1 Nephro-Urology and 2 Histopathology Units, Institute of Child Health, London and 3 Department of Vascular Medicine and Diabetes Research, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, UK
Keywords: cyst; glomerulus; hepatocyte nuclear factor 1ß; hypomelanosis of Ito; kidney disease
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Introduction |
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These clinical features have been considered to be caused by chromosomal or genetic mosaicism, with diverse underlying aberrations, including translocations between the X chromosome and autosomes [1]. Hence hypomelanosis of Ito represents a collection of signs rather than a discrete disease [2]. It should be distinguished from incontinentia pigmenti (MIM #308300), an X-linked dominant, male-lethal, condition where inflammatory skin lesions occur neonatally, later becoming hyperpigmented. Incontinentia pigmenti is caused by mutations in NEMO, a gene on Xq28 involved in modulating immune pathways [3].
We report a female with hypomelanosis of Ito with structural anomalies of the kidneys, including macro- and microscopic cysts.
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Case |
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When 13 years old she complained of increasing lethargy. Her blood pressure was 80/40 mmHg, plasma creatinine 88 µM, 51Chromium EDTA glomerular filtration rate (GFR) 47 ml/min/1.73 m2 and urine albumin/creatinine ratio 0.29 (normal <0.10). There was no haematuria, her urine was sterile and there was no history of urinary tract infection. An ultrasound scan revealed two kidneys which were bright and small (70 mm in length on the left and 86 mm on the right), each below the 5th centile for her age. The right kidney had global cortical thinning with a 0.9 cm diameter cyst in the upper pole, while the left had multiple non-communicating cysts in the lower pole (Figure 1). No cysts were identified in the liver or pancreas. An intravenous urogram showed parenchymal thinning of the right kidney with blunting of the calyces, most prominent in the upper pole. The lower pole of the left kidney had an abnormal shape, consistent with the cysts on the ultrasound scan. A 99Tc-mercaptoacetyl-triglycine isotope renogram showed focal defects in both kidneys compatible with the cysts, and indirect cystography indicated complete urinary bladder emptying with no vesicoureteric reflux. There was no evidence of obstruction of the lower urinary tract on imaging.
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A percutaneous biopsy was taken from the lower pole cortex of the right kidney, a location devoid of macroscopic cysts. Light microscopy revealed a mixed picture (Figure 2). Small cysts were noted, some containing remnants of glomerular tufts, while other glomeruli had dilatation of Bowman's spaces. In addition, foci of tubular atrophy and interstitial fibrosis were apparent. Blood vessels were normal and immunohistochemistry showed only minor mesangial IgM positivity. Electron microscopy revealed patchy fusion of podocyte foot processes with no other definite glomerular abnormalities (Figure 3
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When assessed at 31 years, the patient's mother was normotensive with normal kidneys on ultrasound scan. The father had hypertension but his renal ultrasound scan was normal. The patient had two clinically normal siblings by the same father, but the mother had had a still-birth with a different partner: this baby was reported to have a hole in the heart, lung hypoplasia and a small kidney on one side but further details are not available. As assessed by a clinical geneticist, the living relatives have no features of hypomelanosis of Ito or other syndromes.
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Discussion |
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Eussen et al. [5] described a boy with tuberous sclerosis, polycystic kidney disease, thalassaemia trait and hypomelanosis of Ito. These features could be at least partly explained by a contiguous gene syndrome (e.g. affecting PKD1 and TSC2 and other loci on chromosome 16) and he was found to have an unbalanced translocation of chromosome 16 with chromosome 8, with deletion in 16p13.3-pter and duplication of distal 8q. The authors suggested that either chromosome might be contain a hypomelanosis of Ito gene. Renal biopsy was not performed in this patient. Notably, neither our current patient, nor her parents, had clinical features of tuberous sclerosis. Furthermore, the normal renal ultrasounds of her parents would make inherited autosomal dominant polycystic kidney disease caused by a PKD1 mutation unlikely. Although routine karyotype analyses of our patient's blood leukocytes and skin biopsy did not reveal any gross abnormality such as a translocation affecting chromosome 16, in future it would be interesting to perform detailed genetic analyses of this region.
A second report [6] described a child with hypomelanosis of Ito with glomerulonephritis and glomerular basement membrane abnormalities. In our current patient, glomeruli were also affected, but they demonstrated cystic dilatation of Bowman's spaces and patchy fusion of foot processes, rather than a disorder basement membrane. The observed foot process fusion is consistent with a predominantly glomerular origin of the patient's moderate proteinuria: indeed, markers of tubular proteinuria were normal.
Glomerular cysts can occur as an isolated disorder, which may be inherited, or in association with diverse multiorgan syndromes including [7] autosomal dominant polycystic kidney disease, brachymesomelia-renal syndrome, Jeune asphyxiating thoracic dystrophy, juvenile nephronophtisis, oral-facial-digital syndrome type 1, short rib polydactyly syndrome, trisomies 9, 13, 18, tuberous sclerosis and Zellweger syndromes. However, there were no clinical features in our patient, or her parents, to suggest any of these entities. Our recent description of HNF1ß mutations in familial glomerulocystic kidney disease [4] led us to perform mutation analysis of this gene, but no abnormality was detected.
Although our patient did have glomerular disease on biopsy, her pathology is more complex than this. For example, we consider it would be unusual for glomerular cysts to expand to 3.0 cm in diameter, yet cysts of these dimensions were apparent on ultrasound scans: other nephron segments, not identified on biopsy, are likely to be affected. Furthermore, the kidneys were small with calyceal blunting, suggesting widespread structural disorder. Although vesicoureteric reflux with pyelonephritis can cause calyceal blunting and parenchymal thinning, we found no evidence of reflux at 13 years, and there was no history of urinary tract infection. Hence, the calyceal defects may be related to abnormal growth and development. The patchy and non-symmetrical nature of her macroscopic kidney disease is notable, and we suggest that this may be explained by chromosomal or genetic mosaicism, as described for the skin lesions which occur in this syndrome [1,2]: unfortunately, renal tissue is no longer available for this analysis.
Finally, it has not been possible to obtain more information on the half-sibling of our patient who was still-born with a major cardiac lesion and a small right kidney. Furthermore, it is unknown whether this individual was affected by hypomelanosis of Ito or another defined syndrome associated with renal malformation.
In conclusion, we recommend screening all patients with this rare syndrome using renal functional and structural tests. Only then it will be possible to establish whether kidney disease is a bona-fide part of the syndrome-complex, or just a chance association in a few individuals.
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Acknowledgments |
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Notes |
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References |
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