S. W. Moore

The epidemiology of neonatal tumours

Neonatal tumours occur every 12,500–27,500 live births and comprise 2% of childhood malignancies, but there is little clarity as to their real prevalence, sites of origin and pathological nature as reported series vary. As an entity, neonatal tumours provide a unique window of opportunity to study tumours in which minimal environmental interference has occurred. The majority of tumours present with a mass at birth (e.g., teratomas, neuroblastomas, mesoblastic nephroma, fibromatosis), which are not infrequently identified on antenatal ultrasound. Histologically, teratoma and neuroblastoma remain the two main tumour types encountered with soft tissue sarcoma, renal tumours, CNS tumours and leukaemia being the next most common tumour types identified. Malignant tumours are uncommon in the neonatal period per se and benign tumours may have malignant potential. A particular problem exists in clinical classification, as histological features of malignancy do not always correlate with clinical behaviour. Benign tumours may also be life threatening because of their size and location. Other tumours may demonstrate local invasiveness, but no metastatic potential, and tumours that are clearly malignant may demonstrate unpredictable or uncertain behaviour. Screening programmes have brought more tumours to light, but do not appear to affect the overall prognosis. They may provide clues to the stage at which tumours develop in foetu. The aetiology of cancer in children is multifactorial and includes both genetic and environmental factors. The association between congenital abnormalities and tumours is well established (15% of neonatal tumours). Genetic defects are highly likely in neonatal tumours and include those with a high risk of malignancy (e.g., retinoblastoma), but also genetically determined syndromes with an increased risk of malignancy and complex genetic rearrangements. Tumours are mostly genetically related at a cellular level and factors influencing cellular maturation or apoptosis within the developing foetus may continue to operate in the neonatal period. Cytogenetics of neonatal neoplasms appear to differ from neoplasms in older children, thus possibly explaining some of the observed differences in clinical behaviour. Certain constitutional chromosome anomalies, however, specifically favour tumuors occurring in the foetal and neonatal period. In support of this hypothesis, certain cytogenetic anomalies appear to be specific to neonates, and a number of examples are explored. Other environmental associations include ionizing radiation, drugs taken during pregnancy, infections, tumours in the mother and environmental exposure.

Diagnostic aspects of cervical lymphadenopathy in children in the developing world: a study of 1,877 surgical specimens

Abstract. Chronic cervical lymphadenopathy is a common clinical problem frequently requiring surgical biopsy. To evaluate the characteristics of surgically excised cervical lymph nodes (LN) in children in a developing country, we studied 1,332 children less than 15 years old (1,877 surgically removed cervical LNs) over a 23-year period (1976–1999). Indications for biopsy included failure to respond to antibiotic therapy, rapid increase in size, hard, matted LNs in the preauricular, supraclavicular, and posterior triangle of the neck, and difficulty in diagnosis. Clinical and pathological characteristics investigated included age, malignancy, and granulomatous disease such as tuberculosis (tbc). The mean age was 7 years (tbc 5.8/neoplastic disease 8.5 years). Twenty LNs (1.5%) were histologically normal. There were 637 (47.8%) with nonspecific reactive lymphoid hyperplasia and 484 with chronic granulomatous changes (36.3%). Tuberculous lymphadenitis was confirmed in 332 of these (25%). In 181 (54.5%) Mycobacterium tuberculosis was cultured and a further 149 had acid-fast bacilli. Other granulomatous diseases identified included sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfmann disease) (3), syphilis (4), yaws (2), and toxoplasmosis (1). No mycobacteria other than M. tuberculosis were encountered. More than two-thirds (108) of 154 patients with neoplastic LN involvement had a lymphoma; in a further 10 lymphadenopathy was associated with leukemia. Pyogenic organisms were identified in 32, and 5 were positive for human immunodeficiency virus, 1 of whom had Kaposis sarcoma. A second pathology was identified in 18 of the 637 cases of reactive lymphoid hyperplasia (3 with tuberculosis); in 15 (1.3%) a diagnosis of lymphoma was made from other sites (pleural fluid, etc.) within 6 months of initial biopsy. This represents a diagnostically difficult subgroup requiring further investigation. Chronic lymphadenopathy in children in developing countries has a high incidence of infective causes, including a significant incidence of M. tuberculosis. The incidence of serious pathology in more than one-half of the cervical LNs examined justifies aggressive surgical investigation.

