Constitutional relaxation of insulin-like growth factor II gene imprinting associated with Wilms' tumour and gigantism.

We have examined the imprinting of the insulin-like growth factor II gene (IGF2) in ten normal kidney samples from children with renal embryonal neoplasms. In kidney samples from nine children with normal growth profiles, IGF2 mRNA was transcribed monoallelically, consistent with normal imprinting of the gene. But in one child who had generalized somatic overgrowth, IGF2 was transcribed from both alleles in her kidney, peripheral blood leukocytes and Wilms' tumour. These findings suggest that a defect in genomic imprinting can occur constitutionally, leading to growth abnormalities and predisposition to Wilms' tumour.

Somatic overgrowth associated with overexpression of insulin-like growth factor II.

Overexpression of the normally imprinted fetal insulin-like growth factor II (IGF2) has been implicated in the pathogenesis of the cancer-predisposing Beckwith-Wiedemann syndrome (BWS). We have detected constitutional relaxation of imprinting of IGF2 in four children with somatic overgrowth who do not show diagnostic features of BWS. Three children showed constitutional abnormalities of H19 methylation. All four children showed nephromegaly and two developed Wilms' tumors. Gene methylation is known to be associated with gene silencing, and three children showed constitutional abnormalities of H19 gene methylation. Disruption of H19 methylation, and concomitant relaxation of IGF2 imprinting, provides another mechanism that can increase IGF2 expression in children with overgrowth. The accumulated data on normal and pathologic IGF2 expression are now sufficient to define an entity, "IGF2 overgrowth disorder," of which BWS may be one extreme manifestation. These findings have broad implications for the characterization of idiopathic overgrowth.

Risk factors for asthma at 3.5 and 7 years of age.

BACKGROUND: It has been suggested that factors in early life including exposure to allergens and microbes may influence the development of asthma. OBJECTIVE: To identify risk factors for asthma in early childhood. Methods Eight-hundred and seventy-one children of European mothers were enrolled at birth, of whom 385 (44.2%) were born small for gestational age (SGA) and 486 were appropriate for gestational age (AGA). Data were collected at birth, 12 months, 3.5 years of age (y) and 7 y. The outcome of interest (current wheeze) was defined as a positive response to the question: 'Has your child had wheezing or whistling in the chest in the last 12 months?' RESULTS: Participation rate was 85.4% at 1 y, 63.1% at 3.5 y and 68.0% at 7 y. The prevalence of asthma was 23.8% at 3.5 y and 18.1% at 7 y. Antibiotic use in the first year of life and day care in the first year of life were associated with increased risk of wheeze at 7 y [odds ratio (OR)=4.3 95% confidence interval (CI) (1.8-10.1) and OR=2.8 95% CI (1.2-6.5), respectively], but not at 3.5 y. Exposure to dogs was a risk factor for asthma at both ages [OR=2.1 95% CI (1.1-3.8)] as was sleeping on a used cot mattress in the first year of life [OR=1.8 95% CI (1.0-3.2)]. CONCLUSIONS: There was a significant association between antibiotic use and day care in the first year of life and wheezing at 7 y but not at 3.5 y. This strengthens the argument that these factors increase the risk of asthma. We have also made the novel observation that sleeping on a used mattress in the first year of life is a risk factor for wheezing at 3.5 and 7 y. Capsule summary This prospective study of 871 children made the novel observation that sleeping on a used mattress in the first year of life was a risk factor for wheezing at 3.5 and 7 y.

Maternal stress, social support and preschool children's intelligence.

BACKGROUND: Despite some research suggesting maternal stress may be associated with cognitive impairment in preschool children, there has been little direct investigation of the association between maternal stress, social support and children's intelligence. AIM: To determine whether maternal stress and social support during pregnancy and during the child's early years of life are associated with the intelligence test performance of preschool children. STUDY DESIGN: Five hundred and fifty European mothers and children enrolled in the Auckland Birthweight Collaborative Study at birth were interviewed when the child was 3 1/2 years of age. SUBJECTS: All children were full term gestation and approximately half the sample were small for gestational age at birth (SGA = birthweight < or = 10th percentile). OUTCOME MEASURE: The cognitive ability of children aged 3 1/2 years was assessed using the Stanford Binet Intelligence Scale 4th Edition. RESULTS: In the total sample, maternal stress and lack of social support during pregnancy were significantly associated with lower intelligence test scores of children. In the group of SGA children, maternal stress post pregnancy was significantly associated with lower intelligence test scores in children. There is evidence that for some children the presence of good social support for mothers may reduce the negative effects of maternal stress on children's cognitive development. CONCLUSION: Maternal stress and lack of social support appear to be associated with lower intelligence test scores of preschool children. Social support may attenuate some of the negative effects of maternal stress on intelligence in children born small for gestational age.

