The correct answer is E

The correct answer is C

The correct answer is B

Comment: Prune belly syndrome, also known as Eagle-Barrett syndrome, is a rare disorder characterized by partial or complete absence of the abdominal muscles, failure of both testes to descend into the scrotum (bilateral cryptorchidism), and/or urinary tract malformations.

The urinary malformations may include hydroureteronephrosis and vesicoureteral reflux.

Complications associated with prune belly syndrome may include underdevelopment of the lungs (pulmonary hypoplasia) and/or chronic renal failure. The exact cause of prune belly syndrome is not known.

There is no cure for prune belly syndrome, though treatment options and our understanding of the condition are constantly growing. The prognosis for newborns with this condition varies and depends on the severity of symptoms and kidney function.

Although the cause of prune belly syndrome is unknown, some cases have been reported in siblings, suggesting there may be a genetic component. It is known the prune belly syndrome develops as the fetus is growing before birth. Analysis of these cases suggests that urethral obstruction is an important factor contributing to the development of this syndrome.

Some babies who have prune belly syndrome may die in the uterus at 20 weeks of pregnancy or later (stillborn). Some babies with this condition die a few months after birth.

The correct answer is A

Comment: This case has particular features that are consistent with a diagnosis of ZS, based on clinical phenotype and specific laboratory and genetic abnormalities.

Zellweger spectrum disorders (ZSD) are a group of rare, genetic, multisystem disorders that were once thought to be separate entities. These disorders are now classified as different expressions (variants) of one disease process because of their shared biochemical basis. Collectively, they form a spectrum or continuum of disease. The most severe form of these disorders was previously referred to as ZS, the intermediate form was referred to as neonatal adrenoleukodystrophy, and the milder forms were referred to as infantile Refsum disease or Heimler syndrome, depending on the clinical presentation. ZSD can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. ZSD often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. ZSD are inherited in an autosomal recessive pattern.

ZSD are the result of a mutation in any of the 12 PEX genes, whereas most cases of ZSD are due to a mutation in the PEX1 gene. These genes control peroxisomes, which are needed for normal cell function. Peroxisomes break down toxins and fats. They play an important role in the development of the bones, brain, eyes, nervous and cardiovascular systems, and kidneys.

Symptoms of ZS usually appear soon after birth. Facial abnormalities common in ZS include broad nose bridge, epicanthal folds (skin folds at the inner corners of the eyes), flattened face, high forehead, underdeveloped eyebrow ridges, and wide-set eyes.

Other symptoms include difficulty swallowing, hepatosplenomegaly, gastrointestinal bleeding, hearing and vision problems, jaundice, seizures, underdeveloped muscles, and movement problems.

There is no cure for ZS. Some therapies may ease symptoms, but there are not any treatments that address the cause of ZSD. For example, a baby with difficulty eating may benefit from a feeding tube but will not be able to eat normally on his or her own in the future.

The correct answer is E

Comment: The kidneys develop between the fifth and 12th weeks of fetal life, and by the 13th week they are normally producing urine. When the embryonic kidney cells fail to develop, it leads to renal agenesis. Renal agenesis is often detected on fetal ultrasound because there will be a lack of amniotic fluid or oligohydramnios.

When both kidneys are absent, this condition is not compatible with life. Approximately 40% of newborns with bilateral renal agenesis will be stillborn, and if born alive, will live only a few hours.

Neonates with bilateral renal agenesis will have several unique characteristics: dry loose skin, wide-set eyes, prominent folds at the inner corner of each eye, sharp nose, and large low-set ears with lack of ear cartilage. They will typically have underdeveloped lungs, absent urinary bladder, anal atresia, esophageal atresia, and unusual genitals. The lack of amniotic fluid causes some of the problems (undeveloped lungs, sharp nose, clubbed feet); other problems occur because the kidneys and those affected structures are formed at the same time of fetal life (such as the ears, genitals, and esophagus).

Newborns with unilateral renal agenesis may have no other symptoms at all. Unilateral renal agenesis is more common with intrauterine growth retardation (poor growth during pregnancy) and often results in premature birth. It is also more common when a mother is carrying multiple children, such as twins or triplets). Children with unilateral renal agenesis will generally live normal lives with no developmental effects. In fact, many times the solitary kidney is only detected incidentally when x-rays are done for other purposes. The remaining kidney will enlarge to carry out the function normally done by two kidneys. ^,

The correct answer is E

Comment: Congenital ureter anomalies such as double ureters are uncommon developmental anomalies of the renal system. An abnormal branching pattern of the ureteric bud results in the formation of a double ureter.

Duplication of the ureters is frequently encountered by radiologists. Duplication may be either complete or incomplete and is often accompanied by various complications. ^, Incomplete duplication is most often associated with UPJ obstruction (UPJO) of the lower pole of the kidney. Complete duplication is most often associated with vesicoureteral reflux, ectopic ureterocele, or ectopic ureteral insertion, all of which are more common in girls than in boys. Vesicoureteral reflux affects the lower pole and can be outgrown, as in nonduplicated systems. Ectopic ureterocele and ectopic ureteral insertion affect the upper pole. The ectopic ureterocele produces a filling defect of variable size in the bladder; it can be identified with contrast material studies or ultrasound. Ectopic ureters may function poorly, be difficult to detect, and cause enuresis in girls. A fourth complication, UPJO, occurs only in the lower pole and is seen in more boys than girls. Anatomic variants or anomalies as well as suboptimal imaging techniques can either simulate or obscure duplication, making diagnosis difficult. However, familiarity with the embryology of duplication and an awareness of the potential pitfalls of excretory urography and voiding cystourethrography will foster an understanding of the varied appearances and associated complications of both incomplete and complete duplication.

The correct answer is F

Comment: UPJO is one of the most common causes of hydronephrosis in children. If left untreated, it might cause loss of the affected kidney. ^,

During fetal life, the kidneys develop from the metanephric mesoderm up to the distal tubules. The collecting duct, major and minor calyces, renal pelvis, and ureters arise from the ureteric bud that originates from the mesonephric duct during the fifth week of the intrauterine phase. This explains why the UPJ is wholly made by the ureteric bud rather than the fusion of two different mesenchymal tissues.

UPJO results in impaired urine flow from the renal pelvis into the ureter, and if not detected and treated properly, can result in complete loss of the affected kidney.

Hydronephrosis can be detected as an incidental finding on antenatal ultrasound, which might reflect underlying UPJO.

Common symptoms in older children include periodic abdominal pain (loin pain), usually after diuresis, vomiting, fever, recurrent urinary tract infections, or hematuria secondary to infection.

All patients who have symptoms of UPJO should have a full set of blood tests, including complete blood count, kidney function tests, including creatinine, glomerular filtration rate (GFR), and BUN. A urine sample should be sent for analysis and culture because recurrent urinary tract infections are commonly seen in these patients.

In neonates who were found to have mild to moderate hydronephrosis on an antenatal scan, a follow-up scan should be done after 48 hours to avoid the transient neonatal dehydration period; however, in severe cases, a scan should be performed within the first 48 hours because urgent intervention might be needed.

The Society for Fetal Urology grading system is used to evaluate the severity of hydronephrosis as follows:

• 
  

  Grade 0: No hydronephrosis, intact central renal complex seen on ultrasound

  
  
• 
  

  Grade 1: Only renal pelvis visualized, dilated pelvis on ultrasound, no caliectasis

  
  
• 
  

  Grade 2: Moderately dilated renal pelvis and a few calyces

  
  
• 
  

  Grade 3: Hydronephrosis with nearly all calyces seen, large renal pelvis without parenchymal thinning

  
  
• 
  

  Grade 4: Severe dilatation of renal pelvis and calyces with accompanying parenchymal atrophy or thinness

UPJO is mainly a congenital condition that can be detected by antenatal ultrasound during the second trimester. ^,

Pediatric UPJO might be associated with other congenital anomalies such as an imperforated anus, multicystic kidney, and ipsilateral ureterovesical reflux. In similar patients, UPJO should be treated first because distal ureteric diseases are commonly not severe.

In cases of a duplex renal system, the lower moiety is more commonly affected; in this case, ureterovesical reflux is likely to be found and can be diagnosed using voiding cystourethrogram (VCUG).

