HNF1B Nephropathy
TABLE OF CONTENT
GENETICS AND THE INHERITANCE OF THE HNF1B NEPHROPATHY
- What kind of kidney anomalies can occur in this disease?
- MODY5 diabetes and pancreas insufficiency
- Can the HNF1B variant affect other organs?
DISEASE DEFINITION
What is the HNF1B?
HNF1B stands for hepatocyte nuclear factor-1 ßeta. This is a protein that regulates the function of many other genes and proteins and thus participates in the development of numerous organs of human body, as the kidneys, liver, biliary ducts, pancreas, and the urogenital tract. HNF1B is essential for the development and function of them and abnormal variant of HNFB could disturb the function or development of one or more of those or gans. Very rarely development of all those organs is abnormal, the differences and varying severity of the symptoms could also occur in the same family, in persons having also the same HNF1B variant.
Anomalies (variants) of a specific gene that is called hepatocyte nuclear transcription factor 1-beta gene (HNF1B) gives rise to a protein that regulates the function of many other genes and thus participates in the development of numerous organs, including:
- the kidneys
- the pancreas
- the reproductive system
- the liver
In the kidney HNF1B is required for essential steps of kidney development with nephron patterning (nephron is a basic functional and structural unit of the kidney) and kidney segmentation. The absence of the transcription factor results in rudimentary functional units of the kidney, so called nephrons, lacking mature tubule and this results in disturb tubular functions and the frequent occurrence of kidney cysts. Very rarely development of all the above-mentioned structures in the kidney are disturbed and the restrictions can also be of varying severity.
► This explains why the HNF1B mutation is not responsible for just one particular disease pattern as well one particular kidney disease. Extrarenal manifestations consist of MODY 5 diabetes, neurodevelopmental disorders, genital tract malformations, gout (it is due to abnormally high level of uric acid in the blood) and elevated liver enzymes.
Please note: You will find explanation of some vocabulary below or in the glossary.
The abnormal variant of HNFB1 was originally described as renal cysts and diabetes syndrome (RCAD), as kidney cysts (present in 60% of all patients) and maturity onset diabetes of the young (MODY5) (40% of all patients) are common in those patients. Also, electrolyte disturbances due to disturbed tubular functions are common. The kidney function is impaired in approximately half of the affected children and adults and progresses to kidney failure in 12% of the patients. However, the disease has variable presentation, and not all patients suffer from kidney cysts or diabetes.
What is the HNF1B Nephropathy
HNF1B nephropathy is the “umbrellaterm” that includes the various kidney phenotypes of the disease. These phenotypes are ranging from anatomic abnormalities as congenital anomalies of the kidney and urinary tract (CAKUT), tubular transport abnormalities, to chronic tubulointerstitial and cystic kidney disease, all due to changes in HNF1B gen.
Typical is the varying degrees of kidney impairment, but usually slowly progressive decline of kidney function.
The typicaltubulo-interstitial nephritis, characterized by the clinical presentation of:
- nonsignificant urinalysis
- slowly progressive kidney failure
- a picture of interstitial fibrosis and tubular atrophy (confirmation via kidney biopsy)
- hyperuricemia (anomaly high level of uric acid in the blood)
- gout (complex form of arthritis)
A similar phenotype is usually found in patients with heterozygous variants of UMOD, MUC1, and REN genes, causing an autosomal dominant form of tubulo-interstitial nephritis. Because of this, HNF1B nephropathy is now categorized as part of the group of disorders named autosomal dominant tubulointerstitial kidney disease (ADTKD), together with the ADTKD-UMOD, ADTKD-MUC1, ADTKD-REN, and ADTKD-SEC61A1 mutations.
The term “ADTKD” however is often confined only to HNF1B-related cases in which tubulo-interstitial fibrosis is the leading confirmed manifestation.
These disorders are characterized by:
- autosomal dominant inheritance
- absent-to-mild proteinuria
- slow progression of kidney dysfunction
- normal or small-sized kidneys on ultrasound
- loss of renal concentration ability microscopic
- abnormalities of kidney structures (tubules) and surrounding tissue (“tubulo-interstitial” lesions)
► The anomalies found in the kidneys and urinary tract as well as other organs are explained by the important role of HNF1Beta during organ development in the embryonic phase. However, the symptoms caused by HNF1B variants vary widely. Some patients show changes in the kidney at birth whereas some individuals are diagnosed accidentally only after 40 years of age. Overall, HNF1B nephropathy among children is associated with a slowly progressive course with respect to loss of kidney function.
GENETICS OR INHERITANCE OF HNF1B
HNF1B nephropathy is a rare genetic disease whose frequency has not been accurately determined (probably 1 in 50.000/80.000 people). The disease is inherited in an autosomal dominant way, which means that one affected copy of the gene is enough for the symptoms of the disease to occur. Thus, the descendants of a patient suffering from this disease have a 50 % chance of inheriting and developing the disease.
However, up to 50 % of cases are caused by “de novo” variants in the HNF1B gene, explaining the absence of a family history in many patients. The so-called “de novo” variant means that the unusual variant has not been passed on by any parent (both parents have normal gene), but the gene change/variant in the child occurs spontaneously during the development process. In addition, variants in the HNF1B gene were observed to be very often accompanied by anomalies of at least 14 other genes in the same chromosomes area. This is known as 17q12. MICRODELECTION syndrome. The symptoms that occur, especially neurological symptoms are seen only in the context of this microdeletion syndrome, are not directly related to HNF1B gens variant, but to the deletion of some other genes located in this area of chromosome 17.
Did you know?
The human body consists of millions of cells. Most cells contain a complete set of genes. Genes act as a set of instructions for making proteins, the actual toolkits of a cell, controlling our growth and the functioning of our body. Genes are responsible for many of our characteristics, such as eyes colour or body height, but also determine some diseases when affected/mutated.
Genes are found inside the threaded structures called chromosomes. Chromosomes, and therefore genes, consist of a chemical called DNA (deoxyribonucleic acid). Each person has 46 chromosomes in most cells. Chromosomes are inherited from the parents, 23 from the mother and 23 from the father. Each person thus has 2 full sets of 23 chromosomes or 23 “pairs”. As chromosomes contain many genes, each individual inherits 2 copies of the same gene, one copy from each parent. This is the reason why individuals often have similar characteristics of both parents. Unfortunately, an affected/mutated gene can be inherited by the offspring.
If a child inherits one healthy copy of a gene and one affected copy gene from the parents, and the affected copy is found to be stronger, it is autosomal dominant inheritance. The abnormal copy will dominate the normal gene, thus one affected copy will be enough to develop the disease, as it happens for Marfan syndrome,neurofibromatosis type 1 or also HNF1B nephropathy.