Smoking and the sudden infant death syndrome.

OBJECTIVE: Maternal smoking has been shown to be a risk factor for sudden infant death syndrome (SIDS). The effect of smoking by the father and other household members has not previously been examined. METHODS: A large nationwide case-control study. Four hundred eighty-five SIDS deaths in the postneonatal age group were compared with 1800 control infants. RESULTS: Infants of mothers who smoked during pregnancy had a 4.09 (95% confidence interval [CI] = 3.28, 5.11) greater risk of death than infants of mothers who did not smoke. Infants of mothers who smoked postnatally also had an increased risk of SIDS compared with infants of nonsmokers and, furthermore, the risk increased with increasing levels of maternal smoking. Smoking by the father and other household members increased the risk (odds ratio [OR] = 2.41, 95% CI = 1.92, 3.02 and OR = 1.54, 95% CI = 1.20, 1.99, respectively). Smoking by the father increased the risk of SIDS if the mother smoked, but had no effect if she did not smoke. In analyses controlled for a wide range of potential confounders, smoking by the mother and father was still significantly associated with an increased risk of SIDS. CONCLUSION: Passive tobacco smoking is causally related to SIDS.

The epidemiology of placental infarction at term.

The incidence and associations of placental infarction at term were investigated as part of a population based case-control study of small for gestational age (SGA) infants. 509 placentas from women delivering SGA infants (SGAP) and 529 placentas from women delivering infants with birthweights appropriate for gestational age (AGAP) were examined using fixed protocols for macroscopic identification and microscopic confirmation of infarction. Other information was obtained by maternal interview and from an obstetric database. Infarcts were found in 17.3 per cent of SGAP and 11.7 per cent of AGAP. This difference was in placentas with multiple infarcts not involving the placental margin and was significant in multivariate analysis (OR 1.66; 95 per cent CI 1.12,2.47). Multivariate analysis showed significant associations between the presence of any infarct and maternal hypertension in both SGAP (OR=4.00; 95 per cent CI 1.96,8.16) and AGAP (OR 2.99; 95 per cent CI 1.23,7.32); maternal smoking, associated with a lesser risk in SGAP only (OR=0.31; 95 per cent CI 0.13,0.73); maternal age at first pregnancy in a linear relationship with AGAP only (beta co-efficient 0.09, P=0.0034); and between some ethnic groups. We conclude that at least five factors have independent associations with the incidence of placental infarction and these associations differ by site and age of infarcts.

Proportion of cells with paternal 11p15 uniparental disomy correlates with organ enlargement in Wiedemann-beckwith syndrome.

"Genetic mosaicism" describes the presence of two or more populations of cells within a single individual that differ in their genomic constitution. Although the occurrence of asymmetric overgrowth in Wiedemann-Beckwith syndrome (WBS) suggests that mosaicism has some role in the WBS phenotype, no direct evidence for this has been published. WBS is a congenital overgrowth syndrome with variable phenotype linked to the imprinted gene cluster on chromosome region 11p15. We have performed a molecular survey of multiple organs and tissues in a case of WBS with a high degree of mosaic paternal 11p15 uniparental disomy (UPD). The organs most severely affected were those with the highest percentage of cells with UPD. In particular there was a striking difference in the degree of mosaicism for 11p15 UPD between the extremely enlarged left adrenal and non-enlarged right adrenal gland. This result indicates that the proportion of paternal 11p15 UPD cells correlates with the tissue phenotype of WBS. Our results suggest that high proportions of abnormal cells result from a combination of stochastic events and cell selection. Mosaicism may explain the variable phenotypes including hemihyperplasia and predisposition to childhood cancers in WBS patients.

