Potter Syndrome 

Potter syndrome refers to the typical physical appearance and associated pulmonary hypoplasia of a neonate as a direct result of oligohydramnios and compression while in utero. The term was coined after the pathologist Edith Potter, who in 1946 described the facial characteristics of infants with bilateral renal agenesis.^[1] From her research, she was able to deduce the sequence of events that lead to these features. Other conditions resulting in oligohydramnios, such as obstructive uropathy, cystic kidney diseases, renal hypoplasia, and premature rupture of membranes lead to the same clinical findings. Hence, the terms Potter sequence or oligohydramnios sequence emerged. However, regardless of the root cause for oligohydramnios, the terms Potter syndrome, Potter sequence, and oligohydramnios sequence are used interchangeably in the published literature.

Prior to 16 weeks' gestations, the amount of amniotic fluid is dependent on the transmembrane flow. After that, fetal urine production is the predominant mechanism that determines the amniotic fluid volume. The fetus continuously swallows amniotic fluid, which is reabsorbed by the GI 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 membranes. The resulting oligohydramnios is the cause of the deformities observed in Potter syndrome. The mechanism of lung hypoplasia in this condition is not clear. It is believed that adequate space in the fetal thorax and the movement of amniotic fluid into the fetal lungs is required for the normal development of lungs.

Genetics

During nephrogenesis, multiple genes, transcription factors, and growth factors control the essential interaction between the ureteric bud and the metanephric mesenchyme. For example, the L1M1 and PAX2 transcription factors are essential for the formation of the mesonephric duct, from which the ureteric bud develops. L1M1 -deficient mice have complete renal agenesis. If the PAX2 gene is deficient, there is deletion of the caudal portion of the mesonephric duct, which results in renal agenesis.

WT-1, a zinc-finger transcription factor expressed in the metanephric mesenchyme, is essential for ureteric bud outgrowth. Homozygous null-mutants for WT-1 have complete renal agenesis. Similarly, transcription factor EYA1 from the metanephric mesenchyme is required for ureteric bud outgrowth, and deficiency of this protein is shown to cause branchio-oto-renal syndrome.

The glial cell line–derived neurotrophic factor (GDNF) from the metanephric mesenchyme binds to the C-ret receptor on the branching ureteric bud and is responsible for the branching and elongation of the ureteric bud. Inactivation of either GDNF or the C-ret receptor leads to renal agenesis. Heterozygotes may have a unilateral renal abnormality while the contralateral kidney has normal development.

Limb deformity (ld) gene codes for 4 different spliced formin genes, which are expressed in the mesonephric duct and branching ureteric ducts. Mutation of the ld gene leads to limb deformity with renal agenesis. Mutation of the formin IV gene leads only to kidney abnormalities. Homozygous mutation of the alpha-8 integrin subunit produces abnormalities with similar to ld mutation with deformities including renal aplasia, dysplasia, or hypoplasia.

Transcription factors such as EMX-2, BF-2, fibroblast growth factor 7 (FGF 7), epithelial growth factor receptor (EGF-R), GDNF, retinoic acid receptor alpha, and beta 2 are involved in the branching of the ureteric bud. A heterozygous mutation defect of the growth factor bone morphogenetic protein 4 (bmp 4) leads to renal hypoplasia or dysplasia, ureterovesicular junction obstruction, hydronephrosis, or the bifid/duplex kidney. This is a defect of ureteric branching and not induction of the ureteric bud; thus, renal aplasia does not occur.

The autosomal recessive mutations of genes in the renin-angiotensin pathway result in renal tubular dysgenesis due to failed development of proximal tubules. These are heterogeneous mutations of renin, angiotensin, angiotensin converting enzyme, or type 1 angiotensin II receptor.^[2]

Hepatocyte nuclear factor (HNF)-1beta gene (TCF2) is normally expressed in the Wolffian duct, metanephric tubules, and Mullerian during fetal life. This gene originally described in relation to maturity-onset diabetes, has been now recognized as a cause of cystic renal dysplasis.^{[3, 4]} Uroplakins IIIa is a protein expressed on the mammalian urothelia and has been suggested to be involved in defects of early kidney development like renal hypoplasia/dysplasia.^[5]

Recognized genetic disorders such as renal coloboma syndrome (PAX2 mutation) and branchio-oto-renal syndrome (EYA1 mutation) are therefore associated with renal agenesis or dysplastic kidney abnormalities.^{[6, 7]}

Frequency

United States

Potter syndrome is mostly associated with obstruction of the urinary tract or severe bilateral renal hypoplasia. Bilateral renal agenesis is estimated to occur in about 1 of 5000 fetuses^[8] and is responsible for 20% of Potter syndrome cases. The frequency of other causes of Potter syndrome is not known. The associated maternal high-risk factors for bilateral renal agenesis are maternal body mass index greater than 30, smoking, and binge drinking.^[9]

Mortality/Morbidity

Potter syndrome is usually fatal in the first few days of the patient's life; most often, the cause is pulmonary failure. Bilateral renal agenesis is incompatible with extrauterine life and 33% of fetuses die in utero. Recently, a 70% survival rate has been reported among 23 infants with antenatal oligohydramnios and pulmonary hypoplasia.^[10] The primary disease in these 23 infants included obstructive uropathy, autosomal recessive polycystic kidney disease, renal tubular dysgenesis, and bilateral renal dysplasia.

Neonates with the milder form of Potter syndrome have an increased morbidity rate because of respiratory failure, pneumothorax, and acute renal failure during the neonatal period. During early childhood, patients may have chronic lung disease and chronic renal failure.

A number of abnormalities are associated with bilateral renal agenesis, such as caudal dysgenesis, VATERL ( V  ertebral anomalies, A  nal atresia, C  ardiac defects, T  racheoesophageal fistula, R  enal defects, L imb defects), caudal dysplasia syndrome, and isolated anomalies of the cardiovascular, skeletal, and central nervous systems. These abnormalities can add to the morbidity and increased mortality in these patients.

Race

No racial predilection is known.

Sex

Males have an increased incidence of the Potter syndrome because they have a higher rate of Eagle-Barrett (prune belly) syndrome^[11] and obstructive uropathy secondary to posterior urethral valves.

Age

Patients present as neonates.