Michael J. Lentze

Urinary excretion of in vivo 13 C-labelled milk oligosaccharides in breastfed infants

Recent observations indicate that human milk oligosaccharides (HMO) are involved in a variety of physiological processes in infants. Their metabolic fate, however, is virtually unknown. We investigated metabolic aspects in infants after endogenous 13C-labelling of HMO. An oral bolus of natural and 13C-labelled galactose (Gal; 23 g Gal+4 g 13C-Gal) was given to ten lactating women. Aliquots of milk at each nursing as well as breath samples from the mothers and urine from their infants were collected over 36 h. The 13C-enrichment of HMO and their renal excretion was determined by isotope ratio-MS; characterisation was achieved by fast atom bombardment-MS. After the Gal bolus was given, an immediate 13C-enrichment in milk and in infants urine was observed which lasted 36 h. Mass spectrometric analysis of 13C-enriched urinary fractions confirmed the excretion of a variety of neutral and acidic HMO without metabolic modification of their structures. Components with glucose split off at the reducing end were also detectable. Quantitative data regarding the infants intake of lacto-N-tetraose and its monofucosylated derivative lacto-N-fucopentaose II ranged from 50 to 160 mg with each suckling, respectively; renal excretion of both components varied between 1 and 3 mg/d. Since the intake of individual HMO by the infants was in the range of several hundred mg per suckling, i.e. several g/d, and some of these components were excreted in mg amounts as intact HMO with the infants urine, not only local but also systemic effects might be expected.

The diagnostic significance of IgG cow's milk protein antibodies re-evaluated.

The effect of different feeding regimens, notably the use of hydrolysed cows milk formulas, on the development of allergic reactions and the development of cows milk protein-IgG antibodies is still disputed. We prospectively compared the development of allergic manifestations and cows milk protein-IgG antibodies in a total of 702 infants who were divided into six groups:1.exclusively breast milk for at least 4 weeks (n=206).2.Breast milk plus initial partially hydrolysed formula (n=104).3.Breast milk plus extensively hydrolysed formula (n=50).4.Breast milk plus initial conventional cows milk formula (n=73).5.Conventional cows milk with or without breast milk throughout (n=187).6.Extensively hydrolysed cows milk formula for 2 months, followed by conventional cows milk (n=82).Cows milk protein antibodies were determined by an indirect immuno-fluorescent test. Antibody titres rose slowly in groups 1, 3 and 6. Children in group 5 showed two high peaks. There were no significant differences in the frequency and type of allergic manifestations between the groups. Introduction of cows milk formula during the first trimenon resulted in elevated antibody titres in all breast fed infants compared with introduction at a later date. Conclusion: In contrast to a previous study from the same laboratory, there is no diagnostic significance of cows milk protein-IgG antibodies for allergic manifestations. The occurrence of these antibodies is a physiological phenomenon: the shorter the breast feeding period and the earlier cows milk formula is introduced, the higher the antibody levels.

Identification of mutations in the human hairless gene in two new families with congenital atrichia

Congenital atrichia (AUC) is a form of isolated alopecia with an autosomal recessive mode of inheritance. Patients are born with normal hair but this is shed almost completely during the first weeks or months of life and never regrows. In many families the development of papular lesions is noted as an additional phenotypic feature, which defines a related phenotype designated as atrichia with papular lesions (APL). Using positional cloning strategies and the molecular findings in hairless recessive (hr/hr) mice, an animal model for AUC, mutations in the human hairless gene (HR) have been identified as a cause of AUC and APL. To date, more than 20 different mutations of the HR gene have been reported in AUC and APL including different mutation types scattered over the entire HR gene length. In this report, we describe two families of Saudi Arabian and Jewish Iranian origin comprising a number of individuals with clinical features suggestive of AUC. We therefore hypothesized that affected members may carry mutations in the HR gene. After sequencing the complete coding region of the HR gene in the Saudi Arabian family, we identified a homozygous insertion of a G (c.2661dupG; p.Thr888DfsX38) in exon 12, resulting in a premature stop codon. In a Jewish Iranian patient, we identified a homozygous splice site mutation c.1557-1Gxa0>xa0T in intron 4. The latter mutation has been previously reported in a compound heterozygous state. In the present report, we describe the second exonic insertion mutation in the human HR gene and the first mutation in exon 12. Our study emphasizes the importance of sequencing the complete coding sequence and exon/intron junctions in the molecular diagnostics of AUC and APL.

