Pierson Syndrome: A Novel Cause of Congenital Nephrotic Syndrome
        Rene' VanDeVoorde, David Witte, Jillene Kogan and...
EXPERIENCE & REASON




Pierson Syndrome: A Novel Cause of Congenital
Nephrotic Syndrome
Rene’ VanDeVoorde, MDa, David Wit...
blood pressures 120/80 mm Hg in all 4 extremities,
                                                                       ...
derstood through a review of the glomerular filter. The
                                                                   ...
-actinin 422 and CD2-associated protein (CD2AP)23            tion screening, they confirmed mutations of this gene
have als...
ism in the congenital nephrotic syndrome. J Pediatr. 1982;101:      26. Salomon R, Gubler MC, Niaudet P. Genetics of the n...
Pierson Syndrome: A Novel Cause of Congenital Nephrotic Syndrome
         Rene' VanDeVoorde, David Witte, Jillene Kogan an...
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DOI: 10.1542/peds.2005-3154 published online Jul 24, 2006 ...

  1. 1. Pierson Syndrome: A Novel Cause of Congenital Nephrotic Syndrome Rene' VanDeVoorde, David Witte, Jillene Kogan and Jens Goebel Pediatrics published online Jul 24, 2006; DOI: 10.1542/peds.2005-3154 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/peds.2005-3154v1 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from www.pediatrics.org by on October 20, 2010
  2. 2. EXPERIENCE & REASON Pierson Syndrome: A Novel Cause of Congenital Nephrotic Syndrome Rene’ VanDeVoorde, MDa, David Witte, MDb, Jillene Kogan, MD, PhDc, Jens Goebel, MDa a Pediatric Nephrology and Hypertension and Divisions of bPathology and cHuman Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio The authors have indicated they have no financial relationships relevant to this article to disclose. ABSTRACT 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 2 laminin in the basement membrane. Our patient demonstrated classic histopathologic findings of Pierson syndrome on renal biopsy, including absence of 2 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. N EPHROTIC SYNDROME IS a common pediatric neph- rologic condition constituted by edema, protein- uria, hypoalbuminemia, and hypercholesterolemia. A mal fetal ultrasound at 28 weeks, which revealed large, hyperechoic kidneys. At the 36-week prenatal visit, an- other ultrasound showed oligohydramnios. Conse- majority of patients present between 1 and 6 years of age quently, a biophysical profile was performed, which was with minimal-change disease, a disorder of yet-undeter- decreased (5/10), prompting induction of labor. Delivery mined immunologic etiology that is often responsive to was uneventful, and the infant’s Apgar scores at 1 and 5 corticosteroid therapy. In contrast, congenital nephrotic minutes were 7 and 8, respectively. No umbilical cord or syndrome (CNS), defined as nephrotic syndrome de- placental abnormalities (eg, size) were noted. tected at 3 months of age, is caused by an entirely The patient had initial weight, length, and head cir- different set of disease processes. Primary CNS is caused cumference at the 50th percentile for gestational age. On by genetic alterations of the glomerular microstructure initial newborn examination, the patient had slightly that cause massive proteinuria unresponsive to immu- decreased muscle tone but intact reflexes. Moreover, she nosuppressive therapies, whereas secondary CNS often was found to have bilateral microcoria (ie, pinpoint pu- is caused by an immune-mediated injury to the glomer- pils; Fig 1), prompting a maternal drug screen that was ular basement membrane (GBM). Pierson syndrome, a positive only for caffeine. No other dysmorphology was recently discovered etiology of primary CNS, is caused noted. by GBM alterations resulting from a deficiency of 2 On day-of-life 3, the patient was noted to have slight laminin. Here we describe a newborn female with Pier- edema of her legs and left eyelid. After initially doing son syndrome and the diagnostic considerations for CNS. Key Words: congenital nephrotic syndrome, glomerular basement membrane, CASE REPORT Pierson syndrome, laminin, microcoria A 2665-g female infant was delivered vaginally at 36 Abbreviations: CNS, congenital nephrotic syndrome; GBM, glomerular basement membrane; CNF, congenital nephrotic syndrome of the Finnish type; CD2AP, CD2- weeks of gestation to a 24-year-old gravida 4 para 2 associated