Breastfeeding and the risk of sudden infant death syndrome.

The New Zealand Cot Death Study, a multicentre case-control study, was set up to identify risk factors associated with sudden infant death syndrome (SIDS). In the 3 years of the study there were 485 infant deaths classified as SIDS in the study areas and 1800 infants who were randomly selected as controls. Data were collected by parent interviews and from obstetric notes. A full set of data for this analysis was available from 356 cases and 1529 control infants. The relationship between length of any breastfeeding and SIDS was examined: 92% of the controls were initially breastfed compared to 86% of the cases. As time went by, cases stopped breastfeeding sooner than controls: by 13 weeks, 67% controls were breastfed versus 49% cases. A reduced risk for SIDS in breastfed infants persisted during the first 6 months after controlling for confounding demographic, maternal and infant factors. Infants exclusively breastfed 'at discharge from the obstetric hospital' (odds ratio [OR] = 0.52, 95% confidence interval (CI): 0.35-0.71) and during the last 2 days (OR = 0.65, 95% CI: 0.46-0.91) had a significantly lower risk of SIDS than infants not breastfed after controlling for potential confounders. We have shown a substantial association of breastfeeding with a lowered risk for SIDS. This supports the need for more positive promotion and active community support to further enhance the level and length of exclusive breastfeeding.

Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in young children.

A remarkably high incidence of bronchiectasis and other pulmonary sequelae was observed in young children affected during an epidemic of severe lower respiratory tract infections apparently caused by adenovirus type 21. The histopathological findings are described in four cases in which one or both lungs were obtained for examination at intervals ranging from two months to three years after the acute infections. Widespread bronchiolar obliteration (bronchiolitis obliterans) was a striking finding in all four. The severity of bronchial inflammation and of bronchiectasis was proportional to the time elapsed since the acute infections. Bronchiolar obliteration is a likely sequel of the necrotizing bronchiolitis which may occur during acute adenovirus infections. The role of bronchiolar obliteration in the pathogenesis of bronchiectasis and other chronic lung disease is discussed. Adenoviruses may be a major cause of post-infectious bronchiectasis in childhood.

Histopathology of fatal adenovirus infection of the respiratory tract in young children.

Type 7 adenoviruses were isolated from lung tissue obtained at the necropsies on five children aged 8 to 15 months. The clinical and radiological findings were those of bronchiolitis and pneumonia. Four children had an extensive necrotizing bronchitis and bronchiolitis. The surviving bronchial epithelium, and all bronchial epithelium in the fifth case, was proliferating. There was evidence that this proliferation was a virus-induced effect and not reparative. There was virus tropism to alveolar lining cells with a pneumonia showing mononuclear cellular reaction, necrosis, and hyaline membranes. Distinctive necrotizing lesions were found in the bronchial glands of all cases. Two contrasting types of intranuclear inclusions were present in all lesions and their significance and inter-relationships are discussed. These pathological changes are specific for infections by a limited number of adenovirus serotypes.

Benign sinus histiocytosis with massive lymphadenopathy: transient immunological defects in a child with mediastinal involvement.

A 16-month-old boy presented with cervical lymphadenopathy and a mediastinal mass causing tracheal displacement. Treatment of what at first was suspected to be a malignant neoplasm was limited to low-dose irradiation of the mediastinum and biopsy excision of the cervical lymph nodes. There has been no recurrence of disease in the subsequent four years. The pathological features and clinical course correspond to a benign disease first described in 1969 in which there is massive proliferation of histiocytes in lymph node sinuses. No infectious cause was identified. Consistent but eventually reversible defects in lymphocyte response to phytohaemagglutinin and in augmentation of nitro-blue tetrazolium reduction by neutrophils during phagocytosis were demonstrated in the patient and in his monozygous twin. These defects in cellular immune function are believed to be important in the pathogenesis of the histiocytosis.

Beckwith-Wiedemann syndrome, placental abnormalities, and gestational proteinuric hypertension.

