The correct answers are E, F, and H

Comment: The elevated FEPO ₄ signifies excessive urinary losses of phosphate. Renal phosphate wasting can result from genetic or acquired renal disorders. Acquired renal phosphate wasting syndromes can result from vitamin D deficiency, hyperparathyroidism, oncogenic osteomalacia, and Fanconi syndrome (options E, F, H). ^,

The genetic disorders of renal hypophosphatemic disorders generally manifest in infancy are usually transmitted as XHR.

Choice A is a wrong answer, as serum calcium concentration is elevated in patients with primary hyperparathyroidism. Answers B, C, and D are also incorrect because of the inappropriately high FEPO ₄ . Choice I is the wrong answer because hyperventilation lowers serum phosphate levels by promoting a shift of phosphate into the cells, leading to respiratory alkalosis, and the FEPO ₄ is appropriately low.

Additional laboratory studies revealed 25-hydroxyvitamin D was 71.8 ng/mL (reference range, 30–100 ng/mL); 1,25-dihydroxyvitamin D, 15 pg/dL (reference range for children, 20–70 pg/dL); and intact parathyroid hormone (PTH), 44 pg/mL (4.6 pmol/L; reference range, 10–68 pg/mL). There was no aminoaciduria or glucosuria. Radiographic studies revealed florid signs of rickets, including a rachitic rosary and cupping of the ribs, and fraying and flaying of the radius, ulna, femur, tibia, and fibula.

The correct answer is B

Comment: Currently, there is no specific treatment for Alport syndrome. The goal is to treat the symptoms and help slow the progression of kidney disease. This may include ACE inhibitors or angiotensin-receptor blocker medicines (medications to control high BP), diuretics, and dietary sodium restriction.

Kidney transplantation is usually very successful in patients with Alport syndrome and is considered the best treatment when kidney failure is approaching.

The correct answer is C

Comment: In the great majority of individuals with PKD, the condition is inherited in an autosomal dominant manner, known as autosomal dominant polycystic kidney disease (ARPKD). This is due to mutations in the PKD1 gene on chromosome 16, causing type 1 disease. This accounts for more than 85% of cases. ¹

The correct answer is C

Comment: Autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin ( UMOD ), hepatocyte nuclear factor-1β, renin, and mucin-1 ( MUC1 ).

Multiple names have been proposed for these disorders, including medullary cystic kidney disease (MCKD) type 2, familial juvenile hyperuricemic nephropathy, or uromodulin-associated kidney disease for UMOD-related diseases and MCKD type 1 for the disease caused by MUC1 mutations.

The multiplicity of these terms, as well as the fact that cysts are not pathognomonic, creates confusion.

Kidney Disease: Improving Global Outcomes proposes the adoption of a new terminology for this group of diseases using the term autosomal dominant tubulointerstitial kidney disease appended by a gene-based subclassification and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate the recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

The correct answer is D

Comment: Hereditary vitamin D–resistant rickets (HVDRR) is a rare autosomal recessive disease caused by mutations in the vitamin D receptor (VDR). Patients exhibit severe rickets and hypocalcemia. Heterozygous parents and siblings appear normal and exhibit no symptoms of the disease.

HVDRR is characterized by the early onset of severe rickets, with a complete triad of clinical, biochemical, and skeletal abnormalities. Homozygous or heterozygous mutations in the VDR gene leading to complete or partial target organ resistance to the action of 1α, 25-dihydroxyvitamin D3, are responsible for HVDRR. Theoretically, the therapeutic goal is to overcome this tissue resistance and to normalize calcium and phosphate homeostasis. Practically, the treatment could be oriented to correct the secondary hyperparathyroidism to avoid long-term negative impact on bone health. The conventional therapeutic strategy (high-dose calcium plus active vitamin D metabolites) gives variable responses in magnitude and duration.

The correct answer is C

Comment: Branchiootorenal spectrum disorder is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis.

Symptom and symptom severity can vary greatly from person to person. It can be caused by genetic changes in the EYA1 , SIX1 , or SIX5 genes. It is passed through families in an autosomal dominant fashion.

Conditions to consider in the differential diagnosis of the branchiootorenal spectrum disorder include Alport syndrome and thin-basement membrane disease.

The correct answer is B

Comment: Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease. It is inherited in an autosomal dominant pattern, although the rate of spontaneous mutation is high. Formerly characterized by the triad of mental retardation, epilepsy, and facial angiofibromas, patients with TSC may present with a broad range of clinical symptoms because of variable expressivity. TSC may affect many organs, most commonly the brain, skin, eyes, heart, kidneys, and lungs. Common features include cortical tubers, subependymal nodules, subependymal giant cell astrocytomas, facial angiofibromas, hypomelanotic spots known as Fitzpatrick patches (ash-leaf spots), cardiac rhabdomyomas, and renal angiomyolipomas. Regarding the genetic sources of epilepsy, TSC is among the most common. Epilepsy affects 90% of patients with this neurocutaneous condition, and it first becomes evident in most such individuals in the initial 2 years of life. TSC provides a model for genetic epilepsy development and modification.

Anticonvulsant medication is the first treatment option for seizures, and neurosurgery is rarely required for refractory seizures. MRI, electroencephalography, and positron emission tomography scans to localize brain lesions are important before neurosurgery.

