Growth response to growth hormone therapy following craniospinal irradiation

Nineteen (12 male, 7 female) children, who have received craniospinal irradiation for the treatment of a brain tumour distant from the hypothalamic-pituitary axis, resulting in growth hormone (GH) deficiency (CS-PRGHD), have been treated with GH. Eight have completed growth. Comparison has been made with the growth of seven untreated children, whose heights and growth rates at presentation were normal despite GH deficiency secondary to irradiation. GH produced a significant increase in growth velocity over the first 3 years' treatment in CS-PRGHD patients with a mean first year increment of 3 cm/year. Patients, treated to completion of growth, showed a significant increase in leg length standard deviation (SD) score (SDS+0.2) compared to that of the untreated (SDS–0.9) (P<0.05). Stitting height SD scores decreased irrespective of GH therapy (by -1.7 for the treated and -2.2 for the untreated). The onset of puberty in the irradiated patients occurred at a mean bone age of 10.7 years in males and 9.9 years in females. This limited the time available for GH therapy. These factors resulted in a decrease in standing height SDS of 0.9 at completion of GH therapy in CS-PRGHD, but a decrease of 1.7 in those not treated with GH. Thus GH therapy failed to induce catch-up growth in irradiated patients, but it did prevent further loss of adult stature, with a mean final height SD score of -3.4 in CS-PRGHD patients.Abbreviations GH growth hormone - CS-PRGHD post craniospinal irradiation growth hormone deficiency - change in - SDS standard deviation score - ALL acute lymphatic leukaemia - IGHD isolated growth hormone deficiency - C-PRGHD post cranial irradiation growth hormone deficiency - FSH follicle stimulating hormone - LH luteinising hormone - BA bone age - TSH thyroid stimulating hormone - CA chronological age     

Circulating immunoreactive growth hormone releasing hormone concentrations and growth hormone response to growth hormone releasing hormone in short children

To study the role of peripheral immunoreactive growth hormone releasing hormone (ir-GHRH) concentrations and the GHRH test in the evaluation of growth hormone (GH) secretion in short stature, 46 children with a mean age of 9.4 years (range 1.6–16.3 years) and a mean relative height score of –3.2 SD (range –5.0–2.1 SD) were investigated. The children were divided into prepubertal (n=35) and pubertal (n=11) and the prepubertal children further into three groups based on their maximal GH responses to insulin-induced hypoglycaemia (IIH) and clonidine: (1) GH deficient subjects (maximal GH<10 g/l in both test); (2) discordant responders (maximal GH<10 g/l in one test and 10 g/l in the other); and (3) normal responders (maximal GH10 g/l in both test). Peripheral ir-GHRH concentrations were measured during the IIH test by radioimmunoassay after purification of plasma samples on Sep-pak cartridges. Among the prepubertal children 10 fell into group 1, 16 into group 2 and 9 into group 3. Children in group 1 were older, than those in group 3. There were no significant differences in relative heights and weights or absolute and relative growth velocities between the groups. Subjects in groups 1 and 2 had lower maximal GH responses to GHRH than those in group 3. There were no significant differences in the basal plasma ir-GHRH concentrations between the groups. Nine children (19.6%) had somatotrophs with a poor response to a single dose of exogenous GHRH (maximal GH<10 g/l). These subjects had increased basal plasma ir-GHRH concentrations. All of them had a decreased GH response to IIH and/or clonidine. Pubertal children had higher circulating ir-GHRH levels than the prepubertal subjects. There was an inverse correlation (r=–0.46;P<0.001) between the maximal GH response to GHRH and calendar age in the whole series. These observations suggest that: (1) a substantial proportion of short children have a heterogenous GH response to pharmacological stimuli necessitating complementary evaluation of their spontaneous GH secretion; (2) a poor response to exogenous GHRH is associated with increased ir-GHRH levels in the peripheral circulation; (3) all children with normal GH responses in pharmacological tests respond normally to GHRH and (4) the pituitary sensitivity to GHRH decreases with increasing age. Peripheral ir-GHRH concentrations do not differentiate between short children with growth hormone deficiency (GHD) and those with undefined short stature. The GHRH test is of limited value in the diagnosis of GHD, since a normal GH response does not exclude GHD, although a subnormal response appears to reflect dysfunctional GH secretion.     