If a child inherits one affected copy of a gene and one normal copy of the same gene from the parents, but the affected copy is weaker, it is autosomal recessive inheritance. The affected copy will be dominated by the normal gene. Two affected copies of the gene are necessary to develop the disease; thus, the disease will only come to light when two affected copies are passed on to the offspring, such in the case of Bardet Biedl syndrome, primary hyperoxaluria type 1 or autosomal recessive polycystic kidney disease (ARPKD).
Will the disease affect other family members?
As only one affected copy of a given gene is sufficient for the symptoms of the disease to occur (see above), the chance that the disease occurs in other family member is much higher than in case of diseases inherited in a recessive way. The descendant of person with HNF1B variant has a 50% chance of inheriting this variant and the disease.
The symptoms of the disease occur with very high variability even within the same family, and the specific mild course of the disease in one family member does not guarantee the same clinical picture in his potential descendant.
In addition, incomplete penetrance is common: for example, one family member with the HNF1B gene variant may have CKD, diabetes, and gout; another family member with the same variant may have a solitary kidney and a third one may be asymptomatic.
Please note:
Patients who wish to have children should be offered genetic counselling. Knowledge of the HNF1B variant in the family may allow prenatal screening in case the parents want to find out in early pregnancy whether the foetus carries the variant of HNF1B gen, however detecting the variant we cannot really predict in which kind of phenotype this will result in. When the HNF1B variant is identified, it is also possible to perform a genetic test in the other family members. It may be also worth to screen parents of affected patients, as they may have phenotypes that were not previously detected. As mentioned above, affected patients often carry a de novo variant, thus no other family members will be found carrying this HNF1B gens variant, but the descendant of the affected person could inherit the variant.
SYMPTOMS
HNF1B nephropathy is recognized as disorder with multiple extrarenal manifestations, only a minority of cases will present solely with kidney manifestations. Patients typically have kidney anomalies, such as kidney cysts and kidney dysplasia, associated with diabetes mellitus due to pancreatic atrophy and also possible genital malformations, as well occurrence of elevated liver enzymes, and some other laboratory anomalies as high uric acid level or low magnesium. The spectrum of disease severity and symptoms can vary enormously, ranging from isolated MODY diabetes or isolated kidney involvement to multiorgan disease.
Since HNF1B is expressed predominantly in the liver, intestine, pancreas, kidneys and the urogenital tract, the occurrence of phenotypic anomalies can involve all these organs.
► Kidney malformations with a tubulointerstitial disease appear to be the most common manifestations of the renal disorder, patients can develop chronic kidney disease since childhood; however gradual progression, usually bland urinalysis and slow decline of kidney function throughout adulthood is a hallmark of the disease.
► HNF1B nephropathy is recognized as disorder with multiple extrarenal manifestations, only a minority of cases will present solely with kidney manifestations. Patients typically have kidney anomalies, such as kidney cysts and kidney dysplasia, associated with diabetes mellitus due to pancreatic atrophy and also possible genital malformations, as well occurrence of elevated liver enzymes, and some other laboratory anomalies as high uric acid level or low magnesium.
The spectrum of disease severity and symptoms can vary enormously, ranging from isolated MODY diabetes or isolated kidney involvement to multiorgan disease. Since HNF1B is expressed predominantly in the liver, intestine, pancreas, kidneys and the urogenital tract, the occurrence of phenotypic anomalies can involve all these organs. Kidney malformations with a tubulointerstitial disease appear to be the most common manifestations of the renal disorder, patients can develop chronic kidney disease since childhood; however gradual progression, usually bland urin alysis and slow decline of kidney function throughout adulthood is a hallmark of the disease.
What kind of kidney anomalies can occur in this disease?
Kidney and urinary tract malformations as well as tubulointerstitial anomalies with some defects in tubular transport pose the main risks to the health and life of patients with the HNF1BN. In case of variants in the HNF1B gene, the kidneys are the most affected organs. The kidney presentation varies widely according to age at recognition.
In the foetus, hyperechogenic kidneys with normal or slightly enhanced size is the more frequent kidney phenotype.
In childhood, HNF1BN is typically characterized by anatomic abnormalities such as multicystic or dysplastic kidneys (see below), as well as chronic kidney disease and a number of other extra-kidney manifestations.
In adults, kidney phenotype is less frequently described, and is usually characterized by slowly progressive chronic kidney disease with tubular dysfunctions.
In particular, the presence of hypomagnesemia (low level of magnesium in the blood serum) is an important predictive criterium to suspect the disease. Additionally, hypokalaemia (low level of potassium in the blood serum), hypocalciuria (low calcium urine excretion, hyperparathyroidism (high level of parathormone in the blood serum), and metabolic alkalosis (elevation of the body’s pH level which becomes too alkaline) could be presented. The disease often goes along with hyperuricemia and gout and may also be accompanied by anomalies of other organs.
► Characteristic findings of bland urinalysis, the universal absence of haematuria and urinary protein excretion, the low prevalence of hypertension, and slowly progressive kidney failure are the hallmarks of this disease.
Kidney and urinary tract malformation and kidney cysts
During routine prenatal ultrasounds, it is possible to detect some changes in the kidneys of the baby. These changes include increased brightness and the presence of cysts or abnormalities in the kidney structure. The kidneys may be small or normal-sized, and present bilateral hypoplasia (small kidneys) or dysplasia (incorrectly developed kidney tissue) with or without cysts (fluid-filled cavities).
► Both isolated bilateral hyperechogenic kidneys and cystic dysplasia in the antenatal period can be highly indicative of HNF1B nephropathy and a postnatal diagnostic work-up is strongly encouraged for these newborns including a renal ultrasound in their parents.
Kidney dysplasia may be associated with other anomalies of the urinary tract, including ureteropelvic junction obstruction (subpelvic stenosis) ureterocele. They may lead to hydronephrosis and recurrent urinary tract infections (UTI) which can both lead to kidney damage. Horseshoe kidney or crossed fused ectopia/kidney malposition could be also observed. The urinary tracts anomalies could be detected accidentally, but also could pre-dispose to urinary tract infections, as well decline of renal function over time during childhood.
DID YOU KNOW?
A Kidney cyst is a round fluid collection formed in or on the kidney. There are several types of cysts, and they can subvert the kidney structure and cause loss of kidney function. Kidney cysts are the most frequently detected feature of HNF1B-associated nephropathy. Cysts are usually small, and they can derive from any segment of the nephron (microscopic functional unit of the kidney), including the glomeruli. Kidney cysts are a common finding in adult patients but rare in children.
You can learn more about the structures of your kidneys and possible malformations here.
