Potter Syndrome

Etiology

Potter syndrome is the consequence of a multifactorial inheritance pattern.[2] It involves autosomal dominant and recessive forms, as well as some sporadic cases.[3] Autosomal dominant is the most severe form with incomplete penetrance and variable expressibility. Different abnormal transcription factors, growth factors restrict the induction of ureteric buds from mesonephric tissue. Bilateral renal agenesis is the primary cause of the oligohydramnios. Other causes include obstructive uropathy, polycystic kidney disease, renal hypoplasia, premature rupture of membranes, etc.[4]

Epidemiology

Potter syndrome is a rare condition with an overall prevalence rate of 1 per 2000-5000 births.[5] Generally, it is more prevalent in males than in females.[2][3] The most common age of women involved is between 20-30 years of primigravida.[1]

Pathophysiology

Renal agenesis or hypoplasia is the most common cause of oligohydramnios due to the inability of urine production that determines the amniotic fluid volume. Continuous swallowing of amniotic fluid by the fetus and the absence of urinary excretion leads to decreased amniotic fluid volume corresponding to the gestational age is called oligohydramnios. Urine contribution of amniotic fluid is most prominent in the second and third trimesters. Oligohydramnios causes fetal compression in the uterus by limiting movements of the fetus that leads to deformities of the fetal physical structures. Other mechanisms of Potter syndrome are congenital polycystic kidney disease, urinary obstruction, and premature membrane rupture. So the focal point of Potter syndrome lies in renal agenesis.[6]

Sufficient chest expansion is required for lung development. Also, amniotic fluids provide proline for lung development. Fetal compression by the uterus and fetal intraabdominal organ pressure on diaphragm cause failure of thorax expansion, which keeps alveoli and airways collapsed. Thus the lungs become hypoplastic.

Genetics

Understanding the mechanism of renal agenesis is important to elaborate on the pathophysiology of Potter syndrome. Induction of ureteric buds from mesonephric mesenchymal tissue is required for nephrogenesis, which involves interactions of different genes, transcription factors, and growth factors. Defects of these genes, transcription factors, and growth factors during nephrogenesis cause renal agenesis due to lack of interaction of mesonephros and ureteric bud, and thus mesonephros undergoes apoptosis.[3] Lim1, WT-1, EMX-2, and Pax2 transcription factors play a vital role in the formation of mesonephric ducts and ureteric buds.

The absence of these transcription factors in mice demonstrated renal agenesis. Similarly, the absence of another transcription factor EYA1 required for ureteric bud formation from mesonephros leads to brachio-oto-renal syndrome. Fibroblast growth factor 7, epithelial growth factor receptor, retinoic acid receptor alpha, and beta-2, glial cell line-derived neurotrophic factor is essential for ureteric branching. The involvement of the GREB1L gene is an autosomally dominant mutation in both bilateral and unilateral renal agenesis is found in some cases.[7]

Defects in these growth factors and transcription factors result in hypoplasia or dysplasia but not aplasia. Renal tubular dysgenesis occurs due to the autosomal recessive mutation of renin, angiotensin, type 1 angiotensin II receptor, and angiotensin-converting enzyme.

Histopathology

Histopathology study of lungs shows hypoplasia with inadequate parenchymal development, and in many cases, the respiratory tract and alveoli are lined by cuboidal epithelium. But some cases have no histopathological abnormalities.[1][3] Hyaline membrane formation is prominent in respiratory distress syndrome.[8] Histopathology of gonads reveals hypoplastic gonads with undeveloped seminiferous tubules.[3] Microscopy of renal tissue may show primitive glomeruli, cysts formation with cuboidal or squamous epithelium lining with fluids within dilated cysts.[1]

History and Physical

In recent days, antenatal checkups and screening have been increasing. History of antenatal ultrasonography revealing oligohydramnios, renal agenesis, hydronephrosis, and other renal abnormalities may be conspicuous. Urine output monitoring in neonates supports the clinical diagnosis. Paucity or absence of urine in neonate within 48 hrs of life is highly suspicious of renal agenesis and obstructive uropathy. Neonates suffering from dyspnea, tachypnea, or apnea is an indication of respiratory distress from pulmonary hypoplasia. The presence of associated posterior valves decreases the urinary stream force. Positive family history is present in around 35% of cases with bilateral renal agenesis.

