Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Incomplete (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.0.0
• Status (Pediatric): Incomplete (Consensus scoring is Complete)
• GENE/GENE PANEL: HNF1B
• Condition: Renal cysts and diabetes syndrome (RCAD)
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• HNF1B ⇔ 0007669 (renal cysts and diabetes syndrome): Strong Actionability

Actionability Rationale

The majority of experts agreed with the assertion computed according to the rubric but there is somewhat limited direct evidence. We therefore are extrapolating from normal diabetes and renal management.

Final Consensus Scores

Gene Condition Pairs: HNF1B ⇔ 0007669 (OMIM:137920)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Diabetes-related morbidity and mortality / Evaluation by specialist to guide management	2	3N	2N 1	3	10NN
Kidney-related morbidity / Evaluation by specialist to guide surveillance and management	2	3N	2D	3	10ND

1. Extrapolated from diabetes management in the general population

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The exact prevalence of renal cysts and diabetes syndrome (RCAD) was not identified. Approximately 1.4% of maturity-onset diabetes of the young (MODY) is individuals with HNF1B mutations.
Obtaining accurate prevalence data for maturity-onset diabetes of the young (MODY) is also challenging because of overlapping clinical features with more common types of diabetes (type 1 and type 2) and lack of widespread genetic testing. Studies of population-based childhood diabetes registries estimated the minimum prevalence of monogenic diabetes in children as 2.1 to 4.6/100,000. Monogenic diabetes accounts for up to 6% of children and at least 1-3% of all individuals with diabetes. MODY is the most common type of monogenic diabetes and MODY type 5 accounts for <6% of all individuals with MODY. The prevalence of MODY in members of historically underserved racial and ethnic groups may be underestimated, as many individuals with MODY remain undiagnosed. [1, 2, 3, 4, 5]

Clinical Features

Individuals with HNF1B-related disease, including those with pathogenic variants or exon or whole gene deletions, can have a variety of clinical features. The most commonly occurring features are renal anomalies and MODY5.
Renal developmental anomalies are present in almost all persons with HNF1B pathogenic variants or gene deletions, and constitute the main presentation in children, even in the absence of diabetes. Renal disease is highly variable and can include renal cysts, glomerular tufts, aberrant nephrogenesis, primitive tubules, irregular collecting systems, oligomeganephronia, enlarged renal pelvises, abnormal calyces, small kidney, single kidney, and horseshoe kidney. Some individuals with renal disease have hyperuricemic nephropathy with tubulointerstitial changes, consistent with autosomal dominant tubulointerstitial kidney disease (ADTKD). A minority of individuals with HNF1B-related disease present solely with progressive kidney interstitial fibrosis.
MODY5 is a monogenic form of non-autoimmune diabetes mellitus (DM), and is a multisystemic condition with significant phenotypic heterogeneity. It is characterized by (1) nondiabetic renal disease resulting from abnormal renal development, and (2) diabetes. It is frequently referred to as “renal cysts and diabetes syndrome,” or RCAD due to the higher prevalence of renal phenotypes than early-onset diabetes. Early-onset DM is the most common extrarenal manifestation. Individuals experience insulin deficiency related to pancreatic hypoplasia and show some degree of hepatic insulin resistance, and therefore do not respond adequately to sulfonylureas treatment and require early insulin therapy.
Affected individuals may also have abnormalities of the urogenital tract, including vaginal aplasia, rudimentary uterus, bicornuate uterus, epididymal cysts, and atresia of the vas deferens, hyperuricemia, gout, abnormal liver function, pancreatic exocrine deficiency, and microvascular complications can also occur.
Chromosome 17q12 deletion syndrome is a specific HNF1B-related disorder, and is caused by a deletion of the HNF1B gene. MODY5 is a characteristic of 17q12 syndrome, in addition to additional clinical symptoms such as neurodevelopmental disorders (e.g., autism spectrum disorder) and neuropsychiatric disorders, which seem to be induced by dysfunction of affected neighboring genes. It is also speculated but unknown if other genes included in the deletion region modify the kidney and liver features. [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]

