Spinal nerve root ß-APP staining in infants is not a reliable indicator of trauma.

This preliminary communication describes seven babies with ß-amyloid precursor protein (ßAPP) positive axonal swellings in nerve roots at multiple levels of the spinal cord. All seven babies died of natural causes. Two died in utero providing evidence for nerve root injury in the absence of trauma, two died within one day of birth and the possibility of birth related injury has to be considered. Three babies were over one month of age and had no history or pathological evidence of trauma. These findings show that if axonal injury is carefully sought in every infant death, not just in babies where trauma is suspected, it will be found in a proportion of babies dying from natural diseases. While spinal nerve root axonal injury in infants may suggest trauma, it is not, in itself, diagnostic of trauma.

Pseudo-precocious puberty caused by a juvenile granulosa cell tumour secreting androstenedione, inhibin and insulin-like growth factor-I.

We report a female child who presented at age 3.92 years with a 2-year history of consonant pubertal development caused by a large right-sided ovarian juvenile granulosa cell tumour (JGCT). Although JGCTs causing pseudo-precocious puberty have been previously described, they remain rare and endocrine data are often incomplete. In this case the tumour was associated with raised serum oestradiol, androstenedione, inhibin and IGF-I. Histological changes were consistent with JGCT. Immunohistochemical studies revealed positive reactivity to MIC-2, inhibin, melan A, IGF-I and IGFBP-2.

Dural haemorrhage in non-traumatic infant deaths: does it explain the bleeding in 'shaken baby syndrome'?

A histological review of dura mater taken from a post-mortem series of 50 paediatric cases aged up to 5 months revealed fresh bleeding in the dura in 36/50, the bleeding ranging from small perivascular haemorrhages to extensive haemorrhage which had ruptured onto the surface of the dura. Severe hypoxia had been documented clinically in 27 of the 36 cases (75%). In a similar review of three infants presenting with classical 'shaken baby syndrome', intradural haemorrhage was also found, in addition to subdural bleeding, and we believe that our findings may have relevance to the pathogenesis of some infantile subdural haemorrhage. Recent work has shown that, in a proportion of infants with fatal head injury, there is little traumatic brain damage and that the significant finding is craniocervical injury, which causes respiratory abnormalities, severe global hypoxia and brain swelling, with raised intracranial pressure. We propose that, in such infants, a combination of severe hypoxia, brain swelling and raised central venous pressure causes blood to leak from intracranial veins into the subdural space, and that the cause of the subdural bleeding in some cases of infant head injury is therefore not traumatic rupture of bridging veins, but a phenomenon of immaturity. Hypoxia with brain swelling would also account for retinal haemorrhages, and so provide a unified hypothesis for the clinical and neuropathological findings in cases of infant head injury, without impact or considerable force being necessary.

Lethal acrofacial dysostosis, pre- and post-axial defects of the hands, and bilateral renal agenesis.

We report a female fetus with a previously undescribed form of mandibulofacial dysostosis with mesomelic limb abnormalities, pre- and post-axial defects of the hands, bilateral renal agenesis, bicornuate uterus, and a single umbilical artery.

Omenn's syndrome: differential diagnosis in infants with erythroderma and immunodeficiency.

The clinical differential diagnosis of erythroderma plus immunodeficiency and failure to thrive in neonates includes graft-versus-host-disease (GVHD), Omenn's syndrome (OS), and Netherton's syndrome (NS). In addition to immunological investigations, skin biopsy is an important part of the diagnostic work-up. We reviewed biopsies from 25 patients that were retrieved from the archives of the Department of Histopathology at Great Ormond Street, of which 9 were OS, 11 were GVHD, and 5 were NS. Five patients had two biopsy specimens. Both OS and GVHD show dyskeratosis and basal vacuolation. OS always shows acanthosis and almost always parakeratosis. GVHD shows a flat epidermis and rarely parakeratosis. OS and GVHD can be distinguished after immunohistochemistry for LCA and CD68 by the relative proportions of lymphocytes and macrophages in the dermal infiltrate (predominantly lymphocytes in OS, relatively more macrophages in GVHD). Skin biopsy diagnosis of OS is difficult before 6 weeks of age because the features are poorly developed. NS can be distinguished by psoriasiform acanthosis, thickening of the basement membrane, prominent dermal blood vessels, absence of dyskeratosis, and basal layer vacuolation, and a dermal infiltrate in which lymphocytes and macrophages are equally represented. Thus, the main difference between GVHD and OS is in the proportion of lymphocytes and macrophages in the infiltrate on immunohistochemical staining for LCA and CD68, while OS and NS may be distinguished on H&E morphology alone.

Congenital gastrointestinal stromal tumour is morphologically indistinguishable from the adult form, but does not express CD117 and carries a favourable prognosis.

