Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population

Multiple malformation syndromes (MMS) belong to a group of genetic disorders characterised by neurodevelopmental anomalies and congenital malformations. Here we explore for the first time the genetic aetiology of MMS using whole-exome sequencing (WES) in undiagnosed patients from the Greek-Cypriot population after prior extensive diagnostics workup including karyotype and array-CGH. A total of 100 individuals (37 affected), from 32 families were recruited and family-based WES was applied to detect causative single-nucleotide variants (SNVs) and indels. A genetic diagnosis was reported for 16 MMS patients (43.2%), with 10/17 (58.8%) of the findings being novel. All autosomal dominant findings occurred de novo. Functional studies were also performed to elucidate the molecular mechanism relevant to the abnormal phenotypes, in cases where the clinical significance of the findings was unclear. The 17 variants identified in our cohort were located in 14 genes (PCNT, UBE3A, KAT6A, SPR, POMGNT1, PIEZO2, PXDN, KDM6A, PHIP, HECW2, TFAP2A, CNOT3, AGTPBP1 and GAMT). This study has highlighted the efficacy of WES through the high detection rate (43.2%) achieved for a challenging category of undiagnosed patients with MMS compared to other conventional diagnostic testing methods (10–20% for array-CGH and ~3% for G-banding karyotype analysis). As a result, family-based WES could potentially be considered as a first-tier cost effective diagnostic test for patients with MMS that facilitates better patient management, prognosis and offer accurate recurrence risks to the families.

RELA Fusion-Positive Ependymoma in a Child with Down Syndrome: A Case Report

Introduction: Down syndrome (DS) is the most common multiple malformation syndrome in humans and is associated with an increased risk of childhood malignancy, particularly leukemia. Incidence of brain tumors in patients with DS is limited to sporadic cases. We report the first case of a RELA fusion-positive ependymoma in a 3-year-old boy with DS. Case Presentation: Imaging prompted by new left-sided hemiparesis demonstrated an 8-cm hemorrhagic right temporal-parietal mass. Subsequent image-complete resection confirmed a RELA fusion-positive anaplastic ependymoma with 90% OLIG2 staining. Postoperatively, the patient, unfortunately, experienced fatal recurrence and drop metastases with leptomeningeal involvement. Conclusion: To our knowledge, this is the first reported case of a confirmed RELA fusion-positive ependymoma in a child with DS. We discuss this finding in the context of intracranial tumors in children with DS, as well as the finding of 90% positive OLIG2 expression and its potential as a prognostic marker.

Fetal Megacystis: A New Morphologic, Immunohistological and Embriogenetic Approach

Congenital anomalies of the kidney and urinary tract (CAKUT) include isolated kidney malformations and urinary tract malformations. They have also been reported in Prune-Belly syndrome (PBS) and associated genetic syndromes, mainly 13, 18 and 21 trisomy. The AA focuses on bladder and urethral malformations, evaluating the structural and histological differences between two different cases of megacystis. Both bladders were examined by routine prenatal ultrasound screening and immunohistochemistry, comparing the different expression of smooth muscular actin (SMA), S100 protein and WT1c in megacystis and bladders of normal control from fetuses of XXI gestational age. Considering the relationship between the enteric nervous system and urinary tract development, the AA evaluated S100 and WT1c expression both in bladder and bowel muscular layers. Both markers were not expressed in the bladder and bowel of PBS associated with anencephaly. In conclusion, megacystis could be considered only a macroscopic definition, concerning the size of the fetal bladder rather than the embryologic origin; it may be a single or multiple malformation; the possible association with the bowel and/or encephalic malformations will decide the outcome and prognosis in fetal megacystis.

Cloacal dysgenesis sequence in the first trimester of gestation

The autopsy data in 17 first trimester fetuses with cloacal dysgenesis sequence are presented. The prenatal ultrasound showed dilated bladder. Cytogenetic analysis of 16 cases carried out by chorion villus sampling or obtained from post-abortion tissues demonstrated normal karyotype. The complete autopsy revealed cystic dilated cloaca, smooth perineum, absence of anal opening and a phallus-like structure. There were 12 cases with isolated cloacal dysgenesis sequence and 5 cases with multiple malformations. In the latter group cloacal dysgenesis were associated with VACTERL association and non-classified multiple malformation complex.

Renal and Urinary Tract Anomalies

This chapter reviews background information about the incidence, risk factors, genetics, recurrence risk, and epidemiology of congenital anomalies of the renal and urinary tract (CAKUT) including hydronephrosis, horseshoe kidney, renal agenesis, multicystic dysplastic kidneys, and polycystic kidneys, congenital nephrotic syndromes, bladder and cloacal exstrophy, and obstructive uropathies. The discussion on the differential diagnosis of CAKUT summarizes common causes of various structural and functional renal anomalies and obstructive uropathies, including teratogenic agents, chromosome anomalies, monogenetic renal anomalies, and multiple malformation syndromes. Mendelian renal disorders that feature associated nonrenal anomalies such as craniofacial disorders, eye anomalies, skeletal dysplasias, CNS anomalies, and ciliopathies are reviewed. The chapter gives recommendations for evaluation and management. A clinical case presentation features an infant with renal tubular dysgenesis.