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A previously healthy 8-month-old girl presented to the emergency department with fever and increased work of breathing. She was hospitalized for hypoxia attributed to community-acquired pneumonia, treated with ceftriaxone, and weaned to room air over several days. On the morning of planned discharge, she was noted to have had persistently elevated blood pressures for the past 12 hours.
A previously healthy 8-month-old girl presented to the emergency department with fever and increased work of breathing. She was hospitalized for hypoxia attributed to community-acquired pneumonia, treated with ceftriaxone, and weaned to room air over several days. On the morning of planned discharge, she was noted to have had persistently elevated blood pressures for the past 12 hours. No lethargy, irritability, vomiting, or change in the quantity or quality of urination had been noted.
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The patient had no significant medical history and was current on her immunizations. She was born full term by spontaneous vaginal delivery without complications during pregnancy or after birth.
On physical examination, the patient's heart rate was 130 beats per minute; blood pressure was 122/88 mm Hg; temperature was 97°F (36.1°C); head circumference was 43.5cm (50th percentile); length was 71 cm (75th percentile); weight was 8.2 kg (30th percentile); and weight for length was at the 25th percentile. No edema, ambiguous genitalia, or papilledema were noted. No abdominal mass was felt, nor was an abdominal bruit auscultated. Findings of the rest of the physical examination were normal. Four-extremity blood pressures, with both manual and electronic cuffs, were all consistently elevated above the 99th percentile.
Complete metabolic panel revealed a creatinine of 1.0 mg/dL and albumin of 2.3 g/dL. Urinalysis revealed proteinuria (>300mg/dL).
NEXT: Differential diagnosis
Most childhood hypertension is secondary to an underlying disorder (Table 11,2). Hypertension is defined as systolic or diastolic blood pressure above the 95th percentile for the patient's age, height, and gender on 3 separate occasions.3 The differential diagnosis for hypertension in an otherwise well-appearing infant includes renal parenchymal and arterial diseases, coarctation of the aorta, and endocrinopathies. Clinical history should include an evaluation for symptoms of target end-organ damage and hypertensive emergency, including seizures, irritability (headache, blurry vision), feeding intolerance, and shortness of breath. The physical examination should assess for vital signs including 4-extremity blood pressures, growth parameters, synchronous distal pulses, and an abdominal examination for masses or bruits.4
Renal parenchymal diseases such as nephrotic syndrome or glomerulonephritis are the most common cause of hypertension in preadolescents. Patients typically present with edema, general malaise, and proteinuria and/or hematuria. Renal artery stenosis presents with hypertension but not typically proteinuria. Patients may be asymptomatic or, if stenosis is bilateral, display signs of renal failure. Diagnosis is made with Doppler ultrasound of the renal arteries and angiography of the renal arteries.
Coarctation of the aorta presents with weak and asynchronous distal pulses, an upper and lower extremity systolic blood pressure differential, and cardiogenic shock. Diagnosis is made by echocardiography or abdominal computed tomography. In this case, the patient had synchronous distal pulses with no blood pressure differential and was hemodynamically stable.
Endocrinopathies associated with hypertension in infants include congenital adrenal hyperplasia and Cushing syndrome. Two forms of adrenal hyperplasia, classic 11-beta-hydroxylase deficiency and 17-hydroxylase deficiency, may present with hypertension in the first year of life secondary to high levels of mineralocorticoids. Adrenocortical tumors such as adrenocortical carcinoma are the most common cause of endogenous Cushing syndrome in infancy. Glucocorticoid excess is associated with growth failure, acne, hyperglycemia, and plethora.1
NEXT: Further testing
A urine protein creatinine ratio was elevated (42.3). Triglycerides, low-density lipoprotein (LD), and high-density lipoprotein (HDL) were also elevated. Phosphorous was normal. Complete blood count revealed microcytosis (Hgb, 11.1 g/dL; mean corpuscular volume [MCV], 71 fL). Iron levels were low (level 34 mcg/dL; total iron-binding capacity [TIBC], 19%). Renal ultrasound revealed normal-sized kidneys with increased echogenicity of the renal parenchyma (Figure). Echocardiogram showed normal function and no left ventricular hypertrophy. Karyotype was 46, XX. The patient was diagnosed with infantile nephrotic syndrome.
The patient remained hospitalized for further workup of her hypertension. She was started on enalapril for blood pressure control, iron, and citric acid/sodium citrate. The patient was discharged home to recover from her respiratory illness. One week after discharge, her blood pressure had decreased to 98/64 mm Hg. She underwent open renal biopsy 12 weeks after discharge and pathology showed diffuse mesangial sclerosis. Gene testing revealed an NPHS1 mutation of unknown clinical significance, no NPHS2 mutation, and a positive WT1 mutation.