Mutations in either of two genes ( TSC1 and TSC2 ) have been determined to cause TSC; however, diagnosis continues to be based on clinical manifestations. Molecular analysis is helpful in confirming a diagnosis and genetic counseling.

This article elucidates the various neoplasms, along with their clinical significance, and suggests suitable evaluation and management strategies.

The most common and severe central nervous system manifestations of TSC include seizures, such as infantile spasms, and mental retardation.

Medical care is aimed at seizure control using various anticonvulsants. Begin treatment with monotherapy and increase the dose gradually until seizures are well controlled or the dose is limited by adverse effects.

Lymphangioleiomyomatosis may respond to therapy using progesterone and oophorectomy. Consider inotropic agents in patients with evidence of decreased contractility and cardiomyopathy resulting from rhabdomyoma. Antihypertensive medication may be required in patients with renal disease and subsequent hypertension; an ACE inhibitor may be the first drug of choice.

Kidney surgery for angiomyolipomas usually consists of enucleation or partial nephrectomy. Renal arterial embolization is an additional treatment option.

Some believe that early epilepsy surgery is associated with seizure freedom in children with TSC and intractable epilepsy.

The correct answer is E

Comment: Nail-patella syndrome, which is caused by mutations in a gene encoding for a transcription factor ( LMX1B ) expressed in the podocytes, is not associated with deafness. On the other hand, deafness is a major feature of the branchiootorenal, Alport, Alström, and Fechtner syndromes. Deafness in branchiootorenal syndrome is due to the absence or underdevelopment of the cochlea. A cochlear defect is also responsible for the hearing loss associated with Alport and Fechtner syndromes. COL4A3, AOL4A4, and COL4A5—the proteins mutated in Alport syndrome—are strongly expressed in the matrix that connects the tension fibroblast to the basilar membrane in the lateral aspect of the spiral ligament at the basal turn of the cochlea. MYHIIA—the protein mutated in Fechtner syndrome—is a nonmuscle myosin predominantly expressed in these tension fibroblasts. The structural integrity and function of the tension fibroblasts and matrix are essential to increase the tension of the basilar membrane to the degree needed for high-frequency sound reception. The pathogenesis of deafness in Alström syndrome is not understood.

The correct answer is A

Comment: The clinical presentation and imaging studies in this patient are consistent with Caroli disease (congenital hepatic fibrosis and mild autosomal recessive polycystic kidney disease presenting with ascending cholangitis). Mutations in the recently identified PKHD1 gene have been found in cases of congenital hepatic fibrosis and Caroli disease with minimal or mild renal involvement, as well as in patients with more typical presentations of severe ARPKD. Congenital hepatic fibrosis and dilatation of the intrahepatic bile ducts are much more rarely associated with ADPKD caused by PKD1 or PKD2 mutations. Mutations in TSC2 (causing TSC) or in PRKCSH (causing autosomal dominant polycystic liver disease) would not be consistent with the presentation or findings in this patient. ^,

The correct answer is C

Comment: The pattern of inheritance described in this case is consistent with X-linked dominant or autosomal dominant disease. The former is more likely because autosomal dominant Alport syndrome is very rare. Although X-linked Alport syndrome is usually mild in female heterozygotes, severe disease can occur because of skewed inactivation of the X-chromosome. X-linked Alport syndrome is caused by mutations in COL4A3 or COL4A4 ; therefore, answer A is wrong. Answer B is not correct because less than 3% of Alport patients develop anti-glomerular basement membrane (anti-GBM) disease following renal transplantation and this small risk does not preclude renal transplantation. The Alport syndrome-diffuse leiomyomatosis contiguous gene syndrome is very rare and, although it needs to be kept in mind, specific investigations for its detection (answer D) are not indicated in the absence of suggestive symptoms such as dysphagia, dyspnea, vulvovaginal leiomyomas, or juvenile cataracts. At least some cases of thin-basement membrane disease are heterozygote carriers of autosomal recessive Alport syndrome with COL4A3 or COL4A4 mutations. X-linked Alport syndrome is dominant, and patients with COL4A5 mutations have Alport syndrome, not thin-basement membrane disease; therefore, answer E is wrong.

The correct answer is D

Comment: The imaging criteria for the diagnosis of ADPKD in first-degree relatives of affected individuals have been based on ultrasonography. Current imaging techniques, particularly CT and MR, have a much higher resolution, and therefore the sonographic criteria developed more than a decade ago cannot be indiscriminately applied. Furthermore, although these sonographic criteria have a very high sensitivity for the diagnosis of PKD1 disease, their sensitivity for the diagnosis of PKD2 disease in individuals younger than age 30 years is very low. The presence of two cysts detected by ultrasound in a 10-year-old individual at 50% risk of ADPKD would have met the criteria for a positive diagnosis. This is not the case using CT examinations.

Therefore, answer A is wrong. Answer B is also wrong because the diagnosis of ADPKD (particularly PKD2) cannot be reliably excluded. Answers C and D could be correct, but answer D seems more likely in view of the severity of the disease in the father. Although MRI is the most sensitive technique for detecting renal cysts, it seems unlikely that many cysts detectable by MRI would have been missed by the contrast CT.

