Papillary Pore Counts: A Method of Studying Developmental Aberrations in Diseased Juvenile Kidneys

Counts of the number of pores of primary collecting tubules (ducts of Bellini) on renal papillae, and values calculated by adjusting the counts of compound papillae to those of “virtual” single papillae, were determined for kidneys of patients with end-stage renal failure. Values for chronic glomerulonephritis, Alport's disease, infantile polycystic disease, trisomy 18, and trisomy 13 were not abnormal. Kidneys of patients with CUTO showed significantly low pore counts, indicating that this process in some cases is a true hypoplasia, with mean reduction of number of ducts of Bellini of 26%. FGS showed a high proportion of single papillae (80% vs. normal 60%) with high virtual pore counts, suggesting that a developmental abnormality underlies this disorder (or this outcome of nephrotic syndrome). Cystinosis showed a high proportion of compound papillae (80% vs. 40%) but low virtual pore counts, implying that this genetic disorder causes both maldevelopment and postnatal functional abnormality of the kidneys. A Jeune syndrome kidney produced very low pore counts (mean 8 vs. 16.6 for virtual pore counts), and Down's syndrome also showed low pore counts (mean VPC 15.1 vs. normal 16.6), indicating that the low kidney weights demonstrated by others with Down's syndrome reflect a true hypoplasia.     

Thyroid function in children with Down's syndrome]

The aim of the present study was to evaluate thyroid function in 45 Down's syndrome patients in order to verify the hypothesis of an increased risk of thyroid disorders associated with trisomy 21. A patient with subclinical hypothyroidism (TSH 16.6 microU/ml; T4 6.4 micrograms/dl) was diagnosed in a group of 28 subjects with Down's syndrome studied at a mean age of 6 years and 5 months using T3, T4, FT3, FT4, TSH assays and clinical examination. T4 and TSH values were also measured in 10 of these children at the neonatal screening. One infant presented transient neonatal hyperthyrotropinemia but later became euthyroid. The analysis of thyroid hormone values at the neonatal screening of other 17 subjects with Down's syndrome did not reveal other cases with thyroid function disorders. The results of this study highlight that altered thyroid functions are evident in children with trisomy 21 associated with heart anomalies. A careful clinico-endocrinological follow-up of patients with Down's syndrome is recommended in order to ensure an early diagnosis of thyroid function disorders and/or autoimmune diseases which might complicate the evolution of trisomy and negatively affect outcome.     

Transient myeloproliferative disorder in chromosomally normal newborn infant

Transient myeloproliferative disorder is a condition clinically resembling congenital acute myelogenous leukemia. As in acute leukemias the blast cell population in this disorder may have either normal or abnormal chromosomal complement. Transient myeloproliferative disorder is well recognized in neonates with a complete or mosaic trisomy 21 (Down's syndrome). We report a phenotypically and cytogenetically normal infant with this syndrome in whom only blast cells showed trisomy 21. We postulate that the pathogenesis of the transient myeloproliferative disorder in both Down's syndrome infants and those with a normal chromosomal complement is related to abnormal prenatal production of placental regulatory hemopoietic factors caused by chromosomal defect(s) confined to placental tissues.     

Neonatal thrombocyte values in children with Down's syndrome and other autosome trisomies]

Platelet counts were determined in 70 neonates with trisomy-21, 10 neonates with trisomy-18 and 6 neonates with trisomy-13 during the first days of life. 60% of all infants with trisomy-aberrations were found to have thrombocytopenia. Platelet counts in Down's syndrome averaged 104600 (SD 53000; median 90500; 10- and 90-percentile at 45000 and 175000) per microliter. A correlation with other hematological features of trisomy-21 was examined. There was no significant correlation between platelet counts and hemoglobin concentration. Similarly the difference in platelet counts between trisomy-neonates with and without polycythemia was statistically not significant. In contrast, 27 normal neonates with polycythemia showed significantly higher platelet counts (mean = 13400) than their trisomy-counterparts (mean = 98900; P = 0.01). In addition, there was no correlation, in trisomy infants, between either erythroblastosis or low birth weight and platelet count. These findings point to defective hematopoiesis as a primary cause of thrombocytopenia in trisomy-infants.     

