ESPE Abstracts

Introduction: Polycystic kidney and diabetes syndrome (PCKDD) is an autosomal dominantly inherited disorder caused by HNF-1B mutations associated with a heterogeneous multisystemic phenotype mainly affecting kidney and pancreas, resulting in highly variable nephropathies, and frequently, diabetes diagnosed before the age of 25 yrs. Pancreatic hypoplasia, malformations in the genital tract and hepatic dysfunction may also be observed.

Objectives: Description of the clinical and genetic spectrum of a pediatric and adult patient’s cohort with mutations in HNF-1B.

Subjects: 40 patients (22 females and 18 males) with nephropathy and/or alterations in glycemic control, (age range: 9-64 yrs; 16/40 cases are familial cases).

Methods: Molecular analysis was initially performed by a combination of PCR, HRM and sequencing of HNF-1B exons and intron/exons transitions/ (NM_000458.4 transcript), and MLPA, for the detection of CNVs (Salsa P241-MODY-Mix 1, MRC-Holland). Subsequently, a targeted NGS panel and the CNV-Caller (VarSeq, Golden Helix) for CNVs detection, were used.

Results: 21/40 (52.5%) had a large heterozygous chr 17 deletion including all HNF-1B exons (17q12 deletion syndrome). 19/40 (47.5%) presented heterozygous HNF-1B point mutations (5 frameshift and 14 missense mutations), all classified as pathogenic or probably pathogenic, according to ACMG criteria. 22/40 (55%) had glycemic alterations detected between age 9-41 yrs (onset mean age was 14,75 yrs). At diagnosis, 45.4% of patients had indeterminate glycemic disturbances and diabetes on OGTT. Two patients presented with diabetic ketoacidosis. Only 5/40 patients had pancreatic agenesis/atrophy. Microvascular complications (polyneuropathy, nephropathy and retinopathy) were present in 4 adults. 8/22 patients (36.3% of diabetic patients) are currently on insulin therapy (basal/bolus regimen), and no patient is on oral antidiabetics alone. At molecular diagnosis, 30/40 (75%) had nephropathy diagnosed before 18 yrs, with 62.5% being diagnosed in the neonatal period (25/40). The predominant nephropathy was polycystic disease (68.4%) +/- renal hyperechogenicity, followed by hypomagnesaemia (36.8%), renal lithiasis (13.1%) and hyposthenuria (13.1%). Twelve patients (30%) presented chronic kidney disease of varying severity. Hepatic involvement was described in 6/40 patients (15%), genitourinary malformations in 5/40 patients (12.5%). Other noteworthy findings were dyslipidemia (15%) and neuropsychiatric disorders in 9 patients (22.5%) with a predominance of ADHD.

Conclusion: 1. PCKDD requires a multidisciplinary approach, continuous follow-up and appropriate genetic counseling. 2. Penetrance is incomplete and expression highly variable with disparate phenotypes within the same family, and neonatal onset nephropathies and MODY being predominant. 3. Neuropsychiatric and neurodevelopmental manifestations were more frequent in patients with the 17q12 deletion.