Published online July 24, 2006
PEDIATRICS Vol. 118 No. 2 August 2006, pp. e501-e505 (doi:10.1542/peds.2005-3154)
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EXPERIENCE AND REASON

Pierson Syndrome: A Novel Cause of Congenital Nephrotic Syndrome

Rene' VanDeVoorde, MDa, David Witte, MDb, Jillene Kogan, MD, PhDc and Jens Goebel, MDa

a Pediatric Nephrology and Hypertension
b Divisions of Pathology
c Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio


   ABSTRACT
TOP
 ABSTRACT
CASE REPORT
 DISCUSSION
 REFERENCES
 
In this report, we describe a newborn infant who presented with congenital nephrotic syndrome and renal insufficiency, as well as bilateral microcoria. This constellation of findings is a hallmark of Pierson syndrome, a newly recognized genetic disorder that is caused by a deficiency of ß2 laminin in the basement membrane. Our patient demonstrated classic histopathologic findings of Pierson syndrome on renal biopsy, including absence of ß2 laminin on immunofluorescent staining, and genetic testing confirmed the diagnosis. We conclude that Pierson syndrome should be included in the differential diagnosis for congenital nephrotic syndrome, especially in patients with ocular abnormalities.

Key Words: congenital nephrotic syndrome • glomerular basement membrane • Pierson syndrome • laminin • microcoria

Abbreviations: CNS, congenital nephrotic syndrome • GBM, glomerular basement membrane • CNF, congenital nephrotic syndrome of the Finnish type • CD2AP, CD2-associated protein

Nephrotic syndrome is a common pediatric nephrologic condition constituted by edema, proteinuria, hypoalbuminemia, and hypercholesterolemia. A majority of patients present between 1 and 6 years of age with minimal-change disease, a disorder of yet-undetermined immunologic etiology that is often responsive to corticosteroid therapy. In contrast, congenital nephrotic syndrome (CNS), defined as nephrotic syndrome detected at <3 months of age, is caused by an entirely different set of disease processes. Primary CNS is caused by genetic alterations of the glomerular microstructure that cause massive proteinuria unresponsive to immunosuppressive therapies, whereas secondary CNS often is caused by an immune-mediated injury to the glomerular basement membrane (GBM). Pierson syndrome, a recently discovered etiology of primary CNS, is caused by GBM alterations resulting from a deficiency of ß2 laminin. Here we describe a newborn female with Pierson syndrome and the diagnostic considerations for CNS.


   CASE REPORT
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 ABSTRACT
 CASE REPORT
DISCUSSION
 REFERENCES
 
A 2665-g female infant was delivered vaginally at 36 weeks of gestation to a 24-year-old gravida 4 para 2 white mother and 41-year-old black father. Prenatal care had been sporadic, but maternal laboratory values were normal, including negative HIV and hepatitis B antigen and a nonreactive rapid plasma reagin. The family history was negative for any inheritable disorders, and there was no history of renal or ophthalmologic problems. The pregnancy was remarkable for an abnormal fetal ultrasound at 28 weeks, which revealed large, hyperechoic kidneys. At the 36-week prenatal visit, another ultrasound showed oligohydramnios. Consequently, a biophysical profile was performed, which was decreased (5/10), prompting induction of labor. Delivery was uneventful, and the infant's Apgar scores at 1 and 5 minutes were 7 and 8, respectively. No umbilical cord or placental abnormalities (eg, size) were noted.

The patient had initial weight, length, and head circumference at the 50th percentile for gestational age. On initial newborn examination, the patient had slightly decreased muscle tone but intact reflexes. Moreover, she was found to have bilateral microcoria (ie, pinpoint pupils; Fig 1), prompting a maternal drug screen that was positive only for caffeine. No other dysmorphology was noted.


Figure 1
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  		FIGURE 1 Microcoria of the patient's left eye at 1 month of age.

 
On day-of-life 3, the patient was noted to have slight edema of her legs and left eyelid. After initially doing well, she started to feed poorly, taking only 10 mL per feeding. Because of her ocular finding and slight fussiness, there were additional concerns about drug withdrawal, but a meconium drug screen was also negative.

