Caudal Dysplasia, Femoral Hypoplasia-Unusual Facies Syndrome and Absent Radius: A New Association in Infant of Diabetic Mother?

The Caudal dysplasia syndrome (CDS) and the femoral hypoplasia-unusual facies syndrome (FHUFS) have been reported to be more frequent among infants of diabetic mothers (IDMs). Infact, uncontrolled maternal diabetes is the most common cause of both the syndromes. Till now, there is no case report to suggest absent radius as a manifestation of IDMs. The authors report a rare case of newborn, who presented with features compatible with both CDS and FHUFS with an additional feature of absent radius, which is not reported in the literature so far. The possibility that all these features represent different manifestations of the same disorder is discussed here.     

Caudal regression syndrome - caudal agenesis

BACKGROUND: Neural tube defects are caused by complex genetic and environmental factors. The congenital anomaly most specific to pregnant women with diabetes mellitus is caudal regression syndrome. PATIENT: A 4-year-old boy with a history of mild delay in motor development presented with primary enuresis and encopresis. On physical examination, he had no sensory and motor deficits, but a short anal cleft. On questioning, the mother reported insulin-dependent diabetes mellitus during pregnancy. MRI of the spinal cord demonstrated a thoracic syringomyelia, a dysplastic conus medullaris, and an absence of coccyx and distal sacrum, called caudal regression syndrome or caudal agenesis. CONCLUSION: The caudal regression syndrome refers to sacral agenesis associated with spinal cord anomalies, e.g. syringomyelia. Sacral agenesis is marked by total absence of the coccyx and total or distal absence of the sacrum. An abnormal backside combined with a history of maternal diabetes mellitus in pregnancy is highly suggestive for the presence of caudal regression syndrome.     

Syndromal Associations of Common Origin of the Carotid Arteries

The term “common origin of the carotid arteries” (COCA) has been proposed to replace the older terms “origin of the left carotid artery from the innominate stem” and “bicarotid trunk with anomalous right or left subclavian artery.” These anatomic patterns are usually reported to occur in about 11% of whites and 20-25% of blacks and have been reported to have increased frequency in patients with esophageal atresia-tracheoesophageal fistula, DiGeorge anomaly, and anomalous origin of the left coronary artery from the pulmonary artery. COCA is a significant, if not invariant, feature of the great arteries in the condition usually called in the more recent literature “anomalous origin of the innominate artery,” the most frequent cause of symptomatic tracheal compression by anomalous systemic arteries. Analysis of associations of COCA with various other congenital cardiovascular lesions showed, in addition, significant association with congenital polyvalvular disease, truncus arteriosus, aorticopulmonary window, trisomy 13, 18, and 21 syndromes, acrocephalosyndactyly (especially Apert syndrome), tetralogy of Fallot not associated with DiGeorge anomaly, and clinical Noonan phenotype. Pentalogy of Cantrell was associated with no increase in incidence of COCA.     

Thymic Involution with Loss of Hassall's Corpuscles Mimicking Thymic Dysplasia in a Child with Transfusion-Associated Graft-Versus-Host Disease

A 7-year-old leukemic girl developed pancytopenia following chemotherapy and was given several transfusions of nonirradiated blood. Within 2 weeks she developed a maculopapular rash, fever, abnormal liver function, diarrhea, and wasting. She became septic and died 6 weeks later. Transfusion-associated graft-versus-host disease (GVHD) was suspected clinically. At autopsy, changes diagnostic of GVHD were present in the skin and liver. The remarkable feature of the case was the histopathology of the thymus, which was morphologically “dysplastic,” i.e., minute, lymphoid depleted, devoid of a corticomedullary demarcation, and completely lacking in Hassall's corpuscles. These changes were virtually identical to those seen in the thymus of children with severe combined immunodeficiency disease (SCID). There was no evidence of preexisting immune deficiency. There is compelling experimental evidence that GVHD can produce changes in the thymus that are identical to those of “thymic dysplasia.” These observations have led to the hypothesis that immunodeficiency associated with GVHD may stem, in part, from injury to thymic epithelium resulting in defective T cell maturation. As a corollary of this hypothesis, it has been suggested that the pathogenesis of some forms of SCID may involve GVHD-associated injury to the thymus by a maternal allograft acquired in utero. This report further documents thymic pathology in human GVHD and discusses these changes in the light of these ideas.     

