Dimitris P. Agamanolis

Tumors of skeletal muscle

The most common tumors arising in muscle are soft tissue sarcomas, fibromatoses, and hemangiomas. Rhabdomyosarcoma is primarily a tumor of childhood and adolescence and arises most commonly in extramuscular sites. Most intramuscular rhabdomyosarcomas are alveolar. Increased diagnostic accuracy and the recognition of malignant fibrous histiocytoma have changed understanding of adult, intramuscular, pleomorphic rhabdomyosarcoma. Immunohistochemistry is playing an increasingly important role in the diagnosis of rhabdomyosarcoma, and the correlation between the histologic features and clinical behavior of rhabdomyosarcoma is under investigation. Because of their diversity and overlapping histologic features, muscle tumors are a challenge for the pathologist and require intensive study by current techniques.

Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke

We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud’s phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-α found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411–2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.

Slipped capital femoral epiphysis: a pathological study. I. A light microscopic and histochemical study of 21 cases.

Summary Core biopsy specimens of slipped proximal femoral epiphyseal growth plates and of normal controls were examined by light microscopy and histochemistry. Slipped growth plates showed diminished cellularity with an overall excess of matrix as well as severe disorientation and misalignment of chondrocytes. Decrease in number of argyrophilic fibers in the longitudinal septa suggested deficiency in collagen. Histochemical staining of slipped plates did not deviate from normal except in severely deformed areas. Anatomic and histochemical observations did not conclusively support or exclude biochemical or biomechanical factors in the etiology of epiphyseal slipping.

Histologic Analysis of Placental Tissue in First Trimester Abortions

The value of histologic evaluation in the analysis of material from first trimester abortions is not completely defined. We prospectively analyzed placenta and decidua from 75 first trimester, spontaneous abortions to ascertain if morphologic features were predictive of karyotype. The histologic features analyzed included hydropic villus change, villus fibrosis, villus scalloping with trophoblastic invaginations, atypical stromal cells, aggregates of lymphocytes in placenta or decidua, and acute inflammation of placenta or decidua. Normal karyotypes were observed in 44 cases and abnormal karyotypes were demonstrated in 31. The presence of villus scalloping with trophoblastic invagination was significantly associated with abnormal karyotypes, particularly triploidy, and the demonstration of acute inflammation was seen significantly more often in cases with normal karyotypes. We conclude that histology can provide only a suggestion as to the likelihood of an abnormal karyotype; the findings are not specific enough to obviate the need for karyotyping in the individual case.

Exome sequencing identifies a novel EP300 frame shift mutation in a patient with features that overlap Cornelia de Lange syndrome.

Rubinstein–Taybi syndrome (RTS) and Cornelia de Lange syndrome (CdLS) are genetically heterogeneous multiple anomalies syndromes, each having a distinctive facial gestalt. Two genes (CREBBP and EP300) are known to cause RTS, and five (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) have been associated with CdLS. A diagnosis of RTS or CdLS is molecularly confirmed in only 65% of clinically identified cases, suggesting that additional causative genes exist for both conditions. In addition, although EP300 and CREBBP encode homologous proteins and perform similar functions, only eight EP300 positive RTS patients have been reported, suggesting that patients with EP300 mutations might be escaping clinical recognition. We report on a child with multiple congenital abnormalities and intellectual disability whose facial features and complex phenotype resemble CdLS. However, no mutations in CdLS‐related genes were identified. Rather, a novel EP300 mutation was found on whole exome sequencing. Possible links between EP300 and genes causing CdLS are evident in the literature. Both EP300 and HDAC8 are involved in the regulation of TP53 transcriptional activity. In addition, p300 and other chromatin associated proteins, including NIPBL, SMCA1, and SMC3, have been found at enhancer regions in different cell types. It is therefore possible that EP300 and CdLS‐related genes are involved in additional shared pathways, producing overlapping phenotypes. As whole exome sequencing becomes more widely utilized, the diverse phenotypes associated with EP300 mutations should be better understood. In the meantime, testing for EP300 mutations in those with features of CdLS may be warranted.

The neuropathology of glycine encephalopathy A report of five cases with immunohistochemical and ultrastructural observations

We studied the spongy myelinopathy of glycine encephalopathy in five patients by using specific antisera. The walls of the vacuoles were stained with the myelin basic protein but not with the myelin associated glycoprotein or the glial fibrillary acidic protein immunostains. The pattern suggested that the vacuoles originated in compact myelin and not from the adaxonal portion of the sheath or from glial processes. Ultrastructural study revealed myelin vacuoles resulting from intraperiod splitting, and there were unusual intranuclear and cytoplasmic inclusions in skeletal muscle in two cases. In addition to the action of glycine as an inhibitory neurotransmitter, structural alterations of myelin may be important in the pathogenesis of the neurologic disorder of glycine encephalopathy.

Lipoprotein disorder, cirrhosis, and olivopontocerebellar degeneration in two siblings

Two siblings had olivopontocerebellar degeneration, failure to thrive, hepatic fatty change and cirrhosis, and a dyslipoproteinemia characterized by low cholesterol and elevated triglycerides. This condition was distinct from other cerebellar atrophies and ataxias and was not due to malabsorption or malnutrition. Cerebellar degeneration progressed rapidly during the first year of life, and both children died from intercurrent infections and surgical complications at 11 and 17 months. Stereotyped clinical and pathologic findings in the two patients suggest a previously unreported genetic metabolic disorder affecting the liver and the CNS.

Slipped capital femoral epiphysis: a pathological study. II: An ultrastructural study of 23 cases

Summary Twenty-three core biopsy specimens from patients with slipped capital femoral epiphysis and 11 control growth plates were studied by electron microscopy. Block staining with toluidine blue for demonstration of proteoglycans at the ultrastructural level was also used. The proliferative and hypertrophic zones of slipped growth plates showed diminished cellularity and marked distortion of the architecture with disarray of the cartilage columns. There was a deficiency and abnormality in the supporting collagenous framework of slipped plates. Chondrocyte degeneration and death were seen at all levels of the proliferative and hypertrophic zones, suggesting a disturbance in the life cycle of chondrocytes. The significance of these findings and their relationship to mechanistic, endocrine, and other proposed etiologies of epiphyseal slipping is discussed.

Neonatal glycine encephalopathy: Biochemical and neuropathologic findings

A patient with neonatal glycine encephalopathy who had severe neurologic retardation, spasticity, and seizures died at 17 years of age. Glycine concentration was markedly elevated in brain tissue, especially in the cerebellum. Neuropathologic study revealed spongy myelinopathy throughout the central nervous system and calcium oxalate crystals in the cerebellum, which are probably derived from degradation of glycine. Myelinopathy appeared to be static compared to neonatal patients. The neurologic manifestations of neonatal glycine encephalopathy are probably due to neurotransmitter abnormalities, not to myelin damage.

Prenatal diagnosis of tetralogy of Fallot with obstructed supracardiac totally anomalous pulmonary venous connection

We describe our experience with prenatal diagnosis of tetralogy of Fallot with supracardiac totally anomalous pulmonary venous connection. We also suspected obstruction in the ascending vertical vein as it crossed the right bronchus and coursed superiorly to join the right superior caval vein. This finding was confirmed on postnatal echocardiography, and at autopsy.