Potter syndrome

Potter syndrome is a congenital birth defect and is also known as Potter's Syndrome, Potter's Sequence or Oligohydramnios Sequence. Specifically, Potter Syndrome is a term used to describe the typical physical appearances of a fetus or neonate due to a dramatically decreased amniotic fluid volume oligohydramnios, or absent amniotic fluid anhydramnios, secondary to renal diseases such as bilateral renal agenesis(BRA). Other causes of Potter Syndrome can be obstruction of the urinary tract, polycystic or multicystic kidney diseases, renal hypoplasia and rupture of the amniotic sac. The term Potter Syndrome was initially intended to only refer to cases of BRA, however, it has been mistakenly used by many clinicians and researchers to refer to any case that presents with oligohydramniosor anhydramniosregardless of the source of the loss of amniotic fluid.

History

Bilateral Renal Agenesis (BRA) was first recognized as a defect of human fetaldevelopment in 1671by Wolfstrigel. However, it was not until 1946when Edith Potter (b.1901 - d.1993) extensively and painstakenly described the BRA phenotypeof the human fetus that the defect was fully appreciated (Potter EL. Bilateral Renal Agenesis. J Pediatr. 1946; 29:68.; Potter EL. Facial characteristics in infants with bilateral renal agenesis. Am J Obstet Gynecol. 1946; 51:885.). Up until this time the condition itself was considered to be extremely rare. However, in part to Potter's work it has come to light that the condition presents far more frequently than previously reported. Potter analyzed approximately 5000 autopsycases performed on fetuses and newborn infants over a period of ten years and found that 20 of these infants presented with BRA, all of which had distinctive facial characteristics. These facial characteristics have subsequently be termed as being known as Potter facies. From her analysis she was able to deduce the sequence of events that leads to what is now known as Potter Syndrome, Potter Sequence, or OligohydramniosSequence. Potter went on to become a pioneer in the field of human renal development and her contributions are still employed and appreciated by clinicians and researchers to this day.

Types

Since its initial characterization, Potter Syndrome has been defined into five distinct subclassifications. There are those in the medical and research fields that use the term Potter Syndrome to specifically refer to only cases of BRA, while other groups use the term to loosely refer to all instances of oligohydramniosand anhydramniosregardless of the specific cause. The assignment of nomenclature to the various causes (types) were employed in order to help clarify these descrepancies, but, these subclassifications and nomenclature system have not caught on in the medical and research communities.

Classic form

This term is traditionally used when the infant has bilateral renal agenesis (BRA). True BRA also presents with bilateral agenesis of the ureters. After the creation of the nomenclature system for this syndrome, BRA was recognized as possibly being an extreme variation of Potter Syndrome II. However, some clinicians and researchers still use the term Classic Potter Syndrome so as to emphasize that they are specifically referring to cases of BRA and not another form.

Type I

Type I is due to autosomal recessivePolycystic Kidney Disease(ARPKD), which occurs at a frequency of approximately one in 16,000 infants and is linked to a mutation in the genePKHD1. The kidneys of the fetus/neonate will be enlarged, have many small cysts filled with fluid and will fail to produce an adequate volume of fetal urine. The liver and pancreas of the fetus may also show fibrosisand/or a cystic change. For more information about ARPKD visit the Online Mendelian Inheritance in Man (OMIM) link here [1].

Type II

Type II is usually due to Renal Adysplasia(Buchta et al., 1973), which can also fall under the category known as Hereditary Urogenital Adysplasia or Hereditary Renal Adysplasia (HRA). Renal Adysplasia/HRA is characterized by the complete agenesis or absence of one kidney and the remaining solitary kidney being small and malformed. Bilateral renal agenesis is believed to be the most extreme phenotypic variation of HRA. However, BRA is often referred to as "Classic Potter Syndrome" as it was this particular phenotypeof neonates and fetuses that Potter originally reported in her 1946 manuscripts when characterizing this birth defect. For more information about Hereditary Urogenital Adysplasia visit the OMIM link here [2].

Type III

Type III is due to autosomal dominantPolycystic Kidney Disease(ADPKD) linked to mutations in the genes PKD1 and PKD2. While ADPKD is considered to be an Adult Onset Polycytic Kidney Disease, it can also present in the fetus and neonate in rare cases. Like ARPKD, ADPKD can also present with hepatic cysts and an enlarged spleen. An increased prevalence of vascular disease is also observed in these cases of ADPKD. For more information about ADPKD visit the OMIM link here [3].

Type IV

Type IV occurs when a longstanding obstruction in either the kidney or ureterleads to cystic kidneys or hydronephrosis. This can be due to chance, environment, or genetics. While these types of obstructions occur frequently in fetuses, they rarely tend to lead to fetal demise.

Others

Often cystic kidneys that do not fall under the classification of being Polycystic will be termed as being Multicystic renal dysplasia (MRD). Recently many cases of MRD have been linked to the mutations in the gene PUJO, however, this new possible genetic cause has not been assigned a Potter Syndrome nomenclature number. For more information about MRD visit the OMIM link here [4].

