Potter Syndrome 

Updated: Jan 21, 2015
Author: Sushil Gupta, MD; Chief Editor: Craig B Langman, MD 

Overview

Background

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.

Sonogram obtained before second-trimester amnioinf Sonogram obtained before second-trimester amnioinfusion. This fetus has bilaterally absent kidneys consistent with a diagnosis of Potter syndrome. The cystic structures in the renal fossae are most likely the adrenal glands.

Pathophysiology

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.

Genetics

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] .

Epidemiology

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[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]

International

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] .

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.[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 ( V ertebral anomalies, A nal atresia, C ardiac defects, T racheoesophageal fistula, R enal defects, L 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.

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[40] and obstructive uropathy secondary to posterior urethral valves.

Age

Patients present as neonates.

 

Presentation

History

Features of the history in Potter syndrome may include the following:

  • Antepartum period (Findings of either of the historical factors below requires close follow-up of the neonate during the prenatal and neonatal periods).

    • History of oligohydramnios

    • History of prenatal ultrasonography that reveals renal agenesis or evidence of hydronephrosis (obstructive uropathy) or other renal disorders

  • Neonatal period

    • Absence or paucity of urine output during the neonate's initial 48 hours life

    • Respiratory distress

    • Lack of proper force in the urinary stream in neonates with posterior urethral valves

Physical

Findings at physical examination may include the following:

  • Potter facies: Affected infants have a flattened nose, recessed chin, prominent epicanthal folds, and low-set abnormal ears.

  • Pulmonary hypoplasia: The degree of pulmonary hypoplasia depends on the degree and duration of oligohydramnios, as well as the stage of lung development at which oligohydramnios occurs.

  • Features of Eagle-Barrett (prune belly) syndrome: This is an occasional cause of the Potter syndrome. Neonates have a deficient abdominal wall, undescended testes, dilated ureters, and a renal pelvis[40, 41] .

  • Skeletal malformations: Hemivertebrae, sacral agenesis, and limb anomalies may be present[2] .

  • Ophthalmologic malformations: Cataract, angiomatous malformation in the optic disc area, prolapse of the lens, and expulsive hemorrhage may be present[42] .

  • Cardiovascular malformations: Ventricular septal defect, endocardial cushion defect, tetralogy of Fallot, and patent ductus arteriosus may be present[38] .

  • A study of thirty cases of arthrogryposis associated with longstanding oligohydramnios were identified among 2,500 cases of arthrogryposis and were reviewed for clinical features and natural history. Potter facies and remarkable skin changes were present in all cases.[43]

Causes

Causes of Potter syndrome may include the following:

  • Bilateral renal agenesis

  • Cystic kidney diseases

    • Autosomal recessive polycystic kidney disease

    • Autosomal dominant polycystic kidney disease

    • Multicystic renal dysplasia

  • Obstructive uropathy

  • Early rupture of membranes

A retrospective analysis of children with Potter syndrome found that 21% had bilateral renal agenesis, 47% had cystic dysplasia, 25% had obstructive uropathy, and 5% had other defects. Posterior urethral valves were the most common cause of bladder outlet obstruction (60%).[44]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

See the list below:

  • In patients with suspected Potter syndrome, obtain serum electrolyte tests to evaluate for hyponatremia, hypernatremia, hyperkalemia, hypocalcemia, hyperphosphatemia, and/or metabolic acidosis, which may be present in neonates with renal failure.

  • Serum creatinine levels are used to assess renal function and the glomerular filtration rate (GFR). The GFR can be calculated by using various formulas, such as that reported by Schwartz and colleagues, as follows:

    • In low birth weight (LBW) neonates, the formula is (0.33 X height in cm)/serum creatinine level.

    • In term infants, the formula is (0.45 X height in cm)/serum creatinine level.

    • The serum blood urea nitrogen result is not a good indicator of renal function.

  • Obtain a CBC count with differential to evaluate for anemia secondary to erythropoietin deficiency.

  • Urinalysis is used to reveal either microhematuria or proteinuria.

  • If sepsis is suspected, obtain cultures of the urine, blood, and cerebrospinal fluid.

  • Chromosomal analysis is obtained if the physical examination findings suggest the presence of an associated genetic disorder, such as trisomy 7 or trisomy 13 (Patau syndrome).

  • Other tests, such as evaluations of the urine sodium level, urine creatinine level, urine osmolality, and serum osmolality, are indicated if the neonate has renal failure.

Imaging Studies

See the list below:

  • Prenatal imaging studies

    • Abdominal and transvaginal ultrasonography are effectively used in pregnant mothers with oligohydramnios.

      • Fetal kidneys and adrenal glands are visualized on ultrasound between 12 and 15 weeks' gestations. The differentiation between medulla and cortex of the kidney is appreciated at 20-25 weeks' gestation. The absence of the bladder and kidneys in the fetus implies bilateral renal agenesis.

      • Of fetuses with an empty renal fossa, 47% have been found to have an ectopic kidney[13] . There is a case report of congenital intrathoracic kidney[26] .

