Improvement of pancytopenia and thrombocytopenia with decreasing mosaicism for isochromosome Xp.

We report the unique association of variable constitutional mosaicism 46,X, i(X)(p10)/46,XX with recurrent thrombocytopenia in a child with failure to thrive and apnea in infancy. Her bone marrow had equal distribution of the normal and abnormal cell lines at diagnosis, at nearly 6 years of age. Improvement of her pancytopenia and thrombocytopenia was concurrent with a decreasing level of mosaicism observed in multiple studies over the next 3 years. This suggests that extra copies of genes on the p-arm are inhibitory to blood cell maturation, with long-term selection against the i(Xp)-containing cells.

Down syndrome with low hypodiploidy in precursor B-cell acute lymphoblastic leukemia.

We describe the rare finding of a 33-month-old child neonatally diagnosed with Down syndrome, who presented with pre-B acute lymphoblastic leukemia (ALL) with a pretreatment bone marrow karyotype in which a low hypodiploid cell line (38 chromosomes) was identified in 17/19 cells studied. The abnormal cell line retained the extra constitutional chromosome 21. Hypodiploidy (loss of one or more chromosomes) is seen in approximately 5% of all childhood pre-B ALL cases and in approximately 2.2% cases of individuals with a constitutional trisomy 21. Low hypodiploidy, associated with a high risk of relapse, is rare in pediatric ALL cases in the general population, and, to our knowledge, is previously unreported in patients with trisomy 21.

Mollaret's recurrent aseptic meningitis: relationship to epidermoid cysts. Light microscopic and ultrastructural cytological studies of the cerebrospinal fluid.

Cells, originally called "endothelial" cells, have been described in the cerebrospinal fluid (CSF) of patients developing recurrent aseptic meningitis (Mollaret's meningitis). In an attempt at better establishing their nature, a 6-year-old child was followed for a period of 3 1/2 years. A cytological light microscopic and ultrastructural study was performed on samples of the CSF obtained during 17 attacks. The findings are presented, and the relationship of Mollaret's meningitis to intracranial epidermoid cysts is discussed.

Subependymal giant cell tumor of tuberose sclerosis. A light and ultrastructural study.

In a small number of cases of tuberose sclerosis, tumors develop in the cerebral subependymal region. Their exact nature has been the subject of debate. The cytology, histology and electron microscopy of a tumor which developed in a 16 year old male suffering from tuberose sclerosis are presented and the findings are discussed.

Acute hypoxia-induced alterations of calbindin-D28k immunoreactivity in cerebellar Purkinje cells of the guinea pig fetus at term.

Purkinje cells (PCs) are vulnerable to hypoxic/ischemic insults and rich in calcium and calcium-buffering/sequestering systems, including calcium-binding proteins (CaBPs). Calbindin-D28k is an EF-hand CaBP, which is highly expressed in PCs where it acts primarily as a cellular Ca++ buffer. Elevation of [Ca++] in the cytosol and nuclei of PCs is pivotal in hypoxic/ischemic cell death. We hypothesize that hypoxia results in decreased concentration, or availability of calbindin-D28k in PCs, thereby decreasing their buffering capacity and resulting in increase of intracellular and intranuclear [Ca++]. Cerebellar tissues from normoxic fetuses were compared to fetuses obtained from term pregnant guinea pigs exposed to hypoxia [7% FiO2] for 60 min. The pregnant guinea pigs were either killed upon delivery immediately following hypoxia (Hx0h) or were subsequently allowed to recover for 24 h (Hx24h) or 72 h (Hx72h). Fetal brain hypoxia was documented biochemically by a decrease in brain tissue levels of ATP and phosphocreatine. Compared to normoxic fetuses, there is a predominantly somatodendritic loss or decrease of calbindin-D28k immunohistochemical staining in PCs of Hx0h (p < 0.005), Hx24h (p < 0.05), and Hx72h (p < 0.005) fetuses. Hypoxia-induced alterations of calbindin-D28k immunoreactivity are qualitatively similar at all time points and include a distinctive intranuclear localization in subpopulations of PCs. A similar trend is demonstrated by immunoblotting. Subpopulations of TUNEL+/calbindin-D28k- PCs lacking morphologic features of apoptosis or necrosis are demonstrated in Hx24h and Hx72h fetuses. The present study demonstrates an abrogating effect of perinatal hypoxia on calbindin-D28k immunoreactivity in cerebellar PCs. The perturbation of this Ca++ buffer protein in hypoxia-induced neuronal injury may herald delayed cell death or degeneration.

Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population.

We report the results of a comprehensive and systematic clinical study of 324 patients with hereditary hemorrhagic telangiectasia, selected from a total of 1,270 cases recruited by epidemiological survey. In 94% of the cases, familial occurrence suggested autosomal dominant inheritance; maximum penetrance for at least one manifestation was 97%. Epistaxis was reported by 96% of the patients and, in more than 50%, developed before age 20. Heavy and frequent bleeding occurred mainly in middle-aged patients. Telangiectasia was documented in 74% of cases, half of whom were younger than 30 years. The frequency of involvement of the hands and wrists was 41%, and for the face, 33%. Visceral involvement was present in 25% of patients, with affected lungs and CNS in the young and gastrointestinal tract and liver in older patients. Symptomatic urinary tract involvement was seen in only two/324 patients. Involvement of other internal sites was not observed.

Variable expression of autosomal recessive polycystic kidney disease and congenital hepatic fibrosis within a family.

Blyth and Ockenden [1971] assigned patients with autosomal recessive polycystic kidney disease (ARPCKD) to 4 discrete groups (perinatal, neonatal, infantile, juvenile) on the basis of the age of presentation. They and others speculated that at least 4 genes were responsible for what they considered to be closely related, but different conditions. These views have gained wide but not universal acceptance. Some workers have insisted that the perinatal and neonatal "forms" of ARPCKD differ fundamentally from the juvenile "form." However, others have proposed that ARPCKD-CHF (congenital hepatic fibrosis) and CHF-ARPCKD are manifestations of the same disease with variation of expression in a kindred. We report on a patient who presented at birth (1979) with ARPCKD and respiratory distress. He died at 18 hr. An older sib presented at 16 yr in 1984. She had no symptoms, but her mother wanted reassurance that the daughter did not have a condition similar to that of the deceased sib. Blood pressure was 120/80 mm Hg and there was hepatosplenomegaly. A diagnosis of renal tubular ectasia and CHF was made by ultrasonography, radiologic studies, and a liver biopsy. The evidence from families such as this favors the concept that ARPCKD and CHF presenting as Blyth and Ockenden's perinatal form, and CHF and renal tubular ectasia as their juvenile form, are manifestations of the same genetic disorder, and that the different manifestations are more likely variations in expression than the results of different mutant genes. The manifestations in this family add weight to the growing body of evidence that intrafamilial variability may occur, not only in autosomal dominant conditions, but also in autosomal recessive disorders.

Autosomal dominant inheritance of small kidneys.

We report herein bilateral small kidneys found in a mother and her two sons. This was associated with slowly progressive chronic renal failure. None of the patients had any of the associated clinical manifestations of recognized syndromes in which there is autosomal dominant inheritance of bilateral small kidneys (e.g., branchio-oto-renal syndrome). Nor did they have the clinical symptoms commonly associated with medullary cystic kidney-juvenile nephronophthisis. However, there were some manifestations that have been reported in familial hypoplastic kidneys with glomerular cysts. Without wanting to claim that this is a "new" syndrome, we are, however, unaware of any reports describing a similar kindred. The importance of this report stems mainly from the fact that a woman with mild to moderate stable chronic renal failure associated with, or caused by, bilateral small dysplastic kidneys gave birth to two sons with the same problem.

Truncus arteriosus and other lethal internal anomalies in Goltz syndrome.