protein white mother and 41-year-old black father. Prenatal www.pediatrics.org/cgi/doi/10.1542/peds.2005-3154 care had been sporadic, but maternal laboratory values doi:10.1542/peds.2005-3154 were normal, including negative HIV and hepatitis B Accepted for publication Feb 21, 2006 antigen and a nonreactive rapid plasma reagin. The fam- Address correspondence to Rene’ VanDeVoorde, MD, Pediatric Nephrology and Hypertension, ily history was negative for any inheritable disorders, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail: rene. vandevoorde@cchmc.org and there was no history of renal or ophthalmologic PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2006 by the problems. The pregnancy was remarkable for an abnor- American Academy of Pediatrics PEDIATRICS Volume 118, Number 2, August 2006 e501 Downloaded from www.pediatrics.org by on October 20, 2010
  3. 3. blood pressures 120/80 mm Hg in all 4 extremities, requiring multiple antihypertensive medications to con- trol. 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 dila- tion were also present. Electron microscopy showed thinning of the GBM with diffuse foot process efface- ment and prominent podocytes forming a coronal pat- tern over the GBM (Fig 3). The patient’s ophthalmologic and renal findings were consistent with a clinical diagnosis of Pierson syndrome,1 a condition of absent 2 laminin from the basement FIGURE 1 membranes of the glomerulus and anterior eye struc- Microcoria of the patient’s left eye at 1 month of age. tures. Additional immunofluorescence staining for 2 laminin confirmed its absence in the GBM of our patient (Fig 4). Additional genetic analysis, performed by Martin well, she started to feed poorly, taking only 10 mL per Zenker, MD (Institute of Human Genetics, Erlangen, feeding. Because of her ocular finding and slight fussi- Germany), showed 2 different mutations (compound ness, there were additional concerns about drug with- heterozygosity) of LAMB2, the 2 laminin gene on chro- drawal, but a meconium drug screen was also negative. mosome 3, thus confirming the diagnosis of Pierson After further inquiry revealed the abnormal prenatal syndrome as the etiology of this patient’s CNS. ultrasound findings, a renal profile was obtained on day-of-life 5, showing hyponatremia (sodium: 129 DISCUSSION mmol/dL) and renal insufficiency (creatinine: 2.7 mg/ CNS may be difficult to recognize initially in newborns. dL). A follow-up renal ultrasound was obtained, which It often presents as abdominal distention or swelling,2 confirmed bilaterally enlarged hyperechoic kidneys. Be- which may not be noted initially because of the rela- cause of the patient’s renal failure, she was transferred to tively low abdominal tone in neonates and because de- our facility with a suspected diagnosis of autosomal re- cessive 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. Ab- dominal and pelvic ultrasound revealed a normal liver, spleen, ovaries, and uterus. Follow-up renal ultrasound showed the aforementioned enlarged hyperechoic kid- neys 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 her- pes simplex) infections. High-resolution chromosomal analysis showed a normal 46,XX karyotype. Pediatric FIGURE 2 ophthalmology consultants found continued pupillary Hematoxylin/eosin stain of light microscopy of the patient’s kidney biopsy showing focal constriction despite use of dilating drops and a persistent inflammation of the interstitium and varied appearances of the glomeruli. Some glomer- uli are obscured by crescent formation (solid white arrow), whereas others have loss of hyperplastic primary vitreous of the right eye. The pa- their normal vascular architecture (dashed arrow). Dilated tubules are seen on the left tient was noted to be moderately hypertensive with side of the frame. e502 VanDeVOORDE et al Downloaded from www.pediatrics.org by on October 20, 2010