After further inquiry revealed the abnormal prenatal ultrasound findings, a renal profile was obtained on day-of-life 5, showing hyponatremia (sodium: 129 mmol/dL) and renal insufficiency (creatinine: 2.7 mg/dL). A follow-up renal ultrasound was obtained, which confirmed bilaterally enlarged hyperechoic kidneys. Because of the patient's renal failure, she was transferred to our facility with a suspected diagnosis of autosomal recessive polycystic kidney disease.

Laboratory evaluation after transfer on day-of-life 8 showed significant proteinuria (urine protein: >300 mg/dL on dipstick; urine protein/creatinine ratio: 60 mg/mg), hypoalbuminemia (albumin: 1.5 g/dL), and persistent renal dysfunction (creatinine: 2.9 mg/dL), leading to the diagnosis of CNS with renal failure. Abdominal and pelvic ultrasound revealed a normal liver, spleen, ovaries, and uterus. Follow-up renal ultrasound showed the aforementioned enlarged hyperechoic kidneys with loss of corticomedullary differentiation but no apparent cysts. A head ultrasound was normal as well. Cytomegalovirus antigen was undetectable, and there was no other evidence of TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex) infections. High-resolution chromosomal analysis showed a normal 46,XX karyotype. Pediatric ophthalmology consultants found continued pupillary constriction despite use of dilating drops and a persistent hyperplastic primary vitreous of the right eye. The patient was noted to be moderately hypertensive with blood pressures >120/80 mmHg in all 4 extremities, requiring multiple antihypertensive medications to control. She was also dependent on intravenous albumin and furosemide for edema management.

An open renal biopsy was performed at 3 weeks of life and showed extensive diffuse mesangial sclerosis (Fig 2). Light microscopy revealed a wide variety of glomerular morphology. Nearly half of the glomeruli had crescent formation, whereas others had a fetal appearance with hypercellularity, diffuse matrix proliferation, and nearly complete obliteration of the vascular architecture. Focal interstitial inflammation and tubular atrophy and dilation were also present. Electron microscopy showed thinning of the GBM with diffuse foot process effacement and prominent podocytes forming a coronal pattern over the GBM (Fig 3).


Figure 2
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  		FIGURE 2 Hematoxylin/eosin stain of light microscopy of the patient's kidney biopsy showing focal inflammation of the interstitium and varied appearances of the glomeruli. Some glomeruli are obscured by crescent formation (solid white arrow), whereas others have loss of their normal vascular architecture (dashed arrow). Dilated tubules are seen on the left side of the frame.

 

Figure 3
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  		FIGURE 3 Electron microscopic appearance of the kidney with a thin GBM (only 40–50 nm; reference: 90 nm) (left) and large podocytes that crowd together on the GBM (right).

 
The patient's ophthalmologic and renal findings were consistent with a clinical diagnosis of Pierson syndrome,1 a condition of absent ß2 laminin from the basement membranes of the glomerulus and anterior eye structures. Additional immunofluorescence staining for ß2 laminin confirmed its absence in the GBM of our patient (Fig 4). Additional genetic analysis, performed by Martin Zenker, MD (Institute of Human Genetics, Erlangen, Germany), showed 2 different mutations (compound heterozygosity) of LAMB2, the ß2 laminin gene on chromosome 3, thus confirming the diagnosis of Pierson syndrome as the etiology of this patient's CNS.


Figure 4
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  		FIGURE 4 Immunofluorescent staining for ß2 laminin. Shown is the patient's biopsy specimen (left) with absence of linear immunofluorescent staining for ß2 laminin and a normal adult control glomerulus (right, magnified) with linear fluorescent staining for ß2 laminin of the GBM (open arrows). Cell nuclei (closed arrows) are visible more weakly in both pictures because of counterstaining.