The correct answer is A

Comment: The availability of genetic testing for von Hippel-Lindau disease has, in most cases, eliminated the need for lifelong follow-up of unaffected individuals for the early detection of the life-threatening complications of this disease. On the other hand, genetic testing for ADPKD, TSC, Alport syndrome, and congenital hepatic fibrosis is much more rarely performed because existing clinical criteria are usually adequate for the clinical management of these patients. The lack of effective therapies limits the benefits of early diagnosis, and the yield of mutation analysis is significantly less than 100%. At present, the main indication for genetic testing for ADPKD is the evaluation of living-related donors for renal transplantation when the imaging studies are inconclusive.

The correct answer is D

Comment: Retinal hemangioblastomas are seen in up to 60% of the patients with von Hipple-Lindau disease, and approximately half of the cases are multifocal and bilateral. Fibrofolliculomas and trichodiscomas are characteristic of Birt-Hogg-Dube disease—an autosomal dominant syndrome associated with chromophobe and conventional renal cell carcinomas and with oncocytomas. These skin lesions typically appear as multiple, small, dome-shaped, yellowish or skin-colored papules scattered over the face, neck, scalp, and upper trunk. Facial angiofibromas or forehead plaques and periungual or subungual fibromas, along with hypomelanotic macules and shagreen patches, are major features of TSC.

Cutaneous and uterine leiomyomas, uterine leiomyosarcomas, and papillary renal cell, bladder, and breast carcinomas are part of a recently recognized syndrome caused by mutations in the gene encoding fumarate hydrate—an enzyme of the tricarboxylic acid cycle.

The correct answer is D

Comment: Excessive urinary excretion of L-glyceric acid indicates the diagnosis of primary hyperoxaluria type 2; this is confirmed by mutations in DGDH . Patients with PH2 suffer from kidney stones but, in contrast to PH1, do not have systemic oxalosis, and transplantation is unnecessary. Urinary L-glyceric acid excretion is not elevated in dietary hyperoxaluria. Pyridoxine therapy is useful in some patients with PH1, but its value in PH2 has not been reported.

Because the patient does not have PH1, his children will not be at risk for systemic oxalosis.

The correct answer is B

Comment: Dent disease is inherited in an X-linked fashion, and CLCN5 is located on chromosome X. Father-to-son inheritance is inconsistent with X-linkage. Proteinuria is a hallmark of Dent disease, and hypercalciuria is present in virtually all patients until renal function begins to decline. Rickets, although present in a minority of patients, is a well-recognized feature of the disease.

Although this is clearly a genetic disease, a family history of affected relatives may be absent, either because of incomplete information on family members or as a consequence of the highly variable severity of phenotype even within families.

The correct answer is D

Comment: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is associated with mutations in paracellin-1, which is inherited in an autosomal recessive fashion. The combination of polyuria, nephrocalcinosis, and hyperuricemia in the setting of clinically significant hypomagnesemia would be strongly suggestive of this diagnosis. Unlike the Bartter or Gitelman syndromes, salt-wasting, hypokalemia, and metabolic alkalosis are not features of FHHNC.

Urinary calcium excretion is excessive in FHHNC, presumably reflecting the defect in paracellular reabsorption of divalent cations in the loop of Henle. Serum levels of renin and aldosterone are high in Bartter syndrome but normal in FHHNC. ^–

The correct answer is B

Comment: The history suggests a familial focal segmental glomerulosclerosis (FSGS), probably autosomal recessive. Podocin mutations have been detected in approximately one-half of these patients. The nephritic syndrome recurs in up to one-third of patients with familial FSGS following renal transplantation. In the absence of clues suggesting a mitochondrial disease, such as diabetes mellitus, hearing loss, neurological manifestations, or cardiomyopathy, evaluation for a mitochondrial gene disease is not indicated. Alpha actinin-4 mutations have been associated with a later-onset, autosomal dominant FSGS that is not consistent with the clinical presentation of this patient. Although some patients with familial FSGS can respond to combination regimens, such as methylprednisolone boluses and cyclosporine, responsiveness to glucocorticoid treatment alone is unlikely.

The correct answer is D

Comment: The presence of metabolic acidosis and hyperkalemia in a child with hypertension points to a diagnosis of Gordon syndrome (familial hyperkalemic hypertension) because other familial syndromes of childhood hypertension (such as Liddle syndrome and glucocorticoid-remediable aldosteronism) are associated with hypokalemia and metabolic alkalosis. Hypercalciuria and normal serum magnesium levels are also consistent with Gordon syndrome, which in many respects represents a mirror image of Gitelman syndrome. Gordon syndrome is associated with mutations in the kinases WNK1 and WNL4 that lead to enhanced expression or function of the sodium-chloride cotransport, NCCT. Thus, therapy with thiazide diuretics corrects all of the abnormalities in Gordon syndrome. Diuretics that compete with aldosterone for binding to the receptor (spironolactone), or inhibit the epithelial sodium channel (amiloride), or the NKCC2 transporter (furosemide), have not been shown to be of benefit as the vasodilator hydralazine.