AIMS: The histological and immunohistochemical features of a congenital stromal tumour of the jejunum are compared with those of adult gastrointestinal stromal tumours (GIST). The literature concerning the diagnosis and prognosis of congenital small intestinal stromal tumours is reviewed. METHODS AND RESULTS: A term female infant presented with intestinal obstruction, from birth. Histology of a 15-mm jejunal nodule showed a predominantly spindle-cell tumour with epithelioid areas. There was a low mitotic count and mild nuclear pleomorphism, extensive necrosis and haemorrhage, and focal calcification. Immunohistochemically, tumour cells stained for muscle specific actin and vimentin. Staining for CD117 (c-kit), S100, desmin and CD34 was negative. The features were compared to those of seven adult cases: no morphological feature was specific to the congenital tumour, which was smaller than the adult cases. There were no ultrastructural features specific for a particular line of differentiation. Immunohistochemical staining patterns were similar, except for CD117, which was strongly positive in all adult tumours, but negative in the congenital tumour. CONCLUSIONS: This congenital jejunal stromal tumour morphologically resembled adult GIST, but lack of c-kit expression suggests that it is nosologically distinct. Despite the presence of histological features which would cause the tumour to be categorized as malignant in an adult, it is apparent from previous reports of congenital small intestinal stromal tumours that the prognosis is favourable.

Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy.

Hyperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder that occurs in approximately 1 of 50,000 live births. Histologically, pancreases from HI patients can be divided into 2 major groups. In the first, diffuse HI, beta-cell distribution is similar to that seen in normal neonatal pancreas, whereas in the second, focal HI, there is a discrete region of beta-cell adenomatous hyperplasia. In most patients, the clinical course of the disease suggests a slow progressive loss of beta-cell function. Using double immunostaining, we examined the proportion of beta-cells undergoing proliferation and apoptosis during the development of the normal human pancreas and in pancreases from diffuse and focal HI patients. In the control samples, our findings show a progressive decrease in beta-cell proliferation from 3.2 +/- 0.5% between 17 and 32 weeks of gestation to 0.13 +/- 0.08% after 6 months of age. In contrast, frequency of apoptosis is low (0.6 +/- 0.2%) in weeks 17-32 of gestation, elevated (1.3 +/- 0.3% ) during the perinatal period, and again low (0.08 +/- 0.3%) after 6 months of age. HI beta-cells showed an increased frequency of proliferation, with focal lesions showing particularly high levels. Similarly, the proportion of apoptotic cells was increased in HI, although this reached statistical significance only after 3 months of age. In conclusion, we demonstrated that islet remodeling normally seen in the neonatal period may be primarily due to a wave of beta-cell apoptosis that occurs at that time. In HI, our findings of persistently increased beta-cell proliferation and apoptosis provide a possible mechanism to explain the histologic picture seen in diffuse disease. The slow progressive decrease in insulin secretion seen clinically in these patients suggests that the net effect of these phenomena may be loss of beta-cell mass.

Androgen secreting adrenocortical tumours.

BACKGROUND: Androgen secreting adrenocortical tumours are rare in children and the determination of their malignant potential can be difficult. OBJECTIVES: To assess the presentation, histology, and clinical behaviour of these tumours. SETTING: Two tertiary referral centres. STUDY DESIGN: Retrospective analysis of children diagnosed with an androgen secreting adrenocortical tumour between 1976 and 1996. PATIENTS: Twenty three girls and seven boys aged 0-14 years. RESULTS: Pubic hair was observed in all children, clitoromegaly or growth of the phallus in 23 children, acceleration of linear growth in 22 children, and advanced bone age (> 1.5 years) in 18 children. Hypersecretion of androgens was detected by assessment of serum androgen concentrations alone in four patients and by 24 hour urine steroid excretion profiles in 22 patients. All 16 tumours measuring < 5 cm in diameter were benign. Of the tumours measuring 5-9 cm, three were malignant and seven were benign, whereas all four tumours > 10 cm were malignant. Histological slides were available for reassessment in 25 children. Although mitoses and necrosis were more characteristic of tumours with malignant behaviour, no exclusive histological features of malignancy were seen. CONCLUSION: Histological criteria for malignancy are not reliable, whereas tumour size is important in assessing malignant potential.

Intracardiac epithelial cyst associated with esophageal atresia.

We describe an intracardiac epithelial cyst in association with esophageal atresia. The case is unusual in that the cyst was symptomatic and ultimately fatal. In addition, there was no other cardiac anomaly, although a range of extrathoracic malformations was present. There are three types of intracardiac epithelial cysts: congenital polycystic tumor of the atrioventricular node, a cyst as part of a teratoma, and, as in this case, a gross cyst. All of them are very rare. The association of a cardiac cyst and esophageal atresia in our case supports the theory that intracardiac cysts are derived from misplaced foregut.

Precocious pseudopuberty due to a granulosa cell tumour in a seven-month-old female.

We describe a juvenile granulosa cell tumour resulting in pseudopuberty in an infant female. The progression of the clinical signs of puberty were non-consonant and the diagnosis was complicated by marginally elevated serum alpha-fetoprotein levels. The histological appearance of the resected tumour and binding of MIC2 antibody to tumour cells confirmed the diagnosis.

The significance of hepatic lesions associated with small adrenocortical tumours in childhood.