  4. 4. derstood through a review of the glomerular filter. The glomerular capillary wall forms a size- and charge-selec- tive barrier composed of 3 layers: the fenestrated endo- thelium, 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 syn- drome. FIGURE 3 The prototype of the slit diaphragm disorders is CNS Electron microscopic appearance of the kidney with a thin GBM (only 40 –50 nm; refer- of the Finnish type (CNF). The gene NPHS1, which is ence: 90 nm) (left) and large podocytes that crowd together on the GBM (right). mutated in CNF, was isolated on chromosome 19 in 1998.14 Its gene product, nephrin, is a cell-adhesion pro- tein 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 FIGURE 4 followed by kidney enlargement in infancy. Electron Immunofluorescent staining for 2 laminin. Shown is the patient’s biopsy specimen (left) microscopy of the glomerulus shows various sizes of the with absence of linear immunofluorescent staining for 2 laminin and a normal adult control glomerulus (right, magnified) with linear fluorescent staining for 2 laminin of slit pores between podocytes and absence of the filamen- the GBM (open arrows). Cell nuclei (closed arrows) are visible more weakly in both pic- tous image of the slit diaphragm.19 tures because of counterstaining. Abnormalities of other slit-diaphragm components, although less commonly documented, may also cause CNS. Koziell et al20 found mutations in NPHS2, which pendent edema settles more in the back and legs (as encodes for podocin (an anchoring protein for the slit opposed to the eyes and distal extremities) in this age diaphragm) in 25% of patients with CNF who lacked group. There may be other subtle antenatal or perinatal NPHS1 mutations, although podocin mutations typically signs that may also increase clinical suspicion, such as lead to focal segmental glomerular sclerosis later in life.21 increased amniotic -fetoprotein or placental enlarge- Mutations of genes encoding other components such as ment; therefore, adequate communication of abnormal findings between the obstetrical provider and pediatri- cian may be important. This delay in diagnosis may postpone recognition and treatment of conditions sec- ondary to the protein losses, such as immunosuppres- sion,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 syn- dromes with autosomal recessive inheritance. For pur- poses of clarification, these syndromes may be divided into those with gene products that affect the glomerular slit diaphragm, those that affect genitourinary develop- ment, 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; how- ever, various reports have also implicated toxoplasmo- FIGURE 5 sis,8 rubella,9 cytomegalovirus,10 HIV,11 and hepatitis B.12 Illustration of the glomerular capillary wall with endothelial, GBM, and podocyte layers. Finally, CNS has been reported in infantile systemic The GBM is composed of collagen, laminin, and heparan sulfate proteoglycans. The slit diaphragm contains overlapping nephrin molecules that are “anchored” to the foot pro- lupus erythematosus.13 cess through a structure combining podocin (dark circle), CD2AP (dark square), and The different etiologies of primary CNS are best un- -actinin 4 (curved lines). PEDIATRICS Volume 118, Number 2, August 2006 e503 Downloaded from www.pediatrics.org by on October 20, 2010
  5. 5. -actinin 422 and CD2-associated protein (CD2AP)23 tion screening, they confirmed mutations of this gene have also been shown to cause familial nephrotic syn- and abnormalities in its product, 2 laminin. 2 laminin drome in humans and CNS in mice but have not yet is a normal component of the basement membranes of been linked with CNS in humans. the mature glomerulus38 and structures in the anterior Primary CNS has also been attributed to mutations in eye. In affected subjects, 2 laminin was accordingly the WT1 gene on chromosome 11.24–26 WT1 encodes a found to be absent by immunofluorescence. transcription factor that regulates expression of several The renal histopathologic findings of Pierson syn- target genes in renal and gonadal development. The drome in humans are difficult to reconcile with animal most recognized disorder with CNS and WT1 mutation is models. In our patient, as well as previously diagnosed Denys-Drash syndrome, characterized by rapid progres- patients with Pierson syndrome,1 diffuse mesangial scle- sion to end-stage renal disease, male pseudohermaphro- rosis, accompanied by crescent formation, has been the ditism, and Wilms’ tumor. Patients are karyotypic males predominant finding. However, previous studies in ro- (46,XY) with ambiguous genitalia or have a female phe- dent models have shown either no major changes to the notype and dysgenic gonads. Those with Frasier syn- glomeruli in nephrotic mice37 or failure of the mesan- drome also have WT1 mutations and gonadal dysgenesis, gium to develop in rats,39 potentially indicating