Another cause of Potter Syndrome (oligohydramnios or anhydramnios) can be the rupturing of the amniotic sacsthat contain the amniotic fluid of the fetus. This can happen spontaneously, by chance, environment, maternal traumaand in rare cases - maternal genetics.

Terminology: Syndrome vs. Sequence

Potter Syndrome is not technically a syndromeas it does not collectively present with the same telltale characteristics and symptoms in each and every case. It is more accurately described as a "sequence" or chain of events that may have different beginnings (absent kidneys, cystic kidneys, obstructed uretersor other causes), but which all end with the same conclusion (absent or reduced volume of amniotic fluid) . This is why Potter Syndrome is often called Potter Sequence or Oligohydramnios Sequence by some clinicians and researchers. The term Potter Syndrome is most frequently associated with the condition of oligohydramniossequence regardless of the root cause of the absence or reduced volume of amniotic fluid. However, as noted in this article, the term Potter Syndrome was initially coined in order to refer to fetuses and infants with BRA. It was not until later that the term became more encompassing as it was noted that other causes of failed fetal urine production also resulted in similar physical characteristics and prognoses of the fetuses and infants with BRA (that which Potter originally described in 1946). Since then, the term Potter Syndrome has become a misnomer and experts have attempted to not eliminate the terminology, but to modify it in a way so as to be able to determine the different root causes by creating a nomenclature system. However, this classification system has not caught on in the clinical and research fields.

Classic form

Classic Potter Syndrome occurs when the developing fetushas bilateral renal agenesis, which also presents with agenesis of the ureters. BRA has been estimated to occur at a frequency of approximately 1:4000 to 1:8000 fetuses and neonates. However, recent analysis has estimated that the condition may occur at a much greater frequency. The condition has been reported to occur twice as common in males as in females, suggesting that certain genes of the Y chromosomemay act as modifiers. However, no candidate geneson the Y chromosomehave yet been identified.

BRA appears to have a predominantly genetic etiologyand many cases represent the most severe manifestation of an autosomal dominantcondition with incomplete penetrance and variable expressivity. There are several genetic pathways that could result in this condition. To date, few of these pathways or candidate genes have been considered or analyzed regarding BRA. The majority of possible candidate genetic pathways are autosomal recessivein nature and do not coincide with the frequency or penetrance at which BRA occurs in the human population. Additionally, candidate genetic pathways would be expected to involve genes expressed in the developing urogenitalsystem (UGS). Often, these same genes and/or pathways of interacting genes are also expressed in the developing UGS as well as the Central Nervous System(CNS), gut, lung, limbs, and eyes.

Normal kidney development

In humans, the metanephros (adult kidney) begins as an aggregate of mesenchymal cells that are detectable by the fifth gestational week as two small areas in the intermediate mesodermclose to the pelvic aorta. It is approximately at this time that the nephric ductproduces a finger-like projection called the ureteric bud that has, or will soon invade, the aggregate of cells known as the metanephric mesenchyme. The ureteric bud of the nephric duct is stimulated by genetic signals emanating from the metanephric mesenchyme and the ureteric bud brings with it new genetic signals that will help the kidney form. The ureteric bud will grow into, and branch several times within, the metanephric mesenchyme, like a plant root penetrating and growing within ground soil. Eventually, the ureteric bud will form the collecting ducts of the kidney and the uretersof the excretory system. The primitive nephric duct (pronephros) will degenerate to some degree but portions of it will go on to form the correct gender specific organs (gonads). Once the ureteric bud has invaded the metanephric mesenchyme it will stimulate certain cells within the metanephric mesenchyme to condense around the tips of the branches of the ureteric bud and these cellular condensations will eventually form nephronic units (vascularized glomeruli). In humans, all of the branches of the ureteric bud and the nephronic units have been formed by 32 to 36 weeks of gestation. However, these structures are not yet mature, and will continue to mature after birth. Once matured, humans have been estimated to possess approximately one million nephronic units (approximately 500,000 per kidney) or more.

After inducing the metanephric mesenchyme the lower portions of the nephric duct will migrate caudally (downward) and connect with the bladder, thereby forming the ureters. The ureterswill carry urine from the kidneysto the bladder for excretion from the fetusinto the amniotic sac. As the fetusdevelops, the torsoelongates and the kidneysrotate and migrate upwards within the abdomenwhich causes the length of the uretersto increase.

Importance of fetal urine

Fetalkidneydevelopment begins between 5 and 7 weeks of gestation. Fetalurine production begins in early gestationand comprises the majority of the amniotic fluidin the second and third trimestersof pregnancy. The fetus continuously swallows amniotic fluid, which is reabsorbed by the gastrointestinal tract and then reintroduced into the amniotic cavity by the kidneysvia urination. Oligohydramniosoccurs if the volume of amniotic fluidis less than normal for the corresponding period of gestation. The fetal urine is critical to the proper development of the lungs by aiding in the expansion of the airways - alveoli, by means of hydrodynamic pressure and by also supplying Proline which is a critical amino acidfor lung development. Alveoliare 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). This is the primary cause of death to Potter Syndrome infants secondary to renal failure. The fetalurine also serves to cushion the fetusfrom being compressed by the mother's uterusas it grows.