Die β-Aktivität im EEG des Kindes

Zusammenfassung -Wellen stellen im EEG des Kindes eine labile Aktivitätsform dar. Sie können sowohl spontan erscheinen, als auch durch Reize verschiedener Qualität provoziert werden. Für eine exakte Analyse eignen sich nur die spontanen -Wellen des EEG im Wach-und Schlafzustand, deren formale und topographische Merkmale in den einzelnen Altersstufen aufgezeigt werden. Während die Lokalisation der -Wellen mit geringen Ausnahmen bei allen Kindern über den vorderen Hirnregionen liegt, variieren Frequenz und Amplitude innerhalb bestimmter Grenzbereiche. Die Normalkriterien der spontanen -Aktivität beim Kinde bilden die Grundlage für die Erkennung anormaler -Wellen, wie sie bei cerebralen Erkrankungen auftreten können.     

Recombinant human interferon-γ treatment in severe leucocyte adhesion deficiency

We describe a patient with leucocyte adhesion deficiency (LAD). Clinically, the patient had delayed umbilical cord detachment, omphalitis, impaired wound healing and persistent leucocytosis. The patient had the severe form of LAD, with a total absence of leucocyte cell adhesion molecules (LeuCAMs) and undetectable mRNA for the chain, the common subunit of the LeuCAMs. In vitro neutrophil chemotaxis, aggregation and oxygen consumption were severely impaired. In vitro incubation of neutrophils with recombinant human interferon- (rIFN-) showed an increase in oxygen consumption, but no effect on the expression of the LeuCAMs, or the chain mRNA. In vivo treatment with IFN- was started. The FcRI receptor appeared on the neutrophils, the LeuCAMs remained undetectable, while the neutrophil functions remained disturbed. The patient died of surgical complications after 10 weeks of rIFN- treatment. No new infections or side-effects due to rIFN- were observed.     

“Inborn errors of metabolism” and “chemical individuality” two ideas of Sir Archibald Garrod briefly revisited 50 years after his death

Two ideas of Sir A. Garrod, chemical individuality (1902) and inborn errors of metabolism (1908) have proved fundamental for the development of medical knowledge. The latter idea was more fortunate than the former which, however has been extremely heuristic. On the other hand the two ideas are not entirely independent of each other: in fact, a third Garrodian concept, inborn factors in disease, represents a significant link between them. Inborn errors of metabolism revived the laws of genetics and opened the way to interpretation of the molecular diseases with all their inherent practical modern implications (neonatal screening, prenatal diagnosis, and in perspective, genetic engineering). Chemical individuality still constitutes a valid premise for knowledge of biological individuality (in other words, the biological ego) fundamentally programmed for conservation of self and for continuous discrimination of self versus non-self.     

Mild adrenal 3β-hydroxysteroid dehydrogenase deficiency in children with accelerated growth,premature pubarche and/or hirsutism

We studied eight children (seven girls and one boy, of whom three are siblings) with accelerated growth, premature pubarche and/or hirsutism between the ages of 7 and 9.5 years. These patients were studied for the presence of adrenal steroidogenic defect by adrenocortico tropic hormone (ACTH) stimulation testing (Cortrosyn, 0.25 mg iv bolus dose). Baseline and stimulated 17-hydroxypregnenolone (⁵-17P), 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), androstenedione (⁴-A), testosterone, and cortisol levels were measured. Six children, including three siblings, were diagnosed with a mild form of 3-hydroxysteroid dehydrogenase deficiency based upon the elevated response of serum ⁵-17P and the elevated ratio of ⁵-17P/17-OHP and of DHEA/⁴-A to ACTH stimulation. Thus, a mild form of 3-hydroxysteroid dehydrogenase deficiency may not be uncommon in children with accelerated growth, premature pubarche and/or hirsutism and routine assay of ⁵-steroid metabolites should be generally available.     