BACKGROUND: Beckwith-Wiedemann syndrome is a genetically complex congenital disorder with variable clinical features at birth, including malformations, excessive body and/or organ growth, and endocrine dysfunction. Both maternal gestational proteinuric hypertension and placental abnormalities have been reported infrequently in Beckwith-Wiedemann syndrome, but the occurrence of three cases with both features at one institution within a year suggests that this may be an underreported association. CASES: Severe gestational proteinuric hypertension in three women led to termination of one pregnancy at 22 weeks' gestation, delivery by cesarean in another at 27 weeks of an infant who had hyperinsulinism and died at age 3 days, and stillbirth at 31 weeks in the third. All three infants had features diagnostic of Beckwith-Wiedemann syndrome. Placentomegaly had been identified by ultrasound in each case and was determined pathologically as mainly attributable to stromal expansion of the villous tree. Cysts resulting from hydrops in stem villi were identified ultrasonographically in one placenta; this lesion may be specific for Beckwith-Wiedemann syndrome. The third placenta was associated with a discrete complete hydatidiform mole. CONCLUSIONS: A diagnosis of Beckwith-Wiedemann syndrome should be considered in all cases in which gestational proteinuric hypertension is associated with ultrasound findings of placentomegaly, with or without associated cystic changes in the placenta, and an examination should be made for other confirmatory features.

Intra-alveolar pulmonary siderophages in sudden infant death: a marker for previous imposed suffocation.

Staining for iron showed previously overlooked intra-alveolar siderophages widely distributed in the lungs of two pairs of siblings, all of whom had hospital admissions for apparent life-threatening events (ALTEs) before dying suddenly at home. A mother and babysitter were convicted of their murder and manslaughter respectively. There were no siderophages in the lungs of a fifth infant whose death was included in the murder charge but who had no ALTEs. Bleeding from mouth or nose was observed during six of ten previous ALTEs suffered by these children and three unrelated infants in the same care. Such external hemorrhage is well described in imposed infant suffocation which may be one aspect of "Munchausen syndrome by proxy" child abuse. Our findings imply that there may also be intrapulmonary hemorrhage and that intra-alveolar siderophages can be a marker for previous abuse. Retrospectively we found diffusely distributed intra-alveolar siderophages in the lungs of seven of 158 infants with diagnoses of SIDS. Siderophages in such numbers demand an explanation and if this is not provided by clinical history or other necropsy findings should cause suspicion of previous imposed suffocation and infanticide and require further enquiry. The lungs should be stained for iron in all cases of sudden infant death.

The simultaneous presentation of sarcoidosis and common variable immune deficiency.

Sarcoidosis and common variable immune deficiency can rarely present simultaneously in the same individual. We describe a child who presented with both disorders. The diagnosis of sarcoidosis was delayed because of the atypical appearances of the liver biopsy. She failed to respond to intravenous immunoglobulin but improved once cyclosporin and corticosteroids were added to her treatment regimen. It is important that the co-existence of both disorders is recognised so that treatment with a combination of intravenous immunoglobulin and immunosuppression can be in instituted to treat both the immune deficiency as well as the granulomatous disorder. As illustrated here, patients may fail to respond if either modality is used alone.

Histiocytoid cardiomyopathy of infancy: an unexplained myofibre degeneration.

An unusual multifocal degeneration of the myofibres of all chambers and the conducting system of the heart was found in a 4-month-old female in whom ventricular pre-excitation (Wolff-Parkinson-White syndrome) had been demonstrated. There was a complex malformation of the brain with hydrocephalus and bilateral corneal opacities and microphthalmos. The affected myofibres had a swollen vacuolated or granular cytoplasm and rounded nuclei giving a histiocytoid appearance. Disruption of myofibrils and gross dilation and disorganization of mitochondria were the major fine structural features. Reports of similar lesions in 8 other young female children are reviewed. 'Histiocytoid cardiomyopathy' is the term preferred over others which refer to an increased lipid content. The aetiology is unknown.

Childhood cancer in New Zealand 1990 to 1993.

