Congenital nephrotic syndrome with adrenal calcification and cardiac malformation
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《美国医学杂志》
Department of Pediatrics, St. John's Medical College, Bangalore, India
Abstract
Congenital Nephrotic Syndrome (CNS) with adrenal calcification and CNS with congenital heart disease (CHD) have rarely been reported. However, CNS with both these rare associations has never been previously reported. Here we report a case of CNS with both rare associations, perhaps the first report from India to the best of our knowledge.
Keywords: Congenital nephrotic syndrome; Adrenal calcification; Congenital heart disease
Congenital Nephrotic Syndrome (CNS) is a rare entity of massive proteinuria, severe hypoalbuminemia and oedema presenting within first three months of life. It could be primary as in the case of Finnish type of Nephrotic Syndrome or secondary to intrauterine infections. CNS is rarely associated with adrenal calcification or with congenital heart disease in isolation.[1],[2] The presence of all three associations complicates both the diagnosis and management. Such rare association of CNS with both adrenal calcification and congenital heart disease prompted this case.
Case Report
A four-month-old female, second baby born at term to a second-degree consanguineous couple, presented with the history of progressive abdominal distension of two months duration and symptoms of an acute lower respiratory tract infection. Birth weight was 2.8 Kg. Antenatal, natal and postnatal periods were uneventful.
On examination, she weighed 4.5 Kg. Head circumference was 36.5 cm. She had generalized edema, hypertension (B.P.110/70 mm of Hg), and bronchopneumonia with clinical evidence of patent ductus arteriosus in the form of bounding peripheral pulses and grade IV systolic mumur in the left second and third intercostals spaces. Abdominal examination revealed bilateral palpable kidneys and ascites. External genitalia were normal. There were no signs of intrauterine infections like rash, cataract, microphthalmia, microcornea, choreo-retinitis or hepatosplenomegaly.
Investigation reports were as follows: hemoglobin count 12 gms/dl, total leucocyte count-13,700/mm3 (Polymorphs-70 %, and Lymphocytes-30%), total protein-3.7gm/dl, Serum albumin-1.8 gm/dl, cholesterol-246mg/dl, Blood Urea-11mg/dl, serum creatinine-0.7mg/dl. Urine analysis revealed protein (++++) RBC of 10-12/HPF and protein creatinine ratio of > 17.5. Serology for TORCH IgM, HBsAg, HIV ELISA and VDRL were negative. Echocardiogram was suggestive of patent ductus arteriosus with a left to right shunt. Abdominal X-ray revealed bilateral adrenal calcification. Abdominal ultrasonogram revealed bilateral symmetrical renomegaly (Right Kidney 8.1 X 3cm, Left Kidney 8.2 X 3.4 cm) with smooth contour. There was loss of corticomedullary differentiation with increased parenchymal echogenecity. There was no evidence of obstructive pathology. There was dense bilateral adrenal calcification measuring 1.8 X 1.5 cm. Adrenal glands were normal in size with no suggestion of cysts or tumors. CT Scan abdomen confirmed bilateral adrenal calcifications and renomegaly Figure1. Renal biopsy was consistent with a diagnosis of Finnish type of nephrotic syndrome with dilatation of proximal convoluted tubules and minimal proliferation of mesangial cells Figure2.
The baby was started on enalapril and indomethacin and discharged with counseling. However she was lost to follow up.
Discussion
Congenital Nephrotic Syndrome generally presents with proteinuria, leading to clinical symptoms within first few days to weeks of life. An orbitrary age limit of 3 months has been adopted to separate this entity from the infantile, variety manifesting later in first year of life.[3] Finnish nephrotic syndrome has been considered as the prototype of CNS, the incidence being 1:8200 in Finnish population. This is inherited as an autosomal recessive disorder, caused by mutation in the NPHS1 gene located on chromosome 19. NPHS1 gene encodes a protein nephrin which plays an essential role in the normal function of the glomerular filtration barrier.[4] Secondary causes of CNS include intrauterine infections like syphilis, cytomegalovirus, toxoplasmosis, hepatitis B and HIV infection. Nephrotic Syndrome in such cases is generally less severe and associated with other features of intrauterine infections.
