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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 1  |  Issue : 4  |  Page : 236-239

Finnish variety of congenital nephrotic syndrome in association with cytomegalovirus infection: Double jeopardy


Department of Pediatrics, Noble Hospital and Research Center, Pune, Maharashtra, India

Date of Submission27-Jun-2021
Date of Decision15-Oct-2021
Date of Acceptance06-Nov-2021
Date of Web Publication29-Nov-2021

Correspondence Address:
Dr. Georgeena Elsa Jose
Department of Pediatrics, Noble Hospital and Research Center, 153, Magarpatta City, Hadapsar, Pune - 411 013, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipcares.ipcares_202_21

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  Abstract 

Background: The term “congenital” is used for cases of nephrotic syndrome (NS) that manifests in the first 3 months of life. They are rare diseases mainly due to genetic causes but sometimes attributed to congenital infections. The prognosis depends on the type of mutation in the former and whether remission occurs with specific therapy in the latter. Clinical Description: We describe an 11-week-old baby who presented with generalized edema and features of septic shock that responded to antibiotics. The presence of hypoalbuminemia, proteinuria, and hypercholesterolemia completed the clinical phenotype of NS. Mesangioproliferative glomerulonephritis was confirmed on histopathology. The presence of persistent hepatosplenomegaly, neurological findings, decreased head circumference, and poor nutritional status prompted us to investigate for congenital infections. Positive antibody levels for Cytomegalovirus (CMV) and positive polymerase chain reaction confirmed CMV infection, though we were unable to establish whether it was congenital or acquired postnatally. A novel genetic mutation (c. 712+1G>C) was identified in the NPHS 1 gene. Management: The baby was initiated on specific antiviral therapy and attained partial remission of renal symptoms after 4 weeks. The patient was lost to follow-up after 6 months. Conclusion: The coexistence of the Finnish variety and CMV infection might have caused the severity of phenotype. The authors emphasize the importance of performing a genetic test in cases of congenital NS and also working up for acquired causes on an individualized basis.

Keywords: Congenital nephrotic syndrome, Cytomegalovirus infection, Finnish type, ganciclovir, NPHS 1


How to cite this article:
Lohia S, Jose GE, Pote PD. Finnish variety of congenital nephrotic syndrome in association with cytomegalovirus infection: Double jeopardy. Indian Pediatr Case Rep 2021;1:236-9

How to cite this URL:
Lohia S, Jose GE, Pote PD. Finnish variety of congenital nephrotic syndrome in association with cytomegalovirus infection: Double jeopardy. Indian Pediatr Case Rep [serial online] 2021 [cited 2022 Jan 20];1:236-9. Available from: http://www.ipcares.org/text.asp?2021/1/4/236/331372

Congenital nephrotic syndrome (NS) is defined as NS presenting within the first 3 months after birth. Cases who present later but within the 1st year are referred to as infantile NS. Congenital NS is mainly due to mutations in certain genes that code for the structural proteins forming the glomerular filtration barrier, i.e., NPHS 1, NPHS 2, NPHS 3, WT1, and LAMB2. A minority is secondary to acquired causes which disrupt the podocytes and/or the basement membrane, such as toxins (mercury) or infections with congenital syphilis, congenital toxoplasmosis, or cytomegalovirus (CMV) infection. The exact pathophysiology of CMV-associated glomerulopathies is still unclear.[1] We could only find 12 cases of CMV IgM-positive congenital NS from India on an exhaustive literature search. This may be due to low detection and reduced incidence or simply because of decreased reporting and publication of such cases.[2]

The Finnish type of congenital ns is due to biallelic pathogenic variants in the NPHS 1 gene that encodes for “nephrin,” a protein present in the slit diaphragm of the podocytes.[3] In this report, we describe a young infant with the Finnish variety of congenital NS due to a novel mutation that was complicated by co-existing CMV infection. We share the challenges that we faced in establishing diagnosis and management.


  Clinical Description Top


An 11-week-old girl presented with loose stools for 4 days, generalized swelling of the body for 2 days, and seizures for a day. Though the episodes of loose stools were just 3–4 per day and not associated with blood or mucus, they were semisolid to watery in consistency. The parents noticed swelling of the body, which started as periorbital puffiness and progressed to the abdomen and lower limbs over 2 days. Increased frothiness of the urine and decreased frequency of urination were also noted. On the day of presentation, the baby was brought to the emergency in a depressed state following a single episode of multifocal seizures that lasted for 3 min, involved the upper and lower limbs, and was associated with up rolling of eyes.

The baby was the second issue of a nonconsanguineous union. The antenatal period had been uneventful till the 36th week of gestation, when the mother perceived decreased fetal movements. An ultrasonogram identified moderate oligohydramnios. There were no renal or other organ anomalies. An emergency cesarean section was performed. The Apgar score was 7 and 8 at 1 and 5 min, respectively, and the birth weight was 2200 g (10th percentile). Though the placenta was not weighed, retrospectively, the mother recollected that it had been almost as big as the baby. There was no history of similar complaints or infantile deaths in the family, and the firstborn son was healthy.

At presentation, the baby was afebrile and had impaired perfusion with tachycardia (180/minute) and tachypnea (62/minute). The weight was 3.7 kg (weight for age −2.48 Z), length was 50 cm (length for age −3.48 Z, weight for length 1.07 Z), and head circumference was 35.5 cm (−2.28 Z), indicative of malnutrition and possibly poor head growth. The only salient general physical examination findings were pallor and generalized edema (periorbital, bilateral pedal, and genital). There was no dysmorphism (sutural diastasis, abnormal facies, ambiguous genitalia, absent patella, microcoria, or joint contractures), jaundice, lymphadenopathy, rashes, petechiae or ecchymoses. The abdomen was distended with a palpably enlarged liver (3 cm below the right costal margin) and spleen (2 cm below left costal margin). The cardiovascular system was unremarkable, and air entry was bilaterally equal, with no adventitious sounds. The baby was conscious, but irritable, was moving all four limbs spontaneously, and had normal tone and reflexes.

Management and outcome

This baby was admitted to the pediatric intensive care unit in view of septic shock. Fluid resuscitation was done as per the standard protocol and intravenous antibiotics were started. Blood sugar and serum calcium and electrolyte levels were normal. The hemogram showed hemoglobin levels of 9.4 g/dL, neutrophilic leukocytosis, and a peripheral smear with microcytic hypochromic anemia and anisocytosis. The reticulocyte count, serum iron, and ferritin levels were normal. Blood urea and serum creatinine were normal. Serum bilirubin and liver enzymes were within normal limits, but severe hypoalbuminemia (0.89 g/dL) was noted. The urinary protein dipstick level was 4+, indicative of high proteinuria. The cholesterol level was 211 mg/dL. In view of the hallmark indicators of NS being present, and factoring in the age of presentation, we kept a provisional diagnosis of congenital NS, with septic shock. A lumbar puncture could not be done due to unstable condition.

The baby was given supportive treatment with 20% albumin infusions with furosemide. She also received packed red blood cell transfusions, intravenous third-generation cephalosporin, phenobarbitone, enalapril, and spironolactone. Thyroid-stimulating hormone levels were high (11.48 mIU/L), while free T3 and T4 levels were low, consistent with hypothyroidism due to severe hypoalbuminemia. TSH levels normalized within 2 weeks of treatment with levothyroxine supplements to 5.7 mIU/L.

Ultrasonography of the abdomen showed normal-sized, hyperechoic kidneys with loss of corticomedullary differentiation, moderate ascites, and confirmed hepatosplenomegaly. There were no additional lesions or anomalies. A congenital infection was suspected in view of the hepatosplenomegaly. Thus, we performed serological tests for Toxoplasmosis, Rubella, CMV, and herpes virus infections, which showed CMV IgM positivity. The CMV polymerase chain reaction (PCR) was also positive (9542 copies/mL). Maternal levels of CMV IgG antibodies could not be estimated, hence making differentiation between congenital and perinatal CMV infection not possible. Tests for hepatitis B and C were negative.

Magnetic resonance imaging of the brain showed white matter hyperintensities in the right frontal region without any ventriculomegaly or periventricular calcification in the T2 weighted images (as seen in CMV infection).[4] Electroencephalogram showed generalized epileptiform discharges. Echocardiogram and otoacoustic emission tests were normal. Brainstem-evoked response audiometry was planned on follow-up. Ophthalmological examination revealed no evidence of CMV retinitis. An ultrasound-guided renal biopsy was performed. Analysis of the 32 glomeruli retrieved [Figure 1] showed mesangioproliferative glomerulopathy without diffuse mesangial sclerosis. Electron microscopy revealed occasional endothelial tubuloreticular inclusions with diffuse effacement of podocytes [Figure 2].
Figure 1: Light microscopy of the kidney biopsy specimen with periodic acid silver methenamine staining revealing glomeruli containing focal and segmental mild-to-moderate mesangial hyperplasia

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Figure 2: Electron microscopy of the kidney biopsy specimen showing diffuse effacement of the visceral epithelial foot processes were seen with no electron dense deposits. Tubuloreticular inclusions identified in glomerular endothelial cell cytoplasm

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The clinical diagnosis was congenital NS, probably due to CMV infection; however, since a genetic cause could not be ruled out conclusively, we ordered Sanger sequencing as well. Intravenous ganciclovir (30 mg/kg/day) was initiated and given for 2 weeks, after which she was switched over to oral valganciclovir (30 mg/kg/day) for 2 weeks. Neutropenia was monitored on a weekly basis. CMV DNA became undetectable in plasma after 3 weeks of antiviral therapy [Table 1] and the proteinuria improved. At the end of the antiviral therapy, the baby attained a state of partial remission (>50% reduction in proteinuria from the baseline).
Table 1: Clinical, histopathological, and genetic profile of young infants with cytomegalovirus infection

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The Sanger sequencing result revealed a novel pathogenic homozygous 5' splice site (c. 712+1G>C) variant mutation in the NPHS 1 gene. This was classified as a likely pathogenic variant. The parents were provided prenatal diagnosis and counseled regarding the risk of recurrence in future pregnancies. Angiotensin-converting enzyme inhibitor was started after the completion of antiviral therapy. Follow-up became erratic after the parents relocated to another city. We learned that the baby received 6 weeks of oral prednisolone, which were discontinued when there was no symptomatic improvement. At the age of 2 years, she became terminally ill and died.


  Discussion Top


This patient exhibited features of classical (Finnish type) congenital NS due to a homozygous NPHS 1 pathogenic variant, complicated by a CMV infection. The baby had microcephaly, hepatosplenomegaly, and white matter hyperintensities in the right frontal lobe. The renal histological findings were consistent with what has been described in CMV-related congenital NS reported by Chen et al., including mesangioproliferative lesions, diffuse podocyte effacement, and endothelial tubuloreticular inclusions.[5] This phenotype is more severe, is associated with marked inflammation, and presents earlier.[6] CMV infection is the most common congenital infection reported from low- and middle-income countries, with prevalence rates of 1%–6%.[9] If CMV infection is detected 3 weeks after birth, it may be either perinatal or congenital in original, and it is often difficult to distinguish between the two.[10] There have been reports of congenital NS due to other congenital infections (congenital syphilis and congenital toxoplasmosis) who demonstrated remission with therapy. Our case received anti-CMV therapy for 4 weeks and attained partial remission. The role of anti-CMV therapy in curing CMV-related renal injury is not fully clear, as is the mechanism of CMV-induced glomerular injury. Some studies suggest direct virus-mediated tissue injury, insult mediated by T-cell response, as well as immune complex formation.[11] An extensive literature search of the cases of CMV-associated congenital NS that we identified in PubMed and Google Scholar is depicted in [Table 1].[5],[6],[7],[12],[13] Although there are no guidelines for management of renal involvement in CMV infection, we decided to administer specific therapy after suitable scientific discussion.

The novel homozygous mutation identified in this baby has not been reported in the 1000G and ExAC databases. Genotype–phenotypic correlation will be difficult in this case as the co-existence of CMV infection could have contributed to the severity of presentation. Sinha et al. described genetic mutations in a large proportion of patients (23%) with congenital NS.[2] It is important to perform genetic testing to establish diagnosis, provide genetic counseling, and be able to offer prenatal diagnosis in subsequent pregnancies.



Declaration of patient consent

The authors certify that they have obtained appropriate patient consent form. In the form the patient's parents have given their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Reynolds BC, Oswald RJ. Diagnostic and management challenges in congenital nephrotic syndrome. Pediatric Health Med Ther 2019;10:157-67.  Back to cited text no. 1
    
2.
Sinha R, Vasudevan A, Agarwal I, et al. Congenital nephrotic syndrome in India in the current era: A multicenter case series. Nephron 2020;144:21-9.  Back to cited text no. 2
    
3.
Jalanko H. Congenital nephrotic syndrome. Pediatr Nephrol 2009;24:2121-8.  Back to cited text no. 3
    
4.
Swanson EC, Schleiss MR. Congenital cytomegalovirus infection: New prospects for prevention and therapy. Pediatr Clin North Am 2013;60:335-49.  Back to cited text no. 4
    
5.
Chen Y, Zhang Y, Wang F, et al. Analysis of 14 patients with congenital nephrotic syndrome. Front Pediatr 2019;7:341.  Back to cited text no. 5
    
6.
Besbas N, Bayrakci US, Kale G, et al. Cytomegalovirus-related congenital nephrotic syndrome with diffuse mesangial sclerosis. Pediatr Nephrol 2006;21:740-2.  Back to cited text no. 6
    
7.
Platt JL, Sibley RK, Michael AF. Interstitial nephritis associated with cytomegalovirus infection. Kidney Int 1985;28:550-2.  Back to cited text no. 7
    
8.
Jacob A, Habeeb SM, Herlitz L, Simkova E, Shekhy JF, Taylor A, et al. Case Report: CMV-Associated Congenital Nephrotic Syndrome. Front Pediatr 2020;8:799.  Back to cited text no. 8
    
9.
Blázquez-Gamero, D. Renal involvement in Congenital Cytomegalovirus Infection. Advanced Pediatric infectology: Practical approach 2014; 185-95.  Back to cited text no. 9
    
10.
Congenital Cytomegalovirus (cCMV) CDC. Available from: https://www.cdc.gov/cmv/clinical/congenital-cmv.html. [Last accessed on 2021 Oct 15].  Back to cited text no. 10
    
11.
Platt JL, Sibley RK, Michael AF. Interstitial nephritis associated with cytomegalovirus infection. Kidney Int 1985;28:550-2.  Back to cited text no. 11
    
12.
Frishberg Y, Rinat C, Feinstein S, et al. Mutated podocin manifesting as CMV-associated congenital nephrotic syndrome. Pediatr Nephrol 2003;18:273-5.  Back to cited text no. 12
    
13.
Jacob A, Habeeb SM, Herlitz L, et al. Case report: CMV-associated congenital nephrotic syndrome. Front Pediatr 2020;8:580178.  Back to cited text no. 13
    


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