Diuretic renography is one of the most important studies used to determine the split function of each kidney and identify any renal evidence of obstruction and is the gold standard for the evaluation of the severity of UJPO. The most commonly used agent in renogram studies is technetium 99m mercaptoacetyltriglycine, especially in the pediatric population. The agent is usually secreted by proximal renal tubules in a small amount that should be filtered by renal glomeruli. The kidney is considered to be significantly damaged if the split function in one of the kidneys is less than 40% of the total kidney function; this should be in correlation to the half-life of the agent. In the adult population, other agents can be used, such as diethylenetriamine pentaacetate.

VCUG should be used to rule out the ureterovesical reflux role to hydronephrosis if diuretic demography does not detect UPJO.

In patients with a split renal function of more than 40%, the diuretic renogram should be repeated at 3-, 6-, and 12-month intervals. Surgery is to be performed if function has deteriorated.

The indications for surgical treatment include:

• 1.
  

  UPJO with less than 40% in the split function of the affected kidney on the diuretic renogram.

  
  
• 2.
  

  Renal parenchymal atrophy from severe bilateral UPJO.

  
  
• 3.
  

  Recurrent infections despite using prophylactic antibiotics.

  
  
• 4.
  

  Symptomatic obstructive UPJO or that associated with an abdominal mass.

Dismembered pyeloplasty is the gold standard technique used by surgeons. The main advantage of this procedure is to save the crossing vessel if present. ^,

Nondismembered pyeloplasty is used in case of high insertion of the ureter and no crossing vessel. It is inferior to dismembered pyeloplasty.

Surgical complications of UPJO include:

• 1.
  

  Pyelonephritis

  
  
• 2.
  

  Urinary extravasation and leakage

  
  
• 3.
  

  Recurrent UPJO

  
  
• 4.
  

  Bleeding

  
  
• 5.
  

  Trauma to surrounding organs

The correct answer is E

Comment: Meckel-Gruber syndrome is a lethal, rare, autosomal recessive condition characterized by the triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly. Associated abnormalities include oral cleft, genital anomalies, central nervous system malformations, including Dandy-Walker and Arnold-Chiari malformation, and liver fibrosis. ^, Pulmonary hypoplasia is the leading cause of death. Improvements in ultrasonography have enabled prenatal diagnosis as early as 10 weeks’ gestation.

This syndrome was first described by Johann Friedrich Meckel the Younger in 1822. He described two sibling neonates, a boy and a girl who had the combination of microcephaly with occipital encephalocele, cleft palate, polydactyly, and large cystic kidneys. In the boy, the testes were near the lower pole of the kidneys and the external genitalia were more female-like. Meckel mentioned that he suspected that the infants were an example of heredity because he had seen other instances of anomalies within given families. More than a century after, Gruber reported similar cases he had encountered and added a few more from the literature for a total of 16 cases. Gruber named the disease dysencephalia splanchnocystica and mentioned that it was genetic because many of the abnormalities were among siblings. Meckel syndrome is usually lethal in early infancy because of the severity of renal and central nervous system malformations.

The correct answer is A

Comment: Joubert syndrome is an uncommon autosomal recessive condition characterized by hypoplasia of the cerebellar vermis (demonstrated by MRI as the “molar tooth sign”), intellectual disability, retinal dystrophy, ocular coloboma, rotatory nystagmus, polydactyly, cystic renal dysplasia, and congenital hepatic fibrosis. Its neurologic manifestations usually come to medical attention in infancy. The syndrome was initially described in a French-Canadian family with four affected siblings by pediatric neurologists in Montreal more than 40 years ago. One of the original children had an occipital meningoencephalocele that was removed at birth.

The two different forms of renal disease that have been described in Joubert syndrome are cystic renal dysplasia and nephronophthisis (tubulointerstitial nephritis and cysts at the corticomedullary junction). Clinically, these children present with polydipsia, polyuria, anemia, growth failure, elevated creatinine, and later develop renal failure.

Recently, it has become known that Joubert syndrome is due to ciliary disorders and there is some overlap in clinical presentations with Meckel and Bardet-Biedl syndromes (e.g., occipital meningoencephalocele, congenital hepatic fibrosis, obesity, ambiguous genitalia). So far, the molecular genetics of Joubert syndrome includes eight mutations in the ciliary/basal body genes: INPPFE , AH11 , NPHP1 , CEP290 , TMEM67/MKS3 , RPGR1P1L , ARL13B , and CC2D2A . At a molecular level, it has been demonstrated that Joubert and Meckel syndromes share at least one gene mutation ( TMEM67 / MKS3 ) and it seems logical to infer that in the future more common mutations will be found.

Some individuals may have a mild form of the disorder with minimal motor (movement) disability and good mental development or may have severe motor disability with moderate impaired mental development and multiorgan impairments.

Current treatment options are symptomatic and supportive. Infant stimulation and physical, occupational, and speech therapy may benefit some children, in addition to regularly monitoring symptoms. Routine screening for progressive eye, liver, and kidney complications associated with Joubert syndrome–related disorders is highly recommended.

The correct answer is A

Comment: The VACTER-L acronym stands for vertebral anomalies, anal, and cardiac malformations, tracheoesophageal fistula/atresia, radial and renal anomalies, and limb malformations. The majority of experts in VACTER-L require at least three of these anomalies to establish a diagnosis. When there is esophageal atresia, the first intrauterine manifestation is polyhydramnios. Tracheoesophageal fistula can be documented at autopsy and renal dysplasia is common in these children. ^,

The differential diagnosis includes Baller-Gerold syndrome (certain facial features and radial aplasia or hypoplasia), CHARGE syndrome (besides choanal atresia and coloboma, there can be cardiac and genitourinary anomalies), Currarino syndrome (lumbosacral malformations, constipation, and renal abnormalities), deletion 22q11.2 syndrome (cardiac, vertebral, and renal anomalies), Fanconi anemia (radial hypoplasia/aplasia, thumb anomalies, and hematological conditions), Feingold syndrome (hypoplastic thumb, renal, and cardiac congenital disease), Fryns syndrome (congenital diaphragmatic hernia, cardiac disease, and hypoplastic thumb), MURCS association (müllerian duct, renal agenesis, and cervical vertebral defects), oculoauriculo-vertebral syndrome (vertebral anomalies hypoplasia of maxilla and mandible and ear anomalies), Pallister-Hall syndrome (abnormal digits and imperforate anus), Townes-Brocks syndrome (thumbs, auricular, and anal anomalies), and VACTER-L with hydrocephalus. A careful physical examination and family history are helpful to narrow down which conditions are most likely in a patient with features suggestive of VACTER-L association. For example, autosomal dominant inheritance of certain features may suggest Townes-Brocks syndrome, and the presence of other features not typically seen in VACTER-L association may hint toward other disorders, such as pigmentary abnormalities in Fanconi anemia or hypocalcemia in deletion 22q11.2 syndrome. A panel of experts published an excellent article about the approach to confirm suspected VACTER-L. According to them, the initial workup should include a complete family history and physical examination, a supine anteroposterior chest radiograph, supine anteroposterior and lateral views of the entire vertebral column, including sacral views, and a transthoracic echocardiogram to look for congenital heart disease. In patients with increased oral secretions, choking with feeds, or respiratory distress, an attempt to pass a nasogastric tube will help confirm or exclude esophageal atresia. Anorectal malformations can be detected by physical examination in the majority of cases, but to better determine the extent of anomalies, an abdominal ultrasound should be performed. Radial and thumb anomalies are usually detected by simple inspection, but radiologic examination of the affected extremity will better delineate the malformation. To exclude Fanconi anemia, a complete blood cell count is extremely helpful.

The correct answers are A, B, and D

Comment: Short rib syndrome is one of the lethal osteochondrodysplasias and has been traditionally divided into four types (I, Saldino-Noonan; II, Majewski; III, Verma-Naumoff; and IV, Beemer-Langer).

These autosomal recessive, skeletal ciliopathies are characterized by a narrow thorax resulting from short ribs, cleft lip, and/or cleft palate, cystic renal dysplasia, congenital hepatic fibrosis, pancreatic cysts, ocular and cerebral anomalies, and abnormal genitalia. Polydactyly is variably present. The histology of the kidneys and liver is undistinguishable from the findings in patients with Meckel and Joubert syndromes.

