Helmut Willgerodt

High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype–genotype analysis

BACKGROUND/AIMS Wilson disease is caused by a large number of different mutations in the ATP7B gene. Wilson disease patients from a homogeneous ethnical background (Saxonia) were studied for distribution and phenotypes of ATP7B mutations. METHODS Eighty-two patients were analyzed. The H1069Q mutation was assayed by a polymerase chain reaction-based restriction fragment length polymorphism test. Exons 8 and 15 were sequenced in all, and the entire gene in 30, non-H1069Q-homozygotes. RESULTS Four novel and 12 known mutations were found. Thirty-two (39%) Wilson disease patients were homozygous and 39 (48%) heterozygous for the H1069Q mutation (allele frequency 63%). Together with sequence analysis of exons 8 and 15 mutations in both alleles were identified in 65% of patients. Only one patient had both mutations at other locations. In H1069Q homozygotes symptoms started later (21.3+/-7.2 years) than in H1069Q compound heterozygotes (14.6+/-5.8, P<0.001) or H1069Q negatives (10+/-4.4, P<0.001), and they had more frequently neurologic symptoms (93 vs. 47%, P<0.001) and Kayser-Fleischer rings (82 vs. 51%, P<0.001). Mutation status did not correlate with liver biopsy findings, serum ceruloplasmin levels or (64)Cu-assay results. CONCLUSIONS In spite of many known ATP7B mutations, only few occur in this homogeneous population. Limited genetic testing is useful to confirm Wilson disease in this population.

Variability in the Proteus syndrome: report of an affected child with progressive lipomatosis.

In 1983 the Proteus syndrome was delineated by Wiedemann et al. [12]. We report a 10-month-old girl, a further child affected by the new syndrome. The typical signs are macrodactyly, hemihypertrophy, pigmented nevi, hyperkeratosis, and subcutaneous hamartomatous tumours. Our patient shows an aggressive lipomatosis on the trunk and local relapses after surgical interventions in the regions involved. Histology of the adipose tissue showed considerable anisocytosis and increased cell volume.

Neonatal Thyroid Function in Iodine Deficiency

In adults, impairment of thyroid function due to iodine deficiency occurs only when the iodine intake is drastically reduced, usually to less than 50 μg per day1.

Blood pressure in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND In patients with congenital adrenal hyperplasia (CAH) recording of blood pressure (BP) must be included in monitoring treatment to detect hypertension. AIM To investigate the BP patterns in patients with CAH. METHODS Twenty-three children and adolescents (age 6-17 years) and 11 adult patients (age 18-26 years) were studied (21 females, 13 males; 28 salt-wasting patients). In the whole group BP in the outpatient clinic was compared with BP under hospitalisation and in 11 of the children and adolescents also with 24-hour ambulatory blood pressure monitoring (ABPM). RESULTS BP in the ward in children and adolescents but not in adults was significantly higher than BP in the outpatient clinic, where BP was in the upper normal range. There was also a significant difference between BP in the outpatient clinic and the lower ABPM in the 11 patients tested. Atrial natriuretic peptide (ANP) in blood serum showed normal values. CONCLUSIONS BP measured in outpatients in a relaxed and calm atmosphere meets the requirements for monitoring of treatment. Measurement of BP on the ward leads to falsely high results. ABPM is not necessary. Estimation of ANP provides no additional information.

Long-Term Care and Management of Wilson’s Disease in the GDR

Diagnosis, long-term management and family investigations of Wilsons disease are provided by selected clinical institutions in the GDR. From 187 patients detected since 1949, 111 are alive. In spite of the principal effectiveness of penicillamine treatment, confirmed by the disappearance of most of the central nervous system symptoms and successful professional rehabilitation of many patients, insufficient therapeutic discipline, psychosocial disturbances and penicillamine side-effects forcing its substitution by zinc or triethylenetetramine dihydrochloride in 14 cases need our further attention.

