Case Report: A Novel In-Frame Deletion of GLIS2 Leading to Nephronophthisis and Early Onset Kidney Failure

Variants in the GLIS family zinc finger protein 2 (GLIS2) are a rare cause of nephronophthisis-related ciliopathies (NPHP-RC). A reduction in urinary concentration and a progressive chronic tubulointerstitial nephropathy with corticomedullary cysts are the major characteristic features of NPHP. NPHP demonstrates phenotypic and genetic heterogeneity with at least 25 different recessive genes associated with the disease. We report a female, from a consanguineous family, who presented age 9 years with echogenic kidneys with loss of cortico-medullary differentiation and progressive chronic kidney disease reaching kidney failure by 10 years of age. A novel homozygous in-frame deletion (NM_032,575.3: c.560_574delACCATGTCAACGATT, p.H188_Y192del) in GLIS2 was identified using whole exome sequencing (WES) that segregated from each parent. The five amino acid deletion disrupts the alpha-helix of GLIS2 zinc-finger motif with predicted misfolding of the protein leading to its predicted pathogenicity. This study broadens the variant spectrum of GLIS2 variants leading to NPHP-RC. WES is a suitable molecular tool for children with kidney failure suggestive of NPHP-RC and should be part of routine diagnostics in kidney failure of unknown cause, especially in consanguineous families.

Periventricular nodular heterotopias an atypical manifestation of Joubert syndrome

Joubert syndrome (JS) is characterized by varying degrees of mid and hindbrain malformations. A thickened superior cerebellar peduncle (“molar tooth sign”), varying degree of cerebellar vermian clefting, and an oddly shaped (“bat-wing”) fourth ventricle are essential diagnostic cues on imaging. When JS is associated with renal, ocular, hepatobiliary, or oro-facial abnormalities, the term Joubert syndrome and related disorders (JSRD) is used. We report a classic case of this rare disease in a 5 month old male child who presented to our department for assessment of developmental delay. MRI revealed molar-tooth appearance of midbrain, an abnormally shaped fourth ventricle, and vermian aplasia. Additional findings present in our case were corpus callosum dysgenesis, colpocephaly, generalized cortical atrophy, and periventricular nodular heterotopia. Subsequently, an ultrasound of the abdomen was performed to look for any associated anomalies. It revealed diffuse bilateral echogenic kidneys with attenuated corticomedullary differentiation (likely due to micro cysts in medulla) and few thin-walled peripheral renal cortical cysts. Callosal dysgenesis, colpocephaly, cortical atrophy and cortical heterotopias are less common manifestations of JS/JSRD and periventricular nodular heterotopia has been infrequently reported in cases of Joubert syndrome. Key-words: Joubert Syndrome, MRI, Molar Tooth Sign, Periventricular Nodular Heterotopia, Bilateral Echogenic Kidneys

Correlation of Ultrasonographic Parameters with Serum Creatinine and Estimated Glomerular Filtration Rate in Patients with Echogenic Kidneys

Background: Ultrasonography is widely used to evaluate the kidney status. Serum creatinine and glomerular filtration rate assess the functional status of the kidney. This study tried to find the association between renal parameters in ultrasonography, serum creatinine and estimated glomerular filtration rate in patients with echogenic kidneys. Methods: Study was done in 61 patients. Four sonographic renal parameters (renal echogenicity grade, renal length, cortical thickness, parenchymal thickness) were obtained from patients showing echogenic kidneys irrespective of cause during ultrasonography of abdomen. Glomerular filtration rate was calculated using Modified Diet in Renal Disease formula after obtaining patient’s serum creatinine level. Sonographic renal parameters were compared with serum creatinine and estimated glomerular filtration rate using Pearson’s correlation coefficient and one-way ANOVA tests. Results: The study showed significant correlation of only renal echogenicity grade and parenchymal thickness with eGFR. However, all four sonographic renal parameters showed significant correlation with serum creatinine level. Renal echogenicity grading had strongest correlation with both serum creatinine (r=0.571, p=0.000) and estimated glomerular filtration rate (r= -0.349, p=0.006). Mean serum creatinine (in mg/dL) ± standard deviation was 1.9(±1.5), 4.0(±3.7), 5.8(±3.7), and 15.4(±5.3) for grade I, II, III, and IV echogenic kidneys respectively. Similarly, mean eGFR (in ml/min/1.73m2) ± standard deviation was 50.2(±22.9), 35.9(±40), 15.7(±13.4), and 3.4(±1.1) for Grade I, II, III, and IV echogenic kidneys respectively. Conclusions: Renal echogenicity is a better sonographic parameter that correlated well with both eGFR and serum creatinine. Renal ultrasound should be routinely used for early diagnosis, grading and monitoring of kidney disease. Keywords: Correlation; estimated glomerular filtration rate; renal echogenicity; serum creatinine; ultrasound

Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans

Background An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis. Methods In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD. Results We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient’s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity. Conclusion Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

Severe acute interstitial nephritis secondary to minocycline use in an adolescent girl

Acute interstitial nephritis is an uncommon but classic complication of minocycline therapy for acne. A 14-year-old African American girl was started on oral minocycline for the treatment of acne 6 weeks before presentation. After 4 weeks on minocycline, she developed a generalized rash, anasarca, fever, myalgia, nausea, vomiting, sore throat, and generalized body weakness. The evaluation showed increased levels of serum creatinine, urea nitrogen, and serum alanine and aspartate aminotransferases. Renal ultrasonography showed bilateral enlarged, echogenic kidneys, and percutaneous renal biopsy showed features of acute allergic interstitial nephritis. Treatment included methylprednisolone and intravenous fluids and discontinuation of minocycline. The elevated serum creatinine level (12.9 mg/dL (reference, 0.40–0.70 mg/dL)) suggests marked renal impairment corresponding with Kidney Disease Improving Global Outcomes acute kidney injury classification stage 3. The kidney injury improved from stage 3 to stage 1 within 3 days, and early treatment with steroids might have prevented chronic renal failure. The creatinine level promptly decreased to normal, and liver enzyme results also improved. In summary, the diagnosis of acute interstitial nephritis should be considered in patients who present with renal failure associated with recent use of minocycline, and treatment with corticosteroids should be considered early during the hospitalization.