THE SPECTRUM OF TYPE III LISSENCEPHALY: A CLINICOPATHOLOGICAL UPDATE

A third type of lissencephaly that does not fulfil diagnostic criteria of type I (“classical”) and type II (“cobblestone”) lissencephaly was described by our group as a new entity identified as OMIM 601160. This lethal familial syndrome comprises micrencephaly/lissencephaly and a spectrum of abnormalities lined to a severe fetal akinesia deformation sequence. Neuropathological findings suggest severe neurodegeneration leading to a marked neuronal dropout of the entire central nervous system and atrophy. Similar neuropathological findings have been described in the Neu-Laxova syndrome (NLS), an apparently different lethal malformation syndrome. Neuropathological similarities between OMIM 601160 and NLS raise the question of clinicopathological variability and genetic heterogeneity of type III lissencephaly. To answer this question, we compared our clinicopathological findings in a series of fetuses with OMIM 601160 to pathological data reported in NLS. In the study, 5 unrelated families with 7 affected fetuses were included. Interestingly, we found striking clinicopathological similarities between OMIM 601160 and NLS, which may represent a variability of a single neurodegenerative disease with early prenatal onset. Molecular studies in multiplex families defined through detailed clinicopathological screening are needed to clarify the distinction, if any, between these two entities.     

A Cluster of Hypoplastic Left Heart Malformation in Baltimore, Maryland

Congenital cardiovascular malformations (CCVMs) of the left side of the heart show familial recurrence of various forms of obstructive malformations, including hypoplastic left heart (HLH), interrupted aortic arch, coarctation of the aorta, and aortic stenosis. In a previous population-based study in the Baltimore–Washington region, these malformations were associated with parental reports of occupational or leisure solvent exposure, overt diabetes, and family history of CCVM in first-degree relatives. Spatial analysis in this well-characterized study population may augment self-reported data by revealing additional associations with potential environmental risk factors. We used spatial analysis to identify clusters of HLH as a group. The study population included all live-born cases of hypoplastic left heart syndrome diagnosed in the first year of life between 1981 and 1989 and a random sample of unaffected infant controls matched by year and hospital of birth. The nested case–control cohort in this spatial analysis included 77 HLH cases and 1894 controls in Maryland and the District of Columbia. Nonparametric and regression analyses included personal variables from the interview data set as well as spatial variables. A region of Baltimore was identified that contained HLH at twice the expected frequency based on the distribution of population younger than 5 years of age. The region included 30 of 77 geocoded cases of HLH in the cohort and is significant by spatial scanning at p = 0.056. Within this region, male cases of HLH were disproportionately present compared to females. This cluster is in a region of Baltimore with industrial release of solvents, dioxin, and polychlorinated biphenyls in air. Outside the cluster, HLH is associated with family history of CCVM in a first-degree relative, maternal exposure to miscellaneous solvents, paternal anesthesia, maternal art painting, aspirin ingestion, and maternal diabetes. Inside the cluster, father’s painting and exposure to sympathomimetic drugs were associated risk factors. Spatial analysis of HLH cases delineated an urban region with increased prevalence of this left heart malformation. Within this region, excess male cases of HLH occurred, and industrial release to air of solvents, dioxin, and polychlorinated biphenyl compounds was documented. We propose that both genetic and environmental factors contribute to the phenotype of HLH.     

Labeled Lectin Studies of Renal Tubular Dysgenesis and Renal Tubular Atrophy of Postnatal Renal Ischemia and end-Stage Kidney Disease