 

   DISCUSSION
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
REFERENCES
 
CNS may be difficult to recognize initially in newborns. It often presents as abdominal distention or swelling,2 which may not be noted initially because of the relatively low abdominal tone in neonates and because dependent edema settles more in the back and legs (as opposed to the eyes and distal extremities) in this age group. There may be other subtle antenatal or perinatal signs that may also increase clinical suspicion, such as increased amniotic {alpha}-fetoprotein or placental enlargement; therefore, adequate communication of abnormal findings between the obstetrical provider and pediatrician may be important. This delay in diagnosis may postpone recognition and treatment of conditions secondary to the protein losses, such as immunosuppression,2,3 hypercoagulability,3,4 hypothyroidism,5 or growth delay.4,6

CNS is subdivided into primary and secondary types. Primary CNS has been attributed to a variety of syndromes with autosomal recessive inheritance. For purposes of clarification, these syndromes may be divided into those with gene products that affect the glomerular slit diaphragm, those that affect genitourinary development, and those with gene products that are unknown or are unique in their effect. Secondary CNS is usually caused by perinatal infections. Historically, congenital syphilis has been associated with nephropathy7; however, various reports have also implicated toxoplasmosis,8 rubella,9 cytomegalovirus,10 HIV,11 and hepatitis B.12 Finally, CNS has been reported in infantile systemic lupus erythematosus.13

The different etiologies of primary CNS are best understood through a review of the glomerular filter. The glomerular capillary wall forms a size- and charge-selective barrier composed of 3 layers: the fenestrated endothelium, the GBM, and the podocyte foot processes (Fig 5). The foot processes are interconnected by a bridging structure, the slit diaphragm, which acts as the size-selective pore, whereas the GBM restricts molecules based on their ionic charge. Genetic alterations in this structure can cause proteinuria and nephrotic syndrome.


Figure 5
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  		FIGURE 5 Illustration of the glomerular capillary wall with endothelial, GBM, and podocyte layers. The GBM is composed of collagen, laminin, and heparan sulfate proteoglycans. The slit diaphragm contains overlapping nephrin molecules that are "anchored" to the foot process through a structure combining podocin (dark circle), CD2AP (dark square), and {alpha}-actinin 4 (curved lines).

 
The prototype of the slit diaphragm disorders is CNS of the Finnish type (CNF). The gene NPHS1, which is mutated in CNF, was isolated on chromosome 19 in 1998.14 Its gene product, nephrin, is a cell-adhesion protein that spans the slit diaphragm and is isolated to the glomerulus in humans.14–16 Hence, children with CNF typically present with signs and symptoms of protein deficiency in the first 2 months of life2 without other organ involvement. Classically, these infants are born prematurely with a normal birth weight but notable placental enlargement.17 Ultrasounds show normally sized, hyperechoic kidneys in the first 2 months of life,18 followed by kidney enlargement in infancy. Electron microscopy of the glomerulus shows various sizes of the slit pores between podocytes and absence of the filamentous image of the slit diaphragm.19

Abnormalities of other slit-diaphragm components, although less commonly documented, may also cause CNS. Koziell et al20 found mutations in NPHS2, which encodes for podocin (an anchoring protein for the slit diaphragm) in 25% of patients with CNF who lacked NPHS1 mutations, although podocin mutations typically lead to focal segmental glomerular sclerosis later in life.21 Mutations of genes encoding other components such as {alpha}-actinin 422 and CD2-associated protein (CD2AP)23 have also been shown to cause familial nephrotic syndrome in humans and CNS in mice but have not yet been linked with CNS in humans.