Einführung und Zusammensetzung der Beikost

ZusammenfassungIm 2.xa0Lebenshalbjahr wird die Beikost zu einem zentralen Element der Ernährung. Bei den derzeit rational begründbaren Empfehlungen für die Beikost in ihrer Gesamtheit handelt es sich um ein Zusammenspiel von wissenschaftlicher Evidenz, einem großen Anteil Empirie und gelegentlichem Pragmatismus. In Deutschland gibt das Beikostschema im Ernährungsplan für das 1.xa0Lebensjahr den Stand des Wissens wider. Ernährungs- und entwicklungsphysiologische sowie präventive Gründe sprechen für die Einführung der Beikost frühestens zu Beginn des 5. und spätestens zu Beginn des 7.xa0Lebensmonats bei fortgeführtem Teilstillen. Beikost im Ernährungsplan kann mit einfachen Rezepten selbst angefertigt oder mit industriell hergestellten Mahlzeiten realisiert werden. Wesentliche neuere Erkenntnisse sprechen für Abwechslung in der Lebensmittelauswahl und Verzicht auf diätetische Restriktionen mit dem Ziel der Allergieprävention. Die 3 empfohlenen Typen von Beikostmahlzeiten ergänzen sich zusammen mit der Milch in einem Baukastensystem zu einer weitgehend empfehlungsgerechten Nährstoffzufuhr. Wie die Zufuhr von Eisen, Jod, Protein und Fett mit dem bestehenden Beikostschema zu bewerten ist, steht zur Diskussion. AbstractIn the second six months of life, complementary feeding becomes the central element of the infant diet. The available rational arguments regarding the total of complementary feeding are an interplay of scientific evidence, to a large part empirical knowledge and sometimes pragmatism. In Germany, current knowledge is reflected in the guidelines for complementary feeding of the ‘Dietary schedule for the first year of life’. Nutritional as well as developmental and preventive arguments call for an introduction of complementary feeding at the beginning of the 5th month of life at the earliest and at the beginning of the 7th month at the latest, accompanied by continued breastfeeding. Complementary feeding can either be home made by use of simple recipes or industrially produced meals can be chosen. Recent scientific knowledge calls for a variable selection of foods and renounces any dietary restrictions for allergy prevention. Three types of complementary meals are recommended that complement each other and, taken together with the remaining milk portion, result in an overall nutrient intake conform to the reference values. How dietary intake of nutrients like iron, iodine, protein and fat in complementary feeding can be sensibly evaluated is still debatable.

TNF-α Promoter Polymorphism in Relation to TNF-α Production and Clinical Status in Cystic Fibrosis

The severity of lung disease in cystic fibrosis may be related to the genetic propensity of the host to produce tumor necrosis fector α (TNF-α). A polymorphism in the promoter region of the TNF-α gene at nucleotide 308 relative to the transcription start site may be important in determing the host’s TNF-α response. The aim of this study was to assess the correlation between a TNF-308 promoter polymorphism, ex vivo TNF-α production (before and after lipopolysaccharide (LPS) stimulation), and clinical status [FEV1, weight (z-score), BMI, Shwachman score, incidence of diabetes mellitus, and Pseudomonas aeruginosa infection). Genotyping for the biallelic TNF-308 polymorphism was performed by using a real-time PCR cycler. Patients (homozygous for Delta F 508) were grouped according to genotype (TNF2 carriers, n = 16, median age = 15 yr, female/male = 5/11; TNF1 homozygotes, n = 37, median age = 21 yr, female/male = 18/19). TNF-α was measured using a chemiluminescent immunometric assay. There was a trend toward higher TNF-α values [median TNF2 carriers vs. TNF1 homozygotes: x = 56 vs. 43.5 pg/ml, n.s. (Mann–Whitney U-test] in those carrying the polymorphism and better lung function results [FEV1 (%) 81 vs. 65, n.s.]. These differences equalized [TNF2 carriers vs. TNF1 56 vs. 51 pg/ml, n.s.; FEV1 (%) 84 vs. 79, n.s.] after age adjustment (± 2 yr, n = 15, median age TNF2 vs. TNF1-17/18 yr). There were no significant differences for TNF values after LPS stimulation and the incidence of diabetes mellitus. The TNF-308 promoter polymorphism does not seem to influence TNF-α release in whole blood cells and clinical status.

