Katharina Ericson

Comparison of ultrasound and autopsy findings in pregnancies terminated due to fetal anomalies

Objective. To compare antenatal diagnoses with autopsy findings in pregnancies terminated after ultrasound detection of fetal anomalies. A second aim was to study the quality of antenatal fetal diagnosis over time. Design. Retrospective, multicenter study over two consecutive six‐year periods in Uppsala and Stockholm. Setting. Cases were identified through fetal autopsy reports. Subjects. Three hundred and twenty‐eight fetuses from pregnancies terminated between 1992 and 2003 because of ultrasonographically diagnosed anomalies. Main outcome measures. The findings at the last ultrasound examination were compared with the autopsy reports. Results. In 299 cases (91.2%) ultrasound findings either exactly matched or were essentially similar to the autopsy findings. In 23 cases (7%) ultrasound findings were not confirmed at autopsy, but the postnatal findings were at least as severe as the antenatal ones. In six cases (1.8%) termination was performed for an anomaly which proved to be less severe than was predicted by ultrasound. The number of such cases was the same in both six‐year periods, while the total number of cases increased from 113 in the first to 215 in the second period. Fetal examination provided further diagnostic information in 47% of the cases. In 10% a syndrome was disclosed. Conclusion. Termination of pregnancy was not always based on a correct antenatal diagnosis. All fetuses but one from terminated pregnancies had evident anomalies. In six cases (1.8%) the decision to terminate was based on suboptimal prognostic and diagnostic information. Fetal autopsy by an experienced perinatal pathologist is essential to provide a definitive diagnosis.

Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration

BACKGROUND The reabsorption of filtered plasma proteins, hormones and vitamins by the renal proximal tubules is vital for body homeostasis. Studies of megalin-deficient mice suggest that the large multi-ligand endocytic receptor megalin plays an essential role in this process. In humans, dysfunctional megalin causes the extremely rare Donnai-Barrow/Facio-Oculo-Acustico-Renal (DB/FOAR) syndrome characterized by a characteristic and multifaceted phenotype including low-molecular-weight proteinuria. In this study, we examined the role of megalin for tubular protein reabsorption in humans through analysis of proximal tubular function in megalin-deficient patients. METHODS Direct sequencing of the megalin-encoding gene (LRP2) was performed in a family in which three children presented with classical DB/FOAR manifestations. Renal consequences of megalin deficiency were investigated through immunohistochemical analyses of renal biopsy material and immunoblotting of urine samples. RESULTS In the patients, a characteristic urinary protein profile with increased urinary excretion of vitamin D-binding protein, retinol-binding protein and albumin was associated with absence of, or reduced, proximal tubular endocytic uptake as shown by renal immunohistochemistry. In the absence of tubular uptake, urinary albumin excretion was in the micro-albuminuric range suggesting that limited amounts of albumin are filtered in human glomeruli. CONCLUSIONS This study demonstrated that megalin plays an essential role for human proximal tubular protein reabsorption and suggests that only limited amounts of albumin is normally filtered in the human glomeruli. Finally, we propose that the characteristic urinary protein profile of DB/FOAR patients may be utilized as a diagnostic marker of megalin dysfunction.

Inflammation in the walls of asymptomatic abdominal aortic aneurysms is not associated with increased metabolic activity detectable by 18-fluorodeoxglucose positron-emission tomography.

OBJECTIVE We hypothesized that the general inflammation observed in the wall of large, asymptomatic abdominal aortic aneurysms (AAAs) could be detected in vivo by 18-fluorodeoxglucose (FDG) positron-emission tomography (PET) and, if so, that this method could be used to study if active inflammation is an early pathogenetic finding in small AAAs detected by screening. METHODS In this prospective clinical study, 12 men were examined with FDG-PET computed tomography. Seven had large asymptomatic AAAs (range, 52-66 mm) that required surgery, and five had small AAAs (range, 34-40 mm) under surveillance. In the surgery group, biopsy specimens were taken from the aneurysm wall for histologic examinations. RESULTS Compared with normal segments of the aorta, liver, and blood and compared with healthy controls matched for age and sex, no increased FDG uptake, measured as standardized uptake value, was detected in any of the large or small AAAs. The SUV(mean) difference between infrarenal aorta and blood was -0.3 for cases and -0.1 for controls (P = .06). The corresponding differences between the infrarenal aorta and liver was -0.8 and -0.8 (P = .91) and between infrarenal aorta and suprarenal aorta was -0.2 and -0.1 for cases and controls, respectively (P = .20). The histologic examination of the aneurysm walls showed high inflammatory cell infiltration with T lymphocytes, B lymphocytes, and macrophages. CONCLUSIONS The chronic inflammation observed in the wall of asymptomatic AAAs was not sufficiently metabolically active to result in an increased glucose metabolism detectable by FDG-PET by means of this standard protocol. To study the importance of inflammation in the pathogenesis of AAAs in vivo, PET tracers other than FDG need to be developed.

MuSK : a new target for lethal fetal akinesia deformation sequence (FADS)

Background Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS. Methods and results We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17 weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency. Conclusions To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS.

A nonsense mutation in CEP55 defines a new locus for a Meckel‐like syndrome, an autosomal recessive lethal fetal ciliopathy

Mutations in genes involved in the cilium‐centrosome complex are called ciliopathies. Meckel‐Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS‐like phenotypes, but there are still genes remaining to be discovered. We have used whole‐exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with 2 affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid‐body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.

Diagnosis of placental mesenchymal dysplasia with magnetic resonance imaging: Letter to the Editor

Diagnosis of Placental Mesenchymal Dysplasia with a focus on magnetic resonance imaging (MRI)

Diagnosis of placental mesenchymal dysplasia with magnetic resonance imaging

Diagnosis of Placental Mesenchymal Dysplasia with a focus on magnetic resonance imaging (MRI)

Diagnosis of Placental Mesenchymal Dysplasia with a focus on magnetic resonance imaging (MRI)

Diagnosis of Placental Mesenchymal Dysplasia with a focus on magnetic resonance imaging (MRI)