What are the other Names for this Condition? (Also known as/Symptoms)

• Allanson Pantzar McLeod Syndrome
• Autosomal-Recessive Renal Tubular Dysgenesis (AR-RTD)
• RTD (Renal Tubular Dysgenesis)

What is Renal Tubular Dysgenesis? (Definition/Background Information)

• Renal Tubular Dysgenesis (RTD) is a serious kidney disorder that is found in a developing fetus. Although its prevalence is not known, RTD is more common in children, if the parents are close relatives
• The causes of Renal Tubular Dysgenesis may either be genetic or non-genetic (acquired)
  • Genetic causes include mutations in the ACE, AGT, AGTR1, or REN genes, which are part of the renin-angiotensin system (a vital body regulatory system)
  • Acquired causes of the disorder include the use of certain medications by the expectant mother as well as abnormalities in the developing fetus, due to congenital disorders (such as hemochromatosis)
• Some of the other risk factors associated with Renal Tubular Dysgenesis include an older sibling who was born with low amniotic fluid volume, use of certain types of medication by the mother during pregnancy for high blood pressure, and conditions such as fetal heart defects
• The signs and symptoms of Renal Tubular Dysgenesis before birth include low amniotic fluid in the mother, underdeveloped or absent proximal tubules in the fetal kidney, and abnormalities in the fetal skull bones
• After birth, the baby may have flat facial features, reduced or no output of urine, large gaps between skull bones, and breathing troubles. Breathing difficulties, respiratory failure, very low blood pressure, and worsening kidney functions are some of the complications that can arise due to Renal Tubular Dysgenesis
• The diagnosis of Renal Tubular Dysgenesis is typically undertaken in prenatal stages with the help of ultrasonography to check the volume of amniotic fluid, the morphology of the fetal kidneys and skull. A confirmation is done through genetic testing of the fetal cells for RTD
• The treatment options for Renal Tubular Dysgenesis is to keep the baby free of distress and may include breathing assistance, fresh-frozen plasma infusions, and peritoneal dialysis
• The prognosis for Renal Tubular Dysgenesis is reported to be poor, with nearly 30% of affected fetuses being stillborn. Many neonates succumb to the condition soon after birth, and very few infants survive into early childhood
• The inherited form of Renal Tubular Dysgenesis cannot be prevented. Genetic counseling may be helpful for ‘at-risk’ parents, to understand the condition better. The acquired form of RTD may be preventable by measures, such as seeking medical advice regarding alternative medication in place of renin-angiotensin system blockers, for high blood pressure in expectant mothers

Who gets Renal Tubular Dysgenesis? (Age and Sex Distribution)

• Renal Tubular Disorder is a congenital condition that affects the kidneys. The general prevalence of this disorder is currently not reported
• It is known to affect fetuses of both genders
• No racial or ethnic group predilection is observed
• Renal Tubular Disorder is known to be common in populations, where children are born to parents who are close relatives (such as first cousins)

What are the Risk Factors for Renal Tubular Dysgenesis? (Predisposing Factors)

The risk factors for developing Renal Tubular Dysgenesis may include:

• A family history of Renal Tubular Dysgenesis; and with a sibling having been born prematurely with a condition known as oligohydramnios (insufficient or low levels of amniotic fluid) that became obvious after the 20th week of pregnancy
• Parents who are close (blood) relatives such as immediate or first cousins
• Mother on medication to treat blood pressure: Medicines to block angiotensin-converting enzymes AT1 receptor during pregnancy can increase the risk
• Fetal heart abnormalities
• Fetal congenital hemochromatosis: It is a genetic condition that affects fetal growth and development; it increases the risk of RTD occurrence
• Mother carrying twins, leading to complications known as twin-twin transfusion syndrome (twins share a common placenta, which can lead to uneven blood flow to the fetuses)

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one's chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Renal Tubular Dysgenesis? (Etiology)

Renal Tubular Dysgenesis can be caused by genetic or non-genetic (acquired) factors. The factors are explained below:

Genetic factors for Renal Tubular Dysgenesis:

• There are many genes that are involved in the renin-angiotensin system. The renin-angiotensin system is very critical in maintaining electrolyte balance, fluid balance, and blood pressure control in the body
• These genes regulate the blood pressure and fluid balance in the body, as well as contribute to kidney development in a growing fetus. Some of the genes in the renin-angiotensin system whose mutations are known to cause RTD include ACE, AGT, AGTR1, and REN
• Therefore, a mutation in one or more of the aforementioned genes can potentially impair the renin-angiotensin system, thereby not allowing the kidneys to control blood pressure. This can result in reduced blood flow (hypoperfusion) and insufficient oxygen supply to the tissues of the developing fetus
• As a consequence, the fetal kidney development is affected (in particular, a part of the kidney known as the proximal tubules are affected). This results in Renal Tubular Dysfunction and other defects, such as abnormalities in the skull bones
• The disorder is inherited in an autosomal recessive manner, in which the affected individual needs to have a mutation in both copies of a gene for the disorder to develop

