How often do we incidentally find a fetal abnormality at the routine third-trimester growth scan? A population-based study.

BACKGROUND: Third-trimester scans are increasingly used to try to prevent adverse outcomes associated with abnormalities of fetal growth. Unexpected fetal malformations detected at third-trimester growth scans are rarely reported. OBJECTIVE: To determine the incidence and type of fetal malformations detected in women attending a routine third-trimester growth scan. STUDY DESIGN: This was a population-based study of all women with singleton pregnancy attending antenatal care over a 2-year period in Oxfordshire, UK. Women who had a viable singleton pregnancy at dating scan were included. Women had standard obstetrical care including the offer of a routine dating scan and combined screening for trisomies; a routine anomaly scan at 18 to 22 weeks; and a routine third-trimester growth scan at 36 weeks. The third-trimester scan comprises assessment of fetal presentation, amniotic fluid, biometry, umbilical and middle cerebral artery Dopplers, but no formal anatomic assessment is undertaken. Scans are performed by certified sonographers or clinical fellows (n=54), and any suspected abnormalities are evaluated by a team of fetal medicine specialists. We assessed the frequency and type of incidental congenital malformations identified for the first time at this third-trimester scan. All babies were followed-up after birth for a minimum of 6 months. RESULTS: There were 15,244 women attending routine antenatal care. Anomalies were detected in 474 (3.1%) fetuses as follows: 103 (21.7%) were detected before the anomaly scan, 174 (36.7%) at the anomaly scan, 11 (2.3%) after the anomaly scan and before the third-trimester scan, 43 (9.1%) at the third-trimester scan and 143 (30.2%) after birth. The 43 abnormalities were found in a total of 13,023 women who had a 36 weeks scan, suggesting that in 1 out of 303 (95% confidence interval, 233-432) women attending such a scan, a new malformation was detected. Anomalies detected at the routine third-trimester scan were of the urinary tract (n=30), central nervous system (5), simple ovarian cysts (4), chromosomal (1), splenic cyst (1), skeletal dysplasia (1), and cutaneous lymphangioma (1). Most urinary tract anomalies were renal pelvic dilatation, which showed spontaneous resolution in 57% of the cases. CONCLUSION: When undertaking a program of routine third-trimester growth scans in women who have had previous screening scans, an unexpected congenital malformation is detected in approximately 1 in 300 women.

Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development.

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient.This article has an associated First Person interview with the first author of the paper.

A comprehensive, multidisciplinary, precision medicine approach to discover effective therapy for an undiagnosed, progressive, fibroinflammatory disease.

Precision medicine has generated diagnoses for many patients with challenging undiagnosed disorders. Some individuals remain without a diagnosis despite comprehensive testing, and this impedes their treatment. This report addresses the role of personalized medicine in identifying effective therapy for an undiagnosed disease. A 22-year-old woman presented with chronic severe recurrent trismus, facial pain, progressive multicentric inflammatory and fibrotic masses, and high C-reactive protein. Sites of disease included the pterygomaxillary region, masseter muscles, mandible, lung, pericardium, intrabdominal cavity, and retroperitoneum. A diagnosis was not established after an extensive assessment, including multiple biopsies. The patient was subsequently evaluated under the Undiagnosed Diseases Program at the National Institutes of Health. Large scale genotyping, proteomic studies, and in vitro and gene expression analyses of fibroblasts obtained from a major disease locus were performed. Germline genetic testing did not identify strong candidate genes; proteomic studies of the patient's serum and bronchoalveolar lavage fluid and gene expression analyses of her cells were consistent with dysregulation of the tumor necrosis factor-alpha pathway. The patient's cultured fibroblasts were incubated with selected drugs, and cell proliferation was inhibited by hydroxychloroquine. Treatment of the patient with hydroxychloroquine conferred prolonged beneficial clinical effects, including stabilization of trismus and reduction of corticosteroid dose, C-reactive protein, and size of masses. This case represents an example of precision medicine applied to discover effective treatments for individuals with enigmatic undiagnosed disorders.