Electrolyte disturbances due to tubular transport anomalies
As the HNF1B is not only important for the renal structure development but also for the maintenance of functional kidney tubules, the onset of anomalies of tubular function is frequent since childhood. It may present as increased thirst, impaired concentration capacity of urine and electrolytes imbalance. The first symptoms of HNF1BN can also result from progressive electrolyte disorders, as loss of magnesium and potassium.
Symptoms of potassium deficiency
digestive problems / constipation, muscle cramps, muscle weakness, poor concentration, heart palpitation, contusion, depression, tingling/numbness in arms and legs, breathing difficulties
Symptoms of magnesium deficiency
muscle spasm and cramp, arrhythmia, fatigue muscle weakness, irritability and nervousness, headaches, inability to sleep, hormonal imbalance, mental disorders
► Disorders of tubular transport, including kidney magnesium and potassium loss, affect about 50% of children with HNF1B variants and can appear early in life.
HNF1B regulates expression of channels, and transporters in all segments of the nephron. HNF1B regulates target genes involved in salt handling but also as it is required for nephron development, and the absence of the transcription factor results in rudimentary nephrons lacking mature sections of the tubule. HNF1B is proposed to be important for apical-basolateral polarity and tight junction integrity in the kidney. To what extent this impaired nephron segmentation and apical-basolateral polarity contribute to electrolyte disturbances in HNF1B patients remains yet elusive.
Hypomagnesemia (serum magnesium (Mg2+) <0.7 mmol/l)
is the most common electrolyte disturbance in ADTKD-HNF1B patients. The penetrance of this symptom is estimated to range between 25 and 75% and is caused by hypomagnesuria (increased loss of magnesium in the urine) which is in part due to the control of other gens expression by HNF1B in the distal tubule.
Hypokalemia
resulted from tubular loss of kalium due to disturbed tubular transport and persisted despite worsening renal decline.
Hypercalciuria
is common in patients with ADTKD HNF1B. The exact penetrance of hypercalciuria is unknown because the reference range for renal calcium (Ca2+) excretion has no generally established lower limit. Nevertheless, several studies demonstrated that urinary Ca2+ levels are significantly lower in patients with HNF1B defects.
Hyperuricemia
Patients with the HNF1B variant often have elevated uric acid levels, that may lead to gout symptoms at early age in both sexes.
Gout
is a general term for a variety of conditions caused by persistently elevated levels of uric acid in the blood as uric acid crystallizes and the crystals deposit in joints, tendons, and surrounding tissues, resulting in an attack of gout with red, tender, hot, and swollen joint.
Among patients with kidney dysplasia, hyperuricemia disproportionate to kidney function highly suggests HNF1B nephropathy as underlying cause. Hyperuricemia (serum uric acid>8 mg/dL) is present in 20–30% of all patients with ADTKD-HNF1B. The cause of hyperuricemia in this disease is not well understood, but seems to be a consequence of tubulointerstitial dysfunction, especially expression of renal urate transporter URAT1 in the tubuli, which is regulated by HNF1B. Gout may be the first clinical sign suggestive of the underlying disease, especially when it occurs in the absence of risk factors or typical phenotype characteristics associated with gout, as hypertension, obesity, diabetes, male sex, or old age. In some patients the renal concentrating ability is disturbed. This will lead to polyuria. The urinary losses will be compensated by a higher water intake, resulting in polydipsia.
DID YOU KNOW?
The main task of the kidneys is to remove excess water and waste products from the body by creating urine. Each kidney contains about one million nephrons on average, each consisting of a filter (glomerulus) and a tube called tubulus. In the glomerulus primary urine is formed by filtering circulating blood. These filters are impermeable to blood cells and large proteins. The tubuli are needed to recycle substances which have been filtered in the glomeruli but are valuable to the body such as water, electrolytes (like sodium, chloride, potassium, calcium, magnesium, phosphorus and many others), glucose, amino acids and proteins. They also regulate the acid-base homeostasis. These processes are necessary to maintain a stable balance of body chemicals. In an adult, the kidneys filter about 180 liter of water per day, 99% of which is reabsorbed in the tubuli, leaving about 1.5 liter of final urine. This is possible thanks to the fact that the renal tubules have a total length of 80 km.
They play an important role in the homeostasis of the organism and are the structure with the greater energy requirements of the kidney. The tubular system of nephrons is divided in several segments: proximal tubule, thin limb of Henle, thick ascending limb of, distal tubule, and collecting duct. The tubules correspond to 90% of the renal cortex. Electrolytes are minerals present in the body. They have essential role in nerve and muscle function, balance of blood acidity, body hydration, and they participate in rebuilding damaged tissues. The most important are sodium, calcium, chloride, phosphate, potassium, magnesium; they are found in the bloodstream, urine and other body fluids. Imbalance of the electrolytes can lead to severe disorders. Gout is a type of arthritis caused by the formation of small crystals inside and around the joints. It causes sudden attacks of severe pain and swelling of joints. Gout occurs as a result of the high levels of uric acid in the body that promote the formation of urate crystals. The deposition of urate crystals in the joints is responsible for severe inflammation and intense pain (gout attack).
Chronic Kidney Disease (CKD)
The degree of kidney impairment varies broadly among affected individuals, it ranges from normal to significantly reduced function at birth. Most often, there is a gradual deterioration of kidney function, and the progression of the disease is rather slow during the child development. Impaired kidney function commonly appears in adulthood. Even though the disease usually progresses over the course of several years, it is also possible to make a sudden irreversible progression, leading to kidney failure and the early need for kidney replacement treatment (dialysis or kidney transplant). Despite the prevalence of diabetes mellitus (see below) the so-called diabetic nephropathy (kidney damage induced by diabetes) is extremely rarely in patients with HNF1B variants.
The progression to chronic kidney failure caused by the HNF1B variant, as well as the potential development of diabetic nephropathy, are usually determined by a number of other accompanying factors.
Even in case of severe kidney disease and impaired kidney function, the symptoms can be inconspicuous, especially when the disease develops slowly, and the patient adapts to the changes. It is only over time, at the disease’s advanced stages, that symptoms of renal failure may appear, or otherwise when sudden drop of kidney function occurs, and the body has no time to adapt.
How is chronic kidney failure manifested?
Kidney failure is diagnosed by blood tests through detection of decrease in the so-called glomerular filtration rate (GFR) and increase of creatinine level (waste product). Kidneys have many functions: the clearance of wastes and extra fluid, the regulation of acid-base and electrolytes balance, and furthermore, the production of important substances, like erythropoietin (see below) and vitamin D.
The progressive loss of kidney function may manifest with different symptoms related to the decline of the different renal duties:
Swelling or water retention
If too little urine is excreted, fluid is accumulated in the tissues – swelling of the lower legs at first or swelling of the face is visible especially after night rest.