The correct answer is C

Comment: Familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type 2 are associated with mutations in the UMOD gene. It is not known why the gene encoding the Tamm-Horsfall protein should be associated with hyperuricemia, but it may be worth noting that both the Tamm-Horsfall protein and paracellin-1 are expressed in the thick ascending limb of the loop of Henle, and mutations in both are associated with hyperuricemia. The four genes mutated in Bartter syndrome are different from the NCCT gene that is mutated in Gitelman syndrome, and the same is true for Low syndrome and Dent disease, Liddle syndrome and glucocorticoid-remediable aldosteronism, and both the autosomal recessive and dominant forms of distal renal tubular acidosis.

The correct answer is C

Comment: The basolateral anion exchange AE1 transports bicarbonate to exit the basolateral surface of type A intercalated cells of the collecting duct and is essential to producing acidic urine. Mutations in AE1 occur in both dominant and recessive forms of distal RTA. This same gene is expressed in the erythrocyte, but the mutations associated with distal RTA are different from those associated with hereditary spherocytosis, and patients with RTA invariably do not have spherocytosis. Inherited distal RTA is not associated with ocular abnormalities, although when it occurs in association with mutations in the B1 subunit of the V-type proton ATPase, it may be associated with sensorineural deafness. The sodium-bicarbonate transporter NBC1 is expressed in the proximal tubular cell and in the eye, and mutations in this gene are associated with inherited proximal RTA and ocular abnormalities. Inherited distal RTA does not typically improve with age.

Correct answer is B

Comment: This boy has features of a generalized Fanconi syndrome, hypophosphatemic rickets, renal failure, and a family history consistent with X-linked inheritance. These features alone would be consistent with either Lowe or Dent disease, but several observations are valuable in distinguishing these two entities. Hyperchloremic metabolic acidosis is a common feature in Lowe syndrome but not Dent disease. Renal failure commonly occurs at an earlier age in Lowe syndrome than in Dent disease, most often not developing until the third or fourth decade in Dent disease. Intellectual disability and congenital cataracts are typical features of the oculocerebrorenal syndrome of Lowe but not of Dent disease.

Cystinosis can also be associated with Fanconi syndrome, metabolic acidosis, renal failure, and ocular and neurologic abnormalities. The eye findings in cystinosis, however, involve the retina (or, in the juvenile form, the cornea) rather than the lenses. Furthermore, cystinosis is an autosomal disease, and in this family, there is strong evidence of X-linked inheritance. Distal RTA and primary hyperoxaluria are also autosomal diseases, and neither would explain the full range of clinical abnormalities in this boy.

The correct answer is A

Comment: In ARPKD, affected children typically present in utero with enlarged echogenic kidneys, as well as oligohydramnios secondary to poor urine output. Approximately 30% of the affected neonates die shortly after birth as a result of severe pulmonary hypoplasia and secondary respiratory insufficiency.

Among the survivors, the clinical phenotype variably includes systemic hypertension, renal insufficiency, and portal hypertension resulting from portal tract fibrosis. Marked interfamilial variation has been described in ARPKD and likely reflects the influence of modifier genes. Therefore, ARPKD (choice A) most likely fits the clinical scenario described. Isolated congenital hepatic fibrosis is by definition confined to the biliary tract. The other incorrect choices represent renal cystic diseases not typically associated with symptomatic congenital hepatic fibrosis.

The correct answer is B

Comment: The family history of kidney failure with an autosomal dominant pattern of inheritance and the imaging studies support a diagnosis of medullary cystic kidney disease as the cause of renal insufficiency. The diagnosis of nephronophthisis can be excluded because this is an autosomal recessive disorder that leads to end-stage renal failure in childhood or adolescence. The absence of microhematuria and proteinuria is not consistent with a diagnosis of hereditary nephritis as the cause of renal insufficiency. The development of renal insufficiency in ADPKD is always associated with marked renal enlargement. The autosomal dominant pattern of inheritance and the absence of findings consistent with congenital hepatic fibrosis rule out the diagnosis of ARPKD. ^,

The correct answer is E

Comment: The presence of hexadactyly makes the diagnosis of Bardet-Biedl syndrome likely. Hexadactyly is not a feature of autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, nephronophthisis, or Joubert syndrome.

The correct answer is C

Comment: The history of recurrent episodes of microangiopathic hemolytic anemia with undetectable vWF-CP activity and absence of vWF-CP autoantibodies strongly suggest the diagnosis of inherited thrombotic thrombocytopenic purpura. Inherited thrombotic thrombocytopenic purpura is a recessive disorder caused by homozygous ADAMTS13 mutations. Carriers of ADAMTS13 gene mutations can have partially reduced vWF-CP activities. Transfusions of ADAMTS13 (fresh frozen plasma or cryosupernatant) to maintain the vWF-CP activity over 3% is sufficient to prevent relapses. The only false statement is C. In the absence of ADAMTS13 autoantibodies, plasma exchange is not necessary.

The correct answer is B

Comment: Patients with NPHS2 mutations are less likely to have a recurrence of FSGS in the renal transplant than those without. In addition, because of the possibility that heterozygous NPHS2 mutations could make the recipient and the donor more susceptible to the development of proteinuria and FSGS, caution has been recommended before considering transplantation from a living donor carrying an NPHS2 mutation. Minimal change disease responsive to the administration of steroids is the most common cause of childhood nephritic syndrome. Treatment with steroids is indicated without the need of renal biopsy or genetic testing for NPHS2 .