Natural History

Renal developmental disorders constitute the main presentation in children. Renal manifestations can include structural defects evident before or at birth and later-onset functional defects. Some individuals present in the third decade of life with chronic renal disease (CDK). Renal insufficiency generally has a slow-progressive course though some individuals progress to end-stage renal disease (ESRD). Rarely, ESRD has been reported as early as infancy. Renal magnesium wasting can lead to life-threatening hypomagnesemia, and hyperuricemia, which can manifest as early-onset gout, reported in the teenage years. Age of onset of kidney failure requiring renal replacement therapy (RRT) varies, and usually lies between 20 – 80 years.
Diabetes develops later, typically during adolescence or early adulthood. Onset is usually before 25 years of age (Chen, OMIM; RCAD). Mean age of onset is 24 years but ranges from the neonatal period to late middle age (60 years). Transient neonatal DM has been reported in a few cases. Individuals that present with isolated diabetes are rare. [3, 5, 6, 7, 9, 12, 13, 14]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs in an individual diagnosed with the 17q12 recurrent deletion syndrome, of which MODY5 is a feature, the following evaluations are recommended:
•Kidney structural or functional defects: blood pressure; kidney & bladder ultrasound examination; serum BUN, creatinine, electrolytes (incl calcium, Mg, phosphorus) & uric acid; urine protein, Mg, & creatinine; consultation w/nephrologist
•MODY5: fasting glucose and hemoglobin A1C levels; consultation with endocrinologist (Tier 4) [10]

In general, for individuals with HNF1B-related disease, treatment is symptomatic and interdisciplinary (Tier 4) [13]

To guide management of renal manifestations, all affected individuals with ADTKD, including those with an HNF1B pathogenic variant, should be treated according to established CKD guidelines. Children with HNF1B-related renal disease are likely to benefit from early management, and therefore should be referred to a pediatric nephrologist. (Tier 2) [12]

For individuals with 17q12 deletion syndrome, of which MODY5 is a feature, and who have kidney disease, magnesium depletion is common and can require replacement. Oral magnesium supplements in organic salt forms (e.g., aspartate, citrate, gluconate) may be more bioavailable than inorganic salt forms (e.g., oxide, sulfate, glycerophosphate) (Tier 3) [10]

In HNF1B affected individuals with renal disease and diabetes, combined kidney/pancreas transplantation should be considered. (Tier 2) [12]

Kidney transplantation is the treatment of choice for ESRD caused by any type of ADTKD (including the HNF1B-related type), as the kidney disease is not expected to recur.
•In one study of 8 individuals with RCAD and 4 individuals with MODY3, four patients underwent a kidney and pancreas transplantation and two a kidney transplant alone. After 4.1 years of follow-up, 83% of patients still had a functioning kidney and 75% a functioning pancreas. The study suggested pancreas transplants can be proposed with good results for MODY3 and RCAD patients. (Tier 3) [10]

•Another study reported that 24 out of 152 individuals with HNF1B-related ESRD went on to receive a kidney transplant. (Tier 5) [15]

To guide management of diabetes in all individuals with MODY (including those with MODY5), referral to a specialist in monogenic diabetes or an interested clinical genetics unit is suggested. (Tier 2) [6]

•HNF1B-MODY does not show the same sensitivity to sulfonylureas as HNF1A-MODY. (Tier 4) [3]

•Although initial response to oral antihyperglycemic agents including sulfonylureas is common, clinical course tends to be progressive and most ultimately require treatment with insulin. (Tier 3) [3, 10]

•Insulin is the treatment for MODY5. (Tier 3) [6]

•In a sample of 201 individuals with HNF1B-related diabetes (including individuals with pathogenic variants and deletions), insulin therapy was instituted in half the individuals. After 5 years of treatment, responsiveness to sulfonylureas/repaglinide was observed in 29/51 (57%) and HbA1c decreased from 7.1% to 6.1%. After a median of 12 years of follow-up, the overall proportion of insulin-treated individuals rose to 111/140 (79%). At 12 years, median HbA1c was 7.05% (54 mmol/mol) (Tier 3) [3]

•In general for individuals with MODY, maintaining healthy body weight is also recommended as a high BMI is associated with an earlier age of onset of diabetes. (Tier 3) [1]

