|Year : 2018 | Volume
| Issue : 2 | Page : 93-95
Renal involvement in a child with Donnai-Barrow syndrome
Gurinder Kumar1, Manika Chaudhry2, Khalid Mohamed Mansour Mohamed Faris1, Omar Al Masri1
1 Department of Pediatric Nephrology, Sheikh Khalifa Medical City, Abu Dhabi, UAE
2 Medical Student, Christian Medical College, Ludhiana, Punjab, India
|Date of Web Publication||27-Dec-2018|
Dr Gurinder Kumar
Department of Pediatric Nephrology, Sheikh Khalifa Medical City, Al Karamah Street, Abu Dhabi
Source of Support: None, Conflict of Interest: None
Donnai-Barrow or facio-oculo-acoustico-renal (DB/FOAR) syndrome is characterized by typical craniofacial features, ocular findings, sensorineural hearing loss and agenesis of the corpus callosum along with varying degree of intellectual disability. Renal involvement in the form of low molecular weight proteinuria is commonly reported. We report a case of an 8-year-old girl with DB/FOAR syndrome which was genetically confirmed to have a novel frameshift mutation, c.13139del in exon 72 of LRP2, the gene encoding low density lipoprotein receptor related protein 2 precursor, megalin. The child had chronic kidney disease (CKD) and significant proteinuria with focal segmental glomerulosclerosis on renal biopsy. Our case highlights presentation in childhood with this rare syndrome, with significant renal involvement as nephrotic range proteinuria and CKD. Children with DB/FOAR syndrome need close follow up with nephrologist.
Keywords: Chronic kidney disease, Donnai-Barrow, facio-oculo-acustico-renal syndrome, proteinuria
|How to cite this article:|
Kumar G, Chaudhry M, Mohamed Faris KM, Al Masri O. Renal involvement in a child with Donnai-Barrow syndrome. Asian J Pediatr Nephrol 2018;1:93-5
| Introduction|| |
Donnai-Barrow or facio-oculo-acoustico-renal (DB/FOAR) syndrome is characterized by the following features: typical craniofacial features (ocular hypertelorism and enlarged fontanelle); ocular findings (high myopia, retinal detachment, progressive vision loss, and iris coloboma); sensorineural hearing loss; agenesis of the corpus callosum; intellectual disability; congenital diaphragmatic hernia and/or omphalocele; and renal involvement in the form of low molecular weight proteinuria. We report a case of an 8-year-old female child with genetically confirmed DB/FOAR syndrome with chronic kidney disease (CKD), significant nephrotic range proteinuria and focal segmental glomerulosclerosis on renal biopsy. This case is reported because of the rare nature and relatively recent genetic discovery.
| Case Report|| |
An 8-year-old female child born to first-degree consanguineous parents has been on follow-up in pediatric nephrology clinic since the age of 3 years for abnormal renal function and proteinuria picked up on evaluation. She was diagnosed on the basis of characteristic craniofacial features [Figure 1], including ocular hypertelorism, enlarged fontanelle, frontal bossing, epicanthic folds, depressed nasal bridge, and long nose. Birth history was not significant. There was no family history of similar disease in family and there was a younger male sibling who was clinically normal.
|Figure 1: Facial features of the index patient with Donnai-Barrow syndrome, indicating hypertelorism and depressed nasal bridge|
Click here to view
The vital signs were within normal limits. Weight was at 10th centile and height on 3rd centile of age and sex. Eye abnormalities included high myopia and visual impairment; the child had been using glasses since the age of 2 years. There was also severe sensorineural hearing loss requiring a cochlear implant at the age of 2 years. Rest of the systemic examination was unremarkable.
Whole exome sequencing was performed including sequencing of the entire coding region (exons 1–79) and all intron-exon boundaries of the LRP2 gene that encodes the low density lipoprotein receptor related protein 2 precursor, megalin. We identified an apparently homozygous pathogenic deletion of 1 nucleotide in exon 72 of the LRP2 gene (reference transcript NM_004525.2; c.13139del.) which is predicted to cause frameshift (p. Pro4380HisfsTer46), resulting in a truncated protein, or diminished mRNA synthesis due to decay. This is a novel variant not previously described in other patients nor in controls. Since next generation cannot distinguish between homozygosity for the variant versus heterozygosity in combination with a deletion, Sanger validation in both the parents was recommended but could not be performed due to financial constraints.
Laboratory evaluation showed serum creatinine 1.5 mg/dl and estimated glomerular filtration rate [eGFR] 57 ml/min/1.73 m2 at 8 years of age, while the eGFR at presentation at 3 years was 70 ml/min/1.73 m2. Serum calcium, phosphorus, vitamin D and parathormone levels were within normal limits and urine protein to creatinine ratio was 2.13 g/g. Urine protein electrophoresis showed albumin >25 mg/g, IgG >10 mg/g, and beta-2 microglobulin >14 mg/g creatinine.
Renal ultrasound showed bilateral normal sized kidneys with increased echogenicity. Kidney biopsy revealed segmental sclerosis in 35 of 99 glomeruli. There were mild-to-moderate chronic changes of interstitial fibrosis and tubular atrophy. Immunofluorescence studies were negative.
The child goes to a special needs school and is doing well. The use of angiotensin converting enzyme inhibitor failed to show any significant improvement in proteinuria.
| Discussion|| |
DB syndrome is an autosomal recessive disorder which is characterized by typical craniofacial features, sensorineural hearing loss, eye findings, agenesis of the corpus callosum, and varying degree of intellectual disability. They may present with congenital diaphragmatic hernia and/or omphalocele at birth.