The correct answer is C

Comment: The cardinal manifestations of Bardet-Biedl syndrome are retinitis pigmentosa, obesity, renal dysplasia, polydactyly, learning disability, and hypogenitalism. The diagnosis may be confirmed later as a young adult if the patient presents in childhood only with truncal obesity and learning disabilities but has normal vision and lacks polydactyly or syndactyly and hypogonadism. However, as patients age, visual and renal problems become more severe and virtually 100% of individuals with Bardet-Biedl syndrome will develop poor vision. The possibility of renal insufficiency increases with age. It is inherited in an autosomal recessive manner. Interfamilial and intrafamilial phenotypic variability exist. Prenatal diagnosis in affected families can be made by fetal ultrasound examination with the detection of polydactyly and cysts in the kidneys. Once the affected gene has been detected in a family, it is possible to look for the known gene. Presently, 18 genes have been associated with Bardet-Biedl syndrome: BBS1 , BBS2 , ARL6 ( BBS3 ), BBS4 , BBS5 , MKKS ( BBS6 ), BBS7 , TTC8 ( BBS8 ), BBS9 , BBS10 , TRIM32 ( BBS11 ), BBS12 , MKS1 ( BBS13 ), CEP290 ( BBS14 ), WDPCP ( BBS15 ), SDCCAG8 ( BBS16 ), LTZFL1 ( BBS17 ), and BBIP1 ( BBS18 ). Histologically, the kidneys show extensive replacement of parenchyma by round cysts lined by flat to cuboidal epithelium. The glomeruli are preserved. Persistent fetal lobulations have been described, suggesting a defect in renal maturation. ^,

The correct answer is C

Comment: This syndrome is characterized by hypoplastic lower extremities, caudal vertebrae, sacrum, neural tube, and urogenital system. There may also be an imperforate anus. Renal anomalies include bilateral renal agenesis, renal dysplasia, and horseshoe kidney. Frequently, placentas have a single umbilical artery and less commonly have amnion nodosum secondary to oligohydramnios. ^, These patients may also have congenital heart disease and their mothers frequently have pregestational diabetes mellitus. The association of polysplenia and caudal dysplasia has been reported.

Infants of diabetic mothers have three to four times the incidence of congenital malformations than that in the general population. They can have skeletal, neurologic, genitourinary and digestive tract maldevelopment, and caudal dysplasia syndrome. The brain and proximal spinal cord are normal in children with caudal dysplasia. Surviving children usually have a normal intelligence but tend to have lower extremity difficulties as well as urinary problems and may require extensive intervention by pediatric orthopedics and urologists. Prenatal diagnosis can be made by fetal ultrasound and parental counseling should be offered depending on the severity of malformations.

The correct answer is F

Comment: ADPK is a relatively common condition that affects 1 of every 400 to 1000 live births and accounts for approximately 10% of patients with chronic renal failure requiring dialysis or transplant. ADPK should be considered a systemic disorder that mainly affects adult patients who can also develop hepatic and pancreatic cysts, chronic hypertension, intracranial aneurysms, and cardiac valve anomalies, especially mitral valve prolapse. The likelihood of renal failure increases progressively with age after 40 years, rising to 25% by age 50 years, 40% at 60 years, and 75% at age 70 years. The kidneys of adult patients contain multiple round cysts of variable size filled with urine and blood, becoming extremely large and extending up to 10 times their normal weight. Histology reveals completely disorganized renal parenchyma with large cystically dilated tubules and occasional glomeruli and fibrotic interstitium with chronic inflammation. ^,

For many years, ADPK was considered an untreatable renal disease leading to chronic renal failure and required either dialysis or transplant, but more recently there is some hope of a better treatment by early administration of an arginine-vasopressin (AVP)-V2 receptor inhibitor in individuals with subclinically detected disease. The rationale behind this therapy is that the collecting ducts and distal nephrons (that are the more severely affected by cysts in ADPK) are sensitive to vasopressin. This receptor is the main hormonal regulator of adenyl cyclase activity in collecting ducts. To avoid dehydration, mammals live under the constant action of AVP on the distal nephron and collecting duct. When the individual drinks large volumes of water, plasma AVP levels decrease enough to make the urine more dilute than plasma; therefore, during most of the day, cyst epithelial cells undergo stimulation to secrete fluid. The circulating levels of AVP are likely elevated in patients with ADPK to compensate for the reduced concentrating capacity of the affected kidneys and the AVP effect leads to cyst formation. The administration of an AVP receptor inhibitor delays the cyst formation but does not help the regeneration of tubular epithelium; therefore, it is critical to start treatment as early as possible to prevent cyst formation. Other recommendations are to drink plenty of fluids, up to 3 L/day for adults and proportionately less for children, avoid caffeine, decrease salt and protein intake, add angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers to lower blood pressure and decrease the amount of fat ingested. In addition, prescribe a cholesterol-lowering agent. ^,

The correct answers are D and E

Comment: Autosomal recessive polycystic kidney (ARPK) disease is currently considered a primary ciliopathy that equally affects the kidneys and liver. ARPK has an incidence of 1:20,000 to 1:40,000 live births and a heterozygous carrier rate of 1 in 70. It occurs as a result of a mutation in a single gene named Polycystic Kidney and Hepatic Disease ( PKHD1 ). Severely affected fetuses are born with oligohydramnios, Potter face, and some will develop respiratory insufficiency, but many survive the neonatal period. Of all neonatal survivors, approximately 40% have severe hepatic and renal disease. Of the remaining children, 30% present with severe renal and mild hepatobiliary disease and the other 30% with severe hepatobiliary problems and mild renal disease. ^,

The renal pathology is extremely characteristic because it is always bilateral, the organ is enlarged but maintains its reniform shape, and when opened it transudates a large amount of urine. Histologically, the cysts are elongated and their long axis is perpendicular to the capsule. The hepatic manifestations are congenital hepatic fibrosis (CHF), which is indistinguishable from the CHF found in other ciliopathies such as Meckel, short rib, or polysplenia. Secondary to liver fibrosis, autosomal dominant polycystic kidney (ADPK) disease develop portal hypertension, esophageal varices, hemorrhoids, upper gastrointestinal bleeding, splenomegaly, and hypersplenism. ^,

Genetic studies have demonstrated that ARPK is associated with two genes ( PKD1 and PKD2 ). The former produces the severe form of the disease and its gene product, polycystin-1, is a receptor-like integral membrane protein that seems to be involved in cell-cell matrix interactions and also plays a role in calcium homeostasis through its physical interaction with polycystin-2, the protein product of PKD2 . ^,

Parents of a child born with ARPK who are obligate carriers may be offered preimplantation genetic diagnosis using single-cell multiple displacement amplification products for PKHD1 haplotyping, which significantly decreases the problem of allelic dropout. This specific protocol uses whole-genome amplification of single blastomeres, multiple displacement amplification, and haplotype analysis with 20 novel polymorphic short-tandem repeat markers from the PKHD1 gene and flanking sequences. ^,

Once the child is born with the disease, the current treatment is symptomatic. However, in cases of severe renal and hepatobiliary disease, the combined renal-liver transplant looks promising because the outcome of liver transplant has improved recently and it has been proven that if left unattended, CHF may lead to ascending cholangitis, sepsis, portal hypertension, and gastrointestinal bleeding. All of these complications could impact the ultimate outcome of liver transplant months or years after renal transplant. The future seems more promising for these patients because there are several preclinical trials that hopefully will discover new treatment modalities to block fluid transfer into the tubular epithelial cells and decrease or completely block cyst formation. ^,

The correct answer is F

Comment: CHARGE syndrome is a disorder that affects many areas of the body. CHARGE is an abbreviation for several of the features common in the disorder including coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities. The pattern of malformations varies among individuals with this disorder, and the multiple health problems can be life-threatening in infancy. Affected individuals usually have several major characteristics or a combination of major and minor characteristics. ^,

The major characteristics of CHARGE syndrome are common in this disorder and occur less frequently in other disorders. Most individuals with CHARGE syndrome have a gap or hole in one of the structures of the eye (coloboma), which forms during early development. A coloboma may be present in one or both eyes and may impair a person’s vision, depending on its size and location. Some affected individuals also have abnormally small or underdeveloped eyes (microphthalmia). In many people with CHARGE syndrome, one or both nasal passages are narrowed (choanal stenosis) or completely blocked (choanal atresia), which can cause difficulty breathing. Affected individuals frequently have cranial nerve abnormalities. The cranial nerves emerge directly from the brain and extend to various areas of the head and neck, controlling muscle movement and transmitting sensory information. Abnormal function of certain cranial nerves can cause swallowing problems, facial paralysis, a sense of smell that is diminished (hyposmia) or completely absent (anosmia), and mild to profound hearing loss. People with CHARGE syndrome also typically have middle and inner ear abnormalities, which can contribute to hearing problems, and unusually shaped external ears.