Associated adrenal calcification has been reported earlier in a brief series.[1] Adrenal calcification could be idiopathic, secondary to intrauterine infections, (especially toxoplasmosis and cytomegalovirus), Wolman disease, adrenal hemorrhage, adrenal tumours and neuroblastoma. In this case, TORCH IgM was negative. CT abdomen ruled out neuroblastoma and adrenal tumours. Wolman disease was also ruled out by the absence of organomegaly and normal sized adrenals. The causal relationship between CNS and adrenal calcification is difficult to explain in the absence of intrauterine infections. It has been hypothesized that hypovolemia, secondary to severe hypoalbuminemia, could increase the risk of hemorrhagic infarction of the adrenals, subsequently leading to adrenal calcification.[1]
Congenital heart disease has also been rarely reported in few cases of CNS. The Cardiac lesions described in these children were pulmonary stenosis and subaortic stenosis.[2] However, patent ductus arteriosus has not been reported earlier.
Treatment of CNS is challenging as it responds poorly to corticosteroids and other immunosuppressants. Recurrent infections, impaired growth and development, fluid and electrolyte imbalance are common. Progressive renal failure develops in 1-2 years. Intensive supportive management consists of dialysis, prostaglandin inhibitors, angiotensin converting enzyme (ACE) inhibitors, intravenous albumin infusions, along with unilateral nephrectomy (to reduce proteinuria). This allows time for a possible renal transplantation later in the third year of life when transplantation is technically feasible.[5], [6] Recipient age less than two years is a significant predictor of poor graft survival. Unfortunately, the risk of recurrence of nephrosis following transplantation is 20%-25%.[7],[8]
Prenatal diagnosis of CNS is possible by estimation of high maternal serum alpha-fetoprotein (AFP). If the concentration of AFP is 2,50,000 to 5,00,000 micro gram/L and especially if there is another child with CNS in the family, it is highly suggestive of CNS. However analysis of NPHS 1 gene is now the method of choice for precise diagnosis of CNS.
The occurrence of these two unusual features viz., bilateral dense adrenal calcification with normal sized adrenal glands and congenital heart disease with CNS could be co-incidental or it could be a variant of Finnish nephrotic syndrome. Therefore, the major relevance of identifying this type of presentation of CNS is to consider it as a differential diagnosis to CNS secondary to intra-uterine infection. In terms of prognosis, complications of CHD like congestive cardiac failure and infective endocarditis might adversely affect the outcome.
In conclusion, associated anomalies should be looked for in a child with congenital nephrotic syndrome.
Acknowledgement
We thank Dr. Kanishka Das, Dept. of Pediatric Surgery, for his valuable help in preparing the CT photograph and Dr. Usha kini, Dept.of pathology, for kindly providing renal biopsy photograph .
References
1. Powers RJ, Cohen ML, Williams J. Adrenal Calcification and congenital nephrotic syndrome in three American Indians. Pediatric. Nephrology 1990; 4: 29-31.
2. Grech V, Chan MKH, Vella C, Montalto SA, Rees P, Trompeter RS. Cardiac malformations associated with the congenital nephrotic syndrome. Pediatric Nephrology 2000; 14: 1115-1117.
3. Holmberg C, Jolanko H, Tryggvason K, Rapola J. Congenital nephrotic syndrome. In Barrat TM, Avner ED and Harmon WE, eds. Pediatric Nephrology, 4th edn. Pennsylvania; Lippincott Williams & Wilkins, 1999; 765-774.
4. Vogt BA, Avner Ed. Congenital nephrotic syndrome. In Behrman RE, kleigman Rm, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th edn. New Delhi, Elsevier, 2004; 1757.
5. Kovacevic L, Reid CJD, Rigden SPA. Management of congenital nephrotic syndrome. Pediatric Nephrology 2003; 18: 426-430.
6. Licht C, Eifinger Frank, Gharib M, Offner G, Michalk DV, Querfeld U. A stepwise approach to the treatment of early onset nephrotic syndrome. Pediatric Nephrology 2000; 14: 1077-1082.
7. Patrakka J, Ruotsalainen V, Reponen P et al. Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish Type: Role of nephrin. Transplantation 2002; 73: 394-403.