Primary CNS has also been attributed to mutations in the WT1 gene on chromosome 11.24–26 WT1 encodes a transcription factor that regulates expression of several target genes in renal and gonadal development. The most recognized disorder with CNS and WT1 mutation is Denys-Drash syndrome, characterized by rapid progression to end-stage renal disease, male pseudohermaphroditism, and Wilms' tumor. Patients are karyotypic males (46,XY) with ambiguous genitalia or have a female phenotype and dysgenic gonads. Those with Frasier syndrome also have WT1 mutations and gonadal dysgenesis, although proteinuria and renal dysfunction tend to occur in early childhood. Patients with isolated diffuse mesangial sclerosis have also characteristically been associated with WT1 mutations similar to those seen in Denys-Drash syndrome, but with normal gonadal development.27

Other causes of CNS that do not involve mutations of the slit diaphragm or the WT1 gene include Galloway-Mowat syndrome and nail-patella syndrome. Since its first description in 1968, Galloway-Mowat syndrome has been recognized by the constellation of early-onset nephrotic syndrome, brain malformations (microcephaly, gyral abnormalities), and hiatal hernia.28 Nail-patella syndrome is an autosomal dominant disorder with the association of nail dysplasia, elbow and knee abnormalities, and variable renal involvement. In 1998, it was shown that nail-patella syndrome is caused by mutations in LMX1B, a transcription factor on chromosome 9.29 LMX1B's function on the developing kidney has not been clearly explained but is thought to possibly affect type IV collagen,30 CD2AP,31 and podocin expression.31 An early report by Simila et al32 documented CNS at birth in a patient with nail-patella syndrome, but the proteinuria resolved by 8 months of age, showing the inconsistent renal effects of this disorder. CNS has also been described in association with carbohydrate-deficient glycoprotein syndrome33 and, very recently, respiratory chain disorders.34

Our patient's diagnosis, Pierson syndrome, is another cause of primary CNS not caused by mutations of either WT1 or genes encoding proteins in the slit diaphragm. Although the association of CNS and ocular anomalies was first described by Pierson et al35 in 1963, its genetic basis has been uncovered only recently by Zenker et al,36 who noted 2 consanguineous families with 11 offspring with CNS and distinct eye abnormalities, most frequently microcoria.1 Using homozygosity mapping of these 2 families, they were able to determine a candidate gene region on chromosome 3p. This region contained LAMB2, which had earlier been shown to cause CNS in homozygous-deficient mice.37 With bidirectional mutation screening, they confirmed mutations of this gene and abnormalities in its product, ß2 laminin. ß2 laminin is a normal component of the basement membranes of the mature glomerulus38 and structures in the anterior eye. In affected subjects, ß2 laminin was accordingly found to be absent by immunofluorescence.

The renal histopathologic findings of Pierson syndrome in humans are difficult to reconcile with animal models. In our patient, as well as previously diagnosed patients with Pierson syndrome,1 diffuse mesangial sclerosis, accompanied by crescent formation, has been the predominant finding. However, previous studies in rodent models have shown either no major changes to the glomeruli in nephrotic mice37 or failure of the mesangium to develop in rats,39 potentially indicating that the specific roles of ß2 laminin for renal development differ between rodents and humans. The disorganization of collagen and proteoglycans with the absence of laminin and collagen in the hyalinized glomeruli that can be seen in diffuse mesangial sclerosis can be explained by the lack of laminin subtypes as found in those with Pierson syndrome. Also, in our patient, the presence of crescentic glomeruli can be accounted for by the fragility of the altered GBM and likely exudation of plasma proteins through the membrane.

The patient described here has the first documented case of Pierson syndrome in North America and is one of the first patients reported from a nonconsanguineous family. Pierson syndrome joins collagen type III glomerulopathy and Alport syndrome and its variants as diseases caused by specific mutations of genes encoding constituents of the GBM. Moreover, Pierson syndrome is the first established disorder of the GBM to cause CNS, only recently joined by Herlitz junctional epidermolysis bullosa,40 another disorder of aberrant laminin expression. Therefore, Pierson syndrome should be considered in the differential diagnosis of CNS, especially in patients with associated ocular anomalies.41


   ACKNOWLEDGMENTS
 
We thank Chris Woods for assistance with the light and electron microscopy images as well as his graphic design of the structure of the glomerulus.


   FOOTNOTES
 
Accepted Feb 21, 2006.

Address correspondence to Rene' VanDeVoorde, MD, Pediatric Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail: rene.vandevoorde{at}cchmc.org

The authors have indicated they have no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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