Affected individuals frequently have hypogonadotropic hypogonadism, which affects the production of hormones that direct sexual development. As a result, males with CHARGE syndrome are often born with an unusually small penis (micropenis) and undescended testes (cryptorchidism). Abnormalities of external genitalia are seen less often in affected females. Puberty can be incomplete or delayed in affected males and females. Another minor feature of CHARGE syndrome is tracheoesophageal fistula, which is an abnormal connection (fistula) between the esophagus and the trachea. Most people with CHARGE syndrome also have distinctive facial features, including a square-shaped face and differences in appearance between the right and left sides of the face (facial asymmetry). Affected individuals have a wide range of cognitive function, from normal intelligence to major learning disabilities with absent speech and poor communication.

Less common features of CHARGE syndrome include kidney abnormalities, immune system problems, abnormal curvature of the spine (scoliosis or kyphosis), and limb abnormalities, such as extra fingers or toes (polydactyly) and missing fingers or toes. ^,

The correct answers are A, B, C, and D

Comment: DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a disorder caused when a small part of chromosome 22 is missing. This deletion results in the poor development of several body systems.

The term 22q11.2 deletion syndrome covers what once were thought to be separate conditions, including DiGeorge syndrome, velocardiofacial syndrome, and other disorders that have the same genetic cause, though features may vary slightly.

Medical problems commonly associated with 22q11.2 deletion syndrome include heart defects (VSD, ASD, tetralogy of Fallot, and truncus arteriosus), poor immune system function, hypoparathyroidism, hypoplastic or absence of thymus gland, hypothyroidism, distinct facial features (low-set ears, short width of eye openings, hooded eyes, enlarged nose tip, long face), autism, attention deficit hyperactivity disorders, a cleft palate, complications related to low levels of calcium in the blood, and delayed development with behavioral and emotional problems.

The number and severity of symptoms associated with 22q11.2 deletion syndrome vary. However, almost everyone with this syndrome needs treatment from specialists in a variety of fields. In children, hypoplasia or agenesis of the kidney is the most common feature (17%), followed by multicystic dysplasia, obstructive hydronephrosis (10%), and vesicoureteral reflux (4%).

The correct answer is B

Comment: In recent years, major genome-wide association studies have provided significant insight into the genetic basis of IgA nephropathy. Patients typically have high levels of aberrantly O-glycosylated IgA1 molecules, which become targets of an autoantibody response, leading to immune complex formation. ^– These deposit in the mesangium and spark an unhindered immune response, ultimately leading to fibrosis and kidney failure.

To date, genome-wide association studies for IgA nephropathy have successfully identified many risk loci with candidate genes involved in antigen processing and presentation, gut mucosal immunity, IgA biology, and dysregulation of the alternative complement pathway.

An overall genetic risk can be computed with these genome-wide significant susceptibility variants and has been shown to inversely correlate with the age of diagnosis. Interestingly, the IgA nephropathy genetic risk score is strongly associated with global pathogen diversity, suggesting that the selective pressure from environmental factors may account for variation in risk allele frequency and the geographic variation in disease prevalence among world populations.

There is a significant variability of up to 30% in the incidence of recurrence of IgA nephropathy after transplantation. Recurrence is associated with a higher risk of graft failure and is more common in younger patients with rapidly progressive, crescentic disease in their native kidneys.

Because the risk of allele frequency in disease prevalence among the general population is considerably lower than related donor kidneys, transplantation from the adopted sibling is preferred for transplantation in IgA patients with end-stage renal disease. ^,

The correct answer is D

Comment: The constellation of clinical and laboratory findings, including a positive family history of nephrolithiasis, hypomagnesemia, hypermagnesemia, hypercalciuria, and medullary nephrocalcinosis, are consistent with the diagnosis of FHHNC. Bartter and Gitleman syndromes were ruled out because of normal blood pH and the absence of hypokalemia and metabolic alkalosis. Patients with Dent disease usually have low plasma parathyroid and elevated 1,25(OH)2 vitamin D levels.

FHHNC is a rare autosomal recessive tubular disorder that causes medullary nephrocalcinosis. In addition to presenting the characteristic triad included in the name of the disease, affected individuals may present clinically with polydipsia, polyuria, recurrent urinary tract infections, vomiting, abdominal pain, convulsion, and carpopedal spasm.

Urinary tract infections are the most common clinical manifestation (43%), followed by polyuria and polydipsia (27%). Some patients show extrarenal symptoms, such as hearing impairment or ocular abnormalities. The most important biochemical findings of FHHNC syndrome are hypomagnesemia, hypermagnesemia, and hypercalciuria. Hyperuricemia, hypocitraturia, and elevated PTH levels are also present. The primary defect is impaired reabsorption of magnesium and calcium in the loop of Henle. This defect is due to a mutation in the CLDN16 gene that encodes the paracellular protein claudin-16, which is located in the tight junctions of the thick ascending limb of the loop of Henle. Consequently, patients with FHHNC should not only present with typical clinical and biochemical data; they should also be screened for mutation of the CLDN16 gene.

The correct answers are A, B, and C

Comment: The differential diagnosis in patients presenting with unilateral multicystic renal lesions is multilocular cystic nephroma, unilateral renal cystic disease, segmental multicystic dysplastic kidney disease, and ADPK disease. The therapy for multilocular cystic nephroma is radical nephrectomy because it cannot be differentiated from more aggressive neoplasms such as the cystic variant of Wilms tumor and cystic renal cell carcinoma, which makes it crucial to carefully consider other diagnoses first. The lack of suspect lymph nodes and homogeneous tumor mass as well as the presence of cysts in other areas of the patient’s affected kidney made the diagnosis of cystic nephroma less likely. Unilateral renal cystic disease is a less well-known nonfamilial and nonprogressive entity. Segmental multicystic dysplastic kidney disease was unlikely in our patient because, on the CT scan, there was normal contrast enhancement in the renal tissue adjacent to the cysts and a lack of evidence of duplication of the collecting system. Regardless of the potential diagnosis, in most cases, unilateral multicystic kidney in children usually incurs considerable morbidity for the child, including partial to full nephrectomies and open biopsies.

Our patient presented with a multicystic lesion in the upper pole of his left kidney with completely normal contralateral kidney. Both parents underwent a renal ultrasound to evaluate the presence of cysts. His father had bilaterally enlarged kidneys with numerous cysts. A genetic testing was done for ADPK disease and the patient had a deletion in the PKD1 gene on chromosome 16.

ADPK disease is the clinical manifestation of a genetic defect that is typically a bilateral renal cystic disease of adults because children are most often asymptomatic. ^, Most of these children have bilateral renal cystic disease, but 17% have been identified with an initial presentation of a unilateral cystic kidney.

The correct answer is B

Comment: FHHNC was the most likely diagnosis in our patient. The most striking finding was bilateral medullary nephrocalcinosis, which was demonstrated in the renal ultrasound performed after recurrent urinary tract infections. Nephrocalcinosis refers to diffuse deposition of calcium in the kidney resulting from increased urinary calcium, oxalate, or urate. Medullary nephrocalcinosis may be associated with several disorders including idiopathic hypercalcemia, hypervitaminosis D, Williams-Beuren syndrome, primary neonatal hyperparathyroidism, antenatal Bartter syndrome, Dent disease, Lowe syndrome, cystinosis, renal tubular acidosis, medullary sponge kidney, and FHHNC. None of the clinical or laboratory findings was supportive of the diagnoses other than FHHNC. The patient fulfilled the diagnostic criteria for FHHNC, including hypomagnesemia, hypercalciuria, and nephrocalcinosis. Besides the laboratory findings of the diagnostic triad, hyperuricemia, hypomagnesuria, impaired GFR, and sometimes hypocitraturia are also common in FHHNC, as seen in our case.

Patients with FHHNC usually present during early childhood with recurrent urinary tract infections, polyuria/polydipsia, isosthenuria, and renal stones in addition to vomiting, abdominal pain, tetanic episodes, or generalized seizures. Our patient had a history of recurrent urinary tract infections, polyuria/polydipsia, isosthenuria, and renal stones, but no episodes of seizures resulting from electrolyte imbalance.