An infant with two “half-hearts” who survived for five days: A clinical and pathological report

Summary The case of a five-day-old boy with two half-hearts, diagnosed at necropsy but not clinically, is presented. Each half-heart was totally separated from the other and each had a single atrium and ventricle. The two half-hearts were enveloped in a common pericardium. The left-sided atrium and the right-sided atrium had the morphologic characteristics of left and right atrium, respectively, but the morphology of the two ventricles was less characteristic. There were double truncuses and double superior and inferior venae cavae, too. Pulmonary venous drainage was totally anomalous; splenic abnormalities were not found. An embryologic lack of fusion of the primitive cardiac tubes is a possible starting point for these malformations.     

Transient growth deceleration in normal short children

We have examined the records of 21 short children evaluated for growth hormone deficiency and found not to be deficient. Their growth velocity was evaluated for at least 6 months, both before and after testing. Without any specific therapeutic intervention, growth velocity was significantly higher after testing, as compared with before. We attribute this apparent therapeutic effect of testing to a selection bias, due to the fact that, in normal clinical practice, children are selected for testing immediately following a period of slow growth, and that decelerations of growth are very often transient. Studies of growth-stimulating treatments using children as their own controls should, for this reason, be interpreted with caution.Abbreviation GH growth hormone This is publication no. 87032 of the McGill University-Montreal Children's Hospital Research Institute     

Fetal bile acids in congenital biliary atresia —production in the liver and clinical significance

The 1-hydroxy bile acids have been said to be fetal bile acids. These bile acids were evaluated in eight patients with congenital biliary atresia (CBA) using gas chromatography-mass spectrometry. At the time of operation 1,3,7,12-tetrahydroxy-5-cholan-24-oic acid (CA-1-ol) and 1,3,7-trihydroxy-5-cholan-24-oic acid (CDCA-1-ol) were 0.46 ± 34 g/ml and 0.72 ± 0.45 g/ml, respectively, which was significantly higher than in the control group. The percentage CA-1-ol of total bile acids showed a tendency to decrease as age advanced. The grade of hepatic fibrosis ranged from F₂ to F₃ and the values and percentages of CA-1-ol and CDCA-1-ol were relatively higher in F₂ than F₃ patients. The percentage of total bile acids gradually increased in patients without sufficient bile flow but fell sharply after Kasai's procedure in the patients with sufficient bile flow. It appears that fetal bile acids are produced in the livers of CBA patients in the same way as in fetal liver, and that production continues in patients without good bile secretion even after Kasai's procedure. These results suggest that these hydroxylases are reactivated in CBA patients.     

Die β-Aktivität im EEG des Kindes

Zusammenfassung Im Vergleich zu den in der. I. Mitteilung berichteten Merkmalen der -Wellen beim gesunden Kinde werden die Kriterien der abnormen -Aktivität aufgezeigt und folgende Erscheinungsformen bei cerebralen Erkrankungen festgestellt: Generalisierte -Wellen, Paroxysmen bilateral synchroner -Wellengruppen, Herdveränderungen, die sowohl durch das umschriebene Auftreten abnormer -Wellen, wie auch durch das regionale Fehlen physiologischer -Aktivität im Wach-und Schlaf.-EEG gekennzeichnet sein können.Abnorme -Wellen erscheinen neben anderen EEG-Veränderungen bei folgenden Krankheitsgruppen: l. pharmakologischen Intoxikationen, 2. cerebralen Anfallsleiden, 3. entzündlichen Hirnerkrankungen, 4. intracerebralen Blutungs-bzw. Erweichungsherden, 5. vasomotorischer Labilität.Longitudinaluntersuchungen bei cerebralen Erkrankungen (z. B. Meningitis tuberculosa), erbrachten den Nachweis, daß den -Wellen bei abnormer Ausprägung der gleiche Krankheitswert zukommt, wie anderen EEG-Veränderungen.Der diagnostische Wert abnormer -Aktivität wird besonders bei den exogenen Intoxikationen und den intracerebralen Blutungs-und Erweichungsprozessen erkennbar.     

