ABSTRACT
We report a case of lethal neonatal hypoxic respiratory failure and hypothyroidism in an infant with a novel missense mutation in NKX2.1.
Subject(s)
Congenital Hypothyroidism/genetics , Mutation/genetics , Nuclear Proteins/genetics , Respiratory Distress Syndrome, Newborn/genetics , Transcription Factors/genetics , Biopsy, Needle , Congenital Hypothyroidism/diagnosis , Fatal Outcome , Female , Humans , Immunohistochemistry , Infant, Newborn , Rare Diseases , Respiratory Distress Syndrome, Newborn/diagnosis , Term Birth , Thyroid Nuclear Factor 1ABSTRACT
Clinical studies have associated increased transforming growth factor (TGF)-alpha and EGF receptor with lung remodeling in diseases including bronchopulmonary dysplasia (BPD). BPD is characterized by disrupted alveolar and vascular morphogenesis, inflammation, and remodeling. To determine whether transient increases in TGF-alpha are sufficient to disrupt postnatal lung morphogenesis, we utilized neonatal transgenic mice conditionally expressing TGF-alpha. Expression of TGF-alpha from postnatal days 3 to 5 disrupted postnatal alveologenesis, causing permanent enlargement of distal air spaces in neonatal and adult mice. Lung volume-to-body weight ratios and lung compliance were increased in adult TGF-alpha transgenic mice, whereas tissue and airway elastance were reduced. Elastin fibers in the alveolar septae were fragmented and disorganized. Pulmonary vascular morphogenesis was abnormal in TGF-alpha mice, with attenuated and occasionally tortuous arterial branching. The ratios of right ventricle weight to left ventricle plus septal weight were increased in TGF-alpha mice, indicating pulmonary hypertension. Electron microscopy showed gaps in the capillary endothelium and extravasation of erythrocytes into the alveolar space of TGF-alpha mice. Hemorrhage and inflammatory cells were seen in distal air spaces at 1 mo of age. In adult TGF-alpha mice, alveolar remodeling, nodules, proteinaceous deposits, and inflammatory cells were seen. Immunostaining for pro-surfactant protein C showed that type II cells were abundant in the nodules, as well as neutrophils and macrophages. Trichrome staining showed that pulmonary fibrosis was minimal, apart from areas of nodular remodeling in adult TGF-alpha mice. Transient induction of TGF-alpha during early alveologenesis permanently disrupted lung structure and function and caused chronic lung disease.
Subject(s)
Lung Diseases/physiopathology , Lung/physiopathology , Transforming Growth Factor alpha/physiology , Animals , Crosses, Genetic , Disease Models, Animal , Gene Expression Regulation, Developmental , Lung/embryology , Mice , Mice, Inbred Strains , Mice, Transgenic , Morphogenesis , Transforming Growth Factor alpha/deficiency , Transforming Growth Factor alpha/geneticsABSTRACT
We describe a 2-year-old child with severe pulmonary hypertension due to a patent ductus arteriosus (PDA) with plexiform lesions on lung biopsy. Despite high basal pulmonary vascular resistance with minimal responsiveness to inhaled nitric oxide and other vasodilators, and advanced plexogenic arteriopathy on lung biopsy, her pulmonary hypertension completely resolved after PDA ligation and during 8 years of follow-up.
Subject(s)
Ductus Arteriosus, Patent/complications , Hypertension, Pulmonary/etiology , Child, Preschool , Ductus Arteriosus, Patent/pathology , Ductus Arteriosus, Patent/physiopathology , Ductus Arteriosus, Patent/surgery , Female , Follow-Up Studies , Humans , Hypertension, Pulmonary/pathology , Hypertension, Pulmonary/physiopathology , Lung/pathology , Treatment Outcome , Vascular ResistanceABSTRACT
Navajo neurohepatopathy (NNH) is an autosomal recessive disease of full-blooded Navajo children living in the Navajo Reservation of southwestern United States. Clinical features of NNH include peripheral and central nervous system involvement, acral mutilation, corneal scarring or ulceration, liver failure, and metabolic and immunologic derangement. The cause of NNH is unknown, but the clinical features of NNH are similar to those of patients with mitochondrial DNA (mtDNA) depletion. Therefore, we studied mtDNA concentration in the liver from 2 patients with NNH. Using histochemical, biochemical, and molecular techniques, we found evidence of mtDNA depletion, and we propose that the primary defect in NNH is in the nuclear regulation of mtDNA copy number.
Subject(s)
DNA, Mitochondrial/genetics , Indians, North American , Liver Diseases/genetics , Nervous System Diseases/genetics , Citrate (si)-Synthase/metabolism , DNA, Mitochondrial/analysis , Female , Gene Deletion , Histocytochemistry , Humans , Infant , Liver/chemistry , Liver/pathology , Liver Diseases/epidemiology , Liver Diseases/pathology , NADH Dehydrogenase/metabolism , Nervous System Diseases/epidemiology , Prostaglandin-Endoperoxide Synthases/metabolism , Succinate Cytochrome c Oxidoreductase/metabolismABSTRACT
Alagille syndrome is an autosomal dominant disorder characterized by abnormalities in multiple organ systems, including the liver, and is caused by mutations in JAG1. Chronic cholestasis secondary to paucity of interlobular bile ducts is traditionally both a clinical and a pathologic hallmark of this disease at diagnosis. We describe the biliary changes on serial liver biopsies in a patient who presented with jaundice and extrahepatic stigmata of Alagille syndrome. Her initial specimens at 6 and 10 months of age demonstrated interlobular bile duct proliferation and cholestasis, suggestive of distal biliary obstruction. A specimen at 2 years of age showed near-total absence of interlobular bile ducts, with the classic histologic appearance of bile duct paucity. We present this case to underscore the potential pitfalls in interpreting cholestatic liver morphology in the absence of clinical information. The progression of bile duct abnormalities is discussed in the context of the role postulated for JAG1 in postnatal liver growth and development.