Choice A is therefore incorrect. NPHS2 mutations are found in up to 30% of children with steroid-resistant idiopathic nephritic syndrome. Therefore, choice C is wrong. Choice D is also wrong because patients with mutations leading to retention of podocin in the endoplasmic reticulum have an earlier onset of the disease and a more severe phenotype than those with homozygous mutations expressed on the plasma membrane. Choice E is incorrect because disease-causing podocin mutations cause nephritic syndrome by failing to recruit nephrons into rafts either because of retention in the endoplasmic reticulum or failure to associate with rafts in the plasma membrane.

The correct answer is B

Comment: The immunohistochemical study of a skin biopsy is diagnostic in approximately 80% of patients with X-linked Alport syndrome and avoids the need for a more invasive renal biopsy. Confocal microscopy of the skin with three-dimensional reconstruction of the epidermal basal membrane increases the sensitivity of the test. COL4A5 is usually absent from epidermal and glomerular basal membranes in male patients and has a segmental distribution in female patients. Testing for COL4A5 mutation using sequence analyses identifies more than 60% of mutations in individuals with X-linked Alport syndrome and could be considered as an alternative, but at present it is probably less sensitive than a skin biopsy. Sensorineural deafness, anterior lenticonus, pigmentary changes in the perimacular region, and corneal dystrophy (rare) or alterations in the corneal epithelial basement membrane are features of Alport syndrome. Their occurrence in females is too low to be used for diagnosis. ^,

The correct answer is A

Comment: Cystinosis is an autosomal recessive lysosomal storage disease. It is the most common inherited cause of renal Fanconi syndrome, as well as a multisystem disorder that affects the eyes, muscles, central nervous system, lungs, and various endocrine organs. These patients, however, typically do not have neurocognitive impairment. In contrast, both Lowe syndrome and Dent disease are X-linked disorders. In Lowe syndrome, full expression of Fanconi syndrome typically does not occur in infancy, whereas in Dent disease metabolic acidosis from proximal tubular dysfunction is rarely seen.

The correct answer is B

Comment: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive disorder caused by defects in paracellin-1 function. This disorder is distinguished from other magnesium-losing tubular disorders by clinical presentation during early childhood with recurrent urinary tract infections, polyuria/polydipsia, isosthenuria, and renal stones. Affected children typically have bilateral nephrocalcinosis and develop progressive renal failure. Some seek medical attention because of associated failure to thrive, vomiting, abdominal pain, titanic episodes, or generalized seizures. Besides hypomagnesemia, biochemical abnormalities include hypermagnesemia and hypercalciuria, and impaired GFR is often detected at the time of diagnosis. A substantial percentage of patients have incomplete distal renal tubular acidosis, hypocitraturia, and hyperuricemia.

The correct answer is D

Comment: RTA results from defective bicarbonate reabsorption and is commonly associated with a generalized defect in proximal tubular function (e.g., cystinosis, Lowe syndrome). However, isolated proximal RTA can occur in association with ocular abnormalities, including glaucoma, band keratopathy, and cataracts. This autosomal recessive disorder results from loss-of-function mutations in SLC4A4 , the gene encoding the electrogenic Na+-bicarbonate exchanger, NBCe1. The clinical presentation in this patient is most consistent with isolated proximal RTA from SLC4A4 mutations.

The correct answer is A

Comment: The constellation of clinical findings and laboratory data are most consistent with the diagnosis of Liddle syndrome. Glucocorticoid-remediable aldosteronism is typically associated with high urinary 18-hydroxy cortisol excretion, which was not observed in this patient. Hypokalemic metabolic alkalosis is inconsistent with Gordon syndrome, which is typically associated with hyperkalemic metabolic acidosis.

The correct answer is B

Comment: Gordon syndrome or glucocorticoid-remediable aldosteronism is an autosomal dominant distal renal tubular acidosis. Among the single-gene disorders causing low-renin hypertension, Gordon syndrome is distinguished by the associated hyperkalemia and metabolic acidosis. In contrast, Liddle syndrome, glucocorticoid-remediable aldosteronism, and an activating mutation in the dominant distal RTA are not typically associated with hypertension.

The correct answer is C

Comment: Familial juvenile nephronophthisis and MCKD are similar diseases that develop in children and adults, respectively. NPH is an autosomal recessive disorder that is linked to mutations of genes located at least four chromosome sites. NPH may be associated with cerebroretinal degeneration and hepatic fibrosis. Familial INPH-1 has been mapped to chromosome 2 (2q12-13). The gene NPH-1 is responsible for the synthesis of nephrocystin. These patients develop ESRD at a median age of 13 years.

Familial adolescent NPH-3 has been mapped to chromosome 3 (3q21-22). Patients with NPH-3 mutations develop ESRD at a median age of 19 years. NPH-2 is the autosomal recessive form, having an infantile, perinatal, or prenatal onset. It is linked to chromosome 9q22-31. A fourth gene locus, NPH-4 , has been postulated, accounting for rare cases. Molecular genetic diagnosis is possible. The clinical features of failure to thrive, polyuria, polydipsias, anemia, and ESRD in the presence of normal BP and normal urinalysis are most likely consistent with NPH.