An infant girl of 36 weeks gestational age was found to have cardiovascular and other lethal internal anomalies in addition to characteristic external abnormalities of focal dermal hypoplasia (Goltz syndrome). The internal anomalies included truncus arteriosus type II with truncal origin of hypoplastic pulmonary arteries, cardiac ventricular septal defect, severe hypoplasia of lungs and pulmonary veins, massive diaphragmatic hernia, and absence of the right kidney. Such a combination of severe anomalies has not been reported previously in Goltz syndrome.

Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy.

A male infant with glutaric aciduria II secondary to electron transfer flavoprotein: ubiquinone oxidoreductase deficiency is compared to previously reported cases of glutaric aciduria II. A common pattern of anomalies in patients with malformations (8/16) includes macrocephaly, large anterior fontanelle, high forehead, flat nasal bridge, telecanthus, and malformed ears. Abnormalities such as hypotonia, cerebral gliosis, heterotopias, hepatomegaly, hepatic periportal necrosis, polycystic kidneys, and genital defects in glutaric aciduria II are reminiscent of those in Zellweger syndrome, whereas elevations of glutaric, ethylmalonic, adipic, and isovaleric acids are quite distinctive. A unique ultrastructural alteration of the glomerular basement membrane was observed in the proposita. This manifestation may represent an early stage in renal cyst formation and provide a diagnostic criterion for glutaric aciduria II when enzyme studies are unavailable.

Distinctive cytoplasmic surface activity in benign and leukemic bone marrow cells: ultrastructural definition and clinicopathologic correlation.

A distinctive ultrastructural finding, observed in a case of acute lymphoblastic leukemia (ALL) and previously unreported on the surface of bone marrow cells, is described. The alteration is referred to as distinctive cytoplasmic surface activity (DCSA). For further delineation, study of 130 consecutively submitted bone marrow specimens was undertaken. All samples were obtained from children and included diverse myeloid leukemias, acute lymphoblastic leukemia, normal marrows, and abnormal but non-neoplastic conditions. The DCSA was composed of simple and complex interconnected tubular elements in continuity with the cytoplasmic membrane, probably, sharing its glycocalyx. The intensity of the DCSA varied but, its presence was detected in one third of the 130 cases. Except for rare marrows (three cases) with DCSA bearing polymorphs, all positive cells were lymphoid in origin, usually originating from non-B, non-T ALL patients. In very few non-neoplastic cases, DCSA-positive lymphocytes also were found. Review of the literature shed little light on the subject but disclosed rare instances in which DCSA was illustrated in benign as well as malignant lymphoid cells. Based on this information and the observations made throughout the study, it is surmised that DCSA may be the morphologic expression of a cellular function, probably a form of micropinocytosis. Despite its prevalence in ALL cases, it appears to be nondiagnostic and nonspecific to a cell line.

The pathology of fibrosing colonopathy of cystic fibrosis: a study of 12 cases and review of the literature.

The authors studied eight colectomy and eight biopsy specimens from 12 patients with cystic fibrosis who had developed fibrosing colonopathy, a complication observed in patients receiving high-strength enzyme replacement. The colectomies originated from five male and three female patients ranging in age from 18 months to 6 years. Five individuals had localized strictures of the right colon and three had stenosing fibrosis of the entire colon. The affected colon had a cobblestone appearance, submucosal fibrosis, thickening of the muscularis propria and chronic mucosal inflammation in all patients, with active cryptitis in four. Moderate to severe infiltration by eosinophils, with increase in the number of mast cells, and widespread interruption of the muscularis mucosa were present in every case. Four colectomies were preceded by endoscopic biopsies; four patients who have not undergone surgery also underwent biopsy. All the biopsies showed evidence of active or chronic inflammation, and all had increased mucosal eosinophils. Prolonged colonic mucosal contact with either the enzymes and/or the enteric coating itself may lead to mucosal colonic ulceration and inflammation. Topical allergy may then promote the stenosing fibroplasia.

Shock-related injury of pancreatic islets of Langerhans in newborn and young infants.