Hypertension
i.e., high blood pressure, occurs secondary to an increase in vascular resistance as well as water retention in the body. Elevated blood pressure, in turn, has a negative effect on kidney function and this vicious circle usually requires drugs to avoid it. High blood pressure can be both a cause and a consequence of chronic kidney dis-ease. Blood pressure that is too high damages the tiny blood vessels in the kidneys, leading destruction of kidney tissue. Furthermore, persistent hypertension stresses the heart and damages the blood vessel wall, followed by atherosclerosis. Symptoms suggestive of hypertension include headaches, visual disturbances and others.
These general symptoms usually only appear when the GFR falls way below 20-30 ml/min (normal GFR is 80-120 ml/min) and include fatigue, nausea, decreased appetite, general deterioration of clinical condition, increased susceptibility to infections. Other symptoms of advanced kidney failure (i.e., GFR below 20-30 ml/min) may include:
Anaemia
Occurs due to the decreased kidney production of EPO (Erythropoietin) which stimulates the bone marrow to form new blood. Symptoms of anaemia are fatigue, a decrease in physical form and exercise tolerance, pallor of the skin, susceptibility to infections.
Bone demineralization
As a the result of reduced vitamin D synthesis, increased urinary phosphate excretion, and secondary dysregulation of mineral bone metabolism. It can lead to fractures, bone deformities and growth disorders.
Impaired growth
Low growth results from bone demineralization but also loss of appetite and characteristic tissues resistance to growth hormone.
Stages of CKD and level of kidney function
As standard is the eGFR (estimated glomerular filtration rate) calculated from creatinine, age, sex and skin colour. There are different formulas for this, the current and most recommended is the CKD-EPI formula from 2021, previously the MDRD or Cockcroft-Gault formula was also used. In children up to the age of 16 years GFR is estimated using the Schwarz creatinine clearance calculated from serum creatinine and body length:
GFR = (0.43 x length (cm))/serum creatinine (mg/dl)
As serum creatinine is dependent on muscle mass and therefore prone to error (dystrophy, short stature, reduced muscle mass), GFR is currently also determined using cystatin C and the value for children is currently calculated using both values: serum creatinine and serum cystatin and body length.
The symptoms of HBF1 variant as result of abnormal function and development of pancreas
The pancreas is the second most commonly affected organ in patients with HNF1B variants. The pancreas is located behind the stomach, in the upper left abdomen. It is surrounded by other organs including the small intestine, liver, and spleen. The pancreas secretes hormones into the bloodstream and digestive enzymes into the intestinal lumen, it is therefore both an endocrine and exocrine gland.
The anomalies of pancreas seen in patients with HNF1B variants involve the dysregulation of both functions: dysregulations of the endocrine secretion of insulin that cause the development of diabetes as well the loss of the exocrine function which can cause the so-called fatty stools, absorption deficiency of vitamins and microelements, and weight loss. Structural anomalies of the pancreas as atrophy and hypoplasia are observed in approximately 10% and 6% of patients, respectively.
MODY 5 Diabetes and exocrine pancreas insufficiency
Diabetes affects 50-70 % of patients with HNF1B variants. It usually manifests between 10 to 40 years of age but can occur at any age. The peak incidence occurs during puberty and also during pregnancy for women. The diabetes mellitus associated with HNF1B variants is classified as MODY 5 (maturity-onset diabetes of the young). MODY 5 diabetes lacks sensitivity to oral medicines commonly used in the early stages of type 2 diabetes mellitus, so most of patients switch to insulin treatment quite quickly. The control of blood glucose/sugar levels is mainly under control of insulin, which is produced by the pancreas. Insulin allows glucose to be transported into cells and be metabolized as source of energy. If the pancreas does not produce enough insulin, the transport of glucose into the cells is impaired and symptoms of diabetes develop.
However, under certain circumstances, e.g., after kidney transplantation with concomitant high doses of steroids, tacrolimus, or both, diabetes melitus may be unmasked in HNF1B-positive patients requiring specific treatment and often a change in the immunosuppressive regimen. New-onset diabetes after transplant is a serious complication compromising renal graft function. Therefore, screening for HNF1B variants should be considered pre-transplant for patients with kidney failure caused by (cystic) kidney dysplasia. In a subgroup of patients, HNF1B disease first manifests as a disturbance of glucose metabolism. The impaired glucose tolerance and diabetes melitus are rarely observed in childhood but develop later in the clinical course of HNF1B disease.
DID YOU KNOW?
Diabetes melitus, commonly known as diabetes, is a chronic long lasting health condition that causes a blood sugar level to become too high and in which sugar cannot be taken into cells and used as fuel. It can happen when the insulin production is not sufficient, or the insulin could not effectively work. There are different types of diabetes, the most common is the type 2. In this case, insulin couldn't work properly. Diabetes type MODY (Maturity Onset Diabetes of the Young) is a rare form of diabetes mellitus (2-5% of all cases of diabetes) occurring in young people. The onset is typically before the age of 25 years with a relatively mild course and a good response to treatment with diet and oral medications. Insulin resistance is uncommon.
MODY diabetes occurs within families, often in subsequent generations, underlying its genetic background. The cause of the disease is a defect – variant of – a single gene responsible for the secretion of insulin by beta cells of the pancreas. It is inherited in an autosomal dominant way; the disease develops regardless of gender (no sex-related). So far, there are 14 known different types of MODY associated with variants in different genes. In addition to young age onset, MODY diabetes differs from diabetes mellitus type 2 because affects individuals with slim physique (not associated with obesity), has a mild clinical course, and, in most cases, has a good response to oral therapy. MODY diabetes is often accompanied by additional symptoms and manifestations from different organs, which makes it easier to complete the diagnosis.
A common symptom is a decrease kidney threshold for glucose reabsorption, that results with the appearance of glucose in the urine (normally glucose is absent in the urine), even with a normal concentration of glucose in the blood. MODY diabetes often has an insidious onset. A typical sign is an elevated fasting glucose level, but common symptoms are also fatigue, excessive drowsiness, excessive thirst and polyuria, lack or excessive appetite, weight loss. Due to the young age of the patient, often type 1 diabetes is suspected, but no autoantibodies in the blood are found. Unlike type 1 diabetes, the onset of symptoms in MODY diabetes is gradual (type 1 diabetes typically has sudden onset) and there is a 50% probability of developing the disease when at least one parent is affected (in type 1 diabetes much lower). The absence of obesity and the minimal impact of environmental factors on the disease distinguish MODY diabetes from type 2 diabetes.
Can the HNF1B variant affect other organs?
Liver
Developmental anomalies can affect the liver. The Liver can present cysts and altered liver enzymes, although severe impairment of its function is rare. Elevated liver enzyme activity was detected in 13-40% of patients, thus, there is a high degree of variability among the separate studies. Results of liver ultrasound seem to be normal in most cases reported so far. Elevated liver enzymes in the setting of diabetes, pancreatic atrophy, kidney and genital tract mal-formations should always raise the suspicion for the diagnostic possibility of HNF1B variant.