On physical examination, infants have characteristics facies, defects in lower extremities, and genital tracts.[6] Potter facies is characterized by prominent epicanthic folds, low set ears, flattened nose due to uterine pressure, and recessed chin. Limb anomalies (abnormal positioning, hip dislocation, short lower limb, clubbed feet), absent anal opening, hemivertebrae, and sacral agenesis are the common skeletal deformities. Stage of lung development, degree, and duration of oligohydramnios determine the extent of pulmonary hypoplasia.[3]

Color changes, nose flaring, grunting, chest retractions, and wheezing is the usual findings of respiratory distress syndrome. Associated features of Eagle-Barret (prune belly) syndrome with apparent abdominal wall defect, dilated renal pelvis and ureters, undescended testis, especially in a male child, may be present. Ophthalmic malformations likely cataract, hemorrhage, lens displacement, angiomatosis of the optic disc may be present in a few cases. In rare cases, ventricular septal defects, tetralogy of Fallot, patent ductus arteriosus may be evident.

Evaluation

Certain structural deformities such as facial and pulmonary abnormalities are characteristics of Potter syndrome. A definitive diagnosis is made by visualization of bilateral renal agenesis.

Ultrasonography (USG): Prenatal abdominal and transvaginal USG is the mainstay investigation to accurately evaluate the renal agenesis.[9] The absence of urinary bladder and kidneys indicate bilateral renal agenesis. The discoid appearance of adrenal glands with longer craniocaudal length than normal is appreciated in ultrasonography.[10][11] Sometimes, it is difficult to differentiate discoid adrenal glands from kidneys. With the experience of expertise, adrenals distinguished with the absence of kidneys.[8] USG can detect other causes of oligohydramnios such as polycystic kidney, obstructive uropathy. Doppler ultrasonography visualizes poor angiogenesis in hypoplastic lungs and kidneys. Color doppler ultrasonography is adjunct to ultrasonography. The absence of renal artery visualization is suggestive of renal agenesis.

Other imaging: Antenatal magnetic resonance imaging (MRI) is useful in defining renal malformations in equivocal or inconclusive USG findings. Amnioinfusion is helpful in better visualization in cases of decreased amniotic fluid. Chest radiography is useful in detecting pulmonary hypoplasia and hemothorax. Cardiotocograph helps in detecting any congenital heart defects through the evaluation of fetal heart rate.

Laboratory analysis: In patients with suspected Potter syndrome, electrolyte abnormalities such as hypernatremia, hyperkalemia, hyponatremia, hypocalcemia, or metabolic acidosis are evident due to renal failure. Urinalysis for hematuria, or proteinuria but the serum creatinine level is the best indicator of renal function. Chromosomal analysis is recommended in those with physical findings associated with trisomy 7 or 13. An autopsy is performed only in already dead infants. 

Invasive prenatal diagnosis (amniocentesis) is offered if required. Prenatal checkup and regular follow-up for the amniotic fluid index is required to make an early diagnosis of oligohydramnios and so to prevent the complications.[3]

Treatment / Management

Assessment of renal function and respiratory function is important to provide immediate supportive medical care. Resuscitation and management plans should be addressed according to the further associated anomalies of cardiovascular, gastrointestinal, musculoskeletal systems. Early prenatal diagnosis prevents the need for caesarian section delivery.

Management of Renal Failure

Electrolytes imbalances should be corrected, such as hyponatremia, hypernatremia, hypokalemia, hypocalcemia, etc. Calcium and phosphate abnormalities can be treated with calcium carbonate and vitamin D. Anemia due to renal tubular insufficiency, and lack of erythropoietin production can be treated with iron and erythropoietin stimulating agents. Symptomatic treatments of hypertensive children due to activation of the renin-angiotensin system can be achieved with diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers. Growth hormone supplementation in growth retardation cases and nasogastric feeding may be required for adequate nutrition supplements. Excessive fluids and salt intake are restricted in cases of severe renal failure and hypertensive, respectively.

Pulmonary Hypoplasia

Infants with associated pulmonary hypoplasia show pulmonary distress. Ventilatory support is provided with mechanical ventilation and chest tube placement. Oxygenation may be required, but oxygen saturation should be between 90-95%. 

Surgical Management

Various structural anomalies of urinary and renal systems necessitate surgical manipulation. Peritoneal or central venous line dialysis is indicated in renal failure. Valve ablation or vesicostomy provides a good alternative in the obstructive posterior urethral valve that decreases the hydronephrosis and improves renal function.[12] Nephrectomy and renal transplantation are indicated in the large kidney with multiple cysts.