8. Laine J, Jalanko H, Holthofer H et al. Post transplantation nephrosis in congenital nephrotic syndrome of the Finnish type. Kidney Int 1993; 44: 867-874.(Indumathi CK, Dinakar Chi)
Abstract
Congenital Nephrotic Syndrome (CNS) with adrenal calcification and CNS with congenital heart disease (CHD) have rarely been reported. However, CNS with both these rare associations has never been previously reported. Here we report a case of CNS with both rare associations, perhaps the first report from India to the best of our knowledge.
Keywords: Congenital nephrotic syndrome; Adrenal calcification; Congenital heart disease
Congenital Nephrotic Syndrome (CNS) is a rare entity of massive proteinuria, severe hypoalbuminemia and oedema presenting within first three months of life. It could be primary as in the case of Finnish type of Nephrotic Syndrome or secondary to intrauterine infections. CNS is rarely associated with adrenal calcification or with congenital heart disease in isolation.[1],[2] The presence of all three associations complicates both the diagnosis and management. Such rare association of CNS with both adrenal calcification and congenital heart disease prompted this case.
Case Report
A four-month-old female, second baby born at term to a second-degree consanguineous couple, presented with the history of progressive abdominal distension of two months duration and symptoms of an acute lower respiratory tract infection. Birth weight was 2.8 Kg. Antenatal, natal and postnatal periods were uneventful.
On examination, she weighed 4.5 Kg. Head circumference was 36.5 cm. She had generalized edema, hypertension (B.P.110/70 mm of Hg), and bronchopneumonia with clinical evidence of patent ductus arteriosus in the form of bounding peripheral pulses and grade IV systolic mumur in the left second and third intercostals spaces. Abdominal examination revealed bilateral palpable kidneys and ascites. External genitalia were normal. There were no signs of intrauterine infections like rash, cataract, microphthalmia, microcornea, choreo-retinitis or hepatosplenomegaly.
Investigation reports were as follows: hemoglobin count 12 gms/dl, total leucocyte count-13,700/mm3 (Polymorphs-70 %, and Lymphocytes-30%), total protein-3.7gm/dl, Serum albumin-1.8 gm/dl, cholesterol-246mg/dl, Blood Urea-11mg/dl, serum creatinine-0.7mg/dl. Urine analysis revealed protein (++++) RBC of 10-12/HPF and protein creatinine ratio of > 17.5. Serology for TORCH IgM, HBsAg, HIV ELISA and VDRL were negative. Echocardiogram was suggestive of patent ductus arteriosus with a left to right shunt. Abdominal X-ray revealed bilateral adrenal calcification. Abdominal ultrasonogram revealed bilateral symmetrical renomegaly (Right Kidney 8.1 X 3cm, Left Kidney 8.2 X 3.4 cm) with smooth contour. There was loss of corticomedullary differentiation with increased parenchymal echogenecity. There was no evidence of obstructive pathology. There was dense bilateral adrenal calcification measuring 1.8 X 1.5 cm. Adrenal glands were normal in size with no suggestion of cysts or tumors. CT Scan abdomen confirmed bilateral adrenal calcifications and renomegaly Figure1. Renal biopsy was consistent with a diagnosis of Finnish type of nephrotic syndrome with dilatation of proximal convoluted tubules and minimal proliferation of mesangial cells Figure2.
The baby was started on enalapril and indomethacin and discharged with counseling. However she was lost to follow up.
Discussion
Congenital Nephrotic Syndrome generally presents with proteinuria, leading to clinical symptoms within first few days to weeks of life. An orbitrary age limit of 3 months has been adopted to separate this entity from the infantile, variety manifesting later in first year of life.[3] Finnish nephrotic syndrome has been considered as the prototype of CNS, the incidence being 1:8200 in Finnish population. This is inherited as an autosomal recessive disorder, caused by mutation in the NPHS1 gene located on chromosome 19. NPHS1 gene encodes a protein nephrin which plays an essential role in the normal function of the glomerular filtration barrier.[4] Secondary causes of CNS include intrauterine infections like syphilis, cytomegalovirus, toxoplasmosis, hepatitis B and HIV infection. Nephrotic Syndrome in such cases is generally less severe and associated with other features of intrauterine infections.
