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Glomerulopathy in patients with distal duplication of chromosome 6p
© Jankauskienė et al. 2016
Received: 23 June 2015
Accepted: 17 March 2016
Published: 21 March 2016
The Erratum to this article has been published in BMC Nephrology 2016 17:43
Duplication of the distal part of chromosome 6p is a rare genetic syndrome. Renal involvement has been reported in the majority of patients, including a wide range of congenital abnormalities of kidney and urinary tract and, occasionally, a proteinuric glomerulopathy.
Here, we report a 13-year-old girl with 6p25.3p22.1 duplication who presented with proteinuria in infancy, was later diagnosed as focal segmental glomerulosclerosis, progressed to end-stage renal disease and was successfully transplanted.
A systematic literature review suggests that 15–20 % of individuals with distal 6p duplication develop progressive proteinuric glomerulopathy. Monitoring of kidney function should be recommended in all cases.
Clinical features of the distal chromosome 6p duplication syndrome
IUGR, general hypotonia, feeding problems, pre- and post-natal growth retardation,
Brain malformations (cerebellal hypothrophy, hypoplastic corpus callosum, hypothalamic hamartoma, hydrocephalus internus)
Heart defects (PDA, ASD, VSD, postvalvular (peripheral) pulmonary stenoses, ventricular hypertrophy, tetralogy of Fallot)
GI malformations (choanal atresia, anal atresia, diaphragmatic hernia)
CAKUT (kidney hypoplasia, kidney aplasia, ectopic kidneys, hydronephrosis, vesico-ureteral reflux, horseshoe kidney, cystic abnormality of Potter)
Craniofacial abnormalities (dysmorphy)
Skull (facial asymmetry, craniosynostosis, frontal bossing, flat occiput)
Eye (palpebral ptosis, blepharophimosis, hypotelorism, microophtalmia)
Ear (low-set, malformed lobes, thick helices, malformed pinnae)
Nose (prominent nasal bridge, short nose, tiny nares)
Mouth (small, thin lips; long flat philtrum, high arched palate, small pointed chin, micrognathia, gingival hypertrophy)
Intellectual disability (moderate to severe)
Behavioral problems (autism-spectrum disorders, gentle personality, recurrent laughing spells, low frustration tolerance)
Vision problems (nystagmus, strabismus, cataracts, microcorneas, myopia, retinal pigmentary dystrophy, persistent hyperplastic primary vitreous with retinal detachment)
Growth retardation (proportional microsomy)
Skin pigmentary anomalies, capillary hemangiomas
The Central European descent girl with a complex genomic disorder involving chromosome 6p presented with persistent proteinuria from the age of 9 months. Family history was unremarkable. Birth weight, length and head circumference were below the 3rd centile. General hypotonia and failure to thrive prompted a detailed evaluation, which revealed dysmorphia and multiple congenital defects, including corpus callosum hypoplasia, moderate internal hydrocephalus, brain asymmetry, subvalvular pulmonary stenosis and partial synostosis of 1st and 2nd ribs. Distinctive facial features: craniosynostosis, facial asymmetry, high broad front with frontal bossing, microphthalmia with ptosis and blepharophimosis, broad prominent nose bridge with relatively small nose, microstomia, narrow lips and low-set dysplastic ears were observed. Nystagmus, strabismus and severe bilateral hearing impairment developed and developmental milestones were delayed; she was able to sit without support at 14 months and started walking at 39 months of age. At 13 years she still cannot speak and communicates by basic gestures. She understands and follows simple orders.
At the age of 9 months the girl was hospitalized because of proteinuria (1.5 g/l). On admission, total serum protein was 63 g/l, albumin 38.5 g/l, cholesterol 6.1 mmol/l, creatinine 49 μmol/l with eGFR 70 ml/min/1.73 m2, complement C3 1.54 g/l, C4 0.154 g/l. Serology for prenatal infections was negative. The girl presented no edema or hypertension. Predisolone (15 mg/day) was started but after four weeks proteinuria persisted at 0.75 g/l in spot urine. Predisolone was tapered over two months, and enalapril (1.25 mg/day) was introduced.
Besides persistent proteinuria, in the first 3 years of life the girl presented with at least six febrile episodes of urinary tract infection. No vesicoureteral reflux was revealed by cystography. On ultrasound examination, small kidneys with increased echogenicity and reduced corticomedullary differentiation were noted. Kidney function gradually deteriorated and the child progressed to end-stage kidney disease. Peritoneal dialysis was started at the age of 9.8 years. Six months later kidney transplantation from a living-related donor (mother) was performed and she remains without signs of disease recurrence for 3 years.
