Potter's Syndrome FAQ's

1. What is Potter Syndrome?
Potter Syndrome (PS*) is a term used to describe a typical physical appearance, which is the result of a dramatically decreased amniotic fluid volume (oligohydramnios) secondary to renal diseases such as bilateral renal agenesis (BRA). Other causes are obstruction of the urinary tract, autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant polycystic kidney disease (ADPKD) (in rare cases) and renal hypoplasia.
In 1946 Dr. Edith Potter characterized this prenatal renal failure/renal agenesis and the resulting physical characteristics of the fetus/infant that result from oligohydramnios as well as the complete absence of amniotic fluid (anhydramnios). Oligohydramnios and anhydramnios can also be due to the result of leakage of amniotic fluid from rupturing of the amniotic membranes.

(*: PS is not an accepted acronym for Potter Syndrome by the medical community, but is being used in this text for brevity.)

2. Why is fetal urine important to the development of my baby?
Fetal kidney development begins between 5 and 7 weeks of gestation. Fetal urine production begins in early gestation and comprises the majority of the amniotic fluid in the second and third trimesters of pregnancy. The fetus continuously swallows amniotic fluid, which is reabsorbed by the gastrointestinal tract and then reintroduced into the amniotic cavity by the kidneys. Oligohydramnios occurs if the volume of amniotic fluid is less than normal for the corresponding period of gestation. This may be due to decreased urine production secondary to bilateral renal agenesis, obstruction of the urinary tract, or, occasionally, prolonged rupture of the amniotic membranes. The resulting oligohydramnios is the cause of the physical deformities observed in PS. The fetal urine is also critical to the proper development of the lungs by helping to expand the airways and supplying Proline, a critical amino acid to the lungs.  Alveoli are the small sacs in the lungs that exchange oxygen with the blood. If the alveoli, and thereby the lungs, are underdeveloped at the time of birth the infant will not be able to breathe air properly and will go into respiratory distress shortly after birth due to pulmonary hypoplasia (underdeveloped lungs). The fetal urine also cushions the fetus from being compressed by the mothers’ uterus as it grows.

3. What are the various causes of PS?
Potter Syndrome is not technically a ‘syndrome’ as it does not collectively present with the same telltale characteristics and symptoms in every case. It is technically a ‘sequence,’ or chain of events - that may have different beginnings, but ends with the same conclusion. Below are the different ways that Potter Syndrome (A.K.A Potter Sequence) can begin due to various causes of renal failure. They have been given numbers to differentiate the different forms, but this system
has not caught on in the medical and scientific communities.

Potter Syndrome Type I is due to Autosomal Recessive Polycystic Kidney Disease (ARPKD), which occurs at a frequency of approximately 1:40,000 infants and is linked to a mutation in the gene PKHD1.

Potter Syndrome Type II is due to Renal Adysplasia (RA), which also includes the category known as hereditary renal adysplasia (HRA). Renal adysplasia means that one kidney is absent and the other is very small and malformed. Bilateral renal agenesis (BRA) is considered to be an extreme variation of renal adysplasia and is sometimes called Classic Potter Syndrome. BRA occurs at a frequency of  ~1:3,000 infants, however, others estimate it to occur at 1:1500 to 1:10,000. Our laboratory is primarily concerned with this particular type of PS.

Potter Syndrome Type III is due to Autosomal Dominant Polycystic Kidney Disease (ADPKD) and is linked to mutations in the genes PKD1 and PKD2, however some cases are sporadic. While this form occurs at a frequency of 1:800 people, it is usually only seen in adults and is rarely the cause of oligohydramnios.

Potter Syndrome Type IV occurs when a longstanding obstruction in either the kidney or ureter leads to cystic kidneys. This can be due to chance, environment, or genetics.

Lastly, if the amniotic sac were to rupture and leak fluid, this could also result in PS if it were to happen early in development and went undetected. For a more precise synopsis of PS please visit http://www.kidneygenes.com/Potter%20Synopsis.doc .

4. Why did this happen to my baby?
No one knows the reasons behind every case of PS, that’s why our laboratory is studying this particular birth defect. In some of the cases the genetic causes are already known, such as in ARPKD and ADPKD. But, for the cases of BRA and RA, nobody knows why the kidneys fail to form. Our laboratory is attempting to find out why. Only extensive DNA collection and human genetic research of PS babies and their families can help us identify the genes responsible for BRA and RA.

