Dermatoglyphics in sudden infant death syndrome.

An analysis of digital and palmar dermatoglyphic patterns was conducted in 173 victims of the sudden infant death syndrome (SIDS). The results expose four dermatoglyphic regions with pattern frequencies differing from those in a control population. These are an excess of Sydney creases, hypothenar patterns, open fields (with fewer vestiges) in interdigital region IV, and arches on all digits (females only). These findings indicate a genetic or early intrauterine environmental influence in SIDS infants. An increased incidence of dysmorphism and anomalies including recognition of specific syndromes support this contention. One could speculate that these dermatoglyphic deviations reflect specific genotypes and/or phenotypes particularly vulnerable to postnatal challenges. Differences in multiple dermatoglyphic categories support the concept of heterogeneity of the SIDS population and multicausality of SIDS.

Down syndrome: patterns of disturbed lung growth.

Abnormal pulmonary development characterized by decreased alveolar complexity has been previously reported in patients with Down syndrome. We investigated the state of pulmonary development and found several undescribed patterns of disturbed lung growth. The axial branches of intrasegmental airways were counted in 13 Down syndrome patients; in nine, airway generation was reduced by 25% or more of the predicted number. The radial alveolar counts were evaluated in 11 lungs: five were 143% to 162% above expected (four to above adult values), five were as expected, and one was below expected (82%). No correlation was found between airway number and radial alveolar count. Our finding of the reduction in airway branching in the lungs of patients with Down syndrome suggests interference with development before birth. Disturbances in alveolar multiplication are also found.

Improved survival for children with anaplastic Wilms' tumors.

Combined modality treatment has resulted in cure rates of approximately 80% for children with Wilms' tumor. According to the National Wilms' Tumor Studies (NWTS), a group of patients with histologic features of anaplasia or sarcomatous Wilms' tumors (malignant rhabdoid tumors and clear cell sarcomas) were less responsive to vincristine and actinomycin. The survival rate of patients in this group with unfavorable histologic conditions was 54% compared with 90% for those with favorable histologic conditions. We have reviewed 80 consecutive cases of Wilms' tumor treated with a minimum follow-up interval of 5 years. Two pathologists independently reviewed all histologic specimens that were initially classified as having unfavorable histologic conditions and specimens from children with favorable histologic conditions who subsequently relapsed. One of 13 children with favorable histologic conditions had recurrent disease that was found to have unfavorable histologic conditions on rereview. All five patients with sarcomatous Wilms' tumor had a rapidly progressive course. Treatment of eight children with anaplastic Wilms' tumor with vincristine, actinomycin, cyclophosphamide, and abdominal radiation resulted in good disease-free and overall survival rates (5-year survival rate, 87.5%) that were not significantly different from children with tumors having favorable histologic conditions (5-year survival rate, 94%). All children with sarcomatous histologic conditions, however, did not to respond.

Osteosarcoma in young children.

The clinicopathologic features of osteosarcoma in 12 children younger than 16 years of age treated at The Children's Hospital and Dana-Farber Cancer Institute, Boston, during a 70-year time period are presented. Only one of six children treated before 1972 is a long-term survivor. Four of six children (67%) treated after 1972 are disease-free with an average follow-up of 8.8 years. The year 1972 marked the onset of use of effective chemotherapy in osteosarcoma, namely, high-dose methotrexate and leucovorin rescue. It would appear that the pathologic features and behavior of osteosarcoma in young children is similar to that of osteosarcoma in older children and adolescents. A combination of complete (wide) surgical resection or amputation and aggressive chemotherapy offers the best chance of long-term survival.

Delayed central nervous system myelination in the sudden infant death syndrome.