Surveillance

The following are recommendations for anyone with a HNF1B pathogenic variant or deletion:
•Imaging: All patients should undergo a renal ultrasound scan to look for evidence of a renal structural anomaly. This should be repeated every 3-5 years during childhood even if normal. If abnormal, it should be repeated every 3-5 years throughout lifespan. In adults, it should be sufficient to monitor renal function using serum creatinine and estimated glomerular filtration rate (eGFR). Imaging may also be used to detect genital tract malformations.
•Renal function: All patients should have their renal function checked (serum creatinine and eGFR). If patients have evidence of chronic kidney disease (CKD), they should be monitored in accordance with evidence-based clinical guidelines. Adults with normal renal function should have their serum creatinine and eGFR repeated annually. For children with normal renal function, the frequency of monitoring will depend on their clinical situation – every 2-3 years may be sufficient in some circumstances.
•Diabetes test: Patients with known diabetes will need regular monitoring of HbA1c levels. In adults without a diagnosis of diabetes, an annual check of HbA1c is suggested. In children without a diagnosis of diabetes, annual urinalysis to test for glycosuria may be helpful. Monitor HbA1c when routine blood samples are being collected. Although HbA1c measurement is not appropriate for diagnosing type 1 diabetes in children, diabetes associated with HNF1B disease usually has a more insidious onset. Families should also be educated on the development of diabetes symptoms (polyuria, polydipsia and unexpected weight loss).
•Other tests that are useful in HNF1B disease include liver function tests, serum magnesium to test for hypomagnesaemia, serum urate to test for early onset gout and/or hyperuricaemia. The frequency of monitoring will depend on the clinical situation. (Tier 4) [9]

Surveillance recommendations for individuals with 17q12 syndrome include the following:
•Surveillance for kidney structure/function
oKidney and bladder ultrasound exam to monitor for kidney cysts or other structural abnormalities. In those without known structural defects, 12 months after establishing diagnosis, and then every 2-3 years in childhood/adolescence, then every 3-5 years in adulthood. Presence of any abnormality may warrant more frequent monitoring. (Tier 4) [10]

Abdominal ultrasonography is recommended twice a year to monitor for structural and functional renal abnormalities (Tier 3) [8]

oMonitoring of blood pressure, kidney function, serum concentration of Mg, potassium, uric acid, urine protein:creatinine ratio, urine Mg and creatinine should be done periodically and preferably under guidance of nephrologist. (Tier 4) [10]

Annual or more frequent monitoring for those who have lab findings suggestive of kidney disease, are taking potentially nephrotoxic medications, and genitourinary structural abnormalities. (Tier 3) [10]

•Surveillance for MODY5
oRecommend annual monitoring of HbA1C and self-monitoring by individuals and their families for clinical signs and symptoms of diabetes mellitus (polydipsia, polyuria, polyphagia, fatigue, nausea, vomiting, blurred vision) in order to promote early diagnosis and treatment
oReferral to endocrinologist as indicated depending on clinical manifestations
oMonitoring of fasting glucose and hemoglobin A1C levels; consultation with endocrinologist (Tier 4) [10]

•Other:
oRegular laboratory monitoring and avoidance of liver-damaging toxins is recommended (Tier 3) [3]

Circumstances to Avoid

Diuretics should be used with caution in all individuals with an ADTKD, including those with HNF1B pathogenic variants, as they may aggravate hyperuricemia and volume depletion. Nonsteroidal anti-inflammatory drugs should also be avoided in these individuals, as they can cause acute worsening of renal function. (Tier 2) [12]

For individuals with 17q12 deletions and mental health conditions, mood stabilizers that affect kidney function in the long term, such as lithium, should be carefully considered in the setting of potential underlying anatomic and functional abnormalities. (Tier 3) [10]

A low salt diet is not recommended for individuals with an ADTKD, including those with HNF1B pathogenic variants. (Tier 4) [14]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant
de novo pathogenic variants (ranging from one-third to half of cases). Compared to other ADTKDs, de novo pathogenic variants may be particularly likely in HNF1B. [6, 12, 13]

Prevalence of Genetic Variants

Approximately 33% of HNF1B-MODY is associated with whole-gene or exon deletions. (Tier 3) [2, 3, 5]

