Biomedical subjects
A S Knisely
Publications and source records attributed to A S Knisely.
Cytomegalovirus infection, fetal liver disease, and neonatal hemochromatosis.
Neonatal hemochromatosis is an uncommon disorder, clinicopathologically defined by severe and generally fatal liver disease of intrauterine onset associated with extrahepatic siderosis that spares reticuloendothelial elements (hemochromatotic siderosis). The agent or agents of liver disease in neonatal hemochromatosis are not known. It also is not known if intrauterine liver disease of defined infective etiology can lead to hemochromatotic siderosis. We present two patients with fetal liver disease and hemochromatotic siderosis whose cases help address these points. In the first patient rare hepatobiliary and numerous renal tubular cytomegalovirus (CMV) inclusions were found; CMV infection was confirmed by the polymerase chain reaction. Studies of the mother of the second patient 1, 5, and 9 weeks post-partum showed recent seroconversion against CMV; seroconversion against other infectious agents (toxoplasma, rubella, herpes, parvovirus B19, hepatitis A/B/C) was not present. Histologic, immunohistochemical, in situ hybridization, or polymerase chain reaction evidence of CMV infection was not present in infant tissues, even though peripartum maternal seroconversion against CMV was observed. We conclude that hemochromatotic siderosis may accompany chronic fetal liver disease of defined infective etiology (patient no. 1) and that recent maternal seroconversion against CMV in the presence of severe fetal liver disease does not necessarily mean that transplacentally acquired CMV infection caused the fetal liver disease (patient no. 2). Polymerase chain reaction documentation of infective-agent genomic sequences in fetal or infant tissues permits more accurate interpretation of maternal serologic data.
Neonatal hemochromatosis: diagnosis with MR imaging.
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Morphological diagnosis of parvovirus B19 infection. A cytopathic effect easily recognized in air-dried, formalin-fixed bone marrow smears stained with hematoxylin-eosin or Wright-Giemsa.
Readily identifiable intranuclear inclusions characterize parvovirus B19 cytopathic effect in formalin-fixed, paraffin-embedded material. Such inclusions are not apparent in air-dried smears of bone marrow aspirates. Brief formalin fixation of bone marrow smears, followed by either hematoxylin-eosin or Wright-Giemsa staining, permitted easy detection of parvovirus B19 inclusions in material from a renal transplant recipient with parvovirus B19 infection documented serologically and by electron microscopy. Formalin fixation of bone marrow and peripheral blood smears before hematoxylin-eosin or Wright-Giemsa staining may simplify the morphological diagnosis of parvovirus B19 infection.
Intrapulmonary neuroglial heterotopia.
Nonteratomatous intrapulmonary neuroglial heterotopia not associated with birth trauma or frank vascular embolization has been described rarely. This article briefly reviews the literature, and presents two additional cases of intrapulmonary neuroglial heterotopia. We found 14 cases in the literature. Twelve of these cases had central nervous system disruption, where neuroglial elements were in direct contact with amniotic fluid. Several hypotheses have been proposed, including fetal aspiration of detached neural fragments within amniotic fluid, neural crest migration defects, and vascular embolization with implantation. Of our two cases, one represents the first occurrence where central nervous system abnormalities were secondary to mechanical disruption, rather than to a primary neural tube defect. Our second case represents the youngest documented occurrence (17 weeks gestation) of intrapulmonary neuroglial heterotopia. Additionally, immunohistochemical studies were performed on these lesions, the results of which favor their neural origin. We present these findings and suggest they support the aspiration mechanism for neuroglial heterotopia in lung tissue.
Neonatal hemochromatosis.
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Osteochondrodysplasia with rhizomelia, platyspondyly, callosal agenesis, thrombocytopenia, hydrocephalus, and hypertension.
A female infant born at term to phenotypically normal nonconsanguinous parents had hypertension, thrombocytopenia, hydrocephalus, callosal agenesis, and nonlethal rhizomelic osteochondrodysplasia. Her osteochondrodysplasia was characterized roentgenographically by shortening and metaphyseal broadening of long bones, without bowing, and by platyspondyly, with deficient ossification of dorsal and central portions of vertebral bodies. By light microscopy, the iliac crest growth plate showed expansion of the zone of chondrocyte hypertrophy and degeneration, with faulty columnar alignment, sparse vascular ingrowth, and irregular mineralization at the zone of chondroosseous transformation. These findings appear to define a novel osteochondrodysplasia, which in association with hypertension, thrombocytopenia, hydrocephalus, and callosal agenesis may constitute a new syndrome.
Neural arch stenosis and spinal cord injury in thanatophoric dysplasia.
Bony abnormalities caused by thanatophoric dysplasia affect the base of the skull and the vertebrae as well as the ribs and appendicular long bones. We present our findings in a full-term infant with thanatophoric dysplasia in whom the posterior fossa, the rostral vertebral column, and the neuraxis at and adjoining the craniovertebral junction were studied by dissection, roentgenography, and histologic examination. In this infant, malformations of the vertebral laminae, most prominent in the basiocciput and atlas vertebra, led to compression of the rostral cervical spinal cord, causing gliosis and focal necrosis. Stenosis of the foramen magnum and spinal canal may contribute to the ventilatory insufficiency that often causes death in patients with thanatophoric dysplasia. We suggest that the causes of death in patients with thanatophoric dysplasia and other severe forms of osteochondrodysplasia should be sought in neuraxial injury rather than attributed solely to pulmonary hypoplasia.
Osteochondrodysplasia in Fryns syndrome.