The correct answer is E

Comment: The nephrotic syndrome that is present at birth or develops in the first few weeks of life may be due to several disorders including intrauterine infections (congenital syphilis, congenital cytomegalovirus disease, congenital rubella, congenital toxoplasmosis), focal and segmental glomerulosclerosis, diffuse glomerulosclerosis, and Wilms tumor, in addition to the classic Finnish type of congenital nephrotic syndrome. The Finnish type of congenital nephrotic syndrome is due to mutations of the NPHS-1 gene located on chromosome 19 (19q13.1). This gene determines the synthesis of nephrin, which is a major constituent, of the slit pore diaphragm of the visceral glomerular epithelial cells. These mutations give rise to a nearly total deficiency of nephrin, the absence of the slit foot processes, and a marked increase in glomerular permeability to proteins. Most patients develop renal failure and die of infections or thrombosis before 5 years of age unless vigorously supported by anticoagulants, diuretics, albumin infusions, and antibiotics, as needed. Angiotensin inhibitors, nonsteroidal anti-inflammatory drugs, or glucocorticoids do not reduce proteinuria or prolong life. Renal transplantation may be life-saving, but a new disease may develop in the graft because of the formation and deposition of antinephrin antibodies.

The correct answer is D

Comment: Asphyxiating thoracic dysplasia (Jeune syndrome) is a group of autosomal recessive osteochondrodysplasias that may involve the kidneys.

Patients with Jeune syndrome typically present at birth with a small bell-shaped thoracic cage. Many experience asphyxia, with or without pulmonary infection, within the first few weeks of life. Progressive renal failure usually occurs in those who survive childhood. Histology of the kidney shows manifestations of nephronophthisis.

The nature and degree of renal involvement is variable. Tubular dilatation and atrophy, interstitial fibrosis, glomerular sclerosis, cortical cysts, cystic dysplasia, and diffuse cystic disease have been described. Early renal manifestations include proteinuria, proximal tubular dysfunction, polyuria, and hypertension. A link between Jeune syndrome and familial juvenile nephronophthisis and Laurence-Moon-Biedl syndromes has been suggested. Prenatal diagnosis of Jeune syndrome is possible.

Present knowledge suggests that the locus of the gene associated with Jeune syndrome may be situated at 12p11.2p12.2.

Because of the absence of polydactyly, nail, tooth, and heart defects, differentiation from other kinds of bone dysplasia such as Ellis-van Creveld syndrome is easy.

Ivemark syndrome can be excluded because of the absence of biliary dysgenesis and pancreatic fibrosis. Barnes syndrome and thoracopelvic dysplasia are excluded because they have an autosomal dominant mode of inheritance.

Radiologic manifestations of Jeune syndrome are variable and include a small thoracic cage with short ribs and irregular costochondral junctions. The pelvis exhibits hypoplastic iliac wings and a horizontal angle of the acetabular roof. The long bone is often short and wide. ^–

The correct answer is D

Comment: The neurocutaneous syndrome tuberous sclerosis is inherited as a dominant trait, but 50% of cases appear to be new mutations. The most common skin abnormality is hypopigmented macula, usually oval- or leaf-shaped and present at birth in 80% to 90% of patients. Other cutaneous lesions include adenoma sebaceous and shagreen patches. Central nervous system disease is common and presents as convulsions in most patients. Intellectual delay is frequent. Sclerotic patches (tubers) are scattered throughout the cortical gray matter.

A CT scan of the skull is often diagnostic and reveals intracerebral calcification.

Cardiac rhabdomyomas are found in at least 50% of patients and may lead to arrhythmias.

The classic renal lesion of tuberous sclerosis is angiomyolipomas, which occur in 50% to 80% of patients and often are bilateral and multiple. Renal cysts are the second most common renal lesions and can be present with the angiomyolipomas.

Large kidney cysts can be present at birth. The radiological appearance of the kidneys is often similar to that of adult-type polycystic kidney disease. The cysts are anechoic lesions, varying in size from 2 mm to 2 cm, with thin uniform walls. Most children are asymptomatic; rarely is pain or hematuria the presenting symptom.

Proteinuria can develop. The incidence of renal carcinoma is less than 5%—surgical intervention is then indicated.

Infantile polycystic kidney disease, nephronophthisis, multicystic kidney disease, and medullary sponge kidneys are easily excluded in the absence of hypopigmented skin lesions and intracranial calcification.

The correct answer is A

Comment: The mass present in the right kidney was a Wilms tumor, and renal failure was due to diffuse mesangial sclerosis (DMS). The child had all the features diagnostic of what is now well known as Drash syndrome.

This is a case of congenital nephritic syndrome with a nephritic urinary sediment and severe renal insufficiency associated with ambiguous genitalia and Wilms tumor. Most cases of congenital nephritic syndrome are of the Finnish variety. The major histological difference between diffuse mesangial and Finnish congenital nephritic syndrome is the presence of global and segmental sclerosing glomerular lesions and crescents in DMS. Both types show cystic dilatation of the proximal tubules with fetal or immature glomeruli. Progression to ESRD occurs early in DMS. It is a late or absent feature of surviving infants with DMS. ^,

The correct answer is B

Comment: The striking ultrasonic appearance of the kidneys and the clinical recognition of gout and the very high plasma uric acid level that was disproportionately raised relative to the high serum creatinine were early clues to the presence of uric acid nephropathy and led to the appropriate diagnostic study of measuring hypoxanthine guanine phosphoribosyl-transferase (HGPRT).

