Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants.

PURPOSE: Genetic testing in pediatric cholestasis can be very informative but genetic causes have not been fully characterized. METHODS: Exome sequencing and positional mapping in seven families with cholestatic liver disease and negative clinical testing for known disease genes. RESULTS: KIF12, which encodes a microtubule motor protein with a tentative role in cell polarity, was found to harbor three homozygous likely deleterious variants in three families with sclerosing cholangitis. KIF12 expression is dependent on HNF-1ß, deficiency which is known to cause bile duct dysmorphogenesis associated with loss of KIF12 expression. In another extended family, we mapped an apparently novel syndrome of sclerosing cholangitis, short stature, hypothyroidism, and abnormal tongue pigmentation in two cousins to a homozygous variant in PPM1F (POPX2), a regulator of kinesin-mediated ciliary transport. In the fifth family, a syndrome of normal gamma glutamyltransferase (GGT) cholestasis and hearing loss was found to segregate with a homozygous truncating variant in USP53, which encodes an interactor with TJP2. In the sixth family, we mapped a novel syndrome of transient neonatal cholestasis, intellectual disability, and short stature to a homozygous variant in LSR, an important regulator of liver development. In the last family of three affected siblings, a novel syndrome of intractable itching, hypercholanemia, short stature, and intellectual disability was mapped to a single locus that contains a homozygous truncating variant in WDR83OS (C19orf56), known to interact with ATP13A2 and BSEP. CONCLUSION: Our results expand the genetic heterogeneity of pediatric cholestatic liver disease and highlight the vulnerability of bile homeostasis to a wide range of molecular perturbations.

The Modified Bosniak Classification for Intermediate and High-Risk Renal Cysts.

Background Renal cysts are uncommon among the pediatric population, and their transformation into malignant lesions is also uncommon. Early detection can prevent further complications and protect renal function. Bosniak classification is a computed tomography-based classification for renal cysts developed for adults. Children are more susceptible to CT radiation. Therefore, a modified Bosniak classification for children based on the ultrasound (US) can be used if it shows reliability and accuracy. Aim To apply the modified Bosniak classification system among children with renal cysts. Methods This was a retrospective study that was conducted on pediatric patients who underwent surgery for intermediate and high-risk complex renal cysts in Prince Sultan Military Medical City, Riyadh, Saudi Arabia using radiological information from 2009 to 2022. The collected data included demographics, medical history, radiological findings, and characteristics of renal cysts. SPSS Statistics v. 22 (IBM Corp., Armonk, NY) was used to analyze the data. Results There were 40 children included in the study based on the US-modified Bosniak classification. Around 26.3% of patients had class I and 39.5% had class II renal cysts. Histopathology showed that 10% had Wilms tumor, and 15% had benign lesions. There were significant correlations between pathology findings and US findings (p=0.004), and CT findings (p=0.016). Conclusion The modified Bosniak classification based on the US is sensitive, specific, and sufficiently accurate in the classification of renal cysts among children. Also, the size of the renal cysts can be a diagnostic marker of differentiation of benign and malignant cysts with high sensitivity and specificity.