The underlying genetic defect in FHHNC is a mutation in either the CLDN16 or the CLDN19 gene. ^– CLDN16 and CLDN19 encode tight junction proteins claudin-16 and claudin-19, respectively, which are both important for renal magnesium reabsorption in the thick ascending limb of Henle. ^– Claudin-19 is also expressed at high levels in the retina. Thus, both CLDN16 and CLDN19 mutations result in a similar renal phenotype, whereas CLDN19 mutations cause additional ocular involvement.

The ocular manifestations associated with CLDN19 mutations include macular colobomata, nystagmus, chorioretinitis, and myopia. In addition to the classical findings of FHHNC, ophthalmological examination revealed bilateral maculopathy in our patient. This additional finding led us to search for a mutation in the CLDN19 gene. As expected, a homozygous truncating mutation (W169X) in CLDN19 was identified in our patient.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis generally has a poor prognosis, ending up with end-stage renal disease, and a definitive cure can only be achieved by renal transplantation. Treatment with magnesium salts, thiazides, and potassium citrate do not influence the progression of the disease but may decrease calcium excretion and formation of renal stones and nephrocalcinosis. We planned to continue on potassium citrate and add magnesium salts and thiazides to the treatment in addition to regular ophthalmological examinations.

The correct answer is D

Comment: Our patient presented with chronic constipation from the age of 14 months, which was treated with laxatives. Only after acute urinary retention had developed were further investigations initiated. Histopathologic studies established the diagnosis. The alpha fetoprotein level returned to normal after tumor removal. A CT scan of the abdomen and chest demonstrated secondary deposits in both lungs. A bone scintography was normal. Because the mass involved the sacrococcygeal bone and infiltrated the surrounding tissues, parts of the sacrum and coccyx needed to be removed, and chemotherapy was started.

Sacrococcygeal teratoma are seen in 1:35,000 live births, with a female-to-male ratio of 3:1. Both benign and malignant forms of sacrococcygeal teratomas have been described in children <4 years of age. The clinical presentation depends on the child’s age at the time of diagnosis and tumor localization. It is most often diagnosed prenatally by ultrasound or during the neonatal period and may be clinically silent. In older children, the tumor often presents as a palpable mass that might compress the rectum and bladder, with subsequent complications such as constipation and urinary retention.

In children with malignant abdominal teratoma, urinary retention might be secondary to nervous system involvement, especially in cases of intramedullary infiltration, or from urethral compression and consecutive urinary retention. If late diagnosis is made, hydronephrosis might even occur. Next to teratoma, other tumors such as ependymomas and congenital ependymoblastoma can occur in the sacrococcygeal regions, which might result in similar findings. In our case, urinary retention was most likely from both intramedullary involvement and urethral compression.

The correct answers are A, B, C, and D

Comment: The patient’s lesion in the lung did not respond to antibiotic treatment, which eliminated pneumonia or atelectasis. Diaphragmatic hernia, teratoma, mediastinal neuroblastoma, intra- or extralobar pulmonary sequestration, bronchopulmonary foregut malformations, such as cystic adenomatoid malformation or bronchogenic cysts, and intrathoracic kidney can cause this radiographic appearance. These pathologies should be considered in the differential diagnosis. ^–

A CT scan of the thorax performed because of the consolidated appearance on radiography revealed the presence of the right kidney within the thorax. Right and left renal veins formed a common vascular structure and drained into the enlarged azygos vein, and bilateral accessory renal arteries were observed. The right kidney was above the level of the hemidiaphragm, with dimensions of 65 × 30 × 34 mm, and parenchymal thickness was measured at 7 mm on the ultrasonographic image. The left kidney was observed at its normal location, with dimensions of 63 × 23 × 24 mm and a parenchymal thickness of 7.5 mm.

Patients with a suspected intrathoracic mass require further evaluation, including Doppler ultrasound, CT scan of the thorax with intravenous contrast, or MRI. These studies may delineate the lesion and its associated vasculature and determine whether any communication with the tracheobronchial tree exists. ^, An intravenous pyelogram can be performed in such cases with suspected ectopic kidneys.

All patients should be evaluated for associated congenital disorders, in particular cardiac anomalies. Rotational irregularities with the hilum facing inferiorly, distorted shape, elongated urethra, high origin of renal vessels, and medial deviation of the lower renal pole can be associated with congenital intrathoracic kidney.

The correct answer is A

Comment: The ultrasound scan showed that both kidneys were large for his age (left kidney, 72 mm; right kidney, 73 mm), and it was difficult to differentiate cortex and medulla. Bilateral hydronephrosis, graded according to the Society for Fetal Urology, was grade 3, which means that the renal pelvis dilated beyond the sinus, and calyces were uniformly dilated, with a renal pelvic anteroposterior diameter of 10 mm. Multiple echogenic particles within both renal pelvises without an acoustic shadow, compatible with bilateral renal fungus balls, were seen. An antegrade pyelography revealed no passage of contrast agent to the ureter because of obstruction of fungus balls. The reason for acute kidney injury (AKI) in our case was bilateral urinary system obstruction caused by fungus balls. Both urine and blood cultures were positive for Candida albicans . A urine specimen taken from the renal pelvis via nephrostomy was also positive for C. albicans . The patient had a history of intubation, central catheterization, total parenteral nutrition, long-term and broad-spectrum antibiotic usage in addition to prematurity and low birth weight, all of which are risk factors for the development of renal candidiasis.

The patient was administered intravenous furosemide and sodium bicarbonate at the emergency service; however, lung auscultation signs did not improve and his metabolic acidosis was resistant to medical treatment at the second hour following admission. As a result, it was decided to initiate renal replacement therapy. A peritoneal dialysis catheter was placed and dialysis was performed in the intensive care unit. At hour 16 following the initiation of peritoneal dialysis, his rales completely disappeared and the acidosis was corrected. Because of the presence of bilateral urinary system obstruction, bilateral nephrostomy catheters were placed to provide urinary drainage, after which renal failure resolved rapidly.

In addition to intravenous lipid formula amphotericin B treatment, amphotericin B was also administered through both nephrostomy catheters twice a day. Although fluconazole is the first-choice antifungal agent in treatment of renal candidiasis, it is not recommended in patients with renal failure or hydronephrosis because adequate urinary concentration cannot be achieved. Despite the effectiveness of amphotericin B, it was not used in systemic treatment because of its nephrotoxic side effects. Weekly urinary microscopic examinations, urine cultures, and US examinations were performed to monitor the effectiveness of the treatment. On US examination performed on day 12 of treatment, the echogenic mass and obstruction findings had completely disappeared and the left nephrostomy catheter was withdrawn. After 3 weeks of antifungal treatment, no more yeast was observed in urine microscopy and culture. However, it is recommended to continue antifungal treatment for an additional 3 to 6 weeks after negative conversion of the culture. ^, Despite sterility under culture, on US, the echogenic appearance of the right kidney persisted; therefore, streptokinase was administered via the nephrostomy catheter twice daily (5 mL, 3000 U/mL). At the eighth week of treatment, the echogenic appearance in the right pelvis was still present. However, it was decided that this might persist for a long time and that the nephrostomy catheter might present a risk for new infections, so the catheter was withdrawn at the eighth week of treatment and antifungal treatment was discontinued. The patient has been under follow-up with antibiotic prophylaxis for the past 13 months. During this period, no urinary tract infections have developed, and urine microscopic examinations performed at intervals were normal. Pelvicalyceal dilatation detected on US totally disappeared 5 months after treatment.

The correct answer is B

Comment: Oliguric renal failure from birth is unusual in the absence of a hypoxic-ischemic or toxic insult that causes AKI. Antenatal oligohydramnios and intrauterine growth retardation are reliable antenatal markers, making CKD more likely despite normal size kidneys. Proteinuria associated with AKI from acute tubular necrosis is not usually in the nephrotic range, and urine protein-creatinine measurement of >4 g/mmol should stimulate further exploration of a congenital nephrotic syndrome as an underlying cause. The oligohydramnios at 31 weeks of gestation suggest a low intrauterine GFR from a particularly aggressive sclerosing process.

Reevaluation of the genital appearance prompted karyotype analysis, revealing a 46, XY pattern, leading to a diagnosis of Denys-Drash syndrome (DDS). This diagnosis was subsequently confirmed with targeted analysis of WT1 , which led to the identification of a heterozygous missense variant c.1097 G>A, p (Arg366His) in exon 8.

