American Journal of Medical Genetics 43693-696 (1992)

Brief Clinical Report Nail-Patella Syndrome in a Spontaneously Aborted 18-Week Fetus: Ultrastructural and Immunofluorescent Study of the Kidneys Rosa Monica Drut, Sunita Chandra, Rocco Latorraca, and Enid Gilbert-Barness Departments of Pathology and Laboratory Medicine (R.M.D., S.C., E.G-B.) and Pediatrics (E.G-B.), University of Wisconsin, Madison, and Trinity Memorial Hospital, Milwaukee, Wisconsin (R.L.)

Nail-patella syndrome (NPS),hereditary onycho-osteodysplasia, is an autosomal dominant disorder of nail dystrophy, patellar absence or hypoplasia, incomplete elbow extension, conical posterior iliac horns, and nephropathy. We studied the kidneys of an l&week spontaneously aborted fetus of a mother with the NPS. Ultrastructural examination of the kidney showed thickening of the capillary walls of the glomeruli and mesangium. There was irregular thickening of basement membranes with subendothelial fibrillar electron-dense deposits. Immunofluorescence showed fibrinogen deposition in glomerular basement membranes. Fibrinogen deposition in utero may ultimately lead to glomerular fibrosis and intrabasement membrane collagen deposition as seen in the adult renal lesion of this syndrome. This is the first report of the NPS in which the renal abnormalities have been studied in a fetus. These findings provide support for possible prenatal diagnosis of NPS by intrauterine kidney biopsy. o 1992 Wiley-Lisa, Inc.

INTRODUCTION The nail-patella syndrome (NPS) is an autosomal dominant disorder of nail dystrophy, absence or hypoplasia of the patellae, subluxation of the radial heads at the elbowjoints, presence of posterior conical iliac horns, scapular deformation [homer, 19891, heterchromic irides, and nephropathy. Occasionally, the nephropathy is the only manifestation of the syndrome [Dombros and Katz, 1982; Sabnis et al., 19801. We report on a case of NPS in an 18-week spontaneously aborted fetus with special study of the kidneys by electron microscopy and immunofluorescence.

CLINICAL REPORT The preposita was a spontaneously aborted female fetus a t 18 weeks of gestation. The mother was a 34year-old Caucasian woman with NPS, gravida 0, para 1, abortio 4. Her manifestations included absence of the patellae, hyperextensible fingers, inability to extend at the elbows, and dysplastic nails. There was no clinically apparent renal disease. The maternal grandfather was reported to have NPS. The mother and maternal grandmother also had a qualitative platelet defect manifested by a prolonged bleeding time. The significance of the latter in this case is uncertain. The only living sib of the proposita also had NPS, but no bleeding disorder. The KEY WORDS: Nail-patella syndrome, fetal gestation of this fetus was unremarkable until a sonokidney, electron microscopy, gram showed absence of fetal heart tones a t 18 weeks. immunofluorescence The fetus was spontaneously vaginally delivered. At autopsy, the fetus weighed 450 g and had a 25 cm crown-to-heel length and a 15.5 cm crown-to-rump length. The limbs were symmetrical with marked hyperextensibility of the fingers and inability to extend the legs. Dissection of the knee joint showed rudimenReceived for publication April 29,1991;revision received Sep- tary cartilage representing the patella. Portions of the nail beds were absent. Together the kidneys weighed 5.5 tember 27, 1991. Address reprint requests to Dr. E. Gilbert-Barness, Univ. of g. Grossly the kidneys were normal. The remainder of Wisconsin Hosp. and Clinics, Clinical Sciences Center E5, 600 the external and internal examinations were normal and consistent with the gestational age. Highland Ave., Madison, WI 53792. 0 1992 Wiley-Liss, Inc.


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On microscopic examination, the kidneys showed a slightly prominent mesangial matrix (Fig. 1). PAS staining and methenamine silver showed an increase in mesangial cellularity and matrix (Fig. 2). Immunofluorescence study for fibrinogen showed 4 + positive granularity in the glomerular capillary walls and in the mesangium (Fig. 3). Immunofluorescence for IgG, IgA, IgM, IgE, Clq, and C3 was unreactive. Electron microscopic examination of 3 glomeruli showed diffuse granular and rare fibrillar deposits of electron-dense material within the basement membranes and subendothelial spaces along the capillary walls. The mesangial matrix showed focal and segmental deposition of similar electron-dense material. The capillary walls were irregularly thickened with segmental areas of increased basement-membrane material. The foot processes of the epithelial cells were focally fused with increased cytoplasmic fibrils near the basement membrane (Figs. 4, 5). Although no definitive collagen fibrils were noted, the electron-dense deposits were found in the classical location (mesangium and basement membrane) noted in other cases of NPS.

Fig. 1. Light microscopy showing a glomerulus with slight prominent mesangial matrix. H & E x 400.

Fig. 2. Light microscopy showing a glomerulus with increase in mesangial cellularity and matrix. Methenamine silver stain X 400.

Fig. 3. Diffuse granular immunofluorescent positivity for fibrinogen along capillary walls and in the mesangium.

DISCUSSION The NPS has