Nephrol Dial Transplant (2001) 16: 1267-1269
© 2001 European Renal Association-European Dialysis and Transplant Association
Case Report
Kidney disease in hypomelanosis of Ito
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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Hypomelanosis of Ito (Mendelian Inheritance in Man (MIM) #146150) is a neuroectodermal syndrome, estimated to occur in 1 in 10000 new patients presenting to general paediatricians [1]. It usually occurs sporadically but is occasionally inherited in a dominant manner. The key sign consists of macular hypopigmented skin lesions presenting by 2 years after birth in 90% of patients. The rash can occur unilaterally or bilaterally, in whorls, streaks or patches. Neurological involvement occurs in most patients, varying from mild learning difficulties to seizures caused by neural migration defects. Musculoskeletal involvement occurs in 40–60% with scoliosis, thoracic abnormalities and hemihypertrophy recognised features. Ocular and dental defects are also described [1].
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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The proband was born at 35 weeks gestation by normal vaginal delivery. She was small for dates, weighing 1.99 kg, a small fetal size having been demonstrated by an ultrasound scan at 26 weeks gestation: no internal organ anomalies were noted on this scan. Three weeks after birth, a hypopigmented rash typical of hypomelanosis of Ito was noted on her arms, legs and chest, and it persisted throughout her childhood. Subsequently, she was found to be neurodevelopmentally delayed and attended a school for children with learning difficulties. She was severely myopic, with documented retinal dysplasia. In addition, she had a mild thoracic scoliosis and bifid 11th right rib, and her growth during childhood was along the 3rd centile for height and weight. Analyses from peripheral blood leukocytes and a skin biopsy showed a normal, 46XX, karyotype.
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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When 16 years old, she had transient diastolic hypertension (120/90 mmHg) during progesterone treatment for irregular menstrual periods. Subsequently, blood pressure normalized when this drug was stopped. At 17 years of age, she was reinvestigated: plasma creatinine 138 µM, 51Chromium EDTA GFR 37 ml/min/ 1.73 m2 and urinary albumin/creatinine ratio 0.99. Urinary levels of ‘tubular proteins’ were not significantly elevated: N-acetyl-ß-D-glucosaminidase/creatinine ratio 27 (normal 3–27 units/mmol); retinol binding protein/creatinine ratio 16 (normal 2–43 µg/mmol). Plasma sodium, potassium, phosphate, calcium, magnesium, bicarbonate, glucose and albumin concentrations were within normal limits, as were complement 3 and 4. Antinuclear factor was weakly positive (1:40–1:160). Ultrasound scan showed that renal cysts had not increased in number, but they had increased in size, the largest being 3.0 cm in diameter.
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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We recently reported that some individuals and families with glomerular cysts and calyceal defects have mutations in a transcription factor gene called hepatocyte nuclear factor 1ß (HNFIß) [4]. Direct sequencing of the promoter, coding regions of the nine exons and intron-exon boundaries was performed using an ABI PrismTM 377 DNA Sequencer (Perkin-Elmer Applied Biosystems), as described [4]. No variants were found in the gene sequence.
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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We found two other reported cases of hypomelanosis of Ito with renal disease.
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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This work was undertaken by Great Ormond Street Hospital for Children NHS Trust which received a proportion of its funding from the NHS Executive. C. B. is supported by a National Kidney Research Fund Training Fellowship.
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Notes |
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Correspondence and offprint requests to: Dr R. J. M. Coward, Richard Bright Renal Unit, South mead Hospital, Westbury on Trym, Bristol BS10 5NB, UK.
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References |
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TopIntroductionCaseDiscussionReferences |
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- Hypomelanosis of Ito. OMIMTM Online Mendelian Inheritance in Man. McKusick VA ed. http//www4.ncbi.nlm.nih.gov//omim/
- Kuster W, Konig A. Hypomelanosis of Ito: no entity, but a cutaneous sign of mosaicism. Am J Med Genet1999; 85: 346–350[Medline]
- Smahi A, Courtois G, Vabres P et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinenti Pigmenti (IP) Consortium. Nature2000; 400: 466–472
- Bingham C, Bulman MP, Ellard S et al. Mutations in the hepatocyte nuclear factor-1ß gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet2001; 68: 219–224[Web of Science][Medline]
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Eussen B, Bartalini G, Bakker L et al. An unbalanced submicroscopic translocation t(8;16) (q24;p13.3)pat associated with tuberous sclerosis complex, adult polycystic kidney disease, and hypomelanosis of Ito. J Med Genet2000; 37: 287–291
[Abstract/Free Full Text] - Chevalier C, Colon S, Faraj G, Bouvier R, Pincon JA, Cochat P. Glomerulopathy and hypomelanosis of Ito. Nephrologie1997; 18: 125–127[Web of Science][Medline]
- Risdon RA, Woolf AS. Chapter 26. Developmental defects and cystic diseases of the kidney. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall's Pathology of the Kidney, 5th edition. Lippincott-Raven, Philadelphia-New York, USA, 1998; 1149–1206
Revision received 8.11.00.
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