Complete HGRPT deficiency is associated with presentation in infancy as Lesch-Nyhan syndrome. Uric acid overproduction is associated with developmental delay, choreoathetosis, and spasticity between 1 and 16 years. Gouty arthritis and tophi are seldom seen before puberty. Death usually occurs in the second and third decades because of renal failure or recurrent infections. Patients with a partial HGPRT deficiency often develop uric acid nephropathy and uric acid stones, but they do not develop the characteristic self-mutilation. HGPRT activity in lysed red cells is undetectable in both forms of clinical expression, but patients with partial deficiency demonstrate detectable activity in intact erythrocytes. HGPRT deficiency is X-linked, and thus both clinical syndromes occur only in males. Enzyme kinetic studies on fibroblasts of the mother were normal, implying a mutation in the case of our patient.

Although treatment with allopurinol, combined with alkalinization of the urine, may prevent the renal consequences of excess uric acid production, such therapy appears to have no effect on the distressing neurological manifestations of Lesch-Nyhan syndrome.

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 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; at the other end of the spectrum is the severe motor disability with moderately 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, as well as regularly monitoring symptoms. Routine screening for progressive eye, liver, and kidney complications associated with Joubert-related disorders is highly recommended.

The correct answer is F

Comment: The spectrum of congenital anomalies of the kidney and urinary tract is extremely broad and ranges from mild, asymptomatic malformations such as a double ureter or minimal ureteral pelvic obstructions to severe, life-threatening pathologies such as bilateral renal agenesis or renal dysplasia. Several of these renal abnormalities are part of a syndrome or sequence that can be confirmed and sometimes treated by a multidisciplinary approach, including fetal ultrasonography and vesicoamniotic shunt placement to relieve obstruction while in the fetal period, or by other imaging modalities, molecular analysis, and pathologic examination after birth.

Currently, it is recognized that there are two different types of renal dysplasias: obstructive and nonobstructive. In many instances of obstructive renal dysplasia, a megacystis (massively distended urinary bladder) can be observed, even by fetal ultrasound; however, there are other cases in which the obstructive component is not as obvious, and only a careful examination will detect a stenotic area, a hydroureter, or a dilated renal pelvis. Histologically, when kidneys affected by obstructive renal dysplasia have developed hydronephrosis, they usually exhibit a compressed medulla from the hydrostatic pressure produced by the accumulated urine within the pelvis. The renal cortex tends to have less fibrosis and more glomeruli, whereas the medulla is fibrotic and dysplastic; however, the histology may vary depending on the timing of the intrauterine obstruction.

To better understand the etiology and pathogenesis of renal dysplasia, many efforts have been made to further classify them as syndromic and nonsyndromic and to find the gene or genes involved in the development of the disease.

A comprehensive review article delineates evidence that 2% of the congenital anomalies of the kidney and urinary tract, even if nonsyndromic, are linked to genes. So far, the following genes have been reported: hepatocyte nuclear factor-1 β ( HNF1β ), paired box gene 2 ( Pax2 ), uromodulin ( UMOD ), and eyes absent homolog 1 ( Eya1 ). They have been detected in 2% of patients with nonsyndromic congenital anomalies of the kidney and urinary tract.

A large study by Saisawat et al. applied massive parallel exon resequencing of 30 candidate genes in pooled DNA from 40 patients with congenital anomalies of the kidney and urinary tract and identified seven novel mutations in four genes: RET , BMP4 , FRAS1 , and FREM2 . All of these mutations were absent in healthy controls.

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

Comment: Horseshoe kidney is a condition in which the kidneys are fused together at the lower end or base. By fusing, they form a “U” shape, which gives it the name “horseshoe.”

Horseshoe kidney occurs during fetal development as the kidneys move into their normal position in the flank area (area around the side, just above the waist).

Horseshoe kidney occurs in about one in 500 children.

Horseshoe kidney can occur alone or in combination with other disorders. The most common disorders seen with horseshoe kidney include:

Turner syndrome: a genetic disorder seen in girls that causes them to be shorter than others and to not mature sexually as they grow into adulthood. Sixty percent of girls with Turner syndrome have horseshoe kidneys.

Trisomy 18: a serious chromosome abnormality involving defects in nearly all organ systems, including horseshoe kidney in 20% of children affected.

One-third of people with horseshoe kidneys have at least one other complication involving the cardiovascular system, the central nervous system, or the genitourinary system (which is the reproductive organs and urinary system) such as the following:

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  Kidney stones: crystals and proteins that form stones in the kidney that may lead to a urinary tract obstruction

  
  
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  Hydronephrosis: enlargement of the kidneys that is usually the result of a urinary tract obstruction

Wilms tumor: an embryonic (newly formed) tumor of the kidneys that usually occurs during early childhood renal cancer or polycystic kidney disease hydrocephaly and/or spina bifida various cardiovascular and gastrointestinal conditions, or skeletal problems.

The most common symptoms of horseshoe kidney include urinary tract infection (fever, vomiting dysfunction), kidney stones (flank pain, hematuria), and hydronephrosis.