NEXT: Discussing the diagnosis
Nephrotic syndrome appearing in a patient aged between 4 and 12 months is classified as infantile nephrotic syndrome. This is opposed to congenital nephrotic syndrome, which is defined as starting within the first 3 months after birth. Both are characterized by proteinuria, hypoalbuminemia, and hyperlipidemia.
The differential diagnosis for nephrotic syndrome in children and adolescents includes primary and secondary causes (Table 25,6). Congenital nephrotic syndrome of the Finnish type is an autosomal recessive disease involving a defect in the NPHS1 gene encoding the transmembrane protein nephrin. These patients are often edematous shortly after birth and have marked ascites by 3 months of age.7,8 The patient has an NPHS1 base pair mutation of unknown clinical significance and no NPHS2 mutation.
The patient, who had no edema, has diffuse mesangial sclerosis (DMS), a hereditary disease exclusive to infancy that involves glomerular injury and rapid progression to end-stage renal disease. It remains unclear why her hypertension manifested toward the end of her hospital stay, but it is possible that fluid overload during her intercurrent respiratory illness may have contributed to its progression. Diffuse mesangial sclerosis can be seen alone but is associated with several genotypic disorders including Denys-Drash syndrome, a triad of nephrotic syndrome, male gonadal dysgenesis, and Wilms tumor. Additionally, mutations in 2 genes are implicated in DMS: WT1 and/or PLCE1.9
Management of DMS includes supportive care for maintenance of electrolyte and water balance, adequate nutrition, and treatment of renal failure. Infants with DMS may appear normal at birth but then develop progressive proteinuria, typically before 2 years of age, and progress to end-stage renal disease before age 4 years. Renal transplant is the only definitive cure.
Children with DMS and female phenotype or ambiguous genitalia should be evaluated with karyotype and WT1 gene analysis. The patient is WT1 mutation positive. This WT1 mutation in patients with DMS indicates a predisposition to develop Wilms tumor, often before age 2 years. Such patients should be monitored by renal ultrasonography every 4 to 6 months. Prophylactic nephrectomy may be considered prior to transplantation.10
NEXT: How is the patient doing?
The patient continues to have regular appointments with Nephrology. She displays no edema and her hypertension is controlled on enalapril. She continues on iron and citric acid. Her albumin remains low (3.3 g/dL) but has improved since being placed on 22kcal/oz formula.
The patient was started on growth hormone for growth failure secondary to her renal disease. She will undergo renal ultrasound every 4 to 6 months for Wilms tumor surveillance. She will need eventual renal transplant.
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2. Pappadis SL, Somers MJ. Hypertension in adolescents: a review of diagnosis and management. Curr Opin Pediatr. 2003;15(4):370-378.
3. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(2 suppl 4th report):555-576.
4. Dionne JM, Abitbol CL, Flynn JT. Hypertension in infancy: diagnosis, management and outcome. Pediatr Nephrol. 2012;27(1):17-32. Erratum in: Pediatr Nephrol. 2012;27(1):159-160.
5. Andolino TP, Reid-Adam J. Nephrotic syndrome. Pediatr Rev. 2015;36(3):117-125.
6. Gordillo R, Spitzer A. The nephrotic syndrome. Pediatr Rev. 2009;30(3):94-104. Erratum in: Pediatr Rev. 2009;30(10):408.
7. El Bakkali L, Rodrigues Pereira R, Kuik DJ, Ket JC, van Wijk JA. Nephrotic syndrome in The Netherlands: a population-based cohort study and a review of the literature. Pediatr Nephrol. 2011;26(8):1241-1246.
8. Hinkes BG, Mucha B, Vlangos CN, et al; Arbeitsgemeinschaft für Paediatrische Nephrologie Study Group. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics. 2007;119(4):e907-e919.
9. Vankalakunti M, Jha PK, Madraki RM, Siddini V, Babu K, Ballal SH. Diffuse mesangial sclerosis-report of two cases. Indian J Nephrol. 2012;22(3):213-216.
10. Nso Roca AP, Peña Carrión A, Benito Gutiérrez M, Garcia Meseguer C, Garcia Pose A, Navarro M. Evolutive study of children with diffuse mesangial sclerosis. Pediatr Nephrol. 2009;24(5):1013-1019.
Dr Wang is a pediatric resident, Department of Pediatrics, Children’s Hospital Los Angeles, California. Dr Lerner is associate professor, Department of Pediatric Nephrology, Children’s Hospital Los Angeles. Dr. Thompson is associate director, Pediatric Residency Program, Children’s Hospital Los Angeles. The authors have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.