Denys-Drash syndrome is a triad of nephropathy (typically diffuse mesangial sclerosis), gonadal dysgenesis (with undermasculinized external genitalia in a 46, XY individual), and a propensity to Wilms tumor. ^, It is caused by heterozygous mutations of WT1 on chromosome 11p13, which encodes a zinc finger DNA transcription protein involved in the development of kidneys, urogenital tract, and other organs. Consistent with its critical role in early embryonic development, WT1 mutations are also associated with other phenotypes, including Frasier syndrome, Meacham syndrome, and isolated presentation of nephrotic syndrome or Wilms tumor. DDS is a rare disorder and the incidence is unknown. The vast majority of patients with DDS have a WT1 missense mutation within exons 8 or 9 of the gene. ^, Most missense mutations in these exons affect the zinc-finger domains and impair the DNA binding capacity of WT1 .

The correct answer is A

Comment: In patients with severe symptoms such as severe flank pain, gross hematuria in the absence of hydronephrosis pyelonephritis, kidney stone, or cholangitis should raise the possibility of nutcracker syndrome. A CT angiography of the abdomen and pelvis in our patient showed a dilated left renal vein with narrowing as it crosses between the abdominal aorta and the superior mesenteric artery along with opacification of the gonadal vein, which confirmed the diagnosis.

There are no agreed-on diagnostic criteria for Doppler renal US. The gold standard for diagnosing nutcracker syndrome is left renal vein venography because it allows measurement of the venous pressure gradient between the left renal vein and inferior vena cava and can visualize any collateral veins. A pressure gradient ≥3 mm Hg is considered to be elevated. With the availability of CT angiography and magnetic resonance angiography, it is easy to make the diagnosis of nutcracker syndrome without the need for a more invasive venogram.

Nutcracker syndrome, also known as left renal vein entrapment syndrome, occurs when the left renal vein is compressed between the abdominal aorta and the superior mesenteric artery. Nutcracker syndrome can present with hematuria (microscopic or gross) accompanied by groin or flank pain occurring after physical activity. The proposed pathogenesis of nutcracker syndrome includes an acute aorta-superior mesenteric artery angle, an abnormal branching or origin of the superior mesenteric artery from the aorta, an abnormal course of the left renal vein (coursing behind the aorta or a higher course), and excessive fibrous tissue at the origin of the superior mesenteric artery.

The correct answers are A, B, and C

Comment: The clinical differential diagnosis of renal failure in conjunction with hyperuricemia includes partial hypoxanthine-guanine phosphoribosyltransferase deficiency, MCKD2, and FJHN.

Hypoxanthine-guanine phosphoribosyl-transferase deficiency is an X-linked disorder that results in the overproduction of uric acid. The patient’s female gender and the absence of neurological symptoms, history of nephrolithiasis, or urate granulomas on renal biopsy argued against partial hypoxanthine-guanine phosphoribosyltransferase deficiency. On the other hand, renal US did not demonstrate renal cysts; therefore, the diagnosis of MCKD2 was ruled out. The most likely etiology of the hyperuricemic chronic renal disease could be FJHN. This clinical picture is an autosomal-dominant disorder characterized by hyperuricemia, low fractional renal urate excretion, progressive chronic interstitial nephritis, and chronic renal failure. Renal impairment usually appears between 15 and 40 years of age, leading to end-stage renal disease within 10 to 20 years. This syndrome was first described in 1960 in a family with gout, hyperuricemia, and renal disease. However, presentation is not always with gout, and unusually for gout, FJHN affects young men, women, and children equally.

FJHN is caused by mutations in the uromodulin gene ( UMOD ) located at 16p11.2-12 that encodes for uromodulin or Tamm-Horsfall glycoprotein, the most abundant protein in normal urine. Several mutations in the UMOD gene have been identified in some families. Thus, to achieve exact diagnosis, the patient was tested for UMOD mutations by polymerase chain reaction amplification of genomic DNA and bidirectional automated DNA sequencing of all exons in the coding region of the UMOD gene. Genetic testing detected three novel missense amino acid mutations in codon 317 (Cys to Ser), codon 125 (Thr to Arg), and codon 488 (Gly to Arg), consistent with UMOD -associated kidney disease. In addition, two single-nucleotide substitutions (IVS5+50C>T and IVS9-8C>A) were also detected in the UMOD gene that did not result in amino acid changes. The parents were also tested for UMOD mutations: father (IVS9-8C>A) and mother (IVS5+50C>T) showed single-nucleotide substitutions. Based on these molecular genetic findings, a diagnosis of FJHN was established. On the other hand, immunohistochemical staining for UMOD could be performed, and intracellular UMOD inclusions could be detected by light and electron microscopy. Furthermore, on electron microscopy, the inclusions may appear as abundant fibrillar or granular storage material within bundles of endoplasmic reticulum.

In FJHN, it has been suggested that intracellular UMOD overload impairs sodium reabsorption by the thick ascending limb of Henle, leading to defective urine-concentrating capacity. The resultant volume depletion may be compensated by increased proximal tubular reabsorption of sodium, which in turn may promote heightened proximal tubular urate reabsorption and reduced secretion, similar to the mechanism responsible for hyperuricemia in patients receiving loop diuretics. The cause of the chronic renal disease is not completely understood. UMOD mutations potentially cause disruption of the molecule’s stable tertiary structure, resulting in altered protein folding, accumulation within the endoplasmic reticulum, and impaired trafficking. Retention in the endoplasmic reticulum may lead to formation of the intracellular UMOD aggregates observed in kidney biopsies and is likely a key step in the pathogenesis of FJHN.

The correct answer D

Comment: Our patient’s main problem was the presence of medullary nephrocalcinosis (NC). Nephrocalcinosis is defined as calcification located in the renal parenchyma. It can be divided into two forms, medullary and cortical, with the former usually a bilateral process with symmetric involvement. Medullary NC is the most common form and occurs in various disorders. Based on clinical and laboratory findings, we easily ruled out Cushing syndrome, malignancy, sarcoidosis, sickle cell disease, idiopathic hypercalcemia, chronic pyelonephritis, hypervitaminosis D, hyperparathyroidism, hyper-/hypothyroidism, and drug-associated NC. Renal tubular acidosis, primary hyperoxaluria, and purine/pyrimidine pathway disorders were also not considered realistic diagnoses because of normal acid-base parameters and the excretion of amino acids, oxalate, and uric acid. ^,

The patient was investigated further for diseases that cause hypercalciuria in addition to NC. Bartter syndrome was ruled out because of normal acid-base parameters. The absence of hypokalemia and metabolic alkalosis also excluded Gitelman syndrome. Patients with classic Dent disease generally have low PTH and elevated 1,25(OH) vitamin D levels with low-molecular-weight proteinuria. Our patient has elevated PTH and normal vitamin D levels with both tubular and glomerular proteinuria; the latter could be secondary to chronic renal failure.

After making these differential diagnostic steps as well as taking the presence of hypomagnesemia, hypomagnesuria, and hypercalciuria into consideration, we suggested a rare disease, FHHNC, as the most probable cause of the medullary NC in our patient. In most cases, FHHNC is caused by loss-of-function mutations in the CLDN16 gene encoding claudin-16 (formerly called paracellin-1), renal tight junction protein expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In families with FHHNC and severe ocular involvement, the disease has been shown to be caused by a mutation in the CLDN19 gene encoding claudin-19, another important tight junction protein that is expressed in renal tubules and the eye. Our patient was then investigated for the presence of hearing and ocular abnormalities. The results of the ophthalmologic examination and audiograms were normal. Blood samples were taken from both the patient and her parents for genetic diagnosis of the FHHNC. A homozygous Arg216His mutation in the CLDN16 gene was detected in our patient. Both parents were heterozygous for this mutation. Once the genetic diagnosis was made, the patient was put on a low-salt diet, with high fluid intake, oral magnesium citrate (1 mmol/kg/day), and hydrochlorothiazide (2 mg/kg/day). There was no significant change in her renal function and severity of nephrocalcinosis within the 3 months of follow-up with medications.