Renal tubular dysgenesis (RTD), with hypoplasia especially of renal proximal convoluted tubules and clinical neonatal anuria or oliguria, has been reported as a congenital familial (autosomal recessive) disease, variably with features of oligohydramnios, Potter syndrome, or pulmonary hypoplasia. A similar tubular lesion due to antenatal tubular atrophy has been reported for conjoined twins with twin-twin transfusion syndrome or acardia and in infants of mothers given antihypertensive agents, including angiotensin-converting enzyme (ACE) inhibitors, during pregnancy, and it has been seen as a unilateral lesion in young infants with renal artery stenosis due to arteritis or medial arterial calcinosis. The renal tubular changes in RTD are very like those of the “endocrine kidney” in experimental animals and resemble those of the renal tubular atrophy of end-stage kidney diseases such as glomerulonephritis, tubulointerstitial kidney disease, obstructive uropathy/pyelonephritis, graft rejection of transplanted kidneys, or the renal parenchymal changes seen with protracted dialysis therapy. Labeled lectins that differentially mark proximal convoluted, distal convoluted and connecting, and collecting tubules showed no distinctive differences in stainingpatterns of the hypoplastic renal tubules of infants and children with RTD, postnatal renal artery obstruction, or the various types of end-stage renal disease with the lectins used (PNA, GSL1, UEA, and LTA). The findings suggest that the renal tubular changes in some if not all the conditions studied are the result of renal ischemia. The reported familial RTD with hypernephronic nephromegaly may be a specific disorder, but other forms could reflect renal ischemia acquired in utero or in early or later postnatal life.     

Fatal hypertrophic cardiomyopathy in an infant of a diabetic mother

Summary The case is reported of a male infant with hypertrophic cardiomyopathy (HCM), attributed to maternal diabetes, who, contrary to the usually good prognosis of this condition, died at 11 weeks of age. The clinical, echocardiographic, and pathological findings were indistinguishable from familial HCM, except for the lesser degree of myocardial fiber disarray on microscopic examination.     

Examining the effects of maternal chronic illness on child well-being in single parent families

OBJECTIVE: Chronic illness is highly prevalent among adults with children. It is therefore important to understand how parental illness may or may not have an impact on affected families. Findings thus far have suggested that differences between children with and without a sick parent are minimal, but there are individual and familial moderators of outcome. It is unclear whether these results are generalizable to single-parent families. The purpose of the present study was to examine whether maternal chronic illness affects multiple aspects of child functioning in a large, ethnically diverse sample of single-parent families compared to those not affected by illness. Potential moderators of differences, including maternal distress, parenting variables (aggravation and warmth), functional impairment related to illness, and demographic characteristics were also tested. METHODS: Using data from the Child Development Study (CDS), 812 mother-child pairs were studied. Mothers completed measures of child internalizing, externalizing, and positive behaviors, while children completed a measure of depression. RESULTS: The results indicated that overall there were no differences between children with or without a sick mother on the measures of well-being. Higher symptom levels among both cohorts were associated with maternal distress and aggravation in parenting only. However, children with a sick mother were more likely to have a consultation due to emotional difficulties. CONCLUSION: Several areas for future work on how illness affects single-parent families were identified such as prospectively studying illnesses with a variable course and determining which protective factors promote resiliency for children in this difficult situation.     

Hereditary sacrococcygeal teratoma--not the same as its sporadic counterpart!

Sacrococcygeal teratoma (SCT) can be sporadic or familial and there appear to be different characteristics to these entities. It can be an isolated anomaly or occur as part of the Currarino triad, when it is associated with anorectal malformations and sacral anomalies. We present a case of familial sacrococcygeal teratoma and discuss its relationship to previously published reports, drawing conclusions regarding embryogenesis, diagnosis, screening and management.     

Wiedemann-Beckwith syndrome. Study of an oligosymptomatic form

An infant with an incomplete expression of Wiedemann-Beckwith syndrome during the neonatal period was suspected to suffer from hypothyroidism. However, after exclusion of this tentative diagnosis the phenotypic characteristics lead to the correct diagnosis. In addition to the macroglossia, the typical facial signs of this syndrome such as capillary haemangioma of the glabella, soft tissue folds under the eyes and linear indentations of the ear lobes are demonstrable. Gigantism and umbilical hernia are absent. A tendency to hypoglycaemia and the increased risk of malignancy are the important aspects of this syndrome, which may be expressed in a variety of clinical forms. So far the aetiology of this syndrome is unknown although familial cases implicate the involvement of genetic factors.     

Maternal folate,one‐carbon metabolism and pregnancy outcomes

Single nucleotide polymorphisms and pre‐ and peri‐conception folic acid (FA) supplementation and dietary data were used to identify one‐carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with <800 μg daily FA at 15‐week gestation had a higher incidence of PE (10.3%) compared with women who did not supplement (6.1%) or who supplemented with ≥800 μg (5.4%) (P < .0001). Higher serum folate levels were found in women who later developed GDM compared with women with uncomplicated pregnancies (Mean ± SD: 37.6 ± 8 nmol L⁻¹ vs. 31.9 ± 11.2, P = .007). Fast food consumption was associated with increased risk for developing GDM, whereas low consumption of green leafy vegetables and fruit were independent risk factors for SGA and GDM and sPTB and SGA, respectively. In conclusion, maternal and paternal genotypes, together with maternal circulating folate and homocysteine concentrations, and pre‐ and early‐pregnancy dietary factors, are independent risk factors for pregnancy complications.     