Multiple Acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys,and symmetric warty dysplasia of the cerebral cortex in two newborn brothers

The post mortem and microscopic findings of two newborn male sibling of Turkish origin suffering from multiple acyl-CoA-dehydrogenation deficiency (glutaric aciduria type II) are reported in detail for the first time. The morphological disease pattern was strikingly identical in both siblings: enlarged bilateral polycystic kidneys, symmetric warty dysplasia of the cerebral cortex, and bile duct hypoplasia, cholestasis, siderosis and fatty degeneration of the liver were found in both infants. In addition, features of Potter syndrome (pulmonary hypoplasia and Potter face) were observed only in sibling I, and focal hypoplasia and dysplasia of pancreatic ducts only in sibling II.It appears to be a rather remote chance that the rare metabolic disorder accidently coincided with the equally rare developmental abnormality in both siblings. We believe it to be more likely that both conditions are pathogenetically related in that the accumulation of large quantities of carboxylic acids exerted their effect already in intrauterine life, probably leading to cellular damage and secondary developmental defects of the fetal kidneys, liver, pancreas and brain. From the nature of the observed morphological alterations we speculate that the injury did not occur until after cessation of organogenesis during the fetal period of intrauterine development.Supported by Deutsche Forschungsgemeinschaft, Grant No. Bo 395/5     

Intrahepatic portal venous hypoplasia in Alagille's syndrome

One new case of arteriohepatic dysplasia (Alagille's syndrome) is reported. The case showed signs of progressive portal hypertension with the liver biopsy revealing evidence of hypoplasia of the intrahepatic portal venous branches without evident cirrhosis, next to the characteristic paucity of intrahepatic bile ducts. This venous abnormality might be responsible for the unfavourable outcome observed in some cases with Alagille's syndrome and corresponds to a severe form of the disease.     

Natural killer cell activity and ultrastructure in myeloproliferative reactions in infants with Down's syndrome

In some infants with Down's syndrome, the circulating mononuclear population, when viewed with conventional and electron microscopy, contains many cells that closely resemble leukemic blast cells. In contrast with true leukemia, however, most of these infants with the "leukemia-like reaction in Down's syndrome" (LLR-DS) enter spontaneous remissions. We therefore investigated the natural resistance of such infants to hematological malignancy in vitro by means of natural killer cell assays. Mean natural killer cell determinations in four infants with LLR-DS were 17.5 +/- 9.2% and 37.6 +/- 18.5% against K-562 and Molt-4 target cells, respectively, at diagnosis. Later, during remission, these values were 34.3 +/- 14.3% against K-562 and 32.2 +/- 15.6% against Molt-4. The mean percentage lysis of Molt-4 both at diagnosis and during remission was greater (p less than 0.05) in LLR-DS than in children with acute lymphocytic leukemia and acute myelogenous leukemia at diagnosis. Natural killer cell activity levels in these LLR-DS patients were similar to levels obtained in other infants with Down's syndrome who were hematologically normal, as well as levels obtained in normal control specimens. Two of these LLR-DS patients progressively developed acute myelogenous leukemia with ultrastructural abnormalities several months later; one of these also developed another karyotype abnormality. Both remain in long-term remission exceeding 48 months.     

Neonatal bilirubin production, reflected by carboxyhaemoglobin concentrations, in Down's syndrome.

AIM: To determine whether increased bilirubin production, reflected by blood carboxyhaemoglobin (COHb) values, is responsible for hyperbilirubinaemia in cases of Down's syndrome with no obvious cause for excessive jaundice. METHODS: Blood was sampled on the third day of life for COHb, total haemoglobin (tHb), and serum total bilirubin, from 19 consecutively born neonates with Down's syndrome (a subset of 34 term babies), who had developed hyperbilirubinaemia (serum bilirubin >/= 256 micromol), and from 32 term controls. COHb, measured by gas chromatography, was corrected for inspired CO (COHbc) and expressed as a percentage of tHb. RESULTS: Significantly more of the Down's syndrome subset developed hyperbilirubinaemia than the controls (10/19 (52%) vs 7/32 (22%), relative risk 2.4, 95% confidence intervals (CI) 1.10 to 5.26). Third day serum bilirubin values (mean (SD)) were higher in the Down's syndrome neonates than in controls (214 +- 63 micromol/l vs 172 +- 54 micromol/l, respectively, p=0.015). Mean (SD) COHbc values were significantly higher in the Down's syndrome neonates than in controls (0.92 +- 0. 24% vs 0.63 +- 0.17%; p<0.0001). However, Down's syndrome neonates who became hyperbilirubinaemic had similar COHbc values to those who did not (0.87 +- 0.26% and 0.95 +- 0.23%, respectively). These values contrast with those of the controls, in whom a significant increase in COHbc was associated with hyperbilirubinaemia (0.74 +- 0. 15% vs 0.60 +- 0.16%, respectively; p<0.05). tHb values were similar in both groups. CONCLUSIONS: Down's syndrome neonates had a greater risk of hyperbilirubinaemia, and higher COHbc values, than controls. However, excessive bilirubin production could not be exclusively responsible for the hyperbilirubinaemia. By inference, decreased bilirubin elimination probably plays a greater part in its pathogenesis than in controls. Down's syndrome neonates may have abnormal erythropoiesis, leading to increased haem turnover.     

