INTRODUCTION — This monograph summarizes the interpretation of germline genetic testing of HNF1B (also called TCF2). The resulting disorder has been called renal cysts and diabetes syndrome, although some individuals with HNF1B syndromes have neither renal cysts nor diabetes .
●Congenital anomalies of the kidney and urinary tract (CAKUT), especially kidney cysts
●Genitourinary tract abnormalities such as bicornuate uterus
●Chronic kidney disease (CKD)
●Maturity-onset diabetes of the young
●Hypomagnesemia and hyperuricemia
●Elevated liver function tests (LFTs)
The rarity of this condition, variable penetrance (see 'Inheritance' below), high proportion of de novo pathogenic variants, and lack of specificity of some of the clinical findings can make this condition difficult to diagnose.
HNF1B gene — HNF1B encodes hepatocyte nuclear factor 1 beta, a transcription factor that regulates development and mitochondrial function and is expressed in the kidney, pancreas, liver, and reproductive system. Heterozygous variants in HNF1B result in a syndrome affecting these organs; inheritance is autosomal dominant.
This syndrome can also occur in individuals with a deletion involving 1.4 megabases of chromosome 17 (17q12 deletion syndrome), which includes HNF1B and approximately 14 other genes. This deletion also causes neurodevelopmental and neuropsychiatric manifestations, including intellectual disability, autism spectrum disorder, schizophrenia, and bipolar disorder . (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '17q12 deletion syndrome'.)
How to read the report — Confirm that the result applies to the tested individual and determine whether testing was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory) or if testing should be repeated in a certified laboratory. These and other caveats are summarized in the checklist (table 2).
Interpretation of variants — Gene variants are classified according to the confidence that they are disease-causing (pathogenic) versus benign polymorphisms (table 3). Pathogenicity refers to the link between the variant and the disease, not the likelihood that disease will occur. Some individuals with a pathogenic variant may have other characteristics that protect them from developing disease.
●Pathogenic variants in HNF1B include gene deletions, truncations, and missense variants that result in amino acid substitutions .
●Variants that are clearly not associated with disease may be reported as negative, benign, or likely benign.
●Variants of undetermined significance (VUS) may result in an amino acid substitution not previously associated with disease. A VUS can be reclassified when it is found to be pathogenic or benign.
When evaluating a VUS, the clinician must consider whether clinical findings are consistent with effects mediated by impaired HNF1B function. This often requires communication between a geneticist, genetic counselor, nephrologist, endocrinologist, and/or HNF1B expert. An extensive family history should be obtained that includes at least three generations if possible, and genetic testing should be considered in affected and unaffected relatives to determine the correlation of the variant with clinical findings. Evaluation of family members for unique findings (bicornuate uterus, maturity-onset diabetes of youth, hypomagnesemia, hyperuricemia, elevated LFTs), may help determine the likelihood that the variant is pathogenic. Nonspecific findings such as CKD may result from other conditions and are less helpful.
Diagnostic challenges include incomplete penetrance (likelihood of manifesting disease), variable expressivity (constellation of clinical findings), and variable disease severity, with some individuals developing end-stage kidney disease (ESKD) when young and others having mild CKD.
●Was testing performed for a condition associated with HNF1B variants?
●Were variants identified in other genes that better explain the clinical findings?
●Does the HNF1B variant track with clinical findings in relatives?
●Are there other symptoms not explained by the HNF1B variant that are better explained by a pathogenic variant in a different gene?
Inheritance — Inheritance is autosomal dominant, with a 50 percent risk of transmission from affected parent to a child (algorithm 1). A pathogenic variant in HNF1B need only be present at one allele (heterozygous) to cause clinical findings.
A negative family history cannot be used to exclude the possibility of a germline HNF1B variant, since approximately 30 to 50 percent of HNF1B variants occur de novo rather than being inherited .
Penetrance is incomplete (affected individuals may have all, some, or none of the findings), and expression is variable, with disparate phenotypes within the same family. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)
IMPLICATIONS FOR THE TESTED INDIVIDUAL
Clinical features — Disease penetrance and expressivity (presence of individual clinical characteristics) is highly variable within families, which can make diagnosis difficult. For example, hyperechogenic kidneys may have been identified in utero in the index case; the patient's mother may have a single kidney, and a sibling may have gout, chronic kidney disease (CKD), and hypomagnesemia.
●Congenital anomalies of the kidney and urinary tract (CAKUT) – The most common CAKUT manifestation is bilateral kidney cysts . Other manifestations include solitary kidney, hypoplastic kidneys, horseshoe kidney, dilation of the upper urinary tract, or dysplastic kidneys (identified as hyperechogenic kidneys on prenatal ultrasound). Pediatric cases are often identified by screening neonatal ultrasound, often showing bilateral hyperechogenic kidneys . Pathogenic variants in HNF1B account for 5 percent to 31 percent of cases of CAKUT depending on the phenotypic selection of the cohort [10,11]. Genitourinary abnormalities are more frequent in females and include bicornuate uterus, uterus didelphys, absent uterus, double vagina, and vaginal hypoplasia . (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)
●CKD with a bland urinary sediment – Loss of kidney function usually occurs gradually, with a glomerular filtration rate (GFR) decline of approximately 1 mL/min annually in one pediatric cohort; a more rapid GFR decline is associated with an increasing number of kidney cysts . CKD may present at any age, and the rate of progression is highly variable. In one cohort of 24 affected adults, CKD occurred in 92 percent, at a median age of 35 years, with progression to end-stage kidney disease (ESKD) in four, acute unexplained worsening in three, and a median estimated GFR (eGFR) decline of 2.45 mL/min/1.73 m2/year . (See "Chronic kidney disease in children: Definition, epidemiology, etiology, and course" and "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)
●Maturity-onset diabetes of the young (MODY) – HNF1B pathogenic variants or deletions can cause MODY type 5, which occurs in approximately one-third of adults with HNF1B variants . Progressive loss of beta cell function often occurs. Impaired glucose tolerance is rarely observed in childhood. Pancreatic hypoplasia with subclinical pancreatic dysfunction has been reported in several individuals . (See "Classification of diabetes mellitus and genetic diabetic syndromes".)
