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ADTKD is estimated to account for approximately 2-5% of monogenic causes of chronic kidney disease. The prevalence of HNF1B-related ADTKD is unknown.

HNF1B-related ADTKD is a congenital disorder of kidney development and can manifest as early as in the prenatal period with large and hyperechogenic kidneys. Postnatally, tubulointerstitial kidney disease with or without bilateral cystic kidney dysplasia can be apparent. Chronic renal insufficiency generally has a slow-progressive course; however, some infants present with early manifestation of end-stage kidney disease (ESKD). Additional malformations of the genitourinary tract are diagnosed in the antenatal or immediate postnatal period. In most patients, hypomagnesemia, hyperuricemia, elevated liver enzymes and maturity onset diabetes of the young manifest later during the clinical course (e.g. in school-aged children, adolescents or young adults). Due to the phenotypic overlap with 17.2q microdeletion syndrome, it is currently unclear if HNF1B-related ADTKD is also associated with neuropsychiatric symptoms.

HNF1B-related ADTKD is caused by heterozygous variants in the human transcription factor 2 gene (HNF1B; 17q12) or large heterozygous deletions of 17q12 including HNF1B and a large number of additional genes. HNF1B encodes for hepatocyte nuclear factor-1 beta (HNF-1 beta), a transcription factor that is expressed early in embryonic development. HNF-1 beta acts as a homo- or heterodimer with HNF-1 alpha and plays a key role for tissue-specific regulations of gene expression in various organs such as kidneys, liver, biliary ducts, pancreas and the urogenital tract. However, it must be noted that HNF1B variants are associated with a spectrum of clinical phenotypes ranging from renal dysplasia, multicystic dysplastic kidney and other congenital anomalies of kidneys and urinary tract (CAKUT).

Diagnosis may be difficult due to the heterogenous picture associated with HNF1B variants or gene deletions. Renal biopsy confirms a picture of interstitial fibrosis and tubular atrophy; however, renal ultrasound followed by genetic gene panel testing is the gold standard of diagnostic procedures.

Differential diagnosis is complex, as the disease may mimic a variety of renal disorders. The clinical picture is shared with other forms ADTKD (UMOD-, MUC1-, REN-related). Other cystic kidney diseases (e.g. ARPKD, ADPKD, and other ciliopathies) may also present with renal ultrasound images similar to ADTKD-HNF1B. In 17.2q microdeletion syndrome, neurological involvement is possible in patients initially presenting with the kidney phenotype.

Prenatal diagnosis is possible by fetal ultrasound or where the pathogenic variant has previously been identified in a family member.

The pattern of inheritance is autosomal dominant with de novo variants or gene deletions in about 50% of cases. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. However, there is variable intrafamilial expression and it should be noted that HNF1B is associated with a variable degree of renal insufficiency.

Treatment is symptomatic and interdisciplinary, requiring pediatric nephrologists and diabetologists. Chronic renal disease and diabetes are treated according to international standards. Hypomagnesemia can be managed with magnesium supplementation; hyperuricemia with allopurinol in severe cases. Gene therapy is currently not available.

The prognosis is largely dependent on renal function and sufficient treatment of diabetes at later ages. When kidney transplantation is required, there is no risk of recurrence after transplantation. However, when using steroids and calcineurin inhibitors, especially tacrolimus, there is an enhanced risk of post-transplant diabetes.