Genitalia/Reproductive Organs
Genital tract anomalies resulting from Müllerian duct aplasia and failure of fusion of the Müllerian ducts have repeatedly been described in patients with HNF1B variants. Overall, genital tract malformations are an inconsistent finding. However, when they are combined with kidney anomalies, HNF1B variant analysis seems advised.
- Anomalies in reproductive organs are often found in affected women, for example abnormal development of the uterus (e.g., uterus bicornis)
- These disorders can cause difficulties in getting pregnant and reaching the end of a pregnancy. However, the atypical structure of the uterus does not always prevent a proper course of pregnancy, as well as may allow a healthy offspring
- These anomalies are usually diagnosed using ultrasound
- Sometimes genital anomalies as cryptorchidism or hypospadias are also seen in boys with HNF1BN (please see below the explanation of those terms)
17q12 Microdeletion Syndrome
About a half of patients with HNF1B variants have a deletion of more than one gene in the region of chromosome 17q12, encompassing HNF1B gene plus at least 14 additional genes. Deletion of 17q12 is incompletely penetrant and its expressivity is highly variable, ranging from severe anomalies, leading to kidney failure before birth, to mild or no problems at all.
While 70% of deletions occur de novo, instances where the deletion was inherited from an asymptomatic parent have been reported. This 17q12 microdeletion additionally to symptoms occurring due to HNF1B variants has also been linked with an increased risk of neurodevelopmental disorders, such as autism. Some people with 17q12 deletion syndrome have seizures, and/or anomalies of the eyes, liver, brain, genitalia, or other body systems. The 17q12 microdeletion syndrome is also inherited in an autosomal dominant manner; in most people with this syndrome, the deletion is not inherited from a parent and occurs sporadically.
People with 17q12 microdeletions have a characteristic facial phenotype, albeit a subtle one not usually obvious in daily life. Macrocephaly is common, along with high arched eye-brows, flattening of the malar region, and epicanthic folds. Pathological short stature is possible, and a characteristic „short and stocky“ body shape occurs in many cases. Speech delay is common, regardless of intellectual functioning.
The most striking association between 17q12 microdeletions and neurodevelopment is the raised prevalence of autism spectrum disorder, with significant increases in both diagnosis and subclinical autistic traits. 17q12 microdeletions have been implicated as one of the major genetic causes of high-functioning autistic spectrum disorders. Reproductive system anomalies are also associated with 17q12 microdeletions, particularly in females. 17q12 microdeletions have been linked to uterine malformations, most the uterus and part of the vaginal canal are absent.
Mayer-Rokitansky-Küster-Hauser Syndrom
In this syndrom the uterus and the vagina fail to develop properly, with concomitant normal ovarian function and normal external genitalia. Women with this disorder develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). The exact aetiology is still unknown due to the complexity of the genetic pathways implicated during the embryogenetic development.
The new data demonstrate that several different genetic defects can cause the syndrome and, in this case, the disease can be considered as of multigenic origin, meaning that different genes can independently be responsible for the syndrome.
17q12 Microdeletion syndrome (especially due to LHX1 and HNF1B variants) belongs to the most reported chromosomal regions and the possible genes implicated in.
DIAGNOSIS
The presence of bilateral kidney anomalies, hypomagnesemia, and/or pancreas anomalies are more specific indicators of the disease, but not always those symptoms occur. Patients with HNF1β mutations can also present in a similar fashion as autosomal recessive polycystic kidney disease, oligohydramnios, and enlarged polycystic kidneys. Sometimes the hypomagnesemia or unexplained liver function abnormalities are the solitary symptoms. Diagnosis of HNF1B nephropathy is often challenging, and the differential diagnosis is complex, as the disease may mimic a variety of renal disorders.
► To make a diagnosis, the patient’s medical history is needed, along with records of symptoms, physical examination and the results of laboratory tests. Due to the high variability of clinical manifestations and different age in which they may appear, the disease is often diagnosed at its advanced stage. The introduction of ultrasound tests into routine prenatal control has allowed the detection of several anomalies, including cystic kidneys or kidney dysplasia, already in the early stages of development, thereby ensuring professional controls and diagnosis of the disorder.
Early diagnosis gives a better chance of providing proper medical care, slowing down the progression of the disease and delay the kidney failure development.
Family History
Despite the autosomal dominant inheritance of the disease, the family history is often negative, i.e., neither of the parents have the disease and do not carry any variants. In fact, the gene frequently mutates spontaneously in the course of embryo development (variant “de novo”). It also happens that due to the wide spectrum of disease symptoms, affected individuals don’t share common features even within the same family. For example, the mother can present solely diabetes without concomitant disorders of other organs and the child can show renal cysts or kidney hypoplasia.
Ultrasound examination
Ultrasound can detect kidney cysts or other malformations of the urinary tract or reproductive system. The exam does not cause pain and is carried out using harmless ultrasonic waves. Findings of kidney cystic dysplasia or bilateral kidney hyperechogenicity can be highly indicative of the disease. In such cases diagnostic clarification including a kidney ultrasound in both parents is strongly advised. Ultrasound can detect kidney cysts or other malformations of the urinary tract or reproductive system. The exam does not cause pain and is carried out using harmless ultrasonic waves. Findings of kidney cystic dysplasia or bilateral kidney hyperechogenicity can be highly indicative of the disease. In such cases diagnostic clarification including a kidney ultrasound in both parents is strongly advised.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is an imaging technique that uses a magnetic field, it allows an accurate evaluation of features, number, location and size of cysts. It can be helpful in monitoring the progression of the disease.
Blood and urine tests
Regular blood and urine tests allow the assessment of kidney function, identification of possible electrolyte disorders (mainly low levels of magnesium and potassium), hyperglycemia and diabetes, gout/hyperuricemia, abnormal liver function.
Genetic Testing
The only way to get a definitive diagnosis of the disease is a genetic test detecting a variant in the HNF1B gene. A patient’s blood sample is required to carry out the genetic test, as well as written consent to the test by the parents/legal guardians and/or the patient of legal age. Genetic testing for HNF1B variants is recommended in the case of early onset diabetes and positive family history of diabetes, especially if associated with kidney cysts or other kidney anomalies, as electrolyte disturbances.
Selecting Patients for screening / The HFN1B Score
A simple and accurate tool to provide a more rational approach to select patients suitable for HNF1B screening is the HNF1B score published by Faguer et all. The optimal cutoff threshold for proceed with the genetic test in a suspected individual is more than 8.