Kidney biopsy was performed at age 23 months. Four out of 41 glomeruli were globally obsolescent and two segmentally sclerosed. Immunofluorescence showed weak mesangial positivity for IgM. On electron microscopy, glomerular ultrastructure was generally well preserved, with very few areas exhibiting podocyte foot process effacement, collapse of capillary tuft, and very limited foci of thinning, splintering and lamellation of the glomeruli basement membrane. Mean thickness of the basement membrane was 203 nm. The diagnosis of focal segmental glomerulosclerosis (FSGS) was made.
Mutational screening of 31 glomerulopathy-associated genes using a custom-designed multiplex PCR (Multiplicom, Niel, Belgium) revealed no pathogenic mutation in any of the genes tested, NPHS1, NPHS2 and WT1 included.
In most cases reported, distal trisomy 6p results from an unbalanced inheritance of a parental translocation. The clinical picture of these patients is influenced by the accompanying monosomy of an another chromosomal region. Here, we present an extremely rare case of a pure chromosome 6p duplication resulting from de novo reverse duplication (Fig. 1d). A review of the published cases along with database search [1–7] allowed for identification of 12 individuals whose region of duplication was partially overlapping with the region affected in our case (Fig. 1c).
Renal abnormalities have been observed in approximately half of the patients. Congenital abnormalities of the kidney and urinary tract (CAKUT), such as hypoplastic kidneys, renal cysts, vesicoureteral reflux and hydronephrosis have been described [4, 6, 7]. In addition, proteinuria has been reported in eight patients. These included two cases of a pure 6p duplication [5, 7] and six with a duplication resulting from an unbalanced parental translocation (after [4, 7–9]). The presented case is, however, the first to be comprehensively studied for mutations in all known glomerulopathy-associated genes to rule out co-incidence of two genetic entities.
Based on the findings reported to date, we estimate that at least 15–20 % of patients with terminal 6p duplication might develop proteinuria. This may be an underestimate since kidney disease may still be clinically silent at the time when the genetic diagnosis is established. The age at onset of proteinuria was less than three years in 7/9 subjects including the present case; the remaining two developed glomerular failure before the age of ten years. Six patients underwent kidney biopsy. Of these, three were diagnosed with FSGS, while membranous glomerulonephritis, focal mesangial hypercellularity and periglomerular fibrosis was reported each in one case. Five patients underwent kidney transplant at age 4–18 years; so far no disease recurrence has been reported, suggesting an intrinsic renal rather than a systemic abnormality as the cause of glomerulopathy. Resistance to steroids was observed In two treated subjects including the present case.
Giardino et al.  proposed 6p22– > 6pter as the most likely localization of the putative locus of the causative gene(s). Taking into account breakpoints of a few patients published afterwards including our case, we are able to further narrow the smallest region of the overlap to the 6p25 band. The assigned region comprises 29 protein-coding genes and three miRNAs (Additional file 1: Table S1). None of the established glomerulopathy-associated genes is located within the region of interest. A recent review described candidate genes expected to be involved in phenotypic features of the distal chromosome 6p duplication syndrome . Of these, only one, namely FOXC1, was identified as a player in kidney development and functioning. FOXC1 encodes a transcription factor that, along with Lmx1b, interacts synergistically through a common enhancer site to regulate the expression of podocyte specific genes, including NPHS2 . Mutations in FOXC1 have previously been described in patients with Axenfeld-Rieger anomaly and/or glaucoma (OMIM*601090). Haploinsufficiency studies have identified FOXC1 as a strongly dosage sensitive gene, supporting the hypothesis that FOXC1 may be pathogenic if overexpressed.
Our findings reinforce the hypothesis that the proximal 6p region contains gene(s) involved not only in kidney development but also in postnatal podocyte function. We recommend monitoring of kidney morphology and function in all patients with constitutive distal 6p duplication. Conversely, in patients with features of CAKUT and/or SRNS/FSGS who have associated syndromic disease array-CGH evaluation for chromosome 6p duplication should be performed.
This work was supported by grants from the Polish National Science Centre (011/01/D/NZ2/01600) and the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 2012-305608 (EURenOmics).
The authors thank dr. A. Matuleviciene from Centre of Medical Genetics at Vilnius University Hospital, Lithuania and dr. Mariola Iliszko from Department of Biology and Genetics for conventional cytogenetic (karyotype) studies; dr. Beata Nowakowska from Department of Medical Genetics at the Institute of Mother and Child in Warsaw, Poland for help with FISH studies and prof. Arvydas Laurinavičius from National Pathology Institute, Vilnius, Lithuania for pathology evaluation.
Consent was obtained from the parents of the child to publish details of this case report.
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