Acute ingestion of thyroxine and triiodothyronine in young children

The present observations on 30 children, most of them having accidentally ingested large amounts of triiodothyronine (T3) and thyroxine (T4), demonstrate that amounts as great as 630 lg T3 together with 2500 lg levothyroxine were tolerated without symptoms of severe intoxication as has already been reported for the ingestion of pure levothyroxine alone. Most of those reports are based on the ingestion of high amounts of T4 followed by high T4 levels in serum and there are only occasional reports of high T3 concentrations in the blood following the ingestion of mixtures of T3 and T4 or more rarely pure T3 preparations [4]. In view of this, we report our experience with the accidental ingestion of thyroid hormones in young children to include a representative number of patients with a high concentration of T3 in the blood following ingestion of mixtures of T4 and T3. The data on 30 patients seen between January 1983 and January 2000 in our department because of acute ingestion of thyroid hormones were analysed. Criteria for inclusion in the study were the history of acute ingestion of thyroid hormones in patients less than 5 years old, the documented concentrations of T4 and T3 in the blood and no history of therapeutic thyroid hormone administration. Diagnosis and treatment mainly followed the standard practice in our department. These included an interview with the parents concerning the number of tablets ingested and the time of ingestion. In all children, gastric lavage followed by the administration of activated charcoal and sodium sulphate (0.25 g/kg) were performed in the outpatient department. Until the middle of 1988, all patients were subsequently admitted to the hospital for a minimum of 24 h. Thereafter, patients were admitted only if symptoms of intoxication were present or if the calculated dose exceeded 500 lg of T4. Those children not admitted to the hospital were seen again on the following 1 or 2 days. The time when the first blood was taken varied considerably. Usually the first blood was taken 2–6 h after ingestion. Further estimations of T4 and T3 were undertaken only if the patients exhibited symptoms of intoxication or when very large doses had been ingested. The concentrations of T3 and T4 in serum were estimated using commercial radioimmunoassays. Despite alterations during the 17 years of the study, the results of the assays varied only in very narrow limits because of the continuous use of external and internal standards. To evaluate the influence of thyroid hormones on the myocardium, the systolic time intervals (STI) were estimated in six children. The measured and calculated values for the pre-ejection period (PEP) and left ventricular ejection time (LVET) were compared with normal values. The PEP/LVET ratio, which does not depend on age and frequency, provides the most reliable estimate of myocardial function [1]. As shown in Table 1, most of the children were younger than 4 years of age. 20 children had taken a mixture of four parts T4 and one of T3 (Thyreotom). A total of 23 children were admitted to hospital and seven were observed as outpatients. Despite extremely high T3 levels in some patients, only eight patients presented mild clinical symptoms such as a pulse rate of more than 120/min and raised blood pressure. There were no cases with unconsciousness, seizures or other symptoms of disturbance of the central nervous system. As reported by other authors [4,5], the initial levels of T3 and T4 in serum showed no close correlation with clinical symptoms of intoxication. Only three of six children in whom the STI was estimated showed a reduced PEP/LVET ratio as found in thyrotoxicosis. Surprisingly the index was normal in those children with the Eur J Pediatr (2003) 162: 639–641 DOI 10.1007/s00431-003-1263-2

[Diagnosis of coeliac disease by means of combined gliadine-xylose loading].

SummaryThe urinary excretion of D-xylose was studied for 8 hours following oral administration with 15 g/m2 of D-xylose prior to and following a single administration of 5 g/m2 of gliadine in 20 infants.Infants, free from disease of the small intestines, excreted more than 20% of the administered xylose dose. Gliadine had no effect on the excretion.Xylose elimination was found to be diminished in 3 and within normal limits (17.2±4.76% of the administered dose) in 10 patients with coeliac disease. In the event of xylose being administered 2 hours after gliadine loading, the excretion decreased significantly to 5.4±3.86%. Restored xylose excretion occurred within 24 to 48 hours after gliadine loading.Gliadine had no effect on xylose excretion in 5 infants with noncoeliac malabsorption syndromes.ZusammenfassungBei 20 Kindern wurde unter gliadinfreier Kost die Xyloseausscheidung im 8-Std-Urin nach oraler Zufuhr (15 g/m2) vor und nach einmaliger Gliadinbelastung (5 g/m2) bestimmt.Die Xyloseausscheidung lag bei darmgesunden Kindern über 20% der zugeführten Menge und wurde durch die Gliadinbelastung nicht beinflußt.Bei Kindern mit Cöliakie war vor Gliadinbelastung die Xyloseausscheidung in drei Fällen sicher pathologisch, in zehn Fällen normal (17,2±4,76). Bei Durchführung des Xylosetests 2 Std nach Gliadinbelastung fiel die Xyloseausscheidung in allen Fällen auf pathologische Werte ab (5,4±3,86). 24 und 48 Std nach Glidinbelastung durchgeführte Xylosetests wiesen auf eine rasche Reparation der Dünndarmresorption hin.Bei fünf Kindern mit Malabsorptionssyndrom anderer Genese wurde der Ausfall des Xylosetests durch Gliadin nicht beeinflußt.