Small adrenocortical tumours in children are rarely associated with hepatic pathology. We present two case reports of children with hepatic pathology associated with small adrenal tumours on computed tomography. One child had multiple granulomatous lesions due to toxocariasis and the other had focal nodular hyperplasia. Hepatic lesions seen in association with small adrenal tumours in childhood may represent coincidental rather than metastatic pathology.

Primitive neuroectodermal tumor of the kidney confirmed by fluorescence in situ hybridization.

Peripheral primitive neuroectodermal tumors (PNETs) are rare lesions that form part of the Ewing family of tumors, which includes osseous and extraosseous Ewing's sarcoma and Askins tumor of the thorax. All are characterized by translocations involving the EWS gene at 22q12, usually the translocation t(11;22)(q24;12). PNETs usually occur in soft tissues but occasionally arise within a visceral organ. We describe a PNET of the kidney that showed characteristic microscopic and immunohistochemical appearances of a small, round, dark blue cell tumor with focal rosette formation and strong membrane positivity for the MIC2 gene product. Interphase fluorescence in situ hybridization on touch imprints prepared from frozen tissue using cosmid probes flanking the EWS gene at 22q12 and the FLI1 gene at 11q24 indicated the presence of t(11; = +22)(q24; = +q12), confirming the diagnosis of PNET. This is the first reported PNET of the kidney supported by cytogenetic analysis. We also review the literature on this fascinating tumor in this unusual location.

Primary hepatic malignant tumor with rhabdoid features. A histological, immunocytochemical, and electron microscopic study of four cases and a review of the literature.

Malignant tumors of the liver with rhabdoid features (MTR) are uncommon: Only 14 previous cases are reported in the literature. These tumors are characterised morphologically by sheets of large polygonal cells with abundant eosinophilic cytoplasm containing a periodic acid Schiff's-positive hyaline globular inclusion and vesicular nuclei with a central prominent nucleolus. Immunohistochemically, the inclusions at least show positivity for vimentin and epithelial markers and sometimes for other antigens. Ultrastructurally, the inclusions are composed of whorled intermediate filaments. Despite the superficial resemblance to cells of muscle origin implied in the term rhabdoid, there is no immunohistochemical or ultrastructural evidence to support such a derivation. We describe four additional children with tumors of this type, in three of whom tumor cells showed focal membrane positivity for MIC-2 on immunostaining. Its expression in an hepatic MTR may indicate neuroepithelial differentiation. Hepatic MTR should be considered in the differential diagnosis of an undifferentiated primary liver tumor in an infant in whom the alpha-fetoprotein concentration is normal or only slightly elevated for age.

Inherited ichthyoses: a review of the histology of the skin.

The histology of skin biopsies from 46 cases of different forms of congenital ichthyosis was reviewed. Sections were examined for hyperkeratosis, follicular keratosis, appearance of the granular layer, epidermal thickness, tonofilament clumps, epidermal vacuolation, spongiosis, bullae and dyskeratosis, appearance of the basal layer, inflammation, mitoses, and adnexae. A detailed description of the histological features of each type of ichtnyosis studied is presented. Some ichthyoses can be recognized on routine hematoxylin and eosin staining (bullous ichthyosiform erythroderma, Netherton's syndrome, and neutral lipid storage disease); some forms require frozen sections to demonstrate fat (neutral lipid storage disease) or enzyme activity (Sjögren-Larsson syndrome). Protein electrophoresis and enzymology are necessary for X-linked recessive ichthyosis. A close liaison with the clinicians is essential for the diagnosis of all types of ichthyosis, and combined studies including routine histopathology, electron microscopy, and frozen sections may be required for the diagnosis.

Pathology of the liver in leukaemia and lymphoma. A study of 110 autopsies.

Histopathological findings in the liver in a series of autopsies on 110 patients suffering from leukaemia or lymphoma were reviewed. No treatment had been given to 23 patients, 50 had received chemotherapy alone, 23 chemo- and radiotherapy and 14 underwent bone marrow transplantation. The 23 untreated patients showed neoplastic infiltration in 10 (44%) and fibrosis in 16 cases (70%). The 14 bone marrow recipients showed mainly acute necrosis, zonal in six (43%) and focal in one (7%), and cholestasis in five (36%), together with marked siderosis in 11 (79%). Patients receiving chemotherapy or chemo-/radiotherapy showed similar changes consisting of neoplastic infiltration in 14 (28%) and in five (22%) cases respectively, and fibrosis in 31 (62%) and 17 (74%) cases respectively. Steatosis was seen in 70% of cases in the chemo-/radiotherapy group and in 50% of cases in the other groups. Infections were seen in all groups, particularly in the chemotherapy group (four fungal and two bacterial including one tuberculosis) and in the chemo-/radiotherapy group (one fungal and one bacterial). Cytomegalovirus infection was seen only in the bone marrow transplant group.

Bovine colostrum immunoglobulin concentrate for cryptosporidiosis in AIDS.

Lactobin-R is a commercial hyperimmune bovine colostrum with potent anticryptosporidial activity. It was administered to a 4 year old child with AIDS and severe diarrhoea associated with cryptosporidiosis. There was significant clinical improvement in the diarrhoea and permanent elimination of the parasite from the gut as assessed through serial jejunal biopsy and stool specimens.