Childhood neuromuscular disease with rimmed vacuoles

A 5-year-old boy suffered from a slowly progressive non-familial neuromuscular disease, clinically marked by generalised muscle weakness, atrophy and hypotonia, a myopathic EMG and mildly elevated CK values. His gastrocnemius muscle showed marked myopathy, type I fibre predominance, and numerous rimmed vacuoles. This boy's condition is regarded as a childhood neuromuscular disease with rimmed vacuoles.This paper has been presented at the Annual Meeting of the German Society of Neuropathologists, Bremen, June, 1984     

Influence of short- and long-term inhalation of salbutamol on lung function and β2-andrenoceptors of mononuclear blood cells in asthmatic children

Clinical observations have shown that some asthma patients develop tachyphylaxis to -sympathomimetic drugs. As down-regulation of the number of -adrenoceptors in different human tissues after exposure to catecholamines and -adrenergic drugs is well known, we investigated whether a interrelation exists between -adrenoceptor down-regulation and clinically detectable -adrenergic subsensitivity during -sympathomimetic treatment. The following results were obtained: 1. ₂-Sympathomimetic inhalation treatment with salbutamol in therapeutic doses led to a significant downregulation of ₂-adrenoceptors and consecutive cyclic adenosine monophosphate response to isoprenaline. This effect was already detectable after short-term treatment of 3–7 days in 9 asthmatic children. 2. In the long-term study over 6 months, salbutamol inhalation in 12 asthmatic children led to a significant down-regulation of -adrenoceptor binding sites on mononuclear blood cells (MNC) from 1539±91 to 1115±99 after 14 days, remaining in this range thereafter. 3. The mean airway resistance (R_aw) of these 12 patients decreased significantly within 14 days from 8.1±0.8 to 5.7±0.5 cm H₂O/l/s to remain stable throughout the 6 months of salbutamol treatment. The differences in R_aw before and immediately after inhalation of 0.2 mg salbutamol (2 puffs) were unchanged during the study period. It is concluded, that long-term inhalative treatment with salbutamol over a period of 6 months does not result in refractoriness to -adrenergic drugs in the airways of asthmatic children, even though a significant down-regulation of ₂-receptors on peripheral MNC occurs.     

Tumour necrosis factor in neonatal listeriosis: a case report

A newborn with fatal neonatal listeriosis developed septic shock, neutropenia, thrombocytopenia and profound hypoxaemia due to severe pulmonary hypertension. Tumour necrosis factor , interleukin-1- and interferon- serum concentrations were markedly elevated, suggesting the participation of these cytokines in the aetiopathogenesis of shock induced by Listeria monocytogenes in the neonate.Abbreviations IFN- interferon- - IFN- interferon- - IL-1 interleukin-1 - MPA monocytosis producing agent - TNF- tumour necrosis factor      

Relationship between café-au-lait spots as the only symptom and peripheral neurofibromatosis (NF1): A follow-up study

We re-examined 21 children with the possible diagnosis of peripheral neurofibromatosis (NF1) based on the presence of cafè-au-lait (CAL) spots as the single clinical finding. We evaluated whether typical or atypical appearance of the spots was important for the final diagnosis and whether the co-existence of other nonspecific signs (e.g. pectus excavatum) were of any significance for the final diagnosis. In 8/14 (57.1%) cases with typical CAL spots, the diagnosis of NF1 was finally established on the basis of other criteria. For the other 6 patients the diagnosis is not yet definitive but highly probable on the basis of the presence of macrocephaly, pectus excavatum and/or MRI findings. Only one patient among five with atypical CAL spots possibly has NF1.     