5. Is PS genetically inherited?
At least two causes of PS are known to be genetically inherited, ARPKD & ADPKD. However, our research with mice and a review of the human cases published in the scientific literature suggest that certain cases of BRA and RA are also genetically inherited in humans.

6. If PS can be genetically inherited, why did my doctor tell me it was a ‘fluke’?
The health history of you, your husband and both of your families are taken into account when determining if a birth defect is genetically inherited or not. In many cases a genetic mutation in the affected fetus is not due to inheritance. Sometimes, things go wrong after the sperm fertilizes the egg, and this could cause a genetic mutation that results in a birth defect. This is not an inheritable trait unless the infant survives with the mutation and reproduces. In other cases, a sperm that failed to develop properly managed to fertilize the egg, and this can result in a birth defect. Often, doctors will call these cases “flukes” because of their rare occurrence. Additionally, little has been done to research the possible genetic causes of BRA and provide clinicians with more information to give their patients. Our laboratory is trying to change this.

7. But my doctor took a blood sample from my baby or performed an amniocentesis and told me that it wasn’t genetic because the chromosomes were fine. How can this still be a genetic defect?
When the high risk OB/Gyn or genetic counselor asks for a blood sample from the baby or performs an amniocentesis they may be checking for several things, one of them may be to check for the proper number of chromosomes (called a karyotype) of the baby. Some birth defects are known to be associated with missing a chromosome, having an extra chromosome (such as in Down Syndrome), as well as by having a part of one chromosome break off and relocate to a portion of another chromosome (called a translocation). However, on each of the 23 pairs of chromosomes are thousands of different genes. While chromosomes are easy to visualize under a microscope and count, the genes on them are not. Genes are very small pieces of DNA when compared to the chromosomes they reside on. A gene contains a code for a protein and if the gene is mutated (different from normal) the protein that is made from it may not function properly - if at all. Unfortunately, genetic abnnormalities could still exist despite having normal chromosomes. The only way to determine genetically inherited mutations in the infant is to perform a genome scan of the mother, father, affected infant and any unaffected siblings of the PS baby. These analyses will reveal what genetic mutations are present in the PS baby and by comparing these results to the surviving siblings and parents we can determine what was inherited or not.

8. Is PS more prevalent in males?
Yes, PS does appear to be more prevalent in males, but so are the majority of other urogenital (urinary and genital systems) defects. Additionally, birth rates demonstrate that there are more males born than females per year. The most important evidence that supports this observation of PS prevalence in males is the timing difference between development of the male and female gonads (testes or ovaries). The tissue that gives rise to the gonads and the kidneys is the same in both males and females. In males the testes will begin to form at the same time the kidneys do, whereas in females, the ovaries begin to form after the kidneys do. There may be a gene critical to male testes development that if mutated can influence the development of the kidneys and possibly cause renal agenesis. However, this hypothesis does not explain why females present with bilateral renal agenesis. Often, females with BRA also present with defects of the reproductive organs (bicornuate or unicornuate uterus, agenesis of the upper and sometimes lower vagina as well as agenesis of the ovaries and fallopian tubes). In males, however, abnormality of the genital system is rare, but does occur. The fact female fetus’ present with BRA (and other cases of PS) contradicts that the genes responsible for BRA (and other cases of PS) are sex exclusive. In both sexes abnormalities of the inner ear, central nervous system, eye and gastrointestinal tract are often present. Only extensive genetic analysis and molecular research will reveal the cause behind BRA.

9. Is there any way to save my baby?
Some babies with PS I, PS III, PS IV as well as some with PS II may survive birth and longer. The key component in determining the survivability of these infants is how well the lungs have developed (see Question 2), as the majority of PS babies expire due to pulmonary hypoplasia before renal failure. If the lungs are adequately developed, and there is some renal tissue, the infant may survive with a proper dialysis and nutritional regimen. The infant will also require a kidney transplant once it has reached a sufficient age and body weight.