This study was designed to assess whether development of the central nervous system (CNS) is delayed in victims of the sudden infant death syndrome (SIDS). We selected the parameter of myelination because it is a continuously changing and readily accessible marker of CNS development in the SIDS age-range. We assessed myelination blindly in 61 SIDS and 89 autopsy controls. In 62 sites the degree of myelination was visually graded in myelin-stained histological sections on an ordinal scale of 0-4 using the inferior cerebellar peduncle as an internal standard of degree 3. Cases were stratified by postconceptional age at death and SIDS and controls were compared with respect to myelin degree at each site. Significantly delayed myelination (p less than 0.05) occurred in the SIDS group in 25 of the 62 sites examined. Hypomyelination affected fiber systems in which myelination is initiated before or after birth and which myelinate with different tempos and preferentially affect pyramidal and cerebellar (somatomotor) and prefrontal-temporal-limbic (visceromotor) systems. Hypomyelination was not associated with individual clinicopathologic variables in the SIDS group. Somatic growth and brain weight were significantly greater in SIDS than controls. Therefore, we suggest that SIDS is associated with a developmental CNS disorder. Although delayed CNS myelination most likely shares a common antecedent with sudden death and is not its cause, the role of somato- and viscero-motor systems in central cardiorespiratory control and arousal warrants further analysis in SIDS.

Bone sarcomas as second malignant neoplasms following childhood cancer.

This study explores the relationship between histologic variants of bone sarcomas and previous therapy in patients in whom an unrelated malignant neoplasm had been diagnosed during childhood. Sarcomas of bone were the most common second malignant neoplasm (SMN) reported to the Late Effects Study Group, a 13-institution consortium consisting of pediatric oncology centers from western Europe, Canada, and the United States. The authors attempted to relate the histologic subtypes of the 91 bone tumors to clinical factors such as previous therapy and genetic predisposition because morphologic variants have been shown to have biologic significance in other tumors and may have etiologic import. The literature concerning the subtypes of bone tumors, clinical and experimental, is also reviewed. The authors also investigated the effect of several factors on the time interval from the first diagnosis to the SMN (i.e., the bone sarcoma). Anthracyclines significantly shortened the interval by about 3 years. The primary diagnosis also significantly affected the interval, with leukemia/lymphomas having the shortest interval and retinoblastoma the longest. The authors could not demonstrate any significant relationship between morphologic characteristics of the osteosarcoma and predisposing conditions. However, lesions diagnosed as chondrosarcoma and malignant fibrous histiocytoma occurred almost exclusively in patients who had received radiation therapy to the site in which the SMN developed.

Flow cytometric evaluation of multicystic dysplastic kidneys.

The most appropriate management of the multicystic dysplastic kidney remains controversial. At issue is the long-term risk of the development of malignancy in the multicystic dysplastic kidney. The association between renal dysplasia and neoplasia has not been confirmed, with only 6 cases of malignancy reported. Nephroblastomatosis, a probable precursor of Wilms tumor, has been found in 5 to 7% of the cases of multicystic dysplastic kidney when specifically sought. In an attempt to determine whether a relationship exists between renal dysplasia and neoplasia in terms of abnormalities of cellular deoxyribonucleic acid content we performed flow cytometric evaluation on 30 formalin fixed, paraffin embedded archival specimens of multicystic dysplastic kidneys. None of the kidneys had evidence of malignancy. Nuclear deoxyribonucleic acid ploidy studies were performed on single dissociated nuclei prepared by the technique of McLemore and associates and stained with propidium iodide. All specimens demonstrated a diploid pattern of deoxyribonucleic acid, including 3 specimens with nephroblastomatosis or extensive papillary growth, and no specimen demonstrated a tetraploid or aneuploid pattern. The mean G0/G1 fraction was 85.94% (standard deviation 4.59) and the mean S/G2/M fraction was 12.54% (standard deviation 4.72). These findings do not support or negate the potential for neoplasm associated with multicystic dysplastic kidney, since a diploid deoxyribonucleic acid pattern does not eliminate the possibility of the future development of malignancy.

myc gene amplification and expression in primary human neuroblastoma.

