Jaya Isaac, MD1; Susan Brooks, MD1; Dalya Chefitz, MD1, and Joann Carlson, MD1

1Department of Pediatrics, Rutgers Robert Wood Johnson Medical School

An 11-year-old girl with a history of migraine headaches presented to our hematology clinic for evaluation of leukopenia and thrombocytopenia. The patient had been healthy until approximately six months prior to presentation, when she developed profound fatigue and intermittent abdominal pain. She slept for periods of 16-20 hours at a time and had a decline in school performance. She endorsed easy bruising, epistaxis, blood-tinged sputum, and petechiae on her cheeks. At a routine neurologist visit for migraines, she had been diagnosed with infectious mononucleosis and was found to be thrombocytopenic to 92 thousand/μl and leukopenic to 4.3 thousand/μl.

The patient was born at forty weeks gestation after induction of labor due to oligohydramnios. At two-years-old, the patient was admitted for Salmonella gastroenteritis. She was diagnosed with migraines at age four but was in remission, and only required sumatriptan as needed. At age five, she was hospitalized for pyelonephritis. Ultrasound of the bladder and kidneys showed medical renal disease and a voiding cystourethrogram was negative for vesicoureteral reflux.The patient had a urinary tract infection at age seven that was treated as an outpatient.There was no outpatient nephrology follow up. Linear growth had remained at the second percentile, but development was otherwise normal. According to calculated mid-parental height, she was expected to be at the 29th percentile. Maternal history was significant for leukocytosis, sleep disorder and positive anti-nuclear antibody. Paternal history was significant for myocardial infarction, hypertension, and hypercholesterolemia.

On physical exam, her temperature was 98.1°F, heart rate was 78 beats per minute, and blood pressure was 115/56 mmHg. The rest of her physical exam was normal with no lymphadenopathy or palpable hepatosplenomegaly. Laboratory results were significant for a white blood cell count of 3.7 thousand/μl, hemoglobin of 13.5 g/dL, hematocrit of 40.5%, and a platelet count of 95 thousand/μl. Her neutrophil count was 1.620 thousand/μl. Liver enzymes, blood urea nitrogen, and creatinine levels were all within normal limits for age. Peripheral blood smear and bone marrow biopsy revealed no evidence of malignancy. Antinuclear antibody was negative. The diagnosis remained unclear.
About three months after her initial presentation, her abdominal pain acutely worsened prompting an emergency department visit. Computerized tomography of the abdomen revealed esophageal varices, mild splenomegaly, liver congestion and abnormal kidneys. She was admitted for further evaluation. Magnetic resonance imaging showed a patent hepatic and portal vein, enlarged abnormal kidneys with cortical thinning and tiny cysts, and an enlarged spleen.

Our patient’s presentation was most consistent with a primary congenital kidney disorder with hepatic involvement causing increased portal pressure, varices, congestion in the spleen, splenomegaly, thrombocytopenia, and leukopenia. Imaging findings were suspicious for a cystic kidney disease, either autosomal recessive polycystic kidney disease (ARPKD) or nephronophthisis. Further genetic testing was done which confirmed the diagnosis of ARPKD.

PATIENT COURSE

This patient was found to have two pathogenic variants (c.4030C>T; p.Q1344*) and (c.5360G>T; p.C1787F) in the PHKD1 gene. An esophagogastroduodenoscopy (EGD) showed Stage 1 varices without need for esophageal banding.The patient is currently doing well and is being managed supportively. Her chronic kidney disease remains stable at Stage II. Unlike most patients with ARPKD, our patient remains overall normotensive and has not needed blood pressure medications.

DISCUSSION

Leukopenia with thrombocytopenia in children can be precipitated by many factors.The most common differential diagnoses include malignancy, autoimmune conditions, and hypersplenism. Although infectious mononucleosis was an initial consideration, it is usually not the cause of protracted symptoms. Lymphadenopathy and an enlarged spleen can be found in hematologic malignancy, and blasts can be found on peripheral smear. Bone marrow biopsy can elucidate the specific diagnosis of acute lymphoblastic leukemia or acute myeloid leukemia.

In addition to cytopenias and fatigue, the presence of rashes, joint pain and fever are indicative of autoimmune conditions, such as systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA). Laboratory findings often include an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Positive anti-nuclear antibody can also be a sensitive marker found in SLE.

The entrapment of blood cells within the spleen, also termed hypersplenism, can also be a cause for cytopenias.The cells are morphologically normal on both peripheral blood smear and bone marrow biopsy. Liver disease can cause hypersplenism due to congestion from portal hypertension. Physical exam can show jaundice, spider angiomata, caput medusae, and ascites. Elevated aminotransferases and bilirubin levels can also be seen. Our patient presented with hypersplenism and portal hypertension from liver disease secondary to ARPKD.

ARPKD is a congenital hepatorenal fibrocystic disease that is caused by homozygous or compound heterozygous mutation in the PHKD1 gene that encodes the fibrocystin/ polyductin protein.1 There is no genotype/phenotype correlation and there is often intrafamilial variability of clinical symptoms.2 The exact function of the protein is unknown but appears to be associated with ciliary development and the mitotic spindle. It is primarily expressed in the collecting system of the kidneys, bile ducts and pancreas.1 ARPKD classically presents in neonates with the Potter sequence from oligohydramnios, and massively enlarged kidneys leading to pulmonary hypoplasia. The respiratory distress and limited diaphragmatic excursion can be severe enough to lead to neonatal death. About 30% of affected infants die within the first year of life, but with improvements in neonatal respiratory support and renal replacement therapy, long-term survival is improving.3 As a result, the severity of the pulmonary disease is one of the largest determinants of the overall prognosis of these patients. In addition to renal disease, about 45% of patients also have hepatobiliary complications.4 These include congenital hepatic fibrosis (CHF) and/or intrahepatic biliary duct dilatation, and when found together are referred to as Caroli syndrome. About a quarter of patients with ARPKD present primarily with gastrointestinal manifestations.1

ARPKD should be suspected in a patient with bilateral large echogenic kidneys and no parental history of kidney disease. Cysts are not always apparent on ultrasound. ARPKD has a wide spectrum of disease and although the majority present in the neonatal period, many patients present at older ages with hepatobiliary complications. Liver biopsy can reveal massively dilated biliary ducts and fibrosis around the ductules. Genetic testing showing biallelic pathologic variants in the PHKD1 gene establishes and confirms the diagnosis.2

There is no cure for ARPKD. Patients are followed over time by nephrologists to monitor their labs, urine, blood pressure and growth. Around 75% of patients with ARPKD develop hypertension that can be quite severe and require management with multiple medications.1 Angiotensin converting enzyme inhibitors or angiotensin receptor blockers are usually the first line treatment for hypertension if the creatinine and potassium are normal due to their potential long-term benefits. Blood pressure control can slow the progression of chronic kidney disease. However, many patients do eventually progress to end-stage renal disease (ESRD) and require renal replacement therapy.1 Patients with liver involvement are usually co-managed with gastroenterology. Ultrasound can be used to monitor the progression of portal hypertension and esophageal varices. If gastrointestinal symptoms are severe, treatment includes portosystemic shunting and ultimately liver transplantation. Genetic counseling is important for the family as recurrence risk is 25% for affected siblings.

CONCLUSION

The presentation of kidney disease in children can be subtle. In our patient, clues to her final diagnosis of an underlying kidney disease included oligohydramnios at birth, multiple urinary tract infections, an ultrasound showing medical-renal disease and
short stature. Although ARPKD usually presents in the neonatal period with respiratory distress due to pulmonary hypoplasia and massively enlarged kidneys, 25% of patients with ARPKD can present with gastrointestinal manifestations of portal hypertension from hepatic fibrosis. Our case highlights a later presentation of ARPKD and emphasizes having a broad differential diagnosis when evaluating patients with cytopenias.

  1. REFERENCES:
    Hartung EA, Guay-Woodford LM. Autosomal recessive polycystic kidney disease: a hepatorenal fibrocystic disorder with pleiotropic effects. Pediatrics. 2014;134(3):e833-845.
  2. Sweeney WE, Avner ED. Polycystic Kidney Disease, Autosomal Recessive. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA)1993.
  3. C. ARPKD and early manifestations of ADPKD: the original polycystic kidney disease and phenocopies. Pediatr Nephrol. 2015;30(1):15-30.
  4. Bergmann C, Senderek J,Windelen E, et al. Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int. 2005;67(3):829-848.