TREATMENT
A specific treatment for this disease has not yet been developed, but a proper diagnosis made in early childhood can largely facilitate the start of therapies that may possibly slow the progression of the disease. Patients need expert care from nephrologists, diabetologists, and nutritionist, ensuring optimal therapy for the control of blood pressure, blood glucose levels and other secondary disorders associated with impaired kidney function.
For many people, even with established kidney impairment, treatment is not needed for a long time. However, it is important that kidney function, blood sugar and blood pressure are monitored regularly.
Testing and Consultation
All affected individuals should have a kidney ultrasound and screening for
- liver function test anomalies
- hypomagnesemia
- hyperglycaemia
- hyperuricemia
Based on baseline kidney ultrasound findings and eGFR, patients may need/ should undergo
- annual ultrasounds
- periodic measurements of serum creatinine
- gynaecologic examination for uterine anomalies
All affected individuals should receive
- proper genetic counselling before family planning
- female individuals with genital anomalies need a gynaecological referral before pregnancy
Supplementation
The occurrence of complications such as kidney anaemia, kidney metabolic acido-sis or electrolyte disbalance is an indication for pharmacological correction of the above-called anomalies. If patients develop hypomagnesemia (low blood magnesium level), especially if associated with spasms, it is recommended to use oral magnesium supplements. Some patients also require regular oral potassium supplementation. Patients who develop gout should be treated with allopurinol to prevent recurrent gout over time.
Treatment of specific clinical pictures
Gout
Patients who develop gout should be treated with allopurinol to prevent recurrent gout over time.
TYPE MODY 5
Diabetes usually requires insulin treatment, but the use of dietary modification and oral antidiabetic therapy may play an important role in the early stage of management.
Chronic Kidney Disease (CKD)
CKD is the progressive and irreversible damage of the kidneys and, over the course of months or years, can lead to kidney failure and the need of renal replacement treatment. There is no specific cure for CKD, but there are treatments that can significantly slow the progression of the disease if started early. Different prescription medications are commonly used to manage the symptoms of CKD or prevent later-stage complications. Some aid in reducing anaemia and hypertension, others in normalizing the balance of fluids and electrolytes in the body.
Some dietary changes would be needed, especially if the kidney function is severely impaired. The dietary advice would be based on the stage of chronic kidney disease, which ranges from stage 1 (minimal impairment) to stage 5, the most severe stage called kidney failure. It is usually recommended, particularly in the early stages, to work with a certified dietician to tailor a diet appropriate to your renal disease The goals of a CKD diet are slowing the progression of the disease and preventing the accumulation of waste products and fluids that can harm different organs, predominately the heart and cardiovascular system.
- Reduction of sodium intake is recommended
- according to the current guidelines, the consumption of 6 g of salt a day (2.4g sodium) – around 1 teaspoon- for adults and 1-2.2 g for children and teens should not be exceeded.
- Based on the stage of renal disease, limiting the intake of protein could be eventually recommended
- as the disease progresses and kidney function drops below 70 percent of normal, a restriction of phosphorus and potassium consumption may be recommended, both electrolytes can harm the body when accumulated.
- Several supplements are commonly used to correct nutritional deficits that can occur in later stages of CKD. Among the recommended supplements:
- Vitamin D and calcium supplements are sometimes needed to prevent the softening of bones (osteomalacia) and reduce the risk of bone fractures caused by Vitamin D deficiency and phosphorus-restricted diet. An active form of vitamin D, called calcitriol, may also be used prior prescription.
- Iron supplements are used to treat anaemia that commonly appear since the stage 3 and stage 4 of CKD. By stages 4 and 5, intravenous iron supplementation may be necessary for people who don’t respond to oral therapy
Dialysis and Transplantation
Please note: Not every patient with HNF1B nephropathy will necessarily progress to kidney failure and not everyone will necessarily need dialysis or kidney transplantation.
Though cysts are often present early in life, most children have a slowly progressive increase in cysts with very slow loss of kidney function, with a mean eGFR loss of 0.33 ml/min/1.73 m2/year. Patients who had increasing cysts over time had a more accelerated decline in eGFR of approximately 3 ml/min/1.73 m²/year. Many patients will require drug treatment throughout their entire life, as insulin injection, supplementation of magnesium and/or potassium, and pharmacological correction of disorders resulting from impaired kidney function. In some cases, the development of end-stage kidney disease will require renal replacement treatment with dialysis or kidney transplant.
Patients with HNF1B nephropathy have a good prognosis associated with kidney transplantation.
All patients undergoing kidney transplantation will require immunosuppressive treatment to prevent transplant rejection. Common immunosuppressants are associated with increased risk of diabetes, this fact could limit the choice of immunosuppressive treatment in patients with HNF1B nephropathy. Also, corticosteroids should be tapered as early as possible to reduce the additional risk of developing diabetes. Concomitant pancreatic and kidney transplantation should be considered in patients with both pancreatic and kidney insufficiency.
What will happen to my child in the future? What are the further prospects for treatment and quality of life?
Incomplete penetrance and a varied clinical presentation make diagnosis as well as prediction of clinical courses in patients with HNF1B-associated disease difficult. Once the diagnosis has been made, further tests are likely to be carried out to detect multiple potential anomalies associated with the disease. In general, periodic clinical controls are indicated throughout the whole life:
- blood pressure assessment
- anthropometric measurements (body high, body weight, calculation of body mass index)
- laboratory tests to assess kidney function, liver function, lipid disorders and dia-betes/glucose intolerance
- kidney/urinary tract/genitalia ultrasound examination.
The frequency of tests depends on the type and severity of anomalies found, as well as the stage of development. These checks will be more frequent during periods of intense growth, i.e., early childhood or adolescence, or in case of identified problems that may need frequent evaluation.
The lives of children, adolescents, and adults with HNF1B nephropathy do not differ significantly from lives of healthy subjects. Young patients should continue their education at school, attend kindergarten, play sports, devel-op their passions and interests in the broadest possible way.
In adolescence or early adulthood, it may be very beneficial for patients to
- find a support group
- use the help of a psychologist or take contacts with people affected by the same disease
- perpetuate a habit of healthy eating and an active lifestyle, thereby reducing the impact of other adverse environmental and behavioral factors that could impact the progression of the disease, such as obesity or smoking.
What can you do for your kidneys yourself? How to live with the disease?
HNF1BN is an inherited disease, which means that its occurrence is conditioned by altered information stored in your genetic material. Unfortunately, this cannot be changed, but through the right lifestyle, diet, and compliance with medical recommendations, you can delay the progression of the disease. Delaying the progression of the disease or the need to ininitiate dialysis or perform kidney transplantation is a goal worth fighting for.
Learn to live with the diagnosis and how to protect your kidneys.
Keep track of regular check ups and take care of regular medication intake if necessary.