Acquired factors for Renal Tubular Dysgenesis:

• When a pregnant woman with high blood pressure is on medication to block the renin-angiotensin system, it may lead to the formation of Renal Tubular Dysgenesis in the developing fetus
• In a pregnant woman carrying identical twins (or more), both the fetus may share a single placenta leading to disproportionate blood flow to one of the fetuses. This can result in a condition called twin-twin transfusion syndrome, wherein one fetus has low blood flow, low urine output, causing reduced levels of amniotic fluid. This may be responsible for Renal Tubular Dysgenesis development
• Certain conditions in the fetus, such as heart abnormalities or congenital diseases (including hemochromatosis)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Renal Tubular Dysgenesis?

The signs and symptoms of Renal Tubular Syndrome are observed during the fetal developmental stage. Whether genetic or acquired, the disorder leads to underdevelopment of the kidneys and reduced urine output.

• Fetal urine forms the main component of amniotic fluid, and reduced urine output leads to a condition known as oligohydramnios, or reduced amniotic fluid
• As a result of oligohydramnios, the fetus loses the cushioning effect provided by the amniotic fluid. Additionally, the amniotic fluid contributes to the development of many organs too

Signs and symptoms before birth may include:

• Underdeveloped kidneys in the fetus
• Reduced fetal urine output (anuria)
• Loss of volume of amniotic fluid (oligohydramnios)

Signs and symptoms after birth may include:

• Symptoms  as a result of oligohydramnios, known as the ‘Potter sequence’
  • Flattened nose
  • Ears that are large and set low on the head
  • Abnormal bone structure of the skull, large spaces between skull bones (fontanels)
  • Clubfeet
  • Skin folds owing to excess skin in the body
  • Abnormal fetal lung development (with associated health conditions)
• Anuria or decreased or no urine output
• Respiratory distress
• Low blood pressure

How is Renal Tubular Dysgenesis Diagnosed?

The diagnosis of Renal Tubular Dysgenesis may be undertaken by the following methods:

• Prenatal ultrasonography, wherein abnormal levels of amniotic fluid can be detected
• Ultrasound of the fetus, if abnormality is detected in the amniotic fluid level: It is an examination of the fetus with special emphasis on kidneys and structure of skull
• Genetic testing of fetal cells to confirm inherited forms of Renal Tubular Dysgenesis

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Renal Tubular Dysgenesis?

Renal Tubular Dysgenesis may cause certain complications that include:

• Abnormal ossification (bone formation) of skull
• Very low blood pressure (hypotension)
• Worsening kidney function
• Breathing difficulties, respiratory failure

How is Renal Tubular Dysgenesis Treated?

Many fetuses do not survive the condition and die before birth. If the fetus survives, then the following treatment options for Renal Tubular Dysgenesis may be recommended:

• Infusions of fresh frozen plasma, to improve and maintain blood pressure
• Peritoneal dialysis, to clear waste products
• Respiratory assistance, to help the newborn child breathe better

How can Renal Tubular Dysgenesis be Prevented?

• Currently, there are no specific methods or guidelines to prevent the inherited variation of Renal Tubular Dysgenesis
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• During pregnancy, if a woman has high blood pressure, consulting a healthcare professional to check the possibility of alternative medications in place of renin-angiotensin system blockers, can help prevent Renal Tubular Dysgenesis in the fetus

Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Renal Tubular Dysgenesis.

What is the Prognosis of Renal Tubular Dysgenesis? (Outcomes/Resolutions)

Renal Tubular Dysgenesis is a severe congenital disorder and the prognosis is often reported to be poor.

• The fetuses may die during gestation
• Between 26-30% of neonates with this condition are often stillborn. Also, many neonates die soon after birth
• In rare instances, a newborn baby may survive into childhood. There are reports of children with the disorder surviving near or over the age of 2 years

Additional and Relevant Useful Information for Renal Tubular Dysgenesis:

In a developing fetus, the roles of the genes and sequence of events in regulating kidney function are as follows:

• REN - codes for renin protein
• AGT - codes for the protein called angiotensinogen; angiotensinogen is converted to angiotensin I by renin
• ACE - codes for angiotensin-converting enzyme, which catalyzes conversion of angiotensin I to angiotensin II
• AGTR1 - codes for the angiotensin receptor 1 or AT1 receptor, which binds to angiotensin II, starting a cascade of events
• These events result in increased blood pressure and the production of a hormone known as aldosterone, which regulates kidney function and fluid balance
• The fluid balance in turn influences blood pressure. A proper maintenance of blood pressure is crucial in a developing fetus to deliver oxygen to tissues, which develop quite rapidly