●Hypomagnesemia and hyperuricemia – A low serum magnesium due to decreased magnesium reabsorption in the kidney occurs in approximately 40 percent of children and 63 percent of adults . It may be severe enough to prolong the QTc interval; one report described hypocalcemia and tetany . Reduced uric acid excretion is responsible for hyperuricemia in 37 percent of children with an early onset at a median age of one year. It can occur by early adulthood and can cause gout .
●Increased liver function tests (LFTs) – Mild LFT elevation (transaminases and alkaline phosphatase) is the most frequent hepatic finding; liver ultrasound and biopsy (generally not indicated) are normal . Biliary cysts may be present . (See "Biliary cysts".)
●Other – Other clinical features reported in patients with HNF1B variants include hyperparathyroidism and hearing loss .
Individuals with 17q12 deletion syndrome often have neurodevelopmental and neuropsychiatric disorders (intellectual disability, autism spectrum disorder, schizophrenia, bipolar disorder, speech and motor delay), in addition to findings from loss of HNF1B function [2,19]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '17q12 deletion syndrome'.)
Evaluation — Individuals with a pathogenic variant in HNF1B should undergo the following initial testing if not done already:
●Imaging for kidney cysts, reflux, or other abnormalities. Uterine imaging may be considered for females when age-appropriate.
•Comprehensive metabolic panel, including LFTs
•Hemoglobin A1C, fasting glucose
●If hypomagnesemia is present, electrocardiogram to assess QTc interval.
●CAKUT – Individuals with cystic kidneys or other anatomic urinary tract changes should be referred to a urologist and nephrologist (or pediatric nephrologist, depending on age). Cysts are overwhelmingly likely to be benign, especially in childhood, but annual monitoring with kidney ultrasound should be considered. (See 'Monitoring' below.)
Genitourinary tract abnormalities should be evaluated by a urologist or gynecologist. (See "Evaluation of congenital anomalies of the kidney and urinary tract (CAKUT)".)
●CKD – No specific interventions are available. The value of common interventions for CKD is unknown (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], sodium-glucose transporter 2 [SGLT-2] inhibitors). Management is similar to the general population, including treatment of hypertension and avoidance of nephrotoxic medications. (See "Chronic kidney disease in children: Overview of management" and "Overview of the management of chronic kidney disease in adults".)
●MODY – Oral hypoglycemic therapy may be required initially, although most patients will eventually require insulin due to decreasing insulin production . (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)
●Hypomagnesemia and hyperuricemia – Hypomagnesemia is difficult to treat due to rapid excretion. Frequent administration may be most effective. Mild hypomagnesemia likely does not require therapy, especially if the QTc interval is normal. (See "Hypomagnesemia: Evaluation and treatment".)
Asymptomatic hyperuricemia does not require intervention, but allopurinol is indicated for gout, especially in younger individuals, who are prone to worsening and tophus development if untreated. Allopurinol-allergic individuals can receive febuxostat. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout".)
●LFTs – Mildly elevated LFTs do not require intervention.
Monitoring — Annual monitoring includes (table 1):
●Comprehensive metabolic panel with GFR estimation
●Kidney ultrasound, if cysts develop
●Monitoring of development as appropriate
Testing frequency can be increased if abnormalities develop or worsen.
FIRST-DEGREE RELATIVES — A major benefit of identifying a pathogenic variant in HNF1B is avoiding extensive diagnostic evaluations that may confer risks and costs in the tested individual and their first-degree relatives .
Parents of the affected individual should be tested, even if asymptomatic, to determine if the HNF1B variant was inherited or occurred de novo (algorithm 1).
●If the variant is present in a parent, siblings of the affected individual and siblings of the parent should receive counseling regarding risks and benefits of genetic testing.
●If the variant occurred de novo, testing of other family members is generally not indicated.
●Regardless of whether the variant is inherited or de novo, the individual's children should be tested, and, if positive, associated treatable abnormalities should be evaluated. The timing of HNF1B genetic testing in children should be made in conjunction with a genetic counselor or pediatric geneticist. Testing of children is appropriate because of the need to evaluate and monitor for treatable conditions such as vesicoureteral reflux, hypomagnesemia, and diabetes.
●MODY – (See "Classification of diabetes mellitus and genetic diabetic syndromes" and "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults" and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)
Locating an expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG).
●Genetic counselors – National Society of Genetic Counselors (NSGC). Genetic testing laboratories may also provide virtual (online or telephone) access to a genetic counselor.
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