Although N-myc amplification in neuroblastomas correlates with poor prognosis, not all neuroblastomas which fail to respond to therapy have N-myc amplification. To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-myc, c-myc and L-myc and 26 were studied for transcription of these oncogenes. N-myc amplification was found in 6 of 45 tumors; no tumor had amplification of c-myc or L-myc. Transcription of both N-myc and c-myc occurred in 21 of 26 neuroblastomas. No tumor without N-myc amplification had a level of N-myc expression near that of a tumor or cell line with amplification. One tumor with N-myc amplification was the only specimen with N-myc but not c-myc expression. Five samples had c-myc but not N-myc expression; all had histological features of ganglioneuroma. DNA index did not correlate with myc gene amplification or expression. It is concluded that N-myc and c-myc are commonly expressed in primary untreated neuroblastomas, but in the absence of N-myc amplification, expression of these genes does not appear to correlate with disease progression.

Radiologic and pathologic abnormalities of the trachea in older patients with cystic fibrosis.

The possibility of tracheal enlargement in older patients with cystic fibrosis was investigated by examining chest radiographs of 42 living adults (age range, 30-45 years) who had the disease and by performing postmortem studies (anatomic and histologic) on the tracheas of older adolescents and young adults (age range, 15-33 years) who died with the disease. Anteroposterior tracheal diameters were enlarged in 41 of the living adults. The average diameter was 1.3 +/- 0.9 SD standard deviations above the mean for normal subjects. These increases did not correlate with severity of pulmonary disease as judged radiographically. Enlargement seemed to have developed slowly, over many years or decades. A few tracheas were grossly irregular in outline. One patient had a severely increased transverse diameter of 4.7 standard deviations above the normal mean. The average transverse diameter was 0.3 +/- 1.1 SD standard deviations above the normal mean. The tracheas of adults and older adolescents who had died with cystic fibrosis were abnormally flaccid. Some collapsed suddenly during deflation. Microscopic examination showed instances of severe inflammation, focal epithelial metaplasia, hypertrophy and hyperplasia of the mucous glands, degenerative changes in the muscle of the pars membranacea, and death of cartilage cells. The structural changes shown histologically and the many decades of frequent, vigorous coughing may be important in the enlargement of these tracheas and their flaccidity.

Pneumatosis intestinalis in cystic fibrosis.

We retrospectively reviewed the clinical and radiographic findings in patients with pneumatosis intestinalis (PI), who were identified among 441 patients with cystic fibrosis. Since 1944, the age at onset and the incidence of PI have increased. Pneumomediastinum, pneumothorax, or pulmonary interstitial emphysema was found in 95% of patients with PI compared with 62% of patients without PI. The type, distribution, and severity of PI often changed with time. PI is correlated with the development of obstructive pulmonary disease, which facilitates air dissection into interstitial spaces. Dissection of air is often clinically silent and tends to be self-perpetuating.

Nonexpression of cartilage type II collagen in a case of Langer-Saldino achondrogenesis.

A lethal short-limbed dwarfism was diagnosed at autopsy as the Langer-Saldino variant of achondrogenesis by radiological, histological, and gross pathological criteria. Cartilage was obtained for biochemical and ultrastructural analyses from the ends of long bones, from ribs and from a scapula of the newborn infant. At all sites, it had an abnormal gelatinous texture and translucent appearance. Biochemical analyses of the cartilages to identify pepsin-solubilized collagen alpha-chains and collagen-specific CNBr-peptides failed to detect type II collagen at any site where it would normally be the main constituent. Instead, type I was the predominant collagen present. However, three cartilage-specific minor collagen chains identified as 1 alpha, 2 alpha, and 3 alpha chains by their electrophoretic mobility were present at about 10% of the total collagen. Cartilage-specific proteoglycans also appeared to be abundant in the tissue judging by its high hexosamine content and high ratio of galactosamine to glucosamine. The findings indicate that a chondrocyte phenotype had differentiated but without the expression of type II collagen. In addition to the skeletal abnormalities, the severe pulmonary hypoplasia was also felt to be directly related to the underlying pathology in collagen expression. The term chondrogenesis imperfecta rather than achondrogenesis should be considered a more accurate description of this and related conditions.

An hepatic metabolic profile in sudden infant death (SIDS).