Maxillo-Mandibular Development in Cerebrocostomandibular Syndrome

Cerebrocostomandibular syndrome is a potentially lethal developmental disorder characterized by mental handicap, palatal defects, micrognathia, and severe costovertebral defects. We report a 3-day-old male neonate who died of respiratory difficulty that began at birth. Micrognathia, glossoptosis, high-arched palate, and hypoplasia of the lower half of the face were present. Multiple posterior rib defects and a narrow rib cage were associated with pulmonary hypoplasia. The rib gaps were filled with fibrovascular tissue. A facial bone study showed multifocal growth retardation involving the septal cartilage, vomer, and mandibular condyle, indicative of maxillomandibular growth arrest. The tongue had an abnormal genioglossus muscle and papillae.     

Acute hemiplegia and cortical blindness due to moya moya disease: report of a case in a child with Down's syndrome.

We are reporting what we believe to be the first case of moya moya disease (hemiplegia associated with supraclinoid carotid stenosis and multiple cerebral telangiectasia) in a child with Down's syndrome. On cerebral angiography, multiple collateral vessels and rete mirabile (anastomosis of meningeal vessels with internal cerebral vessels) were noted, in addition to the supraclinoid carotid stenosis. Computerized tomography revealed nonobstructive hydrocephalus and findings consistent with multiple vascular insults or infarcts. It is not clear whether moya moya disease represents a true disease entity (congenital arterial dysplasia) or is a syndrome caused by nonspecific vascular reaction. Since abnormal vascular morphology has previously been described in children with trisomy 21, we suggest that the presence of these two disease entities may not be coincidental. It may represent a genetic predisposition in Down's syndrome toward vascular abnormalities, with variable expressivity which manifested itself in this case by abnormalities in the cerebral circulation.     

Renal and urinary tract abnormalities associated with chromosome aberrations

The frequency of malformations of the kidney and urinary tract is much higher in patients with chromosome aberrations than in the general population. Sixty to 100% of "cat-eye" syndrome, 60 to 80% of Turner, 75% of trisomy 8, 33 to 70% of trisomy 18, 50 to 60% of trisomy 13, and over 50% of triploidy and tetraploidy patients may have such abnormalities. Renal and urinary tract malformations should be looked for in all patients with chromosome aberrations. Moreover, a chromosome study is indicated in any fetus with an ultrasonographic evidence of urinary tract abnormality.     

A Case of 48, XXX, +18 Double Trisomy

We report a case of double trisomy, 48, XXX, + 18 in a newborn female who had low set ears, prominent occiput, receding chin, overlapping fingers, structural heart disease and other malformations. These deformities are similar to the characteristic manifestations of trisomy 18 syndrome. She died on the 10th day. Autopsy revealed VSD, ASD, PDA, coarctation of the aorta, Meckel's diverticulum and cerebellar hypoplasia. Our case showed unilateral anomalies on the right side. These may help to suggest the diagnosis of double trisomy.     

Trisomy 21 associated transient neonatal myeloproliferation in the absence of Down's syndrome

Although usually associated with Down's syndrome, transient neonatal myeloproliferation (TMD) can occur in the absence of a constitutional trisomy 21. This report describes two such cases, both of whom had a trisomy 21 restricted to clonal cells. Unlike in previous such reported cases, spontaneous morphological, cytogenetic, and molecular remission in both cases was followed by re-emergence, in one case, of an evolved clone with a more malignant phenotype which required pharmacological intervention. Awareness that trisomy 21 bearing leukaemia in the neonatal period can be transient even in the absence of Down's syndrome is important to prevent unnecessary treatment. Equally, such cases require indefinite follow up as a proportion may have a recurrence which may require treatment.     