Über das Vorkommen von α-Lactose und β-Lactose in der Frauenmilch und in der Kuhmilch

Zusammenfassung Die Mutarotation von -Lactose läßt sich nicht nur durch Änderung der Temperatur oder OH-Ionen-Konzentration beeinflussen. Organische und anorganische Verbindungen verursachen im geringen Grade eine Beschleinigung oder Hemmung der Mutarotation. In 5% iger Natriumbisulfitlösung kann die Matarotation von -Lactose sogar aufgehoben werden. Der Einfluß der geprüften Stoffe auf die Mutarotation der Lactose ist nur gering.In frischer Frauenmilch kommen - und -Lactose im gleichen Verhältnis vor wie Lactose in wässerigen Lösungen. Auch in gane frischer Frauenmilch läßt sich ein vermehrter Gehalt von -Lactose nicht nachweisen. In ganz frischer Kuhmilch wurde gleiche - und -Lactose-Konzentration wie in Frauenmilch gefunden. Stabilisierende Momente für -Lactose in der Frauenmilch ließen sich nicht nachweisen. Ein günstiger Einfluß der Verfütterung von reiner -Lactose gegenüber -Lactose läßt sich aus vorstehenden Untersuchungen nicht ableiten.     

The developmental change in the Gγ and Aγ globin. Proportions in hemoglobin F

The proportions of ^G and ^A globins in hemoglobin F were determined in fetuses around the 20th week of gestation, newborns, and children 3 weeks to 5 months of age. In the last group, the ^G/^G + ^A ratio decreased continously; there was a good correlation between the decline of ^G with respect to total and the decline of Hb F (r=0.88). In contrast, there was virtually no difference in the globin composition of Hb F between the fetuses and the newborns, i.e. in late pregnancy, the decrease in the synthesis of both globins appears to be proportionate. The ^G and ^A globin genes may be inactivated in a sigmoidal fashion with time, thus producing a ^G/^G + ^A ratio which at first changes only slightly and then declines linearily.Supported by a grant from the Deutsche Forschungsgemeinschaft (Je 56/10)     

Growth retardation due to idiopathic growth hormone deficiencies: MR findings in 24 patients

In this study we evaluated the pituitary-hypothalamic abnormalities of idiopathic growth hormone (GH) deficiency as demonstrated by MR imaging. Twenty-four patients were examined with a 1.5-T unit using spin echo T-1 weighted images. The patients were divided into two groups according to MR findings: those with ectopic posterior pituitary glands (12 patients), and those with normal posterior pituitary glands (12 patients). Ten patients in the former group and four in the latter group had small anterior pituitary glands. All patients in the former group but only four in the latter group had severe GH deficiencies. Multiple hormone deficiencies were found in eight patients in the former group, but in only two in the latter group. Among the 12 patients with posterior pituitary ectopia, 11 were males, 10 had been born by breech delivery, and four had a history of asphyxia. It is speculated that perinatal abnormalities can cause posterior pituitary ectopia and that there is a close correlation between breech delivery and the male disadvantage of posterior pituitary ectopia. Half of our patients with idiopathic GH deficiency had ectopic posterior pituitaries. GH deficiency with posterior pituitary ectopia should no longer be considered idiopathic because organic lesions can now be identified during life.     

Über das “Kerbenohr” beim Exomphalos-Makroglossie-Gigantismus-Syndrom, über Ohrläppchen-Fisteln und über das Vorkommen entsprechender Erscheinungen bei anderweitigen Syndromen sowie bei Gesunden

