Translational strategies to uncover the etiology of congenital anomalies of the kidney and urinary tract.

While up to 50% of children requiring kidney replacement therapy have congenital anomalies of the kidney and urinary tract (CAKUT), they represent only a fraction of the total patient population with CAKUT. The extreme variability in clinical outcome underlines the fundamental need to devise personalized clinical management strategies for individuals with CAKUT. Better understanding of the pathophysiology of abnormal kidney and urinary tract development provides a framework for precise diagnoses and prognostication of patients, the identification of biomarkers and disease modifiers, and, thus, the development of personalized strategies for treatment. In this review, we provide a state-of-the-art overview of the currently known genetic causes, including rare variants in kidney and urinary tract development genes, genomic disorders, and common variants that have been attributed to CAKUT. Furthermore, we discuss the impact of environmental factors and their interactions with developmental genes in kidney and urinary tract malformations. Finally, we present multi-angle translational modalities to validate candidate genes and environmental factors and shed light on future strategies to better understand the molecular underpinnings of CAKUT.

Diagnostic accuracy of ultrasonography to distinguish thyroglossal duct cysts from dermoid cysts in children with a midline neck swelling.

INTRODUCTION: Midline neck swellings are very common in children and mostly caused by thyroglossal duct cysts (TGDCs) or dermoid cysts (DCs). Since DCs can undergo simple excision, whilst TGDCs demand more thorough resection via Sistrunk procedure, it is important to differentiate between both pre-operatively. Previous studies have suggested an ultrasound-score (SIST) based on presence of septae, wall irregularity and solid components could do so. This study aims to evaluate the diagnostic accuracy of this score. METHODS: All patients (≤18 years) undergoing surgery between 2006 and 2018 for a midline neck mass at our tertiary centre with a histopathological diagnosis of TGDC or DC were retrospectively included. The pre-operative ultrasound was evaluated by an experienced radiologist and the SIST as well as location, tract, echogenicity, margin and multilocularity were scored. RESULTS: We included 97 children, of whom 67 (69 %) with TGDCs. The SIST showed a sensitivity of 37 %, specificity of 97 %, a positive predictive value of 96 % and a negative predictive value of 35 % for the SIST-score in detecting TGDCs, which resulted in an AUC of 0.67. In addition, internal echogenicity (P < 0.01) and margin definition (P < 0.01) were significantly associated to TGDC diagnosis whilst location and multilocularity were deemed insignificant following Bonferroni correction. CONCLUSION: We conclude that the SIST-score seems very capable to rule in TGDC. However, the SIST-score is far from making a clear distinction between DC and TGDCs preoperatively. The addition of other ultrasound variables, such as margin definition and echogenicity, might increase the diagnostic accuracy and demands further research.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of ß cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.

Pediatric thyroglossal duct cysts: Post-operative complications.

INTRODUCTION: Thyroglossal duct cysts (TGDCs) result from incomplete involution of the thyroglossal duct and are resected with a Sistrunk-procedure. We studied and graded severity of postoperative complications in children who underwent this procedure, with corresponding risk factors. METHODS: In our electronic health record system we reviewed the medical records of all patients aged <18 years, with surgically treated TGDC between 01-01-2005 and 31-12-2015 in two university hospitals. Risk factors (age, gender, recurrence at presentation, treatment hospital, cyst inflammation, cyst rupture, drain placement, antibiotics or postoperative infection) were studied by univariate analysis. The Clavien-Dindo surgical complication classification was used as postoperative surgical grading system. RESULTS: Of the ninety-one patients, with a mean age of 4.4 years, seven were referred from other hospitals with a recurrent TGDC. 24 patients (26.4%) had a complication. Hemorrhage and resection of thyroid cartilage were the most severe complications. Recurrence and wound infection (both n = 7, 7.7%) were most common. We could not identify risk factors for these complications. CONCLUSIONS: The treatment of children with thyroglossal duct cysts shows a considerable amount of complications. Pre-selected risk factors did not show any significant correlation with these complications.