Potter Syndrome

Potter Syndrome

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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. 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 [2, 3] . 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.

The genetic aspect of renal malformation has not been fully understood yet and there is a lot of current research work in this field.

During nephrogenesis, multiple genes, transcription factors, and growth factors control the essential interaction between the ureteric bud and the metanephric mesenchyme. For example, the Lim1 and Pax2 transcription factors are essential for the formation of the mesonephric duct, from which the ureteric bud develops. Lim1 -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 [4, 5] .

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 [6] .

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 [7] .

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 similar to ld mutation with deformities including renal aplasia, dysplasia, or hypoplasia [8] .

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 [9, 10, 11] .

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. [12, 13] . Some reports have suggested that the clinical picture of renal tubular dysgenesis is similar to the infants born to mothers who had received angiotensin converting enzyme inhibitor or angiotensin II receptor blockers during pregnancy [14, 15] .

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 [16, 17, 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. [18]

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, 19] .

Some of the other reported Mutations associated with Renal Hypodysplasia are, FREM 1 (Causes Bifid Nose, Renal Agenesis and Anorectal Malformation) [20] , FRAS 1/FREM 2 (Fraser syndrome) [21, 22] , LRP4 (Cenani-Lenz syndrome) [23] , GLI3 (Pallister-Hall syndrome) [24] , SALL1 (Townes-Brocks syndrome, which has triad of imperforate anus, dysplastic ears and thumb malformation) [25] , KAL1 (Kallman syndrome) [26] , GATA3 (Renal hypodysplasia is associated with Hypothyroidism and sensory-neural deafness) [27] .

There are case reports on families with both unilateral and bilateral renal agenesis. This condition, termed hereditary renal adysplasia (HRA), is an autosomal dominant trait with incomplete penetrance and variable expression. Associated non-urogenital anomalies have been reported in HRA [28] .

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 [29] 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. [30, 31]


Data from 20 registries of 12 European countries was collected on 709,030 livebirths, stillbirths, and induced abortions. Bilateral renal agenesis was seen in 95 cases and out of this prenatal diagnosis was made in 86 cases [32] . In one other study from Europe’s 17 registries reported 4366 cases diagnosed with 11 severe congenital malformations, out of which 257 cases had bilateral renal agenesis [33] .

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. [34] 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 ( ertebral anomalies, nal atresia, ardiac defects, racheoesophageal fistula, enal defects, imb defects) [35] , caudal dysplasia syndrome, and isolated anomalies of the cardiovascular, skeletal, and central nervous systems [36, 37, 38, 39] . These abnormalities can add to the morbidity and increased mortality in these patients.

No racial predilection is known.

Males have an increased incidence of the Potter syndrome because they have a higher rate of Eagle-Barrett (prune belly) syndrome [40] and obstructive uropathy secondary to posterior urethral valves.

Patients present as neonates.

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Sushil Gupta, MD Associate Professor of Pediatric Nephrology, University of Louisville School of Medicine

Sushil Gupta, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, American Society of Pediatric Nephrology, Indian Medical Association

Disclosure: Nothing to disclose.

Carlos E Araya, MD, FAAP Assistant Professor of Pediatrics, University of Central Florida College of Medicine; Faculty, Florida Hospital; Faculty, Nemours Children’s Hospital

Carlos E Araya, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Frederick J Kaskel, MD, PhD Director of the Division and Training Program in Pediatric Nephrology, Vice Chair, Department of Pediatrics, Montefiore Medical Center and Albert Einstein School of Medicine

Frederick J Kaskel, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, Eastern Society for Pediatric Research, Renal Physicians Association, American Academy of Pediatrics, American Pediatric Society, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Federation of American Societies for Experimental Biology, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research

Disclosure: Nothing to disclose.

Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children’s Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, International Society of Nephrology

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Horizon Pharmaceuticals); ; Dicerna, Jannsen Pharmaceuticals.

Laurence Finberg, MD Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine and Stanford University School of Medicine

Laurence Finberg, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Potter Syndrome

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