Various skeletal abnormalities have been identified in roentgenograms of persons with Fryns syndrome, but to our knowledge, no histopathologic description of bone or cartilage has been published. We describe disordered endochondral and intramembranous bone formation in a premature female infant with Fryns syndrome. This infant and a full sibling (ie, had same set of parents) with Fryns syndrome in addition exhibited delayed ossification of the basiocciput and of cervical vertebral bodies, also previously undescribed in Fryns syndrome. These findings expand the spectrum of Fryns syndrome to include osteochondrodysplasia.
Parvovirus B19 infection in the fetus.
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Iron storage disease in parents and sibs of infants with neonatal hemochromatosis: 30-year follow-up.
Neonatal hemochromatosis (NH), an uncommon and generally fatal disorder of infancy, is defined by hepatic disease of antenatal onset, generally manifest at birth, and by stainable iron in a tissue distribution like that seen in heritable adult-onset hemochromatosis (HH). It is not known if parents and sibs of infants with NH are at risk of iron storage disease in later life. We provide 30-year follow-up for iron overload of a family in which 6 of 9 children died in utero or early in the neonatal period. Four of the 6 came to autopsy, where severe liver disease was found; in 3 of the 4, autopsy material could be reviewed. These 3 children had NH. Studies 30 years later did not identify HH or other iron storage disease in the parents or surviving sibs. These findings suggest that first-degree relatives of persons with NH are not necessarily at increased risk of iron storage disease in later life.
Prenatal diagnosis of Fraser syndrome at 18.5 weeks gestation, with autopsy findings at 19 weeks.
Sonography permitted the diagnosis of Fraser syndrome (cryptophthalmos-syndactyly syndrome) at 18.5 weeks of gestation in a fetus whose parents had had a previous affected child. The karyotype of that child was 46,XX,inv(9)(p11q21); the karyotype of the phenotypically normal father and of the fetus was 46,XY,inv(9)(p11q21). Findings on sonography included oligohydramnios with nonvisualization of kidneys, hypertelorism and microphthalmia, and markedly enlarged lungs. On autopsy at 19 weeks, findings included renal agenesis, cryptophthalmos with multiple abnormalities of the eyes and ocular adnexa, laryngeal atresia, pulmonary hyperplasia with accelerated maturation, absence of the Eustachian tube with connective tissue occupying the tympanic cavity and bone occluding the external acoustic meatus, and soft-tissue webbing between the digits. This is the second reported instance of prenatal diagnosis of Fraser syndrome in the second trimester. The histopathologic findings in Fraser syndrome at this gestational age, in particular the eye and ear, have not been described previously.
Placental siderosis in maternal beta-thalassemia.
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Fetal liver disease may precede extrahepatic siderosis in neonatal hemochromatosis.
Three children of a mother with biopsy-confirmed posttransfusional hepatitis of undetermined etiology (non-A, non-B hepatitis) died in utero or in infancy. All had liver disease of intrauterine onset. The two liveborn children died of the consequences of severe hepatic insufficiency manifest at birth and met clinicopathologic criteria for neonatal hemochromatosis. Although hepatic architecture in the stillborn fetus was markedly disordered, with hepatocyte giant cell transformation, extrahepatic siderosis was not present and hepatic siderosis was minimal. These findings indicate that in some cases of neonatal hemochromatosis, extrahepatic siderosis may be caused by hepatic injury rather than primarily due to excessive transport of iron from mother to fetus and support speculation that in some instances an infective agent may be responsible.
Neonatal hemochromatosis. Genetic analysis of transferrin-receptor, H-apoferritin, and L-apoferritin loci and of the human leukocyte antigen class I region.
Neonatal hemochromatosis (NH), a generally fatal disorder of infancy, is characterized by severe hepatic insufficiency of intrauterine onset and by marked organ iron loading. Its cause is unknown. It has been suggested that NH may represent an unusual manifestation of hereditary hemochromatosis (HH), which is human leukocyte antigen (HLA) linked. Evidence for major rearrangements or deletions at the HLA class I region and at three loci directly involved in iron metabolism (H- and L-apoferritin and the transferrin receptor [TfR]) was sought. The population studied included five probands with NH and 14 first-degree family members in a total of six kindreds. Also sought were HLA associations with NH by collating the results of HLA serotyping in these 19 persons and in 17 members of 7 additional kindreds in which NH has occurred, including 5 probands with NH and 12 first-degree family members. We found no evidence for major rearrangements or deletions in H- or L-apoferritin genes, in TfR genes, or within the HLA locus. We found no evidence for linkage of NH to HLA serotypes. We conclude that while NH and HH are similar in their patterns of iron loading, they are not genetically related.
Megalencephaly in thanatophoric dysplasia and in achondroplasia.
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Cytoferrin, maternofetal iron transport, and neonatal hemochromatosis.
The serum concentration of cytoferrin, a low-molecular-weight iron-binding compound, in an infant with neonatal hemochromatosis was significantly elevated (270X) by comparison with normal adult values. Concentrations of cytoferrin in cord sera from 25 normal term neonates were substantially lower but also were elevated (2X) by comparison with normal adult values. Concentrations of cytoferrin in placental tissues were comparable to values previously obtained for various mammalian tissues, and concentrations of cytoferrin in maternal sera were not elevated. This transplacental gradient in serum concentrations of cytoferrin suggests that cytoferrin may be involved in maternofetal iron transport. Although iron is known to be taken up by the hemochorial placenta via trophoblast brush border receptors for transferrin, further iron handling within the placenta is poorly understood. In particular, the routes or carriers by which iron enters the fetal circulation have not been identified. Cytoferrin may participate in stages of maternofetal iron transport distal to transferrin, and further investigation of the role of cytoferrin in neonatal hemochromatosis and other disorders may be warranted.
Thanatophoric dysplasia in identical twins.
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