Cisapride reduces postoperative gastrocaecal transit time after cardiac surgery in children

ObjectiveTo investigate the influence of the prokinetic drug cisapride on gastrocaecal transit time (GCTT) in children after open heart surgery.DesignProspective, randomized and controlled study.SettingInterdisciplinary paediatric intensive care unit in a tertiary-care childrens hospital.PatientTwenty-one children with a median age of 6.2 years on day 1 after uncomplicated open heart surgery for isolated septal defects, acquired mitral or aortic valve disease or tetralogy of Fallot. Control group consisting of 10 healthy children with a median age of 8.1 years.InterventionsTen children were randomized to receive cisapride 0.2 mg/kg body weight, 30 min prior to measurement of GCTT.Measurements and resultsGCTT was measured using hydrogen breath testing with a test solution containing lactulose and mannitol (0.4 g/kg and 0.1 g/kg body weight respectively). GCTT was markedly delayed in all patients compared to the control group. Within 8 h 8/10 patients in the treatment group versus 4/11 patients in the noncisapride group achieved gastrocaecal transit. No adverse side-effects were observed.ConclusionsCisapride accelerates gastrocaecal transit after open heart surgery in children. In intensive care patients on inotropic support or opioid medication, it may facilitate the earlier reintroduction of enteral feeding.

CASE REPORT: Recurrent Episodes of Necrotizing Enterocolitis Complicating Congenital Microvillous Atrophy

Microvillus atrophy is a rare cause of congenital diarrhea and is characterized on light microscopy by the accumulation of periodic acid–Schiff-positive granules within enterocytes of the small intestine (1). At the ultrastructural level, the occurrence of intracytoplasmic microvillous inclusions concomitant with poorly developed or even absent microvilli on villous enterocytes and a markedly increased number of secretory granules are pathognomonic (1, 2). The molecular mechanisms and exact pathogenesis of this disease, however, remain unknown. There is evidence that a block in exocytosis of the glycocalyx and/or abnormal brush border membrane trafficking in mature, absorptive intestinal epithelial cells plays a critical role in the development of this disorder (2–4). Most frequently, children with microvillous atrophy present in the first days of life with intractable, abundant secretory diarrhea and severe failure to thrive. This condition becomes rapidly life-threatening. The only way to feed these babies is by total parenteral nutrition (TPN). Prognosis, however, is poor, and most children die before the age of 6 years, unless small bowel transplantation is performed (2). In the neonatal period, necrotizing enterocolitis (NEC) is a life-threatening complication (5). Conservative antibiotic therapy and discontinuation of enteral feeding is insufficient in up to 30% of neonatal patients, who require surgical resection of the inflamed intestine/colon. Clinically, these babies are critically ill, with maximal abdominal distension and pain. Serological parameters of inflammation are highly positive, and on abdominal x-rays typical pneumatosis of the intestinal wall is present. In addition, ultrasonography of the portal venous system reveals the presence of gas bubbles. Beyond the neonatal period, pneumatosis intestinalis without signs of systemic inflammation is reported as a rather benign condition with only mild or no symptoms (6).

Münchhausen-by-proxy-Syndrom

ZusammenfassungDas Münchhausen-by-proxy-Syndrom ist eine subtile Form der Kindesmißhandlung. Die Diagnose ist äußerst schwierig. Das liegt zum einen an den oberflächlich betrachtet fürsorglichen Eltern und andererseits an den biologisch-technisch ausgerichteten Medizinern, die entscheidend, aber unwissentlich lange Mitmißhandler sind. Letztere verteilen sich auf viele, miteinander zu wenig kommunizierende Fachdisziplinen und werden oft direkt von den Patienten kontaktiert. Die Erfindung glaubhafter medizinischer Symptome durch die meistens verantwortlichen Mütter beruht oft auf einer eigenen „medizinischen Ausbildung” und/oder in der zunehmenden Medizinalisierung der breiten Öffentlichkeit. Eine Warnliste an Symptomen und Konstellationen sollte den Haus- oder Kinderarzt für artifizielle Krankheiten sensibilisieren, um möglichst früh erste diagnostische Schritte einzuleiten. Es ist entscheidend, daß ein verantwortlicher Kinderarzt die Initiative ergreift und die Fäden in der Hand behält. Die beweisende Diagnose ist oft nur im Team in Zusammenarbeit mit Kinderpsychiatrie, Pädagogik, Justiz und Jugendbehörden möglich und erfordert die Trennung von Mutter und Kind. Erfolgreiche therapeutische Ansätze für die Täter existieren nur vereinzelt. Bei fehlender Trennung von der Familie oder zu frühem Retransfer ist die Prognose für die mißhandelten Kinder sehr ungünstig. Ein wissenschaftstheoretischer Ansatz zum besseren Verständnis der Psychopathologie und zur Entwicklung neuer therapeutischer Alternativen ist erforderlich.SummaryThe diagnosis of Munchausen by proxy syndrome, a subtle form of child abuse, is very difficult. One reason is a seemingly well caring ”ideal” mother who is mainly responsible for the fabricated illness of her child, the other biologically and technically well trained medical doctors maltreating the children unwittingly. Doctors are often separated from each other by their subspecialities but nevertheless directly approached by the mothers. The latter frequently have a medical education. A warning list of ″red flags″ of symptoms and clinical situations should sensitise the pediatrician for artificial illnesses and enable him to start diagnostic work-up early. One responsible doctor should coordinate all activities. The crucial step is a separation of mother and child, but a team approach involving child psychiatry, child wellfare organisations and legal authorities is mandatory. Therapeutic options for the perpetrators are minimal. The prognosis is poor if such a child is not separated from his family or retransferred too early. Research to understand psychopathology and to develop new therapeutic options is needed.