The most important function of the kidneys is to filter the blood and eliminate toxins. If you do not take care of proper hydration, hazardous waste will begin to accumulate in your body and cause serious health problems – even due to poor blood perfusion the kidney can suffer damage. The average amount of fluids you should take in normal condition is about 1.5-2 liters per day. Water demand is influenced by age, health, kidney function and potential kidney disease, body weight, climate, and physical activity. Follow the advice of your doctor who will tell you what the best for you is as in advanced kidney disease patients may be forced to drink less than 0.5 liters per day.
So-called nephrotoxic drugs – which include, among others, commonly used non-steroidal anti-inflammatory drugs (aspirin, ibuprofen, or naproxen). Medicines of this type should be used as directed, in the lowest possible doses and the shortest time possible. These drugs reduce blood flow in the kidneys and adversely affect their work. Even a serious disease known as interstitial nephritis can be a consequence of taking this type of medicine for too long. Therefore, itis important to seek advice from nephrologist on which medicines should be strictly avoided or when to adjust the doses of medicines to the degree of kidney function.
The excess of salt intake can cause water retention in the body, increase the blood pressure and the amount of protein contained in the urine, furthermore, it can accelerate the progression of kidney failure. The recommended daily dose of salt (sodium chloride) for adults is maximum 6 g, approximately one teaspoon. Meanwhile, it is quite common to consume an average of 8 g of sodium chloride per day, most of which comes from industrially processed products. Only about 20% of sodium intake comes from the salt added to food during preparation or at the table. The top-10 culprit foods rich in salt are:
-
smoked, processed and cured meats (ham, bacon, corned beef, frankfurters and sausage)
-
fish
-
salted snacks
-
salad dressings
-
sauces prepackaged
-
frozen foods
-
canned pre-made soups
-
cheese
Limit the consumption of these types of products
Lack of movement and lack of physical activity promotes insulin resistanceand obesity, which also lead to the development of hypertension. Obesity further burdens the work of the kidneys and heart and accelerates the progression of the disease.
Smoking, both active and passive, is a high-risk factor for the progression of atherosclerosis, which can also involve the arteries of the kidneys. Renal artery stenosis is one of the most common causes of end-stage kidney disease (so-called ischemic nephropathy). Smoking is also a risk factor for the development of lung, kidney and urinary tract cancers (e.g. bladder cancer). The long-term effects of smoking have many other adverse consequences on health that indirectly affect kidney function.
No matter how busy you are, remember to empty your bladder regularly. Urinary retention promotes the growth and multiplication of bacteria in the urinary tract, which can further cause kidney problems.
Take into consideration your potential constraints, but don’t give up your goals und fulfill your dreams.
SUPPORTIVE CARE
In case of questions or requests for support, do not hesitate to talk to your family paediatrician, paediatric nephrologist or adult nephrologist.
We recommend that you discuss the development of the disease with your doctor, as the progression of the disease is very variable and depends on several factors.In many countries, there are support groups for patients with kidney diseases. The exchange of information and own experiences can be very helpful for many patients and their families. Please find proved patients organisations here on our ERKNet patients' website.
GLOSSARY
| CAKUT (Congenital Anomalies of the Kidney and Urinary Tract) | are malformations of the urinary system present from birth (congenital). In some cases, depending on the exact issues involved, patients with CAKUT may present symptoms only later in life, in other cases patients with CAKUT may develop life-threatening conditions since infancy. |
| CKD (chronic kidney disease) | is a progressive and irreversible damage of the kidneys, that over the course of months or years can lead to kidney failure. There is no cure for CKD, but there are treatments that can significantly slow the progression of the disease if started early. |
| Creatinine | is a normal body waste product derived from muscles. Measurement of its level in the blood is used to assess the kidney function. Most estimations of the GFR are based on the blood creatinine level. The higher the blood concentration of creatinine, the worse the kidney function. In addition to kidney function, the blood level depends on muscle mass and will, for example, increase if you gain a lot of muscle or eat huge amounts of muscle such as huge steaks |
| Cryptochidism | is the failure of one or both testes to descend into the scrotum. It is the most common birth defect of the male genital tract. |
| Cystatin C | is a protein, and the measurement of its level is used to assess the kidney function (blood test). It is produced by all cells containing a nucleus. It is freely filtered through the glomeruli, and then undergoes reabsorption and complete decomposition. Its level in the blood correlates with the glomerular filtration rate. Since its concentration is slightly dependent on age, weight, height and muscle mass. The measurement of cystatin C concentration is effectively used to assess the glomerular filtration rate, using appropriate formulas. |
| Cyst | is a closed sac of membranous tissue that contains fluid, air, or other substances. |
| Dialysis | is a method to artificially remove metabolic waste products and excess fluid from the blood. There are two main types of dialysis: haemodialysis and peritoneal dialysis. In the case of haemodialysis, HNF1B Nephropathyblood is pumped through a filter using an external machine. Peritoneal dialysis involves repeated administration and removal of dialysis fluid into/out of the abdomen which also cleans the blood. |
| Electrolytes | are minerals present in the body. They have essential role in nerve and muscle function, balance of blood acidity, body hydration, and they partic-ipate in rebuilding damaged tissues. The most important are sodium, calcium, chloride, phosphate, potassium, magnesium; they are found in the bloodstream, urine and other body fluids. Imbalance of the electrolytes can lead to severe disorders. |
| ESKD (End-Stage Kidney Disease) | is the most severe form of kidney disease when the kidneys have stopped working (they may still produce urine which is of very poor quality, however). This means that kidney replacement therapy (dialysis or kidney transplantation) is needed. |
| Epididymal cyst | is a harmless fluid-filled sac on a man’s testicle (testis). They are quite common and don’t usually require treatment. When an abnormal growth is detected in the testicle, it should always be evaluated by a doctor to rule out testicular cancer. Agenesis of the vas deferens is a congenital condition in which the tubes that carry sperm out of the testes (the vas deferens) fail to develop properly. It may either be unilateral or bilateral. The vas deferens may also be obstructed when they are completely absent it causes male infertility. |