Regular follow-up and careful monitoring of renal function, respiratory function, and effects of drugs are required. Genetic counseling is needed because of unpreventable disease. In cases of bilateral renal agenesis and recurrence with positive family history, meticulous examinations of fetuses and routine ultrasonographic examinations should be followed in future pregnancies and relevant relatives.[2][13] Ethically justified counseling of pregnant women about the management of bilateral renal agenesis should be performed.[14](B3)

Differential Diagnosis

• Bilateral Renal Agenesis (Mayer-Rokitansky-Kuster-Hauser Syndrome): It is the primary cause of classic Potter syndrome. But bilateral renal agenesis does not always lead to Potter syndrome. Mayer-Rokitansky-Kuster-Hauser syndrome is associated with bilateral renal agenesis. Still, the presence of other features of this syndrome, such as congenital uterine anomalies and other urogenital dysplasia, helps to distinguish for Potter syndrome.[7]
• Multicystic Renal Dysplasia: Renal dysplasia with multiple non-communicating cysts formation is the common congenital manifestation of children. The dysplastic renal issue can be recognized in between the cysts. It is considered one of the causes of Potter sequence. Renal insufficiency and low urine output due to multiple cysts kidney lead to the oligohydramnios.[15] 
• Polycystic Kidney Disease: It consists of a large kidney with multiple cysts with less or absent intervening parenchyma in between the cysts. It is an autosomal dominant or recessive disease in children as well as adults. Renal failure in a fetus leads to oligohydramnios that resemble the Potter syndrome.
• Posterior Urethral Valves: The presence of the posterior urethral valve increases the chances of vesicoureteric reflux that prevents amniotic fluid contribution.
• Prune Belly Syndrome: It is more commonly associated with a male child with abdominal wall deformities, skeletal, and renal anomalies, but the urinary bladder is usually dilated. Other genital malformations such as cryptorchidism may be present.
• Sirenomelia: It is a rare congenital disorder characterized by caudal regression and pelvic anomalies. It may be associated with oligohydramnios due to bilateral renal agenesis. Other multiple deformities associated with sirenomelia are lower limb fusion, absent external genitalia, or imperforation. Because of oligohydramnios manifestation, it may lead to Potter syndrome.[16] Due to renal agenesis, adrenal glands on imaging show a discoid shape that creates confusion with Potter syndrome, but other distinct structural abnormalities help in differentiation.[17]
• Ectopic Kidney: Patients having an ectopic kidney demonstrate empty renal fossa and discoid adrenal resembling an ultrasonographic study of Potter syndrome.
• Melnick-Fraser Syndrome: This syndrome has renal malformation ranging from hypoplasia to bilateral renal agenesis. Other associations are preauricular pits, ear malformations, and branchial fistula.[18]
• Fraser Syndrome: It is autosomal recessive disease having renal agenesis, laryngeal atresia, syndactyly, and cryptophthalmos.[19]

Prognosis

The outcome of Potter syndrome is poor. All the babies born are either stillborn or die very early.[20] Neonate associated with hypoplastic lungs are at very high risk, and the primary cause of death is due to respiratory distress syndrome within hours or days after birth. According to the experimental study conducted in John Hopkins hospital, regular saline injected in the mother's womb has enhanced the lung development. But dialysis is required throughout his/her life. A prognostic factor is determined by gestational age at diagnosis, type, and location if associated structural abnormalities. The survival rate is high in Potter syndrome with other causes rather than bilateral renal agenesis. The neonatal mortality rate is 100% if no obstetric interventions are done.[14]

Complications

Renal insufficiency is the major complication of Potter syndrome. Major electrolytes imbalances such as hyponatremia, hypernatremia, hyperkalemia, hypocalcemia, and hyperphosphatemia are due to renal failure. Obstructive uropathy favors urinary tract infections and hydronephrosis. Renal tubular dysplasia has many drawbacks likely erythropoietin deficient anemia, vitamin D insufficiency, and alteration of the renin-angiotensin system.

Most cases of Potter syndrome are associated with pulmonary hypoplasia. This ultimately leads to pulmonary insufficiency and respiratory distress syndrome. Such a neonate is cyanotic and suffers from respiratory acidosis due to the accumulation of CO2 and ventilation-perfusion mismatch.

Physical structures deformities are the prominent characteristics associated with Potter syndrome. Insufficient amniotic fluid for proper fetal movement and body parts development, as well as uterine compression of the fetus, leads to deformities of the face and extremities. Genital abnormalities are present in up to 70% of cases. Other congenital heart defects, pancreatic cysts, esophageal atresia, duodenal abnormalities, colonic agenesis, Meckel diverticulum may be present. Subtype II is associated with hepatic fibrosis and biliary tree abnormalities. Multiple pregnancies are reported with intrauterine growth retardation, preterm labor, and preeclampsia.