FHHNC is a rare autosomal recessive tubular disorder that causes medullary nephrocalcinosis. In addition to presenting the characteristic triad included in the name of the disease, affected individuals may present clinically with polydipsia, polyuria, recurrent urinary tract infections, vomiting, abdominal pain, convulsion, and carpopedal spasm. Urinary tract infections are the most common clinical manifestation (43%), followed by polyuria and polydipsia (27%). Some patients show extrarenal symptoms, such as hearing impairment or ocular abnormalities. The most important biochemical findings of FHHNC syndrome are hypomagnesemia, hypermagnesemia, and hypercalciuria. Hyperuricemia, hypocitraturia, and elevated PTH levels are also present. The primary defect is the impairment of the reabsorption of magnesium and calcium in the loop of Henle. This defect is due to a mutation in the CLDN16 gene that encodes the paracellular protein claudin-16, which is located in the tight junctions of the thick ascending limb of the loop of Henle. Consequently, patients with FHHNC should not only present with typical clinical and biochemical data; they should also be screened for mutation of the CLDN16 gene.

The clinical course of FHHNC is heterogeneous. It is frequently associated with progressive renal failure with a variable progression rate, but the reason for this clinical variability has not yet been clarified. ^, The most important aim of treatment should be the reduction of urinary calcium excretion. Hydrochlorothiazide is effective in diminishing calcium excretion in children with hypercalciuria. Oral magnesium supplements and citrate, both well-known inhibitors of renal nephrocalcinosis and lithiasis, may also be given to the patients.

Despite calcium and magnesium substitution, normal serum values could not be achieved in our patient. Medical treatment does not appear to influence the progression of the disease and, as a result, the overall prognosis of FHHNC is poor. A definitive cure can be achieved by renal transplantation.

The correct answer is D

Comment: The present patient had RCAD syndrome diagnosed as part of an investigation of his developmental delay at 3 years of age and thus had known potential for the development of hyperglycemia before commencing rhGH therapy. Fasting glucose and glycated hemoglobin levels before starting rhGH were normal, and we postulate that rhGH acted as the trigger for hyperglycemia in this child. However, an OGTT was not performed before starting treatment and, given the development of hyperglycemia within a short time frame, preexisting impaired glycemic control cannot be completely excluded.

Growth hormone has well-recognized diabetogenic properties with effects on lipid and glucose metabolism and is also believed to promote gluconeogenesis. ^,

RCAD also referred to as maturity-onset of diabetes in the young, type 5, is an autosomal dominant disorder resulting from mutations in HNF1β and is the most commonly identified genetic cause of congenital anomalies of the kidney and urinary tract. HNF1β (located on chromosome 17q12) is involved in tissue-specific regulation of gene expression in various organs but is particularly influential in the embryonic development of the kidney. In addition to cysts, other renal manifestations that have been reported include cystic dysplasia, familial hypoplastic glomerulocystic kidney disease, solitary kidney, oligomeganephronia, hyperuricemic nephropathy with gout, renal magnesium wasting, horseshoe kidney, and hydronephrosis/hydroureter.

Given the potential β-cell dysfunction and changes in insulin sensitivity associated with RCAD, patients with this condition may be expected to be more susceptible to diabetogenic stimuli. Waller and colleagues reported on a 14-year-old boy with posttransplant diabetes.

It has been recommended that an OGTT should be considered in patients with RCAD before starting rhGH therapy along with regular monitoring of glycemic indices after commencing treatment.

The correct answer is B

Comment: A VCUG demonstrated bilateral grade 5 vesicoureteral reflux and bladder with trabeculation. Cystoscopy excluded posterior ureteral valve or obstruction. The spine and spinal cord were seen as normal on MRI. The urodynamic study showed high detrusor pressure (74 cm H ₂ O on micturition) and dyssynergia between the detrusor and the ureteral sphincter.

The patient had functional bladder outlet obstruction without any neurological abnormalities; therefore, he was diagnosed with Hinman syndrome. He did not have any complaints associated with gastrointestinal retention. His smiling was not diagnostic for urofacial syndrome and his family did not have any genetic renal diseases. The urologist started self-clean intermittent catheterization four to six times per day for bladder emptying. Recently, the patient has started antibiotic prophylaxis and is continuing supportive treatment for renal insufficiency. We are currently preparing him for our peritoneal dialysis program.

Hinman syndrome involves a nonneurogenic neurogenic bladder and the most severe form of dysfunctional voiding disorder. The bladder-sphincter discoordination causes damage to the bladder and upper urinary tract if it is not diagnosed early and treated adequately. This case emphasizes the following important message: nighttime wetting is not a benign condition in every child. Parental awareness should be raised about voiding disorders, so that it may be possible to prevent important renal diseases such as Hinman syndrome. We hope that in the future, the definition of mutations will generate new classifications for these diseases. If we can gain more insight into the pathophysiological mechanism of Hinman syndrome, more effective therapies could emerge.

The correct answers are A, B, C, and D

Comment: The patient presented with a renal mass. Based on age, she was at high risk for developing a renal tumor. Clear-cell sarcoma occurs before 4 years of age. Wilms tumors are the most common renal masses occurring in those younger than age 5 years. Rhabdoid tumors and congenital mesoblastic nephroma are seen in infants. On the other hand, renal cell carcinoma is more likely to be diagnosed after 15 years of age.

Xanthogranulomatous pyelonephritis is a rare, severe, and atypical form of chronic renal parenchymal infection, often mimicking neoplastic renal disorder. It is important to distinguish this entity in children that it may be misdiagnosed as childhood renal neoplasm, especially Wilms tumor.

Clinical features are usually associated with nonspecific signs and symptoms such as weight loss, malaise anorexia, recurrent febrile episodes, and abdominal pain, as in adults. The most common symptoms are flank pain and fever. Wilms tumor has similar signs and symptoms such as malaise, pain, hypertension, and microscopic or gross hematuria.

Conventional MRI is useful in the characterization of solid and cystic renal masses, congenital abnormalities, renal vascular disease, and posttraumatic conditions. MRI is sensitive for identifying the accumulation of lipid-laden foamy macrophages as high-intensity signals on T1-weighed images. The hypodense lesion in T2-weighted MRI is in favor of XP as opposed to the hyperintense tumoral masses. The “bear paw” sign, which describes water density–rounded areas in renal parenchyma with calyceal dilatation and abscess cavities with pus and debris can be seen with XP. In this case, the renal pelvis and calyxes are dilated and enlarged mimicking the toe pads of a bear’s paw. The bear paw pattern metaphorically describes the replacement of the renal parenchyma by hypoattenuating masses that are cellular infiltration of lipid-laden macrophages. Renal scintigraphy with technetium-99m dimercaptosuccinic acid (99mTc-DMSA) may be used to evaluate and confirm differential renal function.

The correct answer is B

Comment: Lowe syndrome (oculocerebrorenal syndrome) is characterized by congenital cataracts and glaucoma, severe intellectual disability, hypotonia with diminished to absent reflexes, and renal abnormalities. Fanconi syndrome is followed by progressive renal impairment. End-stage renal disease usually does not occur until the third to fourth decades of life.

Lowe syndrome is transmitted as an X-linked recessive trait. Despite the X-linked inheritance pattern, Lowe syndrome has occurred in a few females. The defective gene codes for inositol polyphosphate 5-phosphatase, OCRL1 , are involved with cell trafficking and signaling.

Light microscopy of the kidney is normal early in the disorder, with endothelial cell swelling and thickening and splitting of the glomerular basement membrane seen by electron microscopy. In the proximal tubule cells, there is a shortening of the brush border and enlargement of the mitochondria.

Cataracts are present at birth and kidney and brain abnormalities are associated with intellectual disabilities.

Almost all boys with Lowe syndrome have developmental and intellectual disability that can range from mild to severe. Seizures occur in approximately half of those by 6 years of age, and behavioral problems are present in some boys with Lowe syndrome. A fraction of affected males develop keloids on the corneas of one or both eyes during late childhood and adolescence. These growths are progressive and can lead to blindness.

Renal Fanconi syndrome is one of the most common kidney involvements in patients with Lowe syndrome. The GFR usually begins to fail during the second decade of life and slowly progresses to end-stage renal failure by 30 to 40 years of age.

Other signs frequent in boys with Lowe syndrome include short stature, dental cysts and abnormal dentin formation of the teeth, skin cysts, and vitamin D deficiency that can lead to soft bones, skeletal changes (rickets), bone fractures, scoliosis, and noninflammatory degenerative joint disease. Some patients have shown a delayed bleeding diathesis following surgery, characterized by normal hemostasis and clot formation, only to be followed a few hours later by sudden recurrence of bleeding. This may be an important consideration with any surgery but especially both cataract surgery and glaucoma surgery in which bleeding inside the eye may have considerable consequences.