Dominant vererbtes Hand-Fuß-Genital-Syndrom: Malformationen der distalen Extremitäten mit Fehlbildungen des Urogenitaltrakts

ZusammenfassungFallbericht. Die vorliegende Kasuistik stellt ein familiäres Auftreten von Brachyklinodaktylien der Hände und Füße in beiden Geschlechtern assoziiert mit Fusionsanomalien der Müller-Gänge bei weiblichen Betroffenen sowie einer Hypospadie beim Indexpatienten dar.Die Diagnose “dominant vererbtes Hand-Fuß-Genital-Syndrom” wurde durch Nachweis einer Polyalaninexpansion (18 Basenpaarduplikation) im Exon 1 des HOXA13-Gens gestellt.nSchlussfolgerung Der vorgestellte Fall eines Patienten mit Hypospadie deutet auf die Relevanz der Beurteilung des gesamten Phänotyps im Zusammenhang mit der molekulargenetischen Aufklärung dieser genitalen Malformation hin.AbstractCase report This case-report presents the familial occurence of brachyclinodactyly of hands and feet in both sexes associated with Müllerian duct fusion anomalies in all females affected and hypospadias in the male patient, respectively.The diagnosis “dominantly inherited hand-foot-genital syndrome” was confirmed by detection of a polyalanine expansion (duplication of 18 base pairs) in exon 1 of the HOXA13 gene.nConclusion The case presented here, points to the relevance of examination of the complete clinical status associated with hypospadias in the context of analyzing genes involved in the aetiology of this genital malformation.

Verabschiedung von Prof. Dr. Dr. Dietrich Reinhardt

Die Monatsschrift Kinderheilkunde verabschiedet sich heute von ihrem langjährigen Schriftleiter Prof. Dr. Dr. Dietrich Reinhardt, der nun in seinen wohlverdienten Ruhestand tritt. Prof. Reinhardt war 19 Jahre für die Monatsschrift Kinderheilkunde tätig. Mitglied der Schriftleitung wurde er 1991. In Zusammenarbeit mit den Professoren Bläker, Wolf, Moll und Butenandt übernahm er 1992 die Rubrik „Aus Klinik und Praxis“ sowie die Redaktion der Rubrik „Weiterbildung“ in Zusammenarbeit mit Prof. Bläker und Prof. Schröter. Ab 1994 betreute er zudem die Rubrik „Bild des Monats“. Im Jahr 2001 schließlich übernahm er zusammen mit mir die Schriftleitung. In dieser Funktion zeichnete er für die Leitthemen, Originalien, Kasuistiken, Bild des Monats und zusammen mit Prof. Wirth für die Konsensuspapiere verantwortlich. In dieser langen Periode hat sich Prof. Reinhardt vorbildlich und stets innovativ für die Monatsschrift Kinderheilkunde eingesetzt. Den Übergang zu einem Schwerpunktthemenkonzept vor 9 Jahren hat er in hervorragender Weise mitgestaltet und der Zeitschrift dabei seinen Stempel aufgedrückt. Bereits zweimal wurde der Julius-Springer-Pädiatrie-Preis für den besten Fortbildungsartikel aus den Leitthemen ausgewählt, die er zusammengestellt hatte. Seinem unermüdlichen Engagement war stets anzumerken, dass ihm die „MoKi“ans Herz gewachsen ist. Durch seine umsichtige und visionäre Arbeit ist die Monatsschrift Kinderheilkunde in ihrer Beliebtheit bei den Leserinnen und Lesern deutlich gestiegen. Für Anregungen der Schriftleiterkollegen und aus seinem Mitarbeiterkreis war er stets aufgeschlossen. So hat sich die Monatsschrift Kinderheilkunde zu einem viel beachteten Fortbildungsorgan der Pädiatrie und damit der Deutschen und Österreichischen Gesellschaft für Kinderund Jugendmedizin entwickelt.