Evolution of renal segmental atrophy (Ask-Upmark kidney) in children with vesicoureteric reflux: radiographic and morphologic studies

A radiographic and morphologic study of nine patients with renal segmental "hypoplasia," whose kidneys were radiographically normal when first examined, showed the lesion to be a form of localized, progressive renal atrophy. The renal abnormality bears a strong relationship to vesicoureteric reflux, which could be demonstrated in every patient. No evidence of renal scarring or atrophy was observed in initial roentgenographic examinations at a mean age of 2.9 years (range 0.1 to 10 years); however, serial studies during five to 14 years after discovery of vesicoureteral reflux demonstrated both a lack of renal growth and a progressive loss of substance irrespective of infection. Radiographic lengths of scarred kidneys, as measures of renal growth, correlated poorly with the radiographic surface areas of the renal parenchymal outlines. The mean time from discovery of vesicoureteric reflux to appearance of a renal scar was 6.1 years, and to onset of hypertension in six patients was 7.8 years. The renal abnormality consisted of lobar atrophy with variable tubular atrophy and glomerular sclerosis and with parenchymal destruction that in some specimens had proceeded to a complete loss of nephronic elements. The occasional presence of relatively well-preserved glomeruli and tubules and of focal segmental sclerosis within persisting glomeruli was taken as evidence of a progressive renal abnormality, as opposed to a static developmental hypoplasia. These observations indicate that renal scarring, the injury presumably having been initiated by vesicoureteric reflux, can progress despite correction of the reflux and despite prevention of urinary tract infection.     

Myelofibrosis in a child suffering from a hypereosinophilic syndrome with trisomy 8: response to corticotherapy

The idiopathic hypereosinophilic syndrome (IHS) is extremely rare in childhood and relationships of this syndrome with myeloproliferative diseases are controversial. We reported the observation of a 7-year-old girl suffering from an IHS with myelofibrosis. A clonal cytogenetic abnormality, trisomy 8, was detected in the bone marrow cells of this child. This is the decisive proof of a myeloproliferative disorder. IHS with myelofibrosis is usually considered as unresponsive to corticotherapy. In our case, corticotherapy resulted in a rapid, complete, and lasting disappearance of myelofibrosis. Complete remission of the disease, however, was not achieved and the trisomy 8 persisted after treatment.     

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.     

Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome)

The package inserts of live viral vaccines include immunodeficiency as a contraindication. Nevertheless, patients with mild forms of immunodeficiency may benefit from vaccination. No published guidelines exist for the administration of these vaccines specifically to patients with chromosome 22q11.2 deletion syndrome. This syndrome is also sometimes called DiGeorge syndrome and is associated with thymic hypoplasia and diminished T-cell numbers and has a wide spectrum of phenotypic features that include cardiac anomalies, dysmorphic facial features, and hypocalcemia. Patients generally exhibit a mild to moderate decrement in T-cell numbers with preservation of T-cell function. The aims of this study were to investigate the incidence of side effects after live viral vaccine administration in a population with chromosome 22q11.2 deletion syndrome. The high frequency of this syndrome in the population (1:3000 children) mandates a greater understanding of the risks and benefits related to live viral vaccine administration. A retrospective analysis of vaccine adverse events was performed. The data acquisition form evaluated the frequency of live vaccine administration and the consequences of both vaccination and withholding the vaccine. Flow cytometric enumeration of T cells was performed as part of an immunologic evaluation. Thirty-two of 59 responders were vaccinated with the varicella vaccine. Only 9% of patients reported adverse events. However, 63% of unvaccinated children developed chickenpox. Comparison of patients who tolerated the vaccine with those who reported adverse events showed no statistically significant differences in current age (7 vs 5.7 years), age at vaccination (3 vs 2.5 years), or T-cell subset counts: CD3 (1951 vs 2083 cells/ microL), CD4 (1283 vs 1463 cells/ microL), and CD8 (530 vs 502 cells/ microL). Fifty-two of 59 responders were vaccinated with measles-mumps-rubella (MMR). Twelve (23%) of 52 reported mild side effects, including fever, rash, and constitutional symptoms. No severe adverse reactions were reported. No patient reported natural disease with measles, mumps, or rubella. There were no statistically significant differences between the T-cell counts in the vaccinated group reporting side effects versus the vaccinated group without side effects (mean CD3 counts: 1928 vs 1736 cells/ microL; CD4 counts: 1250 vs 1127 cells/ microL; and CD8 counts: 528 vs 483 cells/ microL). In our study, patients with chromosome 22q11.2 deletion syndrome had a similar incidence of adverse effects with varicella and MMR vaccines compared with that reported in the general population. All side effects were mild. However, in patients who did not receive the varicella vaccine, an overwhelming 63% contracted the disease. Patients who were not vaccinated against MMR did not develop natural disease. The data suggest that this is a cohort of patients with 22q11.2 deletion syndrome who have tolerated live viral vaccinations without evidence of significant side effects. A prospective study could address whether there are T-cell thresholds below which vaccination is unsafe; however, the information that we present suggests that vaccinating children with chromosome 22q11.2 deletion with live viral vaccines does not carry a significantly higher risk of adverse reactions compared with the general population, provided that they have no evidence of severe immunocompromise.     