Disorders with similar symptoms to Lowe syndrome include congenital rubella, Zellweger syndrome, cataract-dental syndrome (Nance-Horan syndrome), Smith-Lemli-Opitz syndrome, and Dent disease.

The correct answer is D

Comment: Wilms tumors are the most common renal masses younger than age 5 years. Clear-cell sarcoma occurs before age 4 years. Rhabdoid tumors and congenital mesoblastic nephroma are seen in infants. XP is very rare in childhood and often mistaken for renal malignancies. XP should be kept in mind if there is a history of recurrent urinary tract infection and flank tenderness.

The hypodense lesion in T2-weighted MRI is in favor of XP as opposed to the hyperintense tumoral masses. ^, “Bear paw sign,” which describes water density–rounded areas in renal parenchyma with calyceal dilatation and abscess cavities with pus and debris can be seen with XP. In this case, the renal pelvis and calyxes are dilated and enlarged, mimicking the toe pads of a bear’s paw. The bear paw pattern metaphorically describes the replacement of the renal parenchyma by hypoattenuating masses that are cellular infiltration of lipid-laden macrophages. Renal scintigraphy with technetium-99m dimercaptosuccinic acid ( ^99m Tc-DMSA) may be used to evaluate and confirm differential renal function. The nuclear scans usually show a nonfunctioning or poorly functioning kidney in XP.

XP is the result of chronic renal infection. Most commonly, organisms associated with XP are Proteus mirabilis , Escherichia coli , Staphylococcus aureus , Klebsiella , and Pseudomonas . Urine cultures is positive in most of the patients; cultures may be negative in 25% of cases. Sterile urine culture in our case may be undertaken before antibiotic therapy. The inflammatory process can be localized or diffuse and generally unilateral. Most of the XP are unilateral and diffuse in form. A predilection of left kidney, as in our case, has been reported. Complications are flank pain and rarely abscess formation in the psoas, nephrocutaneous, or colonic fistula and paranephric abscess.

Laboratory tests that have been reported in XP are anemia, leukocytosis, thrombocytosis, and increased inflammatory markers (ESR, C-reactive protein levels). Ultrasound imaging will reveal enlargement of the entire kidney and hypoechoic renal areas of calyceal dilatation and parenchymal destruction. The true preoperative diagnosis may be difficult in children but it seems to be possible by the help of dynamic contrast-enhanced MRI.

The management of diffuse and focal XP is different. Nephrectomy is the standard approach for diffuse disease but partial nephrectomy is recommended whenever possible especially for bilateral XP. There are reports of a few patients recovering with antibiotic therapy with the focal form of XP. In this child, a complete nephrectomy was performed because the kidney was nonfunctional. The prognosis for the affected child is excellent.

The correct answer is A

Comment: Renal lymphangioma is a rare and benign renal malformation. It is believed that a developmental malformation of the intrarenal, perirenal, and peripelvic lymphatics causes accumulation of lymph as parenchymal edema or subcapsular and/or hilum cysts. ^, This condition has also been termed renal lymphangioma, peripelvic lymphangiectasia, renal sinus polycystic disease, and renal hygroma. The age of the patient at presentation varies and there is no sex predilection.

The diagnosis of RL can be made according to characteristic radiologic findings. The radiologic features of RL on US, MRI, or CT are well-defined. RL can be unilateral/focal or bilateral/diffuse. There are two radiologic manifestations. In the first pattern, cystic lesions in the renal sinus may be seen. The second pattern reveals lobular perinephric fluid with multiple septations and less apparent renal sinus cysts. US examination may reveal enlarged kidneys, increased renal parenchymal echogenicity, loss of corticomedullary differentiation, and anechoic cysts. On CT, thin-walled, fluid-filled cysts with attenuation on the cyst walls are evident. The cysts on MRI appear as hypointense without enhancement on postcontrast images in T1-weighted and hyperintense in T2-weighted images. Diagnostic aspiration of the cysts or ascites can be performed but is not necessary for diagnosis. The characteristic of the aspirated fluid is usually the same as those for transudate (nonchylous and unremarkable for urea, protein, triglyceride, and LDH). The fluid may however have elevated renin and lymphocyte content.

Autosomal recessive polycystic kidney disease is the most common differential diagnosis in pediatric patients, especially when ascites is present. Other differential diagnoses include autosomal dominant polycystic kidney disease, Wilms tumor, lymphoma, and urinoma.

Treatment is not required for the majority of asymptomatic cases. Diuretic treatment has proven effective in cases with ascites and pleural effusion. Although recurrence is possible, percutaneous aspiration and sclerotherapy of the cysts have been successfully performed in symptomatic cases.

The correct answers are A and B

Comment: The antenatal discovery of tumor in the upper pole of the left kidney with no metaplastic cartilage is typical for a CMN. Wilms tumor/nephroblastoma is the most frequent kidney tumor in childhood, and this diagnosis has to be considered. Additional immunohistochemical staining is helpful to distinguish CMN from Wilms tumor with heterologous differentiation. ^,

Congenital mesoblastic nephroma represents 3% of all pediatric kidney tumors. It is the most common kidney neoplasm diagnosed in the first 3 months of life, and it is frequently detected antenatally, as described in our case. The malignant potential of the tumor is low.

CMN is classified into three histological subtypes: classic, cellular, and mixed type. Classic CMN is composed of braiding bundles of spindle cells and frequent metaplastic cartilage with no capsular boundaries. The tumor often infiltrates the surrounding perirenal fat tissue and parenchyma. ^, Cellular CMN also presents bundles of spindle cells but has a stronger hemangiopericytoma pattern and a higher mitotic activity than the classic type. In contrast, the cellular type less frequently infiltrates the perirenal fat and/or kidney parenchyma. Mixed CMN shows, as the name indicates, a mixture of both the previously mentioned types.

Total nephrectomy is curative for most patients with stage I/II disease. Stage III tumors of the classic and mixed histologic subtypes are also indicated for nephrectomy alone. Stage III tumors of the cellular type treated only surgically have a higher rate of relapse than the other histologic subtypes, requiring chemotherapy or radiotherapy in some cases. However, because of limited data, there are no specific recommendations for adjuvant chemotherapy. ^, The known side effects of radiotherapy particularly in these very young patients limit this treatment modality to selected cases with aggressive tumors not responding to chemotherapy.

The correct answer is C

Comment: This patient suffered from primary X-linked NDI, confirmed by genetic testing that identified a previously described mutation, R106C, in the gene encoding the arginine vasopressin receptor 2 ( AVPR2 ). Polyuria and hydronephrosis in this boy could have been explained by primary hydronephrosis with secondary NDI or vice versa. However, the family history was not consistent with a secondary NDI, and the bladder trabeculation was not explained by high urine flow.

The US showed severe hydronephrosis on the left and moderate hydronephrosis on the right, which is due in part to the high urinary flow consequent to his NDI. Importantly, it also shows a trabeculated, thickened bladder wall. This finding is suggestive of primary urinary tract obstruction, an additional cause for his hydronephrosis. In this boy, the obstructive uropathy was due to a PUV.

The key diagnostic tests are urodynamic assessment and cystoscopy (a micturating cystourethrogram is also a reasonable option). The trabeculated appearance of the bladder raised the suspicion of a bladder outlet or urethral obstruction. An obstructive pattern on subsequent urodynamic investigations confirmed this suspicion. In a boy, this must prompt consideration of PUV. Given his age, it was decided to proceed directly to cystoscopy, rather than pursuing specific diagnostic imaging such as a micturating cystourethrogram.

Hydronephrosis is a recognized complication of primary NDI and thought to be secondary to the high urine flow. ^– The danger, however, is to automatically assume this causality because these conditions can also occur independently in the same patient. Although both are rare diseases, with an estimated incidence of 1 in 5000 (PUV) and 1 in 1,000,000 (X-linked NDI) boys, they are not mutually exclusive, and cooccurrence was indeed reported previously, albeit without genetic confirmation of the NDI because the underlying gene was not known at the time. ^– Here, the key finding suggesting a separate cause for the hydronephrosis was the trabeculated appearance of the bladder on ultrasound.

An interesting aspect is the normal plasma creatinine level in this boy, as the increased urine output from the NDI would be expected to aggravate pressure damage to the kidneys in the setting of urethral obstruction. Indeed, the ultrasound is consistent with reduced cortical mass in the left kidney with less than 5% divided function on a nucleotide scan (not shown). It is unclear why the left kidney has experienced more damage, but it may have buffered most of the back pressure, thus protecting the right kidney.