Case 3: Fatigue, Weight Loss, Pallor, and Polydipsia in 12-year-old Girl

A 12-year-old girl with a history of developmental delay presents for evaluation of 3 months of progressive fatigue and a 5-lb weight loss. For the past 7 days, her mother has noticed that her daughter has decreased activity and increased pallor. She has had no fevers, recent illnesses, or new exposures. The mother adds that her daughter has had polydipsia for the past 3 months.Physical examination reveals a tired-appearing, thin adolescent girl in no acute distress. Her temperature is 36.6°C (97.8°F), heart rate is 72 beats/min, blood pressure is 117/74 mm Hg, and weight is 27.3 kg (< 1st percentile). She has pale conjunctivae and a grade II/VI flow systolic ejection murmur. Abdominal examination reveals nodular hepatomegaly and splenomegaly extending 4 cm and 10 cm, respectively. No edema is appreciated.Laboratory results include:She is hospitalized for further evaluation of her pancytopenia, renal failure, and transaminitis.Abdominal ultrasonography shows small, echogenic kidneys concerning for chronic renal failure, enlarged and lobulated liver parenchyma, and enlarged spleen. Computed tomography scan of the abdomen and pelvis confirms diffuse liver cirrhosis, splenomegaly with multiple formed venous collaterals, and small kidneys with diffuse cortical thinning and a cyst in the left upper pole at the corticomedullary border. A hemodialysis catheter is placed and dialysis initiated.Complete blood cell count and a peripheral smear results are consistent with a normochromic, normocytic anemia. A bone marrow biopsy shows no evidence of a neoplastic disorder. Clinicians conclude that her anemia is due to chronic kidney disease and her thrombocytopenia to sequestration in her enlarged spleen.Upon further questioning, the family reveals that the patient has had night blindness since early childhood. An ophthalmologic examination suggests findings of retinitis pigmentosa. After starting dialysis, the patient’s electrolyte values normalize and her energy improves. Genetic evaluation documents a homozygous deletion of NPHP1 and a diagnosis of juvenile nephronophthisis.Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease caused by defects in more than 13 genes. It is the most frequent genetic cause of renal failure in children, with an incidence of 9 per 8.3 million in the United States and 1 in 50,000 live births in Canada. NPHP genes code for nephrocystin, a protein found in primary cilia or centrosomes of renal epithelial cells and other organ tissues. Mutations in these genes can lead to impaired ciliary function. Mutations involving these proteins may lead to impaired cell-cell signaling, integrity, and polarity. The three forms of NPHP are characterized by the age of onset of end–stage renal disease (ESRD). Infantile type (gene NPHP2) has median onset at age 1 to 3 years and adolescent type (gene NPHP3) has median onset at age 19 years. Juvenile type (gene NPHP1) is the most common form of NPHP, with the median onset at age 13, and gene mutations account for 64% of all identified alleles.Patients initially present with mild symptoms, including polyuria, polydipsia, enuresis, and dehydration due to reduced urinary concentrating capacity and salt-wasting nephropathy. As renal insufficiency progresses, growth retardation and anemia out of proportion to kidney disease are common. Because of the salt-wasting, edema and hypertension occur late in the disease course.Juvenile type NPHP is exclusively associated with extrarenal disease manifestations. One NPHP-associated syndrome is Mainzer-Saldino syndrome, which involves retinal degeneration, cone-shaped epiphyses, and occasional liver fibrosis or cerebellar ataxia. This may apply to the patient in the vignette, who has retinal and liver disease. Senior-Loken syndrome involves concomitant occurrence of NPHP and retinitis pigmentosa. Finally, Joubert syndrome is a developmental disorder combined with coloboma or retinal degeneration, cerebellar vermis aplasia and ataxia, polydactyly, and neonatal dyspnea. Several other juvenile type NPHP-associated syndromes with extrarenal features can be found in medical literature.Imaging usually reveals normal-to-small kidneys. Although the NPHP complex is within a heterogeneous group of renal cystic disorders, renal cysts are not a hallmark of the disease. When present, renal cysts are found at the corticomedullary junction. There should not be cysts in other organs. Laboratory evaluation indicates chronic kidney disease. Urinalysis may show a low specific gravity and proteinuria. Renal biopsy in NPHP reveals a specific triad: tubular basement membrane disintegration, tubular atrophy with cyst development, and interstitial cell infiltration with fibrosis.Genetic testing is possible in many cases and can negate the need for renal biopsy. Screening for gene mutations can be guided by the age of ESRD onset and the presence of extrarenal features. The percentage of affected siblings is notably high. It is possible for affected siblings to exhibit a wide variety of signs and symptoms, and timely screening of siblings may be guided by their signs and symptoms. Asymptomatic siblings can be screened for urinary concentrating defects and abnormalities on ultrasonography rather than undergoing genetic testing.Liver function testing may show impaired liver function. If retinal involvement is suspected, careful ophthalmoscopy should be performed. Peripheral smears and, if warranted, a bone marrow biopsy should be performed for low hematologic counts to rule out other causes of anemia or pancytopenia. If there is ataxia or other neurologic signs, magnetic resonance imaging of the brain should be performed.Other diagnoses to consider include other genetic or acquired renal cystic kidney diseases, namely, autosomal recessive or dominant polycystic kidney disease (PKD). However, PKD presents with enlarged and diffusely cystic kidneys and hypertension. The liver, spleen, and pancreas can also contain cysts. Recessive PKD always presents with congenital hepatic fibrosis. Primary hyperoxaluria, tyrosinemia, hepatorenal syndrome, and infections such as hepatitis or human immunodeficiency virus also are part of the differential diagnosis.Chronic kidney disease with NPHP requires attention to blood pressure control, anemia, and electrolyte imbalances in conjunction with improving nutrition and growth. Dialysis and renal transplantation may be required. The rate of liver disease progression may differ from kidney disease progression in individual patients. Liver transplantation at the same or different time as kidney transplant may be warranted if signs of progressively worsening hepatic function, portal hypertension, or cholangitis are present. This decision involves coordinated care with a gastroenterologist or hepatologist. If present, additional extrarenal features should be managed appropriately. Retinal disease should be followed closely for progression to blindness.This patient has continued to do well with standard ESRD management, including hemodialysis three times weekly for the past 1.5 years. She has had no additional organ involvement. She will undergo a living related donor kidney transplant in the near future. Her retinopathy and liver disease both remain mild and are followed by respective specialists.