Physical characteristics

The failure of the metanephros to develop in cases of BRA and some cases involving unilateral renal agenesis(URA) is due primarily to the failure of the nephric duct to produce a ureteric bud capable of inducing the metanephric mesenchyme. The failed induction will thereby cause the subsequent degeneration of the metanephros by apoptosisand other mechanisms. The nephric duct(s) of the agenic kidney(s) will also degenerate and fail to connect with the bladder. Therefore, the means by which the fetus produces urine and transports it to the bladderfor excretion into the amniotic sac has been severely compromised (in the cases of URA), or completely eliminated (in the cases of BRA). The decreased volume of amniotic fluidcauses the growing fetusto become compressed by the mother's uterus. This compression can cause many physical deformities of the fetus, most common of which is Potter facies. Lower extremity anomalies are frequent in these cases, which often presents with clubbed feet and/or bowing of the legs. Sirenomelia(Mermaid Syndrome) which occurs approximately in 1:45,000 births (Banerjee A, 2003; Indian J Pediatr) can also present. In fact, nearly all reported cases of sirenomeliaalso present with BRA (Siegel MJ, 2000; J Peri.).

Other anomalies of the Classic Potter Syndrome Infant include a parrot beak nose, redundant skin, and the most common characteristic of infants with BRA which is a skin fold of tissue extending from the medial canthusacross the cheek. The ears are slightly low and pressed against the head making them appear large. The adrenal glandsoften appear as small oval discs pressed against the posteriorabdomendue to the absence of upward renal pressure. The bladder is often small, nondistensible and may be filled with a minute amount of fluid. In males the vas deferensand seminal vesiclesmay be absent, while in females the uterusand upper vaginamay be absent. Other abnormalities include analatresia, absence of the rectumand sigmoid colon, esophagealand duodenalatresia, and a single umbilical artery. Presence of a diaphragmatic hernia is also common in these fetuses/infants. Additionally, the alveolar sacs of the lungs fail to properly develop as a result of the reduced volume of amniotic fluid. Labor is often induced between 22 and 36 weeks of gestation(however, some of these pregnancies may go to term) and unaborted infants typically survive for only a few minutes to a few hours. These infants will eventually expire as either a result of pulmonary hypoplasia or renal failure.

In recorded medical and research history BRA has proved to be 100% lethal in all cases of singletonbirths. Various other forms of the syndrome are, or are near, 100% lethal. To date, there has not been a specific genetic mutation or anomaly that has been linked to be the cause of bilateral renal agenesis (BRA).

Genetics

While genetic research has linked certain genetic mutations to be the cause of ARPKD, ADPKD and possibly MRD, to date no genetic mutation or chromosomal anomaly has been linked to be the cause of BRA. Chromosomal anomalies have been have been associated with BRA in certain cases (Chromosomes 1, 2, 5 and 21), but these anomalies were not inherited and have not been observed in subsequent cases. Additionally, neither extreme substance abuse or environmental factors (high power line, mercury, etc.) have been reported to be linked to an increased incedence of BRA or other cause of Potter Syndrome/Sequence. BRA and other causes of Oligohydramnios Sequence have been linked to a number of other Syndromes/Sequences and Associations, to include Down Syndrome, Kallman Syndrome, Branchio-Oto-Renal Syndrome and others.

The High Risk OB/Gynor genetic counselormay ask for a blood sample from the baby or will perform an amniocentesis. These samples are used to perform several tests, one of which 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 chromosomesare easy to visualize under a microscopeand count, the geneson them are not. Genes are very small pieces of DNA when compared to the chromosomes they reside on. A genecontains a code for a proteinand if the geneis mutated (different from normal) the proteinthat is made from it may not function properly - if at all. Unfortunately, genetic abnormalities could still exist despite having normal chromosomes. The only way to determine genetically inheritedmutations in the infant is to perform a genome scan of the mother, father, affected infant and any unaffected siblings of the affected baby. These analyses will reveal what genetic mutations are present in the affected infant, and by comparing these results to the surviving siblings and parents, it can be determined which mutations were inheritedor were not.

Current research

As of June 2005, a research group at the University of Michigan is conducting human genetic analysis of Bilateral Renal Agenesis and other causes of Potter Syndrome and congenital abnormalities of the urogenital system. This research group is currently the only known laboratory conducting this research in the World.

External links

• University of Michigan Potter Syndrome Research Group
• National Potter Syndrome Support Group (website)
• National Potter Syndrome Support Group (discussion forum)

This article is licensed under the GNU Free Documentation License.
It uses material from the http://en.wikipedia.org/wiki/Potter+syndrome Wikipedia article Potter syndrome.