The contribution of associated congenital anomalies in understanding Hirschsprung's disease.

Hirschsprung’s disease (HSCR) is a complex congenital disorder which, from a molecular perspective, appears to result due to disruption of normal signalling during development of enteric nerve cells, resulting in aganglionosis of the distal bowel. Associated congenital anomalies occur in at least 5–32% (mean 21%) of patients and certain syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene–gene interaction in its pathogenesis. Clear-cut associations with HSCR include Down’s syndrome, dominant sensorineural deafness, Waardenburg syndrome, neurofibromatosis, neuroblastoma, phaeochromocytoma, the MEN type IIB syndrome and other abnormalities. Individual anomalies vary from 2.97% to 8%, the most frequent being the gastrointestinal tract (GIT) (8.05%), the central nervous system (CNS) and sensorineural anomalies (6.79%) and the genito-urinary tract (6.05%). Other associated systems include the musculoskeletal (5.12%), cardiovascular systems (4.99%), craniofacial and eye abnormalities (3%) and less frequently the skin and integumentary system (ectodermal dysplasia) and syndromes related to cholesterol and fat metabolism. In addition to associations with neuroblastoma and tumours related to MEN2B, HSCR may also be associated with tumours of neural origin such as ganglioneuroma, ganglioneuroblastoma, retinoblastoma and tumours associated with neurofibromatosis and other autonomic nervous system disturbances. The contribution of the major susceptibility genes on chromosome 10 (RET) and chromosome 13 (EDNRB) is well established in the phenotypic expression of HSCR. Whereas major RET mutations may result in HSCR by haploinsufficiency in 20–25% of cases, the etiology of the majority of sporadic HSCR is not as clear, appearing to arise from the combined cumulative effects of susceptibility loci at critical genes controlling the mechanisms of cell proliferation, differentiation and maturation. In addition, potential “modifying” associations exist with chromosome 2, 9, 20, 21 and 22, and we explore the importance of certain flanking genes of critical areas in the final phenotypic expression of HSCR.

Down syndrome and the enteric nervous system

Down syndrome (DS) is the most common chromosomal abnormality occurring in humans. Up to 77% of DS children have associated gastrointestinal (GI) abnormalities, which may be structural or functional in nature. Functional disturbances may, in turn, affect the outcome of corrective surgical procedures, prompting to caution. It is becoming clear that the processes affecting the enteric nervous system (ENS) in DS not only affect the micro-anatomy but also nerve function, and there is some histological evidence of ENS variations in both human and DS animal models. This suggests that developmental disorders of the ENS are probably fundamental to the functional GI disturbances encountered in patients with DS. The anomalous brain development, function and resulting intellectual impairment associated with DS appears to result from the genetic imbalance created by the trisomy of chromosome 21. The possible links between the brain, GI and ENS involvement are not as yet entirely clear. Neurotropic factors affecting brain development during embryogenesis are probably interlinked with ENS development, but the precise mechanism of how this occurs has yet to be established. This study explores what is known about the ENS dysfunction in DS and reviews the possible importance of chromosome 21 located and other genes in its etiology. Functional motor disturbances of the esophagus and colon are not uncommon and may be congenital or acquired in nature. The most prominent of these include esophageal dysmotility syndromes (e.g. achalasia, gastroesophageal reflux, dysphagia) as well as a higher incidence of chronic constipation and Hirschsprung’s disease (HSCR) (2–15%) occurring in association with DS. Chromosome 21 itself is thought to be the site of a modifier gene for HSCR. Recently identified candidate genetic mechanisms provide unique insights into the genetic background of the neurological and cognitive disorders associated with DS. Although the role of the triplicated chromosome 21 and genetic dosage remain important, the additional role of other chromosome 21 genes in the etiology of ENS developmental anomalies remains undetermined and requires ongoing research.

Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET

Multiple endocrine neoplasia (MEN) type 2 syndromes are autosomal dominant clinical associations characterized by a common clinical feature, medullary thyroid carcinoma (MTC). The ability to accurately predict the risk by genetic RET proto-oncogene analysis has resulted in the active follow-up of children at risk for developing early metastatic tumours and which can be prevented by prophylactic thyroidectomy. The C634 and M918T mutations (associated with MEN2A and MEN2B, respectively) are particularly associated with early aggressive behavior and distant metastatic spread requiring early intervention. RET is known to be involved in cellular signalling processes during development and controls the survival, proliferation, differentiation and migration of the enteric nervous system (ENS) progenitor cells, as well as the survival and regeneration of sympathetic neural and kidney cells. The centrality of RET in the etiology of both MEN2 and HSCR is now well established with fairly consistent associations existing between RET genotype and phenotype in MEN2. The relationship between Hirschsprung’s disease (HSCR) MEN2 syndromes appears to be a highly significant one, sharing a common etiological factor in the RET proto-oncogene. It is now well accepted that most HSCR arises from loss of function, RET mutations, RET haploinsufficiency or RET polymorphisms and haplotypes of the RET promotor region. MEN2 syndromes result from gene up regulation due to germline activating mutations in the RET proto-oncogene (1:500,000). MTC is mostly associated with variations in the 5 cysteine RET radicals and codon-risk management protocols are of considerable value but not infallible. Oncogenic RET mutations may, however, vary between specific population groups. RET analysis in MEN has revolutionized the management of children of MEN2 and allowed surgical prediction and prophylaxis to take place. We discuss the role of genetic testing and possible guidelines for the management of patients from MTC families. The future appears full of promise and the current evaluation of RET-targeting tyrosine kinase and other inhibitors are of considerable interest in the management of these conditions

Diagnostic dilemmas in abdominal tuberculosis in children.

Abstract The authors review 45 pediatric patients with intra-abdominal tuberculosis (ATB) treated between May 1990 and April 1998. The diagnosis was confirmed histologically or by positive culture for Mycobacterium tuberculosis. Clinical presentation was with an abdominal mass (12), subacute obstruction (11), ascites (5), mass and ascites (4), peritonitis (4), and 9 unusual presentations. Mantoux tests were positive in 68% of patients tested. There were radiologic features suggestive of pulmonary TB in 29 patients (64%); abnormal abdominal radiographs were recorded in 21 (47%). Lymphadenopathy was noted on abdominal ultrasound in 23 of 30 patients (77%) and on computed tomography scan in a further 3 of 8 patients investigated. Ascitic fluid adenosine deaminase (ADA) levels were greater than 30 IU/l in 3 of 4 patients (75%), suggesting ATB. All 28 patients screened for human immunodeficiency virus were negative. A surgical procedure was performed in 39 patients. 29 (74%) had an elective diagnostic laparotomy for tissue diagnosis. One (3.4%) developed a postoperative intra-abdominal abscess. Ten (26%) presented with complications requiring surgical intervention including perforated viscus, segmental bowel resection, strictureplasty, adhesiolysis, or ileostomy. One of the latter died due to sepsis after having complications of persistent intestinal obstruction and cecal perforation. The authors recommend an aggressive approach to patients with suspected ATB in order to obtain an early definitive diagnosis, prevent complications, and reduce morbidity and mortality. They emphasize the importance of tissue diagnosis and confirmation by culture.