About one-third of children with horseshoe kidney have no symptoms.

There is no known cure for a horseshoe kidney, but if patients have complications, treatment approaches may include antibiotics (to treat an underlying infection) or surgical intervention for symptomatic kidney stones.

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. ESRD 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 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 involvement in patients with Lowe syndrome. The GFR usually begins to fall 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, ZS, cataract-dental syndrome (Nance-Horan syndrome), Smith-Lemli-Opitz syndrome, and Dent disease.

The correct answer is A

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

Zellweger spectrum disorders (ZSDs) 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. ZSDs 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. ZSDs often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. ZSDs are inherited in an autosomal recessive pattern.

ZSDs are the result of a mutation in any of the 12 PEX genes. 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 system, cardiovascular and kidney.

Symptoms of ZS usually appear soon after birth. Facial abnormalities common in ZSD 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.

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  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 ZS. For example, a baby with difficulty eating may benefit from a feeding tube. But the baby won’t be able to eat normally on his or her own in the future.

The correct answer is D

Comment: ARPKD is currently considered a primary ciliopathy that equally affects the kidneys and liver.

ARPKD 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 kidney is enlarged but maintains its reniform shape, and when opened it transudates a lot of urine. Histologically, the cysts are elongated and their long axis is perpendicular to the capsule. The hepatic manifestations are congenital hepatic fibrosis (CHF) that is undistinguishable from the CHF found in other ciliopathies such as Meckel, short rib, or polysplenia. Secondary to the liver fibrosis, patients 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 ( PC1 ), 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 ARPKD 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 employs 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: ADPKD 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. ADPKD should be considered a systemic disorder that mainly affects adult patients. They 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, 40% at 60 years, and 75% at age 70. The kidneys of adult patients contain multiple round cysts of variable size, filled with urine and blood become extremely large 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, ADPKD 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 AVP (arginine-vasopressin)-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 ADPKD) 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 ADPKD to compensate for the reduced concentrating capacity of the affected kidneys and the AVP effect leads to cyst formation. The administration of an arginine-vasopressin receptor inhibitor delays the cyst formation, but does not help regenerating 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 ACE inhibitors or angiotensin-receptor blockers to lower the blood pressure, decrease the amount of fat ingested, and prescribe a cholesterol-lowering agent.

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

Comment: Trisomy 13: Numerous studies have been reported on children with trisomies 13, 18, and 21 who also have hydronephrosis, horseshoe kidney, duplex kidney/collecting system, cortical cysts and/or cystic dysplasia, glomerular microcysts, or renal hypoplasia.

Trisomy 13 (Patau syndrome) is a lethal chromosomal abnormality characterized by holoprosencephaly, arhinencephaly, macrophthalmos, cleft lip and/or palate, polydactyly, and congenital heart disease. However, associated renal anomalies can be found at autopsy. We examined a fetus that was aborted; amniocentesis demonstrated an extra chromosome. In addition to holoprosencephaly, he had polydactyly and cystic dilatation of renal tubules. The most common renal anomaly is multicystic renal cortex (34%) followed by hydronephrosis (21%).

These children are frequently born preterm and may have scalp defects, congenital heart disease, and Meckel diverticulum. A patient with trisomy 13 and bilateral renal dysplasia has been described. The patient had ectopic splenic tissue in the pancreas and a complex congenital heart disease.

Trisomy 18 primarily affects the cardiovascular system and is better known by its association to ventricular (73%) and atrial septal defects (41%), patent ductus arteriosus, and pulmonary valve anomalies. Its characteristic facial features are a prominent occiput, narrow bifrontal diameter, low-set malformed ears, small oral opening, overlapping of the fingers, and narrow pelvis. On the other hand, trisomy 18 tends to have almost the same incidence of renal anomalies as trisomy. The most common malformations are duplication of the collecting system and horseshoe kidney (25%). Less commonly identified are cortical cysts (17%) and hydronephrosis (15%). One of our patients with trisomy 18 underwent autopsy at 7 days and besides the characteristic facial features, she had agenesis of corpus callosum, overlapping of the fingers, and multicystic dysplastic kidneys.

Trisomy 21 may have renal involvement ranging from cortical microcysts, simple cysts, renal hypoplasia, and immature glomeruli deep in the cortex. These children may also develop obstructive uropathy. The largest autopsy series reported 124 fetuses and children with Down syndrome from three medical centers. These authors found renal hypoplasia in 18 cases, glomerular microcysts in 24% of children, only one of these patients had an anatomical obstruction of the urinary tract, focal tubular dilatation in 10 cases, and seven cases with simple cysts. Immature glomeruli deep into the cortex were present in 18 children (15%). There were eight patients with obstructive uropathy (6%). Four of them had cystic renal dysplasia and the other four had a combination of hydronephrosis and hydroureter. ^–

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 exists. 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. At the present time, 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 E

Comment: Several rare genetic disorders including adenine phosphoribosyltransferase deficiency, cystinuria, Dent disease, FHHNC, and PH can cause chronic kidney disease that can progress to end-stage kidney failure even during early childhood. Patients with these disorders often experience recurring stones, urinary tract infections, and upper tract obstruction requiring frequent hospitalizations that may accelerate the loss of kidney function. ^–