Levels of 18 enzymes and metabolites were measured in liver obtained at autopsy from 41 infants, 28 of whom were found unexpectedly dead at home. Four infants had meningitis, 11 had pathologic findings not clearly sufficient to explain death (SUD), and 13 were considered totally unexplained pathologically (SIDS). The possible contributions of postmortem interval, age and diet to the results are reviewed. No characteristic metabolic profile was recognized amongst SUD and SIDS groups. It is speculated that the amount of glycogen found in liver may provide insight into premortal events and reflect the rapidity of the death mechanism. Five individuals (20%) were suspected of having major metabolic abnormality including glycogenosis (1), urea cycle defect (1), and possibly abnormal levels of carnitine palmityl transferase (3).

Phosphoenolpyruvate carboxykinase activity in human liver.

The activity of phosphoenolpyruvate carboxykinase (EC 4.1.1.32) (PEPCK), a rate-limiting gluconeogenic enzyme, was found decreased by others in genetically determined disorders and in Sudden Infant Death Syndrome (SIDS). To understand these findings, we made a systematic study of normal human hepatic PEPCK activities in specimens obtained under various conditions from patients not suspected of having SIDS. PEPCK was assayed by the method of Ballard and Hanson [J. Biol. Chem., 244 (1969) 5625] and activity reported as units (1 mumol/min) per gram protein. Intra-assay precision was 4.1% (n = 1094); inter-assay precision using the same homogenate was 10.4% (n = 51); and inter-assay precision using different homogenates of the same tissue specimen was 16.3% (n = 17). The assay was linear with time and enzyme concentration for at least 60 min up to 1.3 mU/assay and for at least 5 min up to 20 mU/assay. Biopsy specimens had significantly (P = 0.015) higher PEPCK activity, 12.60 +/- 3.01 U/g (range 3.5-10.4, n = 9) compared to specimens obtained at autopsy, 3.20 +/- 0.45 U/g (range 0-8.6, n = 33). Specific activity was not significantly correlated with the patient's age, fresh vs. frozen tissue, postmortem intervals up to 68 h, or length of storage at -70 degrees C up to 21 years. One patient had activity at autopsy (tissue obtained less than 2 h postmortem) 26% less than was observed in his biopsy specimen. Autopsy samples separated by differential centrifugation into mitochondrial and cytosolic fractions and checked with marker enzymes ornithine transcarbamylase (mitochondrial) and arginase (cytosolic) had considerable cross-contamination between the two fractions in fresh and frozen specimens.

Adamantinoma of the tibia. An ultrastructural and immunohistochemical study.

The light microscopic, ultrastructural, and immunohistochemical characteristics of two tibial adamantinomas are presented. The immunohistochemical studies utilized specific antibodies against Factor VIII-related antigen and keratin protein, considered as markers for endothelial and epithelial cells, respectively. These revealed positive staining for keratin in the tumor cells of both cases, whereas Factor VIII was not found in either. Ultrastructurally, both tumors had tonofilaments, desmosomes, gap junctions, microvillous-like projections, and basement membranes. Patient 1 had disease that was histologically of the classic spindle cell type; the disease of Patient 2 was atypical and closely resembled an epithelioid angiosarcoma. Immunohistochemical and ultrastructural findings in each case indicate an epithelial component in tibial adamantinoma.

Pulmonary vascular disease in fatal meconium aspiration.

Although not proved, it is generally accepted that pulmonary vasospasm is responsible for the persistent pulmonary hypertension frequently associated with meconium aspiration. We have studied the pulmonary vasculature in 11 consecutive infants with fatal meconium aspiration, applying morphometric techniques to pulmonary arteries distended with barium gelatin before fixation. In 10 of the 11 infants, persistent pulmonary hypertension was evident clinically, with right-to-left shunting through the foramen ovale or ductus arteriosus. In all but one, severe structural abnormal muscularization of the smallest intra-acinar arteries was present. These changes must have developed before birth. In only one infant was the structure of the intra-acinar precapillary arteries virtually normal, as would be expected if vasospasm alone had caused the hypertension. The persistent pulmonary hypertension associated with fatal meconium aspiration may be the result of a structurally abnormal pulmonary microcirculation.