Associated adrenal calcification has been reported earlier in a brief series.[1] Adrenal calcification could be idiopathic, secondary to intrauterine infections, (especially toxoplasmosis and cytomegalovirus), Wolman disease, adrenal hemorrhage, adrenal tumours and neuroblastoma. In this case, TORCH IgM was negative. CT abdomen ruled out neuroblastoma and adrenal tumours. Wolman disease was also ruled out by the absence of organomegaly and normal sized adrenals. The causal relationship between CNS and adrenal calcification is difficult to explain in the absence of intrauterine infections. It has been hypothesized that hypovolemia, secondary to severe hypoalbuminemia, could increase the risk of hemorrhagic infarction of the adrenals, subsequently leading to adrenal calcification.[1]
Congenital heart disease has also been rarely reported in few cases of CNS. The Cardiac lesions described in these children were pulmonary stenosis and subaortic stenosis.[2] However, patent ductus arteriosus has not been reported earlier.
Treatment of CNS is challenging as it responds poorly to corticosteroids and other immunosuppressants. Recurrent infections, impaired growth and development, fluid and electrolyte imbalance are common. Progressive renal failure develops in 1-2 years. Intensive supportive management consists of dialysis, prostaglandin inhibitors, angiotensin converting enzyme (ACE) inhibitors, intravenous albumin infusions, along with unilateral nephrectomy (to reduce proteinuria). This allows time for a possible renal transplantation later in the third year of life when transplantation is technically feasible.[5], [6] Recipient age less than two years is a significant predictor of poor graft survival. Unfortunately, the risk of recurrence of nephrosis following transplantation is 20%-25%.[7],[8]
Prenatal diagnosis of CNS is possible by estimation of high maternal serum alpha-fetoprotein (AFP). If the concentration of AFP is 2,50,000 to 5,00,000 micro gram/L and especially if there is another child with CNS in the family, it is highly suggestive of CNS. However analysis of NPHS 1 gene is now the method of choice for precise diagnosis of CNS.
The occurrence of these two unusual features viz., bilateral dense adrenal calcification with normal sized adrenal glands and congenital heart disease with CNS could be co-incidental or it could be a variant of Finnish nephrotic syndrome. Therefore, the major relevance of identifying this type of presentation of CNS is to consider it as a differential diagnosis to CNS secondary to intra-uterine infection. In terms of prognosis, complications of CHD like congestive cardiac failure and infective endocarditis might adversely affect the outcome.
In conclusion, associated anomalies should be looked for in a child with congenital nephrotic syndrome.
Acknowledgement
We thank Dr. Kanishka Das, Dept. of Pediatric Surgery, for his valuable help in preparing the CT photograph and Dr. Usha kini, Dept.of pathology, for kindly providing renal biopsy photograph .
References
1. Powers RJ, Cohen ML, Williams J. Adrenal Calcification and congenital nephrotic syndrome in three American Indians. Pediatric. Nephrology 1990; 4: 29-31.
2. Grech V, Chan MKH, Vella C, Montalto SA, Rees P, Trompeter RS. Cardiac malformations associated with the congenital nephrotic syndrome. Pediatric Nephrology 2000; 14: 1115-1117.
3. Holmberg C, Jolanko H, Tryggvason K, Rapola J. Congenital nephrotic syndrome. In Barrat TM, Avner ED and Harmon WE, eds. Pediatric Nephrology, 4th edn. Pennsylvania; Lippincott Williams & Wilkins, 1999; 765-774.
4. Vogt BA, Avner Ed. Congenital nephrotic syndrome. In Behrman RE, kleigman Rm, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th edn. New Delhi, Elsevier, 2004; 1757.
5. Kovacevic L, Reid CJD, Rigden SPA. Management of congenital nephrotic syndrome. Pediatric Nephrology 2003; 18: 426-430.
6. Licht C, Eifinger Frank, Gharib M, Offner G, Michalk DV, Querfeld U. A stepwise approach to the treatment of early onset nephrotic syndrome. Pediatric Nephrology 2000; 14: 1077-1082.
7. Patrakka J, Ruotsalainen V, Reponen P et al. Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish Type: Role of nephrin. Transplantation 2002; 73: 394-403.
8. Laine J, Jalanko H, Holthofer H et al. Post transplantation nephrosis in congenital nephrotic syndrome of the Finnish type. Kidney Int 1993; 44: 867-874.(Indumathi CK, Dinakar Chi)