      • Prenatal ultrasonographic findings may suggest the presence of other conditions, such as multicystic dysplastic kidney, polycystic renal disease, and obstructive uropathy[45] . In the literature there are potter-classifications, depending on the sonographic appearance of the kidney parenchyma[46] .

    • Doppler ultrasonography

      • Presence of fetal renal arteries helps to distinguish the severe renal hypoplasia from renal agenesis.

      • Doppler ultrasonography can be helpful in depicting fetal pulmonary hypoplasia by revealing poor angiogenesis in the lung and enabling the measurement of the blood-flow velocity waveform of the pulmonary artery[47] .

    • Antenatal MRI has also been used to define the complete renal malformation.[48]

    • Amnioinfusion

      • In case of very low amniotic fluid, amnioinfusion can be helpful to visualize fetus in better way and hence make an accurate Diagnosis.[49]

  • Neonatal imaging studies

    • Abdominal ultrasonography is used to confirm the renal abnormalities detected in the prenatal period.

    • Sonograms also provide useful information related to the bladder and ureters, and they are useful in depicting obstructive uropathy.

    • Chest radiography is used to reveal spontaneous pneumothorax and pulmonary hypoplasia, which has a known association with the Potter syndrome.

    • Other examinations that may be indicated include voiding cystourethrography and nuclear renal scanning.

Other Tests

In neonates who die from this condition, an autopsy is recommended.

Procedures

See the list below:

  • Chest tube placement may be required in neonates with spontaneous pneumothorax.

  • A peritoneal dialysis line or a central venous catheter may be placed in children who have renal failure and require dialysis.

 

Treatment

Medical Care

The renal function and respiratory status of neonates born with Potter syndrome must be assessed.[50] Associated anomalies of the GI, cardiovascular, and musculoskeletal systems should also be evaluated. Once the long-term prognosis of survival is determined, resuscitation and management plans should be addressed.

  • In neonates with bilateral renal agenesis, severe neonatal respiratory distress due to associated pulmonary hypoplasia, and spontaneous pneumothorax, further treatment may not be indicated. The decision should be made after discussion with the parents and all consultants involved.

  • Children with Potter syndrome due to conditions such as infantile polycystic kidney disease, multicystic dysplastic kidney, hypoplastic kidney, Prune-Belly syndrome, and rupture of membranes during gestation have a higher survival rate than children with Potter syndrome due to other conditions.

  • Children who survive the disease require management of the following:

    • Pulmonary hypoplasia: Mechanical ventilation and chest tube placement may be indicated for ventilatory support and for the treatment of spontaneous pneumothorax.

    • Renal function: This is assessed with imaging studies and calculation of the glomerular filtration rate (GFR) by using the serum creatinine concentration.

  • Management of renal failure may be required.

    • Nutrition: Adequate nutrition is required. Nasogastric feeding may be indicated in infants.

    • Electrolyte abnormalities such as hypocalcemia and hyperphosphatemia can be treated with medications, including calcium carbonate and vitamin D.

    • Anemia is treated with oral or parenteral iron and erythropoietin stimulating agents.

    • Children may have hypertension from either fluid-related causes or activation of the renin-angiotensin system. Antihypertensives that may be given include diuretics, beta-blockers, calcium channel blockers, and ACE inhibitors.

    • Growth: The use of growth hormone is indicated in children with a low GFR who do not grow at a healthy rate.

Surgical Care

See the list below:

  • A peritoneal dialysis catheter or a central venous line may be placed for dialysis, if indicated.

  • In patients with posterior urethral valves, vesicostomy or valve ablation may be indicated[51] .

  • Nephrectomy may be indicated in case of Large size polycystic kidney.

  • G-tube placement may be required for adequate nutrition.

Consultations

A neonatologist, pediatric nephrologist, pediatric pulmonologist, pediatric Urologist, geneticist, and pediatric surgeon should be consulted as needed.

Diet

See the list below:

  • Appropriate restriction of fluid during renal failure is indicated.

  • Nutrition with adequate protein and caloric intake is indicated.

  • Children with hypertension must avoid excessive salt intake.

Activity

No restriction of physical activity is needed for children who survive the neonatal period.

 

Medication

Medication Summary

Multiple medications are typically indicated in patients with acute or chronic renal failure. The treatment should address fluid and electrolyte disturbances, hypertension, anemia, calcium and phosphorus disorders, and growth failure.

Treatment regimens for hypertension are designed to reduce blood pressure and other risk factors of coronary heart disease. Diuretic agents help relieve fluid overload associated with renal failure. Additional pharmacotherapy for hypertension associated with renal failure should be individualized based on the patient's age, race, known pathophysiologic variables, and concurrent conditions. Treatment goals are not only to lower blood pressure safely and effectively but also to prevent or reverse hyperlipidemia, glucose intolerance, and left ventricular hypertrophy. For complete information, see the pediatric topics Hypertension and Neonatal Hypertension.

