Cindy Miller

Marrow Cell Transplantation for Infantile Hypophosphatasia

An 8‐month‐old girl who seemed certain to die from the infantile form of hypophosphatasia, an inborn error of metabolism characterized by deficient activity of the tissue‐nonspecific isoenzyme of alkaline phosphatase (TNSALP), underwent the first trial of bone marrow cell transplantation for this heritable type of rickets. After cytoreduction, she was given T‐cell‐depleted, haplo‐identical marrow from her healthy sister. Chimerism in peripheral blood and bone marrow became 100% donor. Three months later, she was clinically improved, with considerable healing of rickets and generalized skeletal remineralization. However, 6 months post‐transplantation, worsening skeletal disease recurred, with partial return of host hematopoiesis. At the age of 21 months, without additional chemotherapy or immunosuppressive treatment, she received a boost of donor marrow cells expanded ex vivo to enrich for stromal cells. Significant, prolonged clinical and radiographic improvement followed soon after. Nevertheless, biochemical features of hypophosphatasia have remained unchanged to date. Skeletal biopsy specimens were not performed. Now, at 6 years of age, she is intelligent and ambulatory but remains small. Among several hypotheses for our patients survival and progress, the most plausible seems to be the transient and long‐term engraftment of sufficient numbers of donor marrow mesenchymal cells, forming functional osteoblasts and perhaps chondrocytes, to ameliorate her skeletal disease.

Cranial Ultrasound Lesions in the NICU Predict Cerebral Palsy at Age 2 Years in Children Born at Extremely Low Gestational Age

Our prospective cohort study of extremely low gestational age newborns evaluated the association of neonatal head ultrasound abnormalities with cerebral palsy at age 2 years. Cranial ultrasounds in 1053 infants were read with respect to intraventricular hemorrhage, ventriculomegaly, and echolucency, by multiple sonologists. Standardized neurological examinations classified cerebral palsy, and functional impairment was assessed. Forty-four percent with ventriculomegaly and 52% with echolucency developed cerebral palsy. Compared with no ultrasound abnormalities, children with echolucency were 24 times more likely to have quadriparesis and 29 times more likely to have hemiparesis. Children with ventriculomegaly were 17 times more likely to have quadriparesis or hemiparesis. Forty-three percent of children with cerebral palsy had normal head ultrasound. Focal white matter damage (echolucency) and diffuse damage (late ventriculomegaly) are associated with a high probability of cerebral palsy, especially quadriparesis. Nearly half the cerebral palsy identified at 2 years is not preceded by a neonatal brain ultrasound abnormality.

Observer variability assessing US scans of the preterm brain: the ELGAN study

BackgroundNeurosonography can assist clinicians and can provide researchers with documentation of brain lesions. Unfortunately, we know little about the reliability of sonographically derived diagnoses.ObjectiveWe sought to evaluate observer variability among experienced neurosonologists.Materials and methodsWe collected all protocol US scans of 1,450 infants born before the 28th postmenstrual week. Each set of scans was read by two independent sonologists for the presence of intraventricular hemorrhage (IVH) and moderate/severe ventriculomegaly, as well as hyperechoic and hypoechoic lesions in the cerebral white matter. Scans read discordantly for any of these four characteristics were sent to a tie-breaking third sonologist.ResultsVentriculomegaly, hypoechoic lesions and IVH had similar rates of positive agreement (68–76%), negative agreement (92–97%), and kappa values (0.62 to 0.68). Hyperechoic lesions, however, had considerably lower values of positive agreement (48%), negative agreement (84%), and kappa (0.32). No sonologist identified all abnormalities more or less often than his/her peers. Approximately 40% of the time, the tie-breaking reader agreed with the reader who identified IVH, ventriculomegaly, or a hypoechoic lesion in the white matter. Only about 25% of the time did the third party agree with the reader who reported a white matter hyperechoic lesion.ConclusionObtaining concordance seems to be an acceptable way to assure reasonably high-quality of images needed for clinical research.

Pustular psoriasis with chronic recurrent multifocal osteomyelitis and spontaneous fractures

Chronic recurrent multifocal osteomyelitis is rarely associated with pustular psoriasis in children. We describe a child with severe pustular psoriasis in whom multiple fractures, bone deformities, and severe growth failure from chronic recurrent multifocal osteomyelitis developed. The recurrent fractures led to an incorrect assumption of child abuse. Both the bone disease and pustular psoriasis responded to treatment with etretinate.