Variable degrees of injury of the pancreatic islets of Langerhans, with sparing of the acinar pancreas, were observed in three infants (age range, 1 day to 3 months) who died of profound shock. The duration of shock varied from 19 to 48 hours. In two of the infants, the shock stemmed from hypovolemia; in the remaining infant, the shock followed blood loss, sepsis, and heart failure. The islet lesions were devoid of cellular infiltrates, hemorrhage, and fibrin thrombi. Tissue manifestations of shock included acute renal tubular necrosis, massive hepatic centrilobular necrosis, ischemic enteropathy, and "shock" lung. Study of pancreatic sections from 30 children (age range, 13 hours to 15 years) with clinical and/or morphologic evidence of shock showed no additional instances of islet injury. These findings suggest that pancreatic islets in the young may be vulnerable to shock-induced ischemia. Studies are in progress in an animal model to test this hypothesis.

Hyperdiploidy and trisomy 12 in the cystic partially differentiated nephroblastoma.

The karyotype of a cystic partially differentiated nephroblastoma (CPDN) was found to be 51, XY, +7, +8, +12, +13, +17. A review of the literature disclosed three other cytogenetically analyzed CPDNs. As in this case, they were all hyperdiploid. The only chromosomal anomaly common to all four cases was trisomy 12, suggesting this chromosome might have a pathogenetic role. Earlier reports had tentatively attributed this role to chromosome 8.

De novo circumscribed pulmonary lobar cystic lymphatic anomaly in a young boy. A possible sequela of bronchopulmonary dysplasia.

This report describes a massive pulmonary lymphatic cystic anomaly affecting the right lower lobe of a nine-year-old boy. A year earlier, only an ill-defined small infiltrate could be seen in the affected lobe radiologically. The pathogenesis of this highly unusual lesion is discussed, taking into consideration the possible role of three months of mechanical ventilation in the neonatal period.

Trilateral retinoblastoma. Report of two cases.

Two children had bilateral retinoblastoma and a morphologically similar intracranial neoplasm localized to the region of the pineal gland as shown on computed tomography and at postmortem examination. The first child's intracranial malignant neoplasm produced symptoms that indicated its probable presence when the ocular tumors were first diagnosed. With the second child, there was a latent period of more than three years between the diagnosis and initial management of the ocular neoplasms and the onset of symptoms from the pineal tumor. We diagnosed both cases as trilateral retinoblastoma, which in our experience is a relatively frequent cause of mortality in patients with heritable retinoblastoma.

Bednar tumor pattern in recurring giant cell fibroblastoma.

Giant cell fibroblastoma (GCF) and Bednar tumor (BT) have been perceived as two rare, not directly related, soft tissue neoplasms. Recent studies, separately conducted on each process, have presented evidence indicating that, in each instance, the tumor seemed to be related to the dermatofibrosarcoma protuberans. The case being reported provides additional evidence supporting those previous results and, for the first time, documents a direct link between GCF and BT, as seen in this girl who had a vulvar GCF resected at 1-year of age, with recurrence, 1.5 years later, as a mixed BT-GCF.

Rasmussen encephalitis: complementary role of multitechnique neuroimaging.

Rasmussen encephalitis is a chronic, progressive inflammation of the brain of unknown origin. Early diagnosis and treatment with immunoactive agents and/or hemispherectomy are sought to prevent the progressive cognitive decline that accompanies this disease. Combined anatomic and functional neuroimaging may serve to focus the diagnostic workup and to hasten brain biopsy for definitive diagnosis. Two biopsy proved cases of Rasmussen encephalitis are presented. The importance of MR imaging, single-photon emission computed tomography, and proton MR spectroscopy in the workup of this disease is discussed.

A newly recognized cause of wheezing: AIDS-related bronchial leiomyomas.

We present two human immunodeficiency virus-infected children who developed wheezing and radiological evidence of pulmonary air trapping due to intra- and peribronchial leiomyomas. At autopsy, leiomyomas were also found in their spleens, which to our knowledge, has never been reported. The smooth muscle tumors were strongly positive for the Epstein-Barr virus, as demonstrated by in situ hybridization to Epstein-Barr virus-encoded ribonucleic acid, confirming the findings of recent investigators and linking these tumors to the Epstein-Barr virus.