Erythropoietin is essential for red blood cell production and may be required because of decreased erythropoietin levels in renal failure. Vitamin D analogs are essential to provide homeostasis for calcium regulation. Growth hormone may be required because of inadequate growth in children with renal failure.

Pituitary hormones

Class Summary

The anterior lobe of the pituitary gland is responsible for the secretion of adrenocorticotrophic hormone (corticotropin); gonadotrophic hormones (gonadotropins), including follicle-stimulating hormone and luteinizing hormone; growth hormone (somatropin); lactogenic hormone (prolactin); and thyroid-stimulating hormone (thyrotropin). The secretion of anterior pituitary hormones is regulated by a complex interaction between stimulatory and inhibitory neural and hormonal influences. Hypothalamic releasing factors stimulate the release of anterior pituitary hormones into the systemic circulation. Some pituitary hormones (eg, growth hormone) are controlled with a system of double regulation (ie, the hypothalamus secretes a release-inhibiting factor).

Human growth hormone (Genotropin, Humatrope, Nutropin, Serostim, Saizen)

Used to treat inadequate growth in children with chronic renal failure. Stimulates growth of linear bone, skeletal muscle, and organs. Stimulates erythropoietin, which increases red blood cell mass.

Erythropoietin

Class Summary

Glycoprotein is normally produced in the kidneys. It is responsible for the stimulation of red blood cell production. Anemia occurs because of deficient erythropoietin production during renal failure.

Epoetin alfa (Epogen, Procrit)

Derived via recombinant DNA techniques. The amino acid sequence is identical to that of endogenous erythropoietin. Stimulates division and differentiation of committed erythroid progenitor cells; induces reticulocyte release from bone marrow into blood stream.

Colony-stimulating Factor

Darbepoetin (Aranesp)

Darbepoetin is used in anemia associated with chronic kidney disease. It is also used for the treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies. It is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary growth factor produced in kidney that stimulates the development of erythroid progenitor cells.

The mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red blood cell production. It differs from epoetin alfa (recombinant human erythropoietin) in containing 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3. It has a longer half-life than epoetin alfa (may be administered weekly or biweekly).

Diuretic agents

Class Summary

Diuretic agents promote the excretion of water and electrolytes by the kidneys. They are used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention results in edema or ascites. They may be used as monotherapy or in combination to treat hypertension. In renal failure, hypertension is due to fluid overload.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. Dose must be individualized to the patient.

Vitamin D analogs

Class Summary

These agents regulate serum calcium via their actions on calcium and phosphorus metabolism at intestinal, renal, and skeletal sites. The kidney appears to play a central role in this system. It produces calcitriol (ie, 1,25-dihydroxyvitamin D, the primary active metabolite of vitamin D3), which acts on distal organs; at the same time, it is the target organ of PTH; calcitonin; and, possibly, calcitriol.

Calcitriol (Rocaltrol)

Vitamin D analog used in the treatment of vitamin D deficiency. Increases calcium levels by promoting the absorption of calcium in the intestines and its retention in kidneys

Antacid

Calcium carbonate

Calcium carbonate successfully normalizes phosphate concentrations in dialysis patients. It combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces. It is marketed in a variety of dosage forms and is relatively inexpensive.

 

Follow-up

Further Outpatient Care

See the list below:

  • Depends on the underlying renal condition and renal function

  • Close follow-up with a pediatric nephrologist is needed

  • Involves careful monitoring of renal function

  • Requires careful monitoring of respiratory function

  • Includes careful monitoring of medications and their adverse effects.

Further Inpatient Care

Neonates with Potter syndrome should be admitted to the neonatal ICU (NICU).

Inpatient & Outpatient Medications

See the list below:

  • Medications that are used in the treatment of hypertension include beta-blockers, calcium-channel blockers, ACE inhibitors, and diuretics.

  • Diuretics can be used in the treatment of fluid overload and related hypertension.

  • Calcium carbonate is used to treat hypocalcemia and hyperphosphatemia.

  • Vitamin D is used to treat hyperparathyroidism.

  • Erythropoietin is used in the treatment of anemia associated with renal failure.

  • Growth hormone is used in children with growth failure associated with chronic renal failure.

  • Oral or parenteral iron may be required to treat anemia associated with chronic renal failure.

Transfer

Transfer the patient to a center where pediatric subspecialists are available for consultation.

Deterrence/Prevention

No preventive measures are known for any causes listed above.

Complications

See the list below:

  • Associated pulmonary complications include the following:

    • Spontaneous pneumothorax due to pulmonary hypoplasia

    • Neonatal respiratory distress due to pulmonary hypoplasia

  • Associated renal complications include the following:

    • Hypertension that requires antihypertensive drug therapy

    • Hyperkalemia

    • Hypocalcemia

    • Hyperphosphatemia

    • Hyponatremia

    • Acute renal failure

Prognosis

See Mortality/Morbidity.

Patient Education

See the list below:

  • Prenatal care should be provided with the help of a perinatologist.

  • Parents should be fully aware of and educated about oligohydramnios and its long-term consequences on the developing fetus.