Developmental Correlates of Head Circumference at Birth and Two Years in a Cohort of Extremely Low Gestational Age Newborns

OBJECTIVES To evaluate the developmental correlates of microcephaly evident at birth and at 2 years in a cohort born at extremely low gestational age. METHODS We assessed development and motor function at 2 years of 958 children born before the 28th week of gestation, comparing those who had microcephaly at birth or 2 years with children with normal head circumference while considering the contribution of neonatal cranial ultrasound lesions. RESULTS A total of 11% of infants in our sample had microcephaly at 2 years. Microcephaly at 2 years, but not at birth, predicts severe motor and cognitive impairments at 2 years. A total of 71% of children with congenital microcephaly had a normal head circumference at 2 years and had neurodevelopmental outcomes comparable with those with normal head circumference at birth and 2 years. Among children with microcephaly at 2 years, more than half had a Mental Developmental Index <70, and nearly a third had cerebral palsy. The risks were increased if the child also had cerebral white matter damage on a cranial ultrasound scan obtained 2 years previously. CONCLUSION Among extremely low gestational age newborns, microcephaly at 2 years, but not at birth, is associated with motor and cognitive impairment at age 2.

Spectrum of chest radiographic abnormalities in children with AIDS and Pneumocystis carinii pneumonia

This report aims to provide a description of the spectrum of radiographic findings in children with AIDS andPneumocystis carinii pneumonia (PCP). The chest radiographs of all children with perinatally transmitted HIV infection who had PCP were reviewed. Thirtyeight episodes of PCP were noted in 32 children. The age range was 2–17 months. The radiographic findings were characterized as to pattern, severity, presence of pulmonary air cyst, thoracic air leak, thoracic lymphadenopathy, and pleural effusion. The initial distribution of disease was as follows: diffuse (n=20), patchy (n=12), focal (n=4), normal (n=2). In nearly one-third of children parenchymal abnormalities were mild enough that most normal lung markings were visible. During the course of the illness pneumothorax was noted in eight cases, pulmonary air cyst in five, and pneumomediastinum in one. Pleural effusions were noted in three (5%) cases. Thoracic lymphadenopathy was not observed in any case. The authors concluded that the initial chest radiographic appearance of PCP in children with AIDS is variable. The initial chest radiograph may be normal. The distribution was patchy or focal in nearly one-half of all cases with parenchymal abnormalities. Pulmonary air cysts or thoracic air leaks were noted during the course of the illness in approximately one-third of all cases.

Reliability of CXR for the diagnosis of bronchopulmonary dysplasia.

Background. Bronchopulmonary dysplasia (BPD) continues to be prevalent, despite new treatment, in part because of increased survival in less mature infants. Investigations of new treatments have been hampered by a lack of universally accepted diagnostic criteria. Radiographic scoring systems have been developed to provide objective assessment of lung injury and risk for chronic lung disease. Objective. We sought to test the reliability of a recently reported system using chest radiography as the main tool for diagnosis of BPD. Materials and methods. One hundred chest radiographs, half demonstrating BPD and the other half without BPD, were analyzed by pediatric radiologists and by a neonatologist, using the Weinstein score (1–6, depending on increasing radiographic severity). The reliability of this scoring system was tested by kappa (k) statistics. Results. Reliability at the lowest threshold (dividing score 1 from score ≥ 2) was unacceptably low in this population. Reliability increased with inclusion of higher BPD scores in the comparison groups: 1–3 versus 4–6. Conclusion. Using the chest radiograph for the prediction of BPD is not reliable between different observers except at the two extremes of the disease.

Mechanisms of injury to white matter adjacent to a large intraventricular hemorrhage in the preterm brain.

The purpose of this article is to investigate the hyperechoic lesion seen adjacent to a lateral ventricle that contains blood but is not distended. The literature on ependymal barrier dysfunction was reviewed in search of mechanisms of injury to the white matter adjacent to an intraventricular hemorrhage. The clinical literature on the clinical diagnosis of periventricular hemorrhagic infarction was also reviewed to find out how frequently this diagnosis was made. Support was found for the possibility that the ventricular wall does not always function as an efficient barrier, allowing ventricular contents to gain access to the white matter where they cause damage. Hemorrhagic infarction may not be the only or the most frequent mechanism of white matter damage adjacent to a large intraventricular hemorrhage.

Reader Variability in the Use of Diagnostic Terms to Describe White Matter Lesions Seen on Cranial Scans of Severely Premature Infants: The ELGAN Study

To evaluate reader variability of white matter lesions seen on cranial sonographic scans of extreme low gestational age neonates (ELGANs).

Pulmonary veno-occlusive disease: a misnomer?

Pulmonary veno-occlusive disease (PVOD) is a rare entity with non-specific signs and symptoms and is nearly always associated with a dismal prognosis. This review will first consider pulmonary hypertension in general and then will focus on PVOD specifically with particular attention to the pathophysiology of the disease. Classically PVOD is described as a disease primarily involving obstructed venules, with the arterial side of the circulation involved to a lesser degree. This article discusses the demographics of affected individuals; the ways in which an accurate diagnosis can be made, including imaging features; predisposing diseases and associated disorders; and potential treatment.