An epidemiological study of childhood cancer in New Zealand identified 409 children aged 0 to 14 years with malignant neoplasms newly diagnosed between 1990 and 1993 inclusive. The original microscopic material on which the diagnoses were based was reviewed in 398 cases and the neoplasms were allocated into the 12 major groupings and 48 further subcategories of the International Classification of Childhood Cancer (ICCC). The pathology reviewers agreed with group and subcategory classification of the confirmed cancers in all but one case of acute leukemia and three cancers of the central nervous system. Changes were also made in the FAB classification of three cases of acute non-lymphocytic leukemia and in the further subcategorisation of three Hodgkin's lymphomas and ten astrocytomas. The results show a high level of diagnostic accuracy for confirmed childhood neoplasms in that time period. Nine of 15 cases of malignant melanoma notified to the study were not confirmed for various reasons, which included a change in the pathological diagnosis in four cases. Compared with Victoria (Australia), New Zealand has a high incidence rate of lymphomas in boys and an unusual female preponderance of Wilms' tumor cases.

Maternal nutritional risk factors for small for gestational age babies in a developed country: a case-control study.

AIMS: To assess the effect of maternal diet during pregnancy on the risk of delivering a baby who is small for gestational age (SGA). METHODS: Case-control study of 844 cases (SGA) and 870 controls (appropriate size for gestational age (AGA)). Only term (37+ completed weeks of gestation) infants were included. Retrospective food frequency questionnaires were completed at birth on the diet at the time of conception and in the last month of pregnancy. RESULTS: At the time of conception, mothers of AGA infants ate significantly more servings of carbohydrate rich food and fruit, and were more likely to have taken folate and vitamin supplements than mothers of SGA infants. There was some evidence that mothers of AGA infants also ate more servings of dairy products, meat, and fish (0.05 < p < 0.1). However, after adjustment for maternal ethnicity, smoking, height, weight, hypertension, and occupation, fish intake (p = 0.04), carbohydrate-rich foods (p = 0.04), and folate supplementation (p = 0.02) were associated with a reduced risk of SGA. In the last month of pregnancy, only iron supplementation was associated with a reduced risk of SGA (p = 0.05) after adjustment for potential confounders. CONCLUSIONS: This study suggests that small variations in maternal diets within the normal range during pregnancy in developed countries are associated with differences in birth weight.

Prenatal cranial haemorrhages in 47 Pacific Islander infants: is traditional massage the cause?

Intracranial haemorrhage is usually a very rare occurrence in the fetus before the onset of labour but we have identified major, mostly subdural, prenatal intracranial haemorrhages in 47 infants of immigrant Pacific Islander parentage. Forty-four infants have been stillborn and the numbers from 1983 to 1986 were sufficient to account for the stillbirth rate for Pacific Islanders in Auckland being approximately 60% higher than rates for Europeans or Maoris. Two of three liveborn infants survived with neurological sequelae. Similar haemorrhages may be the cause of a congenital hydrocephalus in Pacific Islanders. A bleeding disorder can be excluded in most cases, as can trauma from accidents or assaults. Trauma during attempts at cephalic version of breech presentations by traditional methods could explain why 53% of deliveries were breech and other pathological and clinical features. Advice at antenatal clinics about possible dangers of traditional massage has coincided with a reduction in the incidence of haemorrhages since 1986.

Drug reaction simulating malignant lymphoma: a case due to pyrimethamine.

A 9 1/2-year-old boy who had been treated with pyrimethamine and sulphadimidine presented with generalised lymphadenopathy, fever, and an unusual sun-tanning. He was found to have mild anaemia, severe leucopenia and thrombocytopenia. The bone marrow was megaloblastic. Lymph node biopsy was initially interpreted as showing malignant lymphoma. No treatment for neoplasia was given and he was well 4 1/2 years later. We consider that the seemingly malignant changes were due to pyrimethamine.

Chronic granulomatous disease: an inherited disorder of phagocytosis in a Maori ancestry.

Chronic granulomatous disease, in which abnormal susceptibility to infection is caused by an inherited defect in phagocytic cells, has been diagnosed in three brothers. Two brothers had repeated bacterial infections of the skin, superficial lymph nodes and lungs from infancy and died aged 27 months and 13 months. Characteristic suppurating granulomata were found in many organs. The diagnosis was established in both during life, and in the third asymptomatic brother shortly after birth, by studies of phagocytic function which included tests for nitroblue-tetrazolium reduction, hexose monophosphate shunt activity and bactericidal capacity. Their mother and a maternal aunt, both Maoris with no known Caucasian ancestry, were identified as carriers of the presumed sex-linked recessive gene. The clinical features of the disease and the laboratory methods for diagnosis are described.