The gene implicated is LRP2, which encodes the low-density lipoprotein receptor-related protein 2 precursor megalin. Dysfunctional megalin may result in abnormalities with varied phenotypes. Renal involvement is reported in the form of low molecular weight proteinuria as the megalin/cubilin/amnionless complex is essential for albumin and low molecular weight protein reabsorption by proximal convoluted tubules [Table 1]. The genetic variation in our index case was a frameshift mutation which may have caused truncation of the protein. This could explain the severe albuminuria since there would functionally be no megalin for proximal tubular retrieval of the filtered albumin.
|Table 1: Renal involvement in Donnai-Barrow syndrome: Review of literature|
Click here to view
Dachy et al. described a 3-year-old girl with DB/FOAR syndrome with significant proteinuria (albumin and low molecular weight protein) and normal renal ultrasound and renal function. Storm et al. found that in the absence of tubular uptake, urinary albumin excretion was in the microalbuminuric range, suggesting that limited amounts of albumin are filtered in human glomeruli, similar to our child who had urine albumin to creatinine ratio of around 84 g/g. Khalifa et al. reported four patients from two unrelated Saudi families with DB syndrome who had low molecular weight proteinuria. The review of the cases reported in the literature is shown in [Table 1]. Most of the literature shows renal findings of low molecular weight proteinuria. Our patient had nephrotic range proteinuria (urine protein: urine creatinine ratio >2 g/g) over the past 3 years. Tubular proteinuria was also noted.
DB/FOAR syndrome shows a limited phenotypic overlap with a number of other rare syndromes including Pallister–Killian syndrome, Fryns syndrome, and craniofrontonasal syndrome; however, low-molecular-weight proteinuria has not been reported in any of these disorders. Storm et al. also suggested that in the presence of characteristic facial features and ocular and hearing abnormalities along with distinct urinary protein excretion seen in DB/FOAR patients, the diagnosis of this syndrome can be made without the need to sequence the large LRP 2 gene.
| Conclusions|| |
We report a case of DB/FOAR syndrome, a rare autosomal recessive disorder, with renal involvement in the form of low molecular weight proteinuria, focal segmental glomerulosclerosis and progressive CKD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. The legal guardian has given his consent for images and clinical information to be reported in the Journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.
| References|| |
Dachy A, Paquot F, Debray G, Bovy C, Christensen EI, Collard L, et al.
In-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction. Pediatr Nephrol 2015;30:1027-31.
Kantarci S, Donnai D, Noonan KM, Pober BR. Donnai-Barrow Syndrome. 2008 Aug 28. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al
, editors. GeneReviews®
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1878/
Khalifa O, Al-Sahlawi Z, Imtiaz F, Ramzan K, Allam R, Al-Mostafa A, et al.
Variable expression pattern in Donnai-Barrow syndrome: Report of two novel LRP2 mutations and review of the literature. Eur J Med Genet 2015;58:293-9.
Schrauwen I, Sommen M, Claes C, Pinner J, Flaherty M, Collins F, et al.
Broadening the phenotype of LRP2 mutations: A new mutation in LRP2 causes a predominantly ocular phenotype suggestive of stickler syndrome. Clin Genet 2014;86:282-6.
Storm T, Tranebjærg L, Frykholm C, Birn H, Verroust PJ, Nevéus T, et al.
Renal phenotypic investigations of megalin-deficient patients: Novel insights into tubular proteinuria and albumin filtration. Nephrol Dial Transplant 2013;28:585-91.
|This article has been cited by|
||Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease
| ||Jennifer R. Charlton,Weizhen Tan,Ghaleb Daouk,Lisa Teot,Seymour Rosen,Kevin M. Bennett,Aleksandra Cwiek,Sejin Nam,Francesco Emma,François Jouret,João Paulo Oliveira,Lisbeth Tranebjærg,Carina Frykholm,Shrikant Mane,Friedhelm Hildebrandt,Tarak Srivastava,Tina Storm,Erik Ilsø Christensen,Rikke Nielsen |
| ||American Journal of Physiology-Renal Physiology. 2020; 319(6): F988 |
|[Pubmed] | [DOI]|
||Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function
| ||Mathilda Bedin,Olivia Boyer,Aude Servais,Yong Li,Laure Villoing-Gaudé,Marie-Josephe Tête,Alexandra Cambier,Julien Hogan,Veronique Baudouin,Saoussen Krid,Albert Bensman,Florie Lammens,Ferielle Louillet,Bruno Ranchin,Cecile Vigneau,Iseline Bouteau,Corinne Isnard-Bagnis,Christoph J. Mache,Tobias Schäfer,Lars Pape,Markus Gödel,Tobias B. Huber,Marcus Benz,Günter Klaus,Matthias Hansen,Kay Latta,Olivier Gribouval,Vincent Morinière,Carole Tournant,Maik Grohmann,Elisa Kuhn,Timo Wagner,Christine Bole-Feysot,Fabienne Jabot-Hanin,Patrick Nitschké,Tarunveer S. Ahluwalia,Anna Köttgen,Christian Brix Folsted Andersen,Carsten Bergmann,Corinne Antignac,Matias Simons |
| ||Journal of Clinical Investigation. 2019; |
|[Pubmed] | [DOI]|