Neonate with Down's syndrome and transient congenital leukemia. In vitro studies

A white female neonate with clinical manifestations of Down's syndrome was found to have a peripheral white count of 74,000/mm3 with 65% blast forms. Bone marrow aspirate revealed 36% blasts. On chromosomal analysis of bone marrow and peripheral blood, two cell lines were found, one with trisomy 21 and another with pentasomy 21. Colony cultures on the patient's bone marrow cells revealed an adequate growth pattern of CFU/GM. Cells were reactive with myeloblast alloantisera. At the age of 3 weeks, peripheral counts were within normal limits as was morphology of the repeat bone marrow aspirate. Chromosome analysis at that time showed complete absence of pentasomy 21 cell line, and repeat cell colony studies revealed normal growth, differentiation, and maturation of CFU/GM. Maternal serum totally inhibited colony growth of the patient's remission marrow and allogeneic blast cells. This serum inhibitor actually disappeared 1 month postpartum. The patient has had no recurrence of blast cells up to the present age of 3 years.     

Skeletal abnormalities in fetuses with Down's syndrome: a radiographic post-mortem study

Objective. To evaluate skeletal abnormalities on post-mortem radiographs of fetuses with Down's syndrome. Materials and methods. Biometrical and morphological criteria, which are used for US prenatal detection of trisomy 21, were assessed. Limb long bones, biparietal diameter (BPD)/occipito-frontal diameter (OFD) ratio, ossification of nasal bones and appearance of the middle phalanx of the fifth digit (P2) in 60 fetuses with Down's syndrome were analysed and compared with 82 normal fetuses matched for gestational age (GA) from 15 to 40 weeks' gestation (WG). Results. We observed reduced growth velocity of limb long bones during the third trimester in both groups, but the reduction was more pronounced in the trisomic group. Brachycephaly was found as early as 15 WG in Down's syndrome and continued throughout gestation (sensitivity 0.28, specificity 1). Ossification of the nasal bones, which can be detected in normal fetuses from 14 WG, was absent in one quarter of trisomic fetuses, regardless of GA. The middle phalanx of the fifth digit was evaluated by comparison with the distal phalanx (P3) of the same digit. We found that P2 was not ossified in 11/31 trisomic fetuses before 23 WG, and was either not ossified or hypoplastic in 17/29 cases after 24 WG (sensitivity 0.56, specificity 1). Conclusions. Three key skeletal signs were present in trisomic fetuses: brachycephaly, absence of nasal bone ossification, and hypoplasia of the middle phalanx of the fifth digit. All these signs are appropriate to prenatal US screening. When present, they fully justify determination of the fetal karyotype by amniocentesis. Received: 19 May 1998 Accepted: 19 February 1999     

The trisomy 4p syndrome: A case report

Partial trisomy of the short arm of chromosome 4 is considered to be a rare chromosomal disorder. Its clinical and dermatoglyphic features tend to make it a clinically recognizable syndrome. This paper describes a 2 year-old female child with the characteristic findings of frontal bossing, deep-set eyes, broad nasal bridge giving the appearance of hypertelorism, wide nares, midfacial hypoplasia, large dysplastic ears, prognathism and various hand and foot malformations.Chromosomal studies showed her to be trisomic for the distal two-thirds of the short arm of number 4. The etiology of this chromosomal aberration in most instances is unknown, but may occur as a result af an unbalanced translocation in one of the parents as in the case reported here.