Fulminanting necrotising enterocolitis : outcome and prognostic factors

Abstract In order to determine the outcome of infants with fulminant necrotising entercolitis (NEC), the records of 128 surgically-treated neonates were reviewed. Fifty-two were found to have severe, rapid-onset disease. The 30-day survival was determined and correlated with birth weight, gestational age, laboratory and radiological findings, and extent of disease. Seven patients did not respond to resuscitative measures and were treated by percutaneous drainage with a uniformly fatal outcome. For patients who could be made fit for surgery, the only absolute predictor of survival was extent of disease. Pan-necrosis occurred in 19 patients and all of these died. Conversely, patients who had resectable disease had a 30-day survival of 61%. Pan-necrosis could not be determined preoperatively by radiological findings. Patients with severe, rapid-onset NEC and evidence of gangrene who respond to resuscitation should have active surgical management, as approximately one-half of them have resectable disease and a reasonable short-term outcome may be expected. Patients who do not respond to resuscitative measures and those with a surgical finding of pan-necrosis had a uniformly fatal outcome in this study, and if resources are limited, it is reasonable to withdraw active management in this group of patients.

Retrospective Surveillance of Intussusception in South Africa, 1998–2003

BACKGROUND Intussusception is a common gastrointestinal emergency in children and appears to have a somewhat different clinical spectrum in developing countries. Its etiology is still unclear, but a link to infective agents and viruses has been highlighted. This study aimed to assess the clinical spectrum and prevalence of intussusception in children from the diverse South African population. METHODS Retrospective data were obtained from 9 participating pediatric referral units on the occurrence of intussusception in South African children (<14 years old) during a 6-year period (1998-2003). Results were correlated with national population statistics. Intussusception was anatomically classified into ileoileal, ileocolic, and colocolic types. The clinical features, management, outcome, and possible causes were examined. RESULTS We reviewed the occurrence and clinical spectrum of intussusception in 423 children (age, 0-14 years) presenting with acute intussusception to 9 pediatric surgical centers. The mean duration of symptoms was 1.5 days, but a delayed presentation was common (median delay, 2.3 days). Intussusception occurred throughout the year, with a peak in the summer months. The majority of patients (89%) were <2 years old, and 78% presented at age 3-18 months of age. Crude population estimates indicate an occurrence of 1 case per 3123 population <2 years old. Only 11% of patients presented after 2 years of age, and the age at presentation was significantly lower (P < .05) in black African patients. All ethnic groups were affected. In 84% of patients, intussusception occurred at the ileocolic region junction, in 7% it was ileoileal, and in 9% it was colocolic. Colocolic intussusception appeared more common in black African patients, and associated pathologic conditions (polyps and Burkitts lymphoma) occurred mainly in older children. Surgical intervention was required in 81% of patients and involved resection of gangrenous bowel in 40%. CONCLUSION Intussusception appears to be a relatively frequent occurrence in children in South Africa. Although the clinical spectrum appears to vary, there is an apparent link to intestinal infection, which requires further investigation. A collaborative approach is required to ascertain the relationship of intussusception to preventable infections and to improve its diagnosis and management.

Non-familial visceral myopathy: clinical and pathologic features of degenerative leiomyopathy

Abstract Degenerative leiomyopathy (DL) is a distinctive form of acquired degenerative visceral myopathy of uncertain etiology that occurs largely in Africa and results in intestinal pseudo-obstruction (IP). In this review of 39 patients from the Western Cape region of South Africa, the mean age at presentation was 9.5 years (range 6 months to 16 years). Characteristic clinical features included a chronic, insidious history of repeated attacks of abdominal distension, abdominal pain, and vomiting. Marked gaseous distension with atony and IP, especially of the colon, was noted on X-ray films. Megacolon was the most common radiologic feature, but pseudo-obstruction extended proximally into the small intestine in some patients with advanced disease. In the majority of cases the condition was progressive and eventually affected the entire gastrointestinal (GI) tract.

Familial and genetic aspects of neuronal intestinal dysplasia and Hirschsprung's disease

A familial occurrence of Hirschsprungs disease and neuronal intestinal dysplasia (NID) is reported. Familial occurrence of NID in a parent and long-segment Hirschsprungs disease in two children in a family as well as a further report of NID in monozygotic twins is described. The linkage of these neurodevelopmental conditions is explored and a common etiologic mechanism for the two conditions is postulated.