atrioventricular (AV) canal was normally divided in 12 cases (44%) and a common AV canal was present in 15 (56%). When the accessory orifice was at the anterolateral commissure, the AV canal usually was normally divided (8 of 11, 73%). But when the accessory orifice was at the posteromedial commissure, a common AV canal almost always was present (11 of 12, 92%). Functionally, the mitral valve was normal in 13 (48%), regurgitated in 7 (26%) and stenotic in 7 (26%). The key to the diagnostic and surgical understanding of the double-orifice mitral valve is the underlying tensor apparatus.

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.

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.

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.

Diagnostic and therapeutic problems with an unusual congenital cystic hygroma of the orbit.

A case of an extensive congenital cystic hygroma in an unusual situation in the orbit is presented. The lesion occurred as an ulcerative, rapidly--growing and repeatedly--bleeding tumour with destruction of the left orbit, parts of the middle face, the nose and the base of skull. Despite X-ray investigation, computed tomography, nuclear magnetic resonance imaging and angiography it was impossible to give a reliable diagnosis. Because of the rapid growth of the tumour and its uncertain nature a radical resection with exenteration of the orbit, resection of the zygoma, the soft tissues of the cheek and parts of the nose and skull base was performed. One year after the resection there was no sign of recurrence.

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.

[Reversible cor pulmonale in central disorder of respiratory regulation]. / Reversibles Cor pulmonale bei zentraler Atemregulationsstörung.

Irreversible increase of pulmonary vascular resistance is a well known complication of chronic hypoxemia. In our 12 months old patient a central ventilation disorder caused severe hypoxemia and hypercapnea at sleep. With 9 months of age pulmonary hypertension was found echocardiographically and was verified by catheterization. Massive increase of pulmonary vascular resistance was measured. A controlled oxygen therapy normalized oxygen partial pressure at sleep, and a rapid regression of the echocardiographic signs of pulmonary hypertension became evident. However, the central ventilation disorder was not significantly influenced.

[The diameter of the large arteries in the first 3 years of life. An echocardiography study]. / Durchmesser der grossen Arterien in den ersten 3 Lebensjahren. Eine echokardiographische Studie.

The diameters of the great arteries at their origin and also more distal are important parameters for deciding which operation technique should be performed in cyanotic congenital heart diseases. In 130 normal newborn and infants (age between 1 day and 3 years, with a weight of 2,2 through 20 kg) who were examined because of heart murmur diameters of main pulmonary artery, right pulmonary artery, left pulmonary artery, aortic root, ascending aortae, aortic arch, and isthmic region were measured echocardiographically. Then correlations between age and diameters, and weight and diameters were calculated. The mean diameter of ascending aorta grew from 0.84 cm through 1.4 cm, of main pulmonary artery from 0.75 cm through 1.4 cm, of right pulmonary artery from 0.43 cm through 0.86 cm, of left pulmonary artery from 0.42 cm through 0.88 cm, of aortic arch from 0.68 cm through 1.44 cm, and of isthmic region from 0.47 cm through 0.83 cm. The best correlation was found using linear functions between weight and diameters. The "growing-velocity" of ascending aorta was 0.043 cm/1 kg weight gain and 0.05 cm/1 kg weight gain for main pulmonary artery (0.033 cm/1 kg weight gain for right and 0.035 cm/1 kg weight gain for left pulmonary artery). The great arteries grow linearly within the first 3 years of life. The echocardiography was a reliable tool to calculate "growing-velocities".

[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.

[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.

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.

[Primary hyperlipoproteinemia Type I in the neonatal period]. / Primäre Hyperlipoproteinämie Typ I im Neugeborenenalter.

Newborn infants with inborn errors of lipid metabolism are relatively rare. There are only a few reports of hyperlipoproteinemia in infancy. In a six-day-old "healthy" newborn infant with a weight of 2960 gm a milky blood serum was found. Diagnosis of primary hyperlipoproteinemia type I was established by exclusion of other diseases and by analysis of blood lipids. Lack of lipoprotein lipase activity in postheparin plasma confirmed the diagnosis. The parents of the patient were normolipemic but showed reduced lipoprotein lipase activity. Thus, they were recognized as heterozygotes. A low fat (6-19 gm fat/d, 2-3 gm fat/kg bodyweight/d) diet with a high proportion of medium-chain triglycerides (78% MCT) lowered the initially extremely high serum triglyceride level (3674 mg/dl) significantly (214-711 mg/dl). Until the age of 7 months body weight and length followed the 10. percentile, head circumference followed the 50. percentile. Unexpectedly the patient died of pulmonary infection at the age of 8 months.

[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.