Germline mosaicism in Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) is a genetic disorder associated with delayed growth, intellectual disability, limb reduction defects, and characteristic facial features. Germline mosaicism has been a described mechanism for CdLS when there are several affected offspring of apparently unaffected parents. Presently, the recurrence risk for CdLS has been estimated to be as high as 1.5%; however, this figure may be an underrepresentation. We report on the molecularly defined germline mosaicism cases from a large CdLS database, representing the first large case series on germline mosaicism in CdLS. Of the 12 families, eight have been previously described; however, four have not. No one specific gene mutation, either in the NIPBL or the SMC1A gene, was associated with an increased risk for germline mosaicism. Suspected or confirmed cases of germline mosaicism in our database range from a conservative 3.4% up to 5.4% of our total cohort. In conclusion, the potential reproductive recurrence risk due to germline mosiacism should be addressed in prenatal counseling for all families who have had a previously affected pregnancy or child with CdLS.

Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta.

The bone disorder osteogenesis imperfecta (OI) is genetically heterogeneous. Most affected individuals have an autosomal dominant disorder caused by heterozygous variants in either of the type I collagen genes (COL1A1 or COL1A2). To date, two reports have linked Mesoderm Development LRP Chaperone (MESD) to autosomal recessive OI type XX. Four different biallelic pathogenic variants in MESD were shown to cause a progressively deforming phenotype, associated with recurrent fractures and oligodontia in five individuals in five families. Recently, compound heterozygosity for a frameshift predicted to lead to a premature termination codon in exon 2 of the 3-exon gene and a second frameshift in the terminal exon in MESD were detected in three stillbirths in one family with severe OI consistent with the neonatal lethal phenotype. We have identified four additional individuals from four independent families with biallelic variants in MESD: the earlier reported c.632dupA (p.Lys212Glufs∗19) and c.676C>T (p.Arg226∗)-which are associated with a severe form of OI-and one new pathogenic variant, c.603-606delTAAA (p.Asn201Lysfs∗15), which causes a neonatal lethal form of OI. MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface. Our report broadens the phenotypic and genetic spectrum of MESD-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation.

Placenta accreta: spectrum of US and MR imaging findings.

Placenta accreta (PA) encompasses various types of abnormal placentation in which chorionic villi attach directly to or invade the myometrium. PA is a significant cause of maternal morbidity and mortality and is now the most common reason for emergent postpartum hysterectomy. Its prevalence has risen tenfold in the United States over the past 50 years, primarily due to the increasing percentage of pregnant patients undergoing primary and repeat cesarean sections. Placenta previa and previous cesarean section are the two most important known risk factors for PA. Accurate prenatal identification of affected pregnancies allows optimal obstetric management. Ultrasonography (US) remains the diagnostic standard, and routine US examination at 18-20 weeks gestation affords an ideal opportunity to screen for the disorder. Placental lacunae and abnormal color Doppler imaging patterns are the most helpful US markers for PA. In recent years, there has been increased interest in magnetic resonance (MR) imaging for the evaluation of PA, since it can provide information on depth of invasion and more clearly depict posterior placentas. The most reliable MR imaging findings are uterine bulging, heterogeneous placenta, and placental bands. Focal interruptions in the hypointense myometrial border may also be helpful. PA is a clinical and diagnostic challenge that is being encountered with increasing frequency. Clinicians should be aware of the clinical issues, risk factors, and imaging findings associated with PA to facilitate optimal case management.

Utility of fetal muscle biopsy for diagnosis of nemaline myopathy.

OBJECTIVES: To report and discuss prenatal diagnosis of nemaline myopathy (NM) using fetal muscle biopsy. METHODS: A consanguineous couple, with a history of a child with a clinical diagnosis of NM but no molecular genetic confirmation, was referred for prenatal diagnosis in two subsequent pregnancies. Fetal muscle biopsy with ultrasound guidance was undertaken at 22 and 21 weeks, respectively. RESULTS: Immunohistochemical and ultrastructural analysis of the fetal muscle specimen from the first 'at-risk' pregnancy was consistent with a diagnosis of NM and that pregnancy was terminated. Analysis of the fetal muscle specimen from the subsequent pregnancy revealed no pathologic abnormality. The pregnancy continued, and the child is unaffected. CONCLUSION: This represents the first reported prenatal diagnosis of NM by fetal muscle biopsy. Pathologic changes characteristic of NM can be identified in mid-second trimester fetal muscle.