| Gene | is the genetic unit containing the instruction (“recipe”) how to produce each protein in the body |
| Gout | is a general term for a variety of conditions caused by persistently elevated levels of uric acid in the blood as uric acid crystallizes and the crystals deposit in joints, tendons, and surrounding tissues, resulting in an attack of gout with red, tender, hot, and swollen joint. |
| GFR (Glomerular Filtration Rate) | describes the rate at which the kidneys filter waste products from the blood. GFR is normally higher than 90 ml/min/1.73 m2, a lower value indicates impaired kidney function. A value below 30 ml/min/1.73 m² corresponds to severe kidney failure, at about 10 ml/min/1.73 m² kidney replacement therapy is necessary. |
| Hyperuricemia | occurs if the body produces too much uric acid or does not get rid of enough of it. Too much uric acid in the blood can lead to crystals forming in the joints and tissues, which may cause inflammation and gout symptoms. |
| Hypospadia | is a congenital defect of penis development in which the opening of the urethra is not located at the tip of the penis. |
| Kidney transplantation | means the surgery putting a healthy kidney into a person whose kidney has stopped working (end-stage renal disease). |
| Kidney tubule | is part of the nephron, where the primary urine from the glomerulus is modified by resorption and secretion of molecules. In the tubules about 150 liters of primary urine is modified resulting in about 1.5 liters of urine excreted in the bladder. The tubule consists of several sections: proximal tubule, Henle loop, distal tubule, and collecting duct. |
| Nephron | is a basic functional and structural unit of the kidney. It consists of two parts: the renal filter (glomerulus) and the tubule where reabsorption takes place. |
| Nycturia | means purposeful urination at night, waking from sleep; typically caused by augmented nocturnal urine volume production. |
| Parathyroid hormone (PTH) | is a hormone releases from parathyroid glands to control the serum calcium levels through its effects on bone, kidney, and intestine. PTH influences bone remodeling, which is an ongoing process in which bone tissue is alternately resorbed and rebuilt over time. PTH is secreted in response to low blood serum calcium (Ca2+) level It also controls phosphorus and vitamin D levels. If the body has too much or too little parathyroid hormone, it can cause symptoms related to abnormal blood calcium levels. |
| Polydipsia | means an excessive drinking. This can be a symptom of a number of diseases causing water losses and resulting in excessive thirst |
| Polyuria | is abnormally large urine production (e.g., more than 3 liter per day in adults). |
| Proteinuria | is the presence of abnormal quantities of protein in urine, which may indicate damage to the kidneys. |
| Renoprotection | means the measures taken to prevent damage to the kidney from any cause. |
| Tubulopathies | are kidney diseases in which renal tubular function is impaired while the glomeruli are functioning normally. |
| Uric acid | is a waste product in the body. It’s created when the body breaks down chemicals called purines. Most uric acid dissolves in the blood, passes through the kidneys and leaves the body in urine. Having some uric acid in the blood is normal. However, if uric acid levels go above or below a healthy range, this can result in health problems. At high levels, uric acid crystallizes and the crystals deposit in joints, tendons, and surrounding tissues, resulting in an attack of gout. |
REFERENCES
Bleyer AJ, Wolf MT, Kidd KO, Zivna M, Kmoch S. Autosomal dominant tubulointerstitial kidney disease: more than just HNF1beta. Pediatr Nephrol. 2021,22:10.1007/s00467-021-05118-4. doi: 10.1007/s00467-021-05118-4. Online ahead of print. PMID: 34021396 Review.
Faguer S, Chassaing N, Bandin F, Prouheze C, Garnier A, Casemayou A, Huart A, Schanstra JP, Calvas P, Decramer S, Chauveau D. The HNF1B score is a simple tool to select patients for HNF1B gene analysis. Kidney Int. 2014 Nov;86(5):1007-15. doi: 10.1038/ki.2014.202. Epub 2014 Jun 4. PMID: 24897035
Lim SH, Kim JH, Han KH, Ahn YH, Kang HG, Ha IS, Cheong HI. Genotype and Phenotype Analyses in Pediatric Patients with HNF1B VariantVariants. J Clin Med. 2020, 21; 9(7):2320. doi: 10.3390/jcm9072320. PMID: 32708349
Bockenhauer D, Jaureguiberry G. HNF1B-associated clinical phenotypes: the kidney and beyond. Pediatr Nephrol. 2016 May;31(5):707-14. doi: 10.1007/s00467-015-3142-2. Epub 2015 Jul 8. PMID: 26160100
Bascur P MN, Ceballos O ML, Farfán U M, Gajardo H I, López C J. Detection of variantvariants of the HNF1B gene in children with congenital anomalies of the kidney and urinary tract]. Rev Chil Pediatr. 2018;89(6):741-746. doi: 10.4067/S0370-41062018005001204.PMID: 30725063
Okorn C, Goertz A, Vester U, Beck BB, Bergmann C, Habbig S, König J, Konrad M, Müller D, Oh J, Ortiz-Brüchle N, Patzer L, Schild R, Seeman T, Staude H, Thumfart J, Tönshoff B, Walden U, Weber L, Zaniew M, Zappel H, Hoyer PF, Weber S. HNF1B nephropathy has a slow-progressive phenotype in childhood-with the exception of very early onset cases: results of the German Multicenter HNF1B Childhood Registry. Pediatr Nephrol. 2019;34(6):1065-1075. doi: 10.1007/s00467-018-4188-8. Epub 2019 Jan 21. PMID: 30666461
Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C. HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat Rev Nephrol. 2015;11(2):102-12. doi: 0.1038/nrneph.2014.232. Epub 2014 Dec 23. PMID: 25536396 Review
Ferrè S, Igarashi P. New insights into the role of HNF-1β in kidney (patho)physiology. Pediatr. Nephrol. 2019; 34:1325–1335. doi: 10.1007/s00467-018-3990-7
Cleper R, Reches A, Shapira D, Simchoni S, Reisman L, Ben-Sira L, Yaron Y, Wolman I, Malinger G, Brabbing-Goldstein D, Ben-Shachar S. Improving renal phenotype and evolving extra-renal features of 17q12 deletion encompassing the HNF1B gene.Transl Pediatr. 2021 ;10(12):3130-3139. doi: 10.21037/tp-21-386.
Faguer S, Decramer S, Chassaing N at all. Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood Kidney Int. 2011;80(7):768-76. doi: 10.1038/ki.2011.225. Epub 2011 Jul 20. PMID: 21775974 DOI: 10.1038/ki.2011.225
Tholen LE, Hoenderop JGJ, de Baaij J. Mechanisms of ion transport regulation by HNF1β in the kidney: beyond transcriptional regulation of channels and transporters. Pflugers Arch.2022; 474 (8): 901-916. doi: 10.1007/s00424-022
Bleyer AJ, Wolf MT, Kidd KO, Zivna M,Stanislav Kmoch S. Autosomal dominant tubulointerstitial kidney disease: more than just HNF1β. Pediatric Nephrology 2022, 37, 933–946
Țuțulan-Cuniță Pavel A, Dimos L, Nedelea M, Ursuleanu A et all. Phenotypic Variability of 17q12 Microdeletion Syndrome - Three Cases and Review of Literature. Balkan J Med Genet 2022 24(2):71-82. doi: 10.2478/bjmg-2021-0025.
Izzi C, Dordoni C, Econimo L et all. Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease. Kidney Int Rep. 2020 Dec; 5(12): 2341–2350. doi: 10.1016/j.ekir.2020.09.042