that the although proteinuria and renal dysfunction tend to oc- specific roles of 2 laminin for renal development differ cur in early childhood. Patients with isolated diffuse between rodents and humans. The disorganization of mesangial sclerosis have also characteristically been as- collagen and proteoglycans with the absence of laminin sociated with WT1 mutations similar to those seen in and collagen in the hyalinized glomeruli that can be seen Denys-Drash syndrome, but with normal gonadal devel- in diffuse mesangial sclerosis can be explained by the opment.27 lack of laminin subtypes as found in those with Pierson Other causes of CNS that do not involve mutations of syndrome. Also, in our patient, the presence of crescen- the slit diaphragm or the WT1 gene include Galloway- tic glomeruli can be accounted for by the fragility of the Mowat syndrome and nail-patella syndrome. Since its altered GBM and likely exudation of plasma proteins first description in 1968, Galloway-Mowat syndrome through the membrane. has been recognized by the constellation of early-onset The patient described here has the first documented nephrotic syndrome, brain malformations (microceph- case of Pierson syndrome in North America and is one of aly, gyral abnormalities), and hiatal hernia.28 Nail-patella the first patients reported from a nonconsanguineous syndrome is an autosomal dominant disorder with the family. Pierson syndrome joins collagen type III glo- association of nail dysplasia, elbow and knee abnormal- merulopathy and Alport syndrome and its variants as ities, and variable renal involvement. In 1998, it was diseases caused by specific mutations of genes encoding shown that nail-patella syndrome is caused by muta- constituents of the GBM. Moreover, Pierson syndrome is tions in LMX1B, a transcription factor on chromosome the first established disorder of the GBM to cause CNS, 9.29 LMX1B’s function on the developing kidney has not only recently joined by Herlitz junctional epidermolysis been clearly explained but is thought to possibly affect bullosa,40 another disorder of aberrant laminin expres- type IV collagen,30 CD2AP,31 and podocin expression.31 sion. Therefore, Pierson syndrome should be considered An early report by Simila et al32 documented CNS at in the differential diagnosis of CNS, especially in patients birth in a patient with nail-patella syndrome, but the with associated ocular anomalies.41 proteinuria resolved by 8 months of age, showing the inconsistent renal effects of this disorder. CNS has also ACKNOWLEDGMENT been described in association with carbohydrate-defi- We thank Chris Woods for assistance with the light and cient glycoprotein syndrome33 and, very recently, respi- electron microscopy images as well as his graphic design ratory chain disorders.34 of the structure of the glomerulus. Our patient’s diagnosis, Pierson syndrome, is another cause of primary CNS not caused by mutations of either REFERENCES WT1 or genes encoding proteins in the slit diaphragm. 1. Zenker M, Tralau T, Lennert T, et al. Congenital nephrosis, Although the association of CNS and ocular anomalies mesangial sclerosis, and distinct eye abnormalities with microcoria: an autosomal recessive syndrome. Am J Med Genet was first described by Pierson et al35 in 1963, its genetic A. 2004;130:138 –145 basis has been uncovered only recently by Zenker et al,36 2. Huttunen NP. Congenital nephrotic syndrome of Finnish type: who noted 2 consanguineous families with 11 offspring study of 75 patients. 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  7. 7. Pierson Syndrome: A Novel Cause of Congenital Nephrotic Syndrome Rene' VanDeVoorde, David Witte, Jillene Kogan and Jens Goebel Pediatrics published online Jul 24, 2006; DOI: 10.1542/peds.2005-3154 Updated Information including high-resolution figures, can be found at: & Services http://www.pediatrics.org/cgi/content/full/peds.2005-3154v1 References This article cites 39 articles, 12 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/peds.2005-3154v1#BI BL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Genitourinary Tract http://www.pediatrics.org/cgi/collection/genitourinary_tract Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Reprints Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml Downloaded from www.pediatrics.org by on October 20, 2010

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