In a review of 254 individuals with HNF1B genetic anomalies, the following genotypes were reported:
•Pathogenic variants: 71.3%
•Exon deletions: 1.1%
•Whole gene deletions: 27.6% (Tier 5) [2, 3, 5]

Another study of 461 genetically confirmed individuals with MODY5 found that 73% had pathogenic variants in HNF1B, while 27% had partial or whole-gene deletions. (Tier 5) [2, 3, 5]

Penetrance

In a review of 254 individuals with confirmed HNF1B genetic anomalies, 211 had phenotype information. Of the 211 individuals the following was reported:
•Renal structural anomalies (RSA) in 89.6% of all individuals, and 96.6% in those under 25 years of age
•Impaired renal function (55.5%) and ESRD (12.8%)
•DM was detected in 45% of all individuals (77% of which were on insulin therapy), and 21.6% in those under 25 years of age
•Other features included:
oPancreas: pancreatic exocrine dysfunction (6.6%) and structural abnormalities (10.4%)
oLiver: asymptomatic liver dysfunction (15.2%) and structural abnormalities (4.3%)
oGenital tract anomalies (total of 13.3%, detected in 18% of females and 10% of males) (Tier 5) [5]

Another study of 201 adults with genetic anomalies in HNF1B (50.2% with pathogenic variants; 49.8% with whole gene deletions), found:
•HNF1B-related renal disease in 98% (Kidney morphological abnormalities in 91%, CKD stages 3–4 in 44%, and ESRD in 21%)
•82% had diabetes
•Additional complications included:
oPancreas exocrine dysfunction (76%; 29/38)
oPancreas structural abnormalities (62%; 59/95)
oLiver laboratory test abnormalities (71%; 101/142)
oLiver imaging abnormalities (32%, 31/97)
oLiver biopsy abnormalities (54%; 13/24)
oGenital tract abnormalities in females (50%; 28/56) and males (80%; 16/80)
There is also evidence of some diabetes-related complications including retinopathy and/or peripheral neuropathy in 40% of individuals after a median 12-year diabetes duration (Tier 5) [15]

Relative Risk

No information on relative risk was found.

Expressivity

HNF1B pathogenic variants result in variable extrarenal manifestations. The rate of decline of renal function for individuals is also highly variable (Tier 3) [12]

The phenotype is highly variable even within families sharing the same pathogenic variant. (Tier 3) [6]

HNF1B pathogenic variants are associated with a spectrum of clinical renal phenotypes ranging from renal dysplasia, multicystic dysplastic kidney and other congenital anomalies of kidneys. HNF1B is associated with a variable degree of renal insufficiency. Additionally, HNF1B-related ADTKD has variable intrafamilial expression (Tier 4) [13]

4. What is the Nature of the Intervention?

Nature of Intervention

Treatment is symptomatic and interdisciplinary, requiring pediatric nephrologists and diabetologist. Surveillance involves routine blood tests. Treatment for diabetes with an oral sulfonylurea can cause hypoglycemia, which may limit their use in some patients. Hypoglycemia is generally mild, though can be severe especially in combination therapy with insulin. There are concerns regarding placental transfer of sulfonylureas. Treatment for renal manifestations can include RRT and kidney transplantation. [3, 12, 13]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Without a genetic diagnosis, persons with MODY may be incorrectly diagnosed with T1D or T2D (Tier 3). It has been estimated that around 80% of cases are misdiagnosed as type 1 or type 2 diabetes. This can lead to suboptimal treatment, delays in obtaining a correct diagnosis, and potential progression of disease sequalae. Obesity has become so common in children that children and adolescents with monogenic diabetes may also be obese and can be very difficult to distinguish from type 1 diabetes. (Tier 3) [6]

HNF1B-related renal phenotypes may mimic a variety of renal disorders, including other ADTKDs (of which there are 3), other cystic renal diseases, and other ciliopathies. (Tier 4) [13]

Subclinical renal disease, prior to a genetic diagnosis, is possible. Early recognition of renal disease at diabetes diagnosis may help correct etiological diagnosis. (Tier 5) [2, 5]

Date of Search: 02.05.2024

Reference List

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