Zusammenfassung Neben sehr deutlich ausgeprägten linearen Ohrläppchen-Einkerbungen (Kerbenohr) kommt beim EMG-Syndrom eine Fülle von kleinen Dysmorphien im Bereich der Ohrmuschel vor. Die Variabilität der Befunde ist groß, konstante Veränderungen sind nicht erkennbar. Die Kerben, Dellen, Grübchen usw. müssen dem Bereich der Auricularfisteln zugerechnet werden. Schwachformen aller im Rahmen des EMG-Syndroms beobachteten Ohrveränderungen, selten auch deutlichere Kerbenohren, lassen sich bei Gesunden und selbstverständlich ebenfalls bei kranken und speziell bei dysplastischen Kindern nachweisen. Das stark ausgeprägte Kerbenohr des EMG-Syndroms bleibt jedoch ein sehr ungewöhnliches Phänomen von hohem pathognomonischem Wert; es dürfte in etwa 50% der Fälle dieses Krankheitsbildes vorliegen. Hinweise auf autosomal-dominante Vererbung des Kerbenohrs sind gegeben.

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On the Kerben-Ohr (inherited slit-like indentations of ear-lobes) in the exomphalos-macroglossia-gigantism syndrome, on auricular fistulae and on the presence of analogous findings in other syndromes and in normal individuals

Beside slit-like indentations of the ear-lobes (Kerben-Ohr) there exist in the exomphalos-macroglossia-gigantism syndrome an abundance of minor anomalies of the auricle. There is considerable variability of the findings and no constant changes are present. The indentations, shallow grooves, small dimples etc. are variants of the auricular fistulae. Minor manifestations of all the ear-changes observed in the EMG-syndrome, and, to a lesser degree, more marked changes, are seen in normal individuals and, more frequently, in sick, and particularly in dysmorphic children. The prominent Kerben-Ohr of the EMG syndrome is, however, an extremely unusual phenomenon with pathognomonic value. It is present in approximately 50% of the cases of this condition. The Kerben-Ohr may follow an autosomal dominant mode of hereditary transmission.

Herrn Dr. Thordar Quelprud, Oslo, dankbar zugeeignet.     

„Ich habe alles nur aus absolutem Mitleid getan“

ZusammenfassungHintergrund Eine Form der systematischen Tötung somatisch oder psychisch Kranker zurzeit der nationalsozialistischen Herrschaft ist die Kindereuthanasie in Kinderfachabteilungen, die durch einen Reichsausschuss eingesetzt wurden.Methoden Die Auswertung von Krankengeschichten, Korrespondenzen Vernehmungs- und Sektionsprotokollen gibt für eine Kinderfachabteilung Bayerns, Kaufbeuren-Irsee, Aufschluss über deren Beitrag zur und dem Umfang der Euthanasie im nationalsozialistischen Medizinwesen.Ergebnisse Zwischen 1941 und 1945 wurden dort 221 Kinder durch Applikation von Pharmaka (Veronal, Luminal, Skopolamin) und Nahrungsentzug ermordet. Die Kinder der Anstalt wurden zudem Opfer von Tb-Impfexperimenten. Ihre Organe waren Gegenstand medizinischer Forschung im Hirnpathologischen Institut der Deutschen Forschungsanstalt für Psychiatrie, München.Schlussfolgerungen Die Ergebnisse lassen sich auf Grundlage weiterer Studien verallgemeinern: Kinderfachabteilungen leisteten einen systematischen Beitrag zur Euthanasie, waren Labor für Humanexperimente und Organpräparatelieferanten.Die hier dargestellte Version des Beitrags weicht in folgenden Punkten von der am 26. Juni 2004 publizierten ab:In der am 26. Juni 2004 publizierten Version des Beitrags wurde im Abschnitt Humanexperimente, im Abschnitt Neuropathologische Forschung sowie im Literaturverzeichnis die Referenz 13a versehentlich nicht angegeben.     

Small bowel volvulus in children: Its appearance on the barium enema examination

Two children with small bowel volvulus diagnosed on barium enema examination are reported. In one patient the volvulus was associated with malrotation and in the other patient there was a post-operative peritoneal adhesion. In both cases the diagnosis was based on beaking of the head of the barium column at the site of volvulus. Radiographic demonstration of a beak sign in the small bowel on barium enema examination should suggest a diagnosis of small bowel volvulus, and indicates the need for immediate surgery.