In regards to those infants with BRA, the outcome is unfortunately not bright. There has not yet been a BRA baby (no kidneys, no ureters and which also has pulmonary hypoplasia) that has been reported to survive more than a few days past birth. Hopefully this will change in the future.

One thing for a doctor to keep in mind when diagnosing a BRA fetus is whether or not the ureters (the tubes that carry urine to the bladder for excretion) of the fetus have developed or not. In ‘true’ cases of BRA the ureters will not be present, if the ureters are present, then at some point during renal development urine may have been produced. This in turn means that at the top of that ureter there is renal tissue capable of producing urine, even if it is a minimal amount.

In the majority of PS cases (especially RA) where the infant survived past birth there was mechanical replacement of amniotic fluid (called an amnioinfusion). This procedure is often used in order to help visualize the fetus during ultrasound when the amniotic fluid volume is low. However, it has been recently used as a therapy in some cases to maintain an adequate amniotic fluid volume so that the lungs of the fetus properly develop. With each injection of fluid there is a risk for infection to the mother and the fetus, as well as miscarriage and death of the fetus. In the majority of cases involving a BRA or RA fetus this procedure has proven to be unsuccessful. The fluid most often used is sterile saline, which doesn’t contain all of the essential proteins and chemicals for lung development.  If you are considering this interventional therapy please discuss the possible outcomes with your doctors. Even in the event of successful therapy, the fetus could still not develop properly and die at birth or shortly thereafter from other complications. In the event of a successful birth, the infant will be on dialysis for an extended period until they can receive a kidney transplant (assuming that this is the only defect).

10. What are the chances of this happening again during my future pregnancies?
 The health history of you and the father of the baby, as well as those of your families will be key factors in determining recurrence risk. For the majority of mothers the risk is quite minimal. However, there are mothers who are at a minimal risk or have had 2 or more PS babies. The PS babies from these families are probably carrying a genetically inherited mutation that was passed from either the mother or the father. Your family should consult a genetic counselor and give them as much information about your health histories as possible.

11. What should I tell my doctor and/or genetic counselor about the health histories of myself, my husband and our families?
This is a critical area as there is an information gap between the non-clinical research laboratories and the clinicians, as it often takes years for non-clinical data to be accepted or made aware to the medical community. There are many genes that are important for the proper development of the kidneys that are also important for the proper development of the eyes, inner ears, limbs, nervous system, genitals, reproductive systems, and endocrine system (particularly the thyroid, gonads and digestive tract). It is often difficult for a clinician to stay current with every scientific update if they are primarily involved with seeing patients. So, any genetic problems in your family or other diseases that run in your family should be discussed with your doctor/genetic counselor. Tell them everything and between the doctor, genetic counselor and the non-clinical researcher they should be able to give you a very accurate diagnoses/prognosis.

12. What are scientists doing to find the causes of PS?
Our laboratory is collecting blood and DNA from PS families for analysis in an attempt to find the mutated genes that cause PS. As far as our laboratory is aware, we are the only ones’ in the World conducting such research. We will collect as many samples until as we need until we deem that we can begin analysis. Our primary requirement is that we collect DNA from families with at least one BRA infant and at least one unaffected infant. These siblings will be used as a comparison for inheritance.

13. What does your laboratory need from myself and my family to conduct your research?
We are primarily interested at this time in families that have a fetus/infant with true bilateral renal agenesis (BRA). We first require that an autopsy be performed on the infant as this is the only way to confirm the diagnosis of BRA. Secondly we require that a 10mL blood draw be performed on the mother and father of the PS baby. In regards to the PS baby, we will need at least one of the following: a cell culture from the umbilical cord, a 5mL blood draw, or a cell culture taken during the autopsy. As stated, an autopsy must be performed on the BRA fetus/infant as this is the only way to confirm the diagnosis of BRA. Thereby, we will also need the autopsy report to review the records and concur that the stated diagnosis is in-fact BRA. The autopsy is often the key factor where families decide not to participate. The autopsy is a mandatory procedure for our genetic research that is conducted with the utmost respect and with the sole intent of finding the causes behind death of the infant. Additionally, it is not billed to the insurance companies of families. This is particularly important to low income families, or those on hard times. After the examination the infant will be returned to the family for remembrance and a proper burial.

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