Tight junctions, leaky intestines, and pediatric diseases

Background: Tight junctions (TJs) represent the major barrier within the paracellular pathway between intestinal epithelial cells. Disruption of TJs leads to intestinal hyperpermeability (the so-called “leaky gut”) and is implicated in the pathogenesis of several acute and chronic pediatric disease entities that are likely to have their origin during infancy. Aim: This review provides an overview of evidence for the role of TJ breakdown in diseases such as systemic inflammatory response syndrome (SIRS), inflammatory bowel disease, type 1 diabetes, allergies, asthma, and autism.

Conclusion: A better basic understanding of this structure might lead to prevention or treatment of these diseases using nutritional or other means.     

Comparison of parenting stress between Malaysian mothers of four-year-old very low birthweight and normal birthweight children

A study was carried out to compare parenting stress between 116 mothers of very low birthweight (VLBW) children and 96 mothers of normal birthweight (NBW) children at 4 y of age, using the Parenting Stress Index (PSI). Multiple regression analysis was used to determine factors associated with child-domain stress (CDS) and parent-domain stress (PDS). There was a significantly higher proportion (39.7%) of mothers of VLBW children with high CDS scores >90th percentile than mothers of NBW children (20.8%). No significant differences were observed for PDS scores. Lower intelligence quotient (IQ) scores and adverse child behaviour, as evidenced by higher Child Behavior Checklist (CBCL) scores, were significantly associated with higher CDS scores (p < 0.001). Factors associated with higher PDS scores were higher CBCL scores (p < 0.001), mothers who were the primary caregivers (p < 0.001), male sex (p = 0.018) and lower level of maternal education (p = 0.048). These factors remained statistically significant even when physically and cognitively impaired children were excluded from the analysis. Conclusion: Specific child characteristics and the social environment appear to have a greater impact on parenting stress than the biological risk of VLBW birth per se.     

Environmental risk factors for type 1 diabetes in Rome and province

Background: In subjects genetically susceptible to type 1 diabetes, exposure to environmental factors during the gestational period, the neonatal period, and the first years of life is thought to play an important role in triggering the immune process leading to ß cell destruction. Aims: To investigate risk factors for inhabitants of continental Italy. Methods: A case-control study of 150 type 1 diabetes cases and 750 control subjects (age range 6–18 years) was carried out in Rome and its province, measuring the exposure to environmental risk factors. Results: Three environmental factors were found to occur significantly more in the diabetic group than in the controls. During the mothers'' pregnancies, the one risk factor which proved to be higher in diabetics than in controls was maternal infectious disease. During the neonatal period, no risk factors associated with the disease were detected. During early life, eczema and a short duration of breast feeding (less than three months), occurred significantly more in diabetic cases than controls. Conclusion: Eczema and breast feeding for less than three months are risk factors for type 1 diabetes in a southern European population. The type, duration, and mode of treatment for infectious diseases during pregnancy need additional investigation as risk factors for type 1 diabetes.     

Prevalence of self-perceived allergic diseases and risk factors in Italian adolescents

The aim of the study was to assess the symptoms prevalence of allergic diseases in a population of 11–15 yr old schoolchildren, to evaluate the associations between asthma and other symptoms and identify risk factors for asthma, rhinitis and eczema syndromes. A sample of 481 students was studied using an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Prevalence of different kind of self-reported symptoms was calculated. Using a logistic regression approach, we tried to identify risk factors for three syndromes – rhinitis, eczema and asthma. The highest and the lowest prevalence rates of self-reported symptoms were recorded for rhinitis (43.6%) and for eczema (8.1%), respectively. The prevalence of asthma was 15.7%. Univariate analysis showed a mutual association between wheeze and rhinitis symptoms. Multivariate logistic regression model for eczema syndrome revealed female gender as a significant risk factor. The polytomic logistic multivariate regression revealed female gender and family history of allergy as significant risk factors for rhinitis syndrome only, and maternal smoking and familial allergy for rhinitis and asthma together. In particular, familial allergy yields a 400% higher chance of developing asthma and rhinitis together. The synergistic effect of familial allergy on rhinitis and asthma syndromes suggests the implementation of preventive measures in children with family history of these diseases.     

Maternal nutritional status, diabetes and risk of macrosomia among Native Canadian women

Multivariate methods were used to identify risk factors for macrosomia (birth weight >4000 g) among 741 singleton births to Native Canadian women from Sioux Lookout Zone, Ontario, Canada, in 1990–1993. The average birth weight was 3691±577 g, and 29.2% of infants weighed more than 4000 g at birth. Macrosomic infants were born at later gestational ages and were more likely to be male. Women delivering macrosomic infants were taller, entered pregnancy with higher body mass indexes (BMI) and gained more weight during pregnancy, but were less likely to smoke cigarettes. They were more likely to have previously delivered a macrosomic infant and to have had gestational diabetes mellitus (GDM). Risk of macrosomia was associated with maternal glycemic status; women with pre-existing diabetes were at greatest risk, followed by those with GDM A₂ (fasting glucose ≥6 mmol/l). Women with GDM A₁ (fasting glucose <6 mmol/l) were not at increased risk for delivering a macrosomic infant, but glucose-tolerant women with high glucose concentrations 1 h after the 50 g challenge were at somewhat increased risk. Maternal glycemic status and maternal nutritional status before and during pregnancy are important determinants of macrosomia in this native population.     

Genetics of idiopathic nephrotic syndrome

Nephrotic syndrome (NS) is a pathological entity characterized by massive proteinuria and has diverse etiology. Although it is one of the most common renal diseases in children, the etiological factors responsible for idiopathic NS/FSGS remain largely unknown. Previous studies had implicated a variety of factors including genetic factors, although NS is generally regarded as a sporadic disease. Familial cases of NS have however been reported periodically, and both autosomal dominant and recessive forms have been identified. Studies of familial NS /FSGS have led to the discovery of several genes that are expressed in podocytes and are associated with proteinuria. These discoveries have shifted the focus from glomerular basement membrane (GBM) to recognition of the central role of podocytes in maintaining glomerular perm selectivity and pathogenesis of NS/FSGS. Associations with various genes (NPHS1, ACTN4, NPHS2, WT-1) and linkage to several chromosomal regions (such as 19q13,11q21,11q24) have been reported in patients with familial NS/FSGS.     

Growth Hormone Treatment and Diabetes: Survey of the Kabi Pharmacia International Growth Study

Out of a total of 8136 children registered in the Kabi Pharmacia International Growth Study, 12 have been reported to have diabetes either before or during treatment with growth hormone (GH). Two of these have non-insulin-dependent diabetes mellitus (NIDDM), of whom one had risk factors for the development of his condition, namely gross obesity and familial occurrence of NIDDM. One is a rare case of McCune-Albright's syndrome with insulin-dependent diabetes mellitus (IDDM), and 9 other patients have IDDM. Of these 9, 6 have idiopathic GH deficiency. In 8 of the 9 patients with IDDM, the condition was diagnosed before GH therapy was commenced, at ages ranging from less than 2 years to 16 years. The association is probably fortuitous, however, as the onset of IDDM in 7 patients was immediately before or during puberty, as often occurs in IDDM in general.     

The rare syndromic forms of monogenic diabetes in childhood

The most frequent form of diabetes in the childhood is type 1 diabetes. Moreover, the rare forms of diabetes have been also identified in children. Besides of neonatal diabetes caused by the mutations in KCNJ11, SUR1 and GCK genes, other forms of monogenic diabetes are associated with different chronic disorders. These rare forms of syndromic diabetes are related to mutations in genes which lead to Wolfram syndrome, Alstr?m syndrome, Wolcott-Rallison syndrome or Roger's/TRMA syndrome. In this paper we discuss the clinical features of rare syndromic forms of monogenic diabetes, which gave suggestions on pathogenic mechanism of the diagnosed diabetes in childhood. This may be helpful for appropriate classification of the epidemiological, clinical and genetic data. It may be useful in the future to the form of the Polish National Survey of rare syndromic forms of monogenic diabetes in childhood.