Clinical Pearls & Morning Reports

Posted by Carla Rothaus, MD

Published November 22, 2023


What are some of the clinical manifestations of HNF1B-related disease?

The underlying causes of chronic kidney disease that develops in childhood or adolescence are usually different from those of adult-onset chronic kidney disease, which is often due to diabetes or hypertension associated with kidney disease. Read the NEJM Case Records of the Massachusetts General Hospital here.

Clinical Pearls

Q: What is the most common cause of chronic kidney disease that develops in childhood or adolescence?

A: The most common causes of chronic kidney disease that is diagnosed in childhood or adolescence include congenital anomalies of the kidneys and urinary tract (CAKUT), glomerular diseases, renal cystic ciliopathies, hemolytic–uremic syndrome, and ischemic kidney failure. CAKUT is the most common cause (accounting for approximately 50% of cases), followed by glomerular disease (20%) and renal cystic ciliopathies (5%).

Q: How often is a genetic cause implicated in cases of chronic kidney disease in childhood or adolescence?

A: Alterations in hundreds of genes have been identified as single-gene causes of chronic kidney disease. A genetic cause is implicated in approximately 30% of cases of chronic kidney disease that is diagnosed in childhood or adolescence. Among patients with chronic kidney disease, the diagnostic yield of genetic testing varies markedly according to the patient’s clinical presentation, geographic region, and ethnic group. Uncovering the underlying genetic cause of chronic kidney disease can increase diagnostic accuracy and contribute to personalized treatment and monitoring strategies. It may also obviate the need for kidney biopsy in certain cases. For these reasons, the possibility of a diagnosis of chronic kidney disease in childhood or adolescence should trigger consideration of genetic testing.

Morning Report Questions

Q: What are some of the clinical manifestations of HNF1B-related disease?

A: This autosomal dominant disorder has substantial phenotypic heterogeneity. The phenotype can vary considerably among persons carrying the same HNF1B mutation, even among members of the same family. HNF1B is a transcription factor that plays a role in the development of multiple organ systems, including the kidneys, liver, and pancreas. Consequently, HNF1B-related disease can manifest as a multisystemic disease affecting multiple organs, or it can manifest as an isolated kidney or urinary tract malformation. HNF1B mutations or deletions are the most common genetic cause of CAKUT. Cystic kidney malformations are considered to be one of the most common kidney phenotypes of this condition. Extrarenal manifestations vary widely, often including asymptomatic abnormal results of liver-function tests. In addition, pancreatic hypoplasia has been reported.

Q: Describe features of HNF1B-related maturity-onset diabetes of the young (MODY).

A: MODY is the most common type of monogenic diabetes. MODY is characterized by primary pancreatic beta-cell dysfunction that is diagnosed during adolescence or early adulthood. HNF1B-related MODY accounts for less than 5% of cases of MODY. As compared with the more common subtypes of MODY (related to GCK, HNF1A, or HNF4A), MODY related to HNF1B (previously known as MODY5) has an increased likelihood of the following features: extrapancreatic manifestations, including morphologic abnormalities of the kidneys and chronic kidney disease at the time of diabetes diagnosis; wide variation in the age at diabetes onset; de novo mutations and the absence of a strong family history of diabetes; pancreatic anomalies, including exocrine dysfunction; and reduced insulin sensitivity. Although some patients with HNF1B-related MODY may have well-controlled blood glucose levels with the use of noninsulin medications for a period after diagnosis, the vast majority of patients with HNF1B-related MODY eventually receive insulin treatment.

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