CLINICAL SPECTRUM OF CYSTIC KIDNEY DISEASES IN CHILDREN AND GENETIC EVALUATION

Introduction:

Cystic kidney diseases (CyKD)  encompasses a heterogenous group of hereditary, non-hereditary, and acquired pathologies that demand a multidisciplinary approach to treatment.

The diagnosis is usually based on clinical and ultrasound (USG ) characteristics and the final diagnosis is often difficult to be made. It is vital to detect these conditions timely and provide effective management , as these have serious implications in vulnerable population.

Whole exome sequencing  ( WES ) may help the clinicians to arrive at a diagnosis. So we intended  to study the detailed clinical spectrum and genetic evaluation using WES of cystic kidney diseases in children.

Methods:

Objective – To study the detailed clinical spectrum of genetically proven cystic kidney diseases in children and to  establish the genotype and phenotype co relation.

Study design - Single center prospective study

Study period - 2011-2023

Setting - This was a single center descriptive study wherein children (< 18 years) with clinically suspected or USG detected CyKD  were recruited for evaluation and molecular testing through WES. 

Inclusion criteria –

Ø Any child <18 years age with observation of two or more kidney cysts on imaging

Ø Any child with one kidney cyst measuring >1 cm and with a family history of cystic kidney disorder

Ø Any child with a proven genetic diagnosis of cystic kidney disorder

Ø Typical presentation of Polycystic kidney disease (ARPKD/ADPKD)

Ø Prenatal diagnosis of large hyperechogenic kidneys and or renal cysts and /or oligohydramnios with family history of cystic kidney disease

Exclusion criteria - Children with single cyst without extra renal manifestations and without familial renal /liver cyst

Cystic tumoral process: nephroblastoma etc , Multicystic dysplastic kidneys were excluded

The test results were interpreted as per the American College of Medical Genetics (ACMG) classification.

Results:

We enrolled 42 children ,27 were boys and 15 girls. 15 out of 42  (35%) had ARPKD , second most common being ADPKD in 7 children (16%) clinically.

Clinical presentation - Six out of 42 (14%) had antenatal presentation , in 10 children (23 %)  it was detected incidentally ( most commonly during evaluation for pain abdomen )  . Twenty one percent  (9 out 42 ) presented with renal failure.

Extra renal manifestations found in 42 % (18 out 42 )  including anemia (17) , failure to thrive (11) , hepatic cyst /fibrosis (5) polyuria and polydipsia (5) , subungal fibroma , skin manifestations  (5) hematuria (3) , retinitis pigmentosa (4) , abdominal mass (3) polydactyly , obesity (3) , renal calculi (2)  , sensory neural hearing loss , seizure disorder (4) and cleft palate (2).

Genetic analysis - The underlying pathogenic variants were detected in 64 % of patients (n = 27), no or only one (in case of autosomal recessive inheritance) pathogenic variant was found in 21 % of patients (n = 9). The result of WES correlated with the clinical diagnosis made before the WES in 61% of patients (n = 26 ), in the remaining  children ( 38%) the result of WES revealed another type of cystic kidney disease that was suspected clinically before or did not find causal mutation in suspected genes.

Overall,  11 pathogenic or probably pathogenic variants were detected in the PKHD1 gene, 6 variants in the PKD1 gene, 4 mutations in NPHP1 gene , 2 variants in the HNF1B gene ,  BBS1,  Ch 16 del  and IQCB1 genes ( for Senior-Loken ) respectively.

Table 1 – Genetic diagnosis of children with cystic kidney diseases

Figure 1 - Clinical presentation of cystic kidney diseases in our cohort 

Figure 2 - Genetic evaluation of children with cystic kidney diseases 

Conclusions:

Genetic analysis , WES is a valuable tool in the diagnosis of various forms of cystic kidney diseases. Its results changed the clinically based diagnoses in 19% (n=8) of the children. Identifying monogenic causes aids in establishing a diagnosis, allows informed treatment and helps in detecting and monitoring extra-renal complications.

The extra-renal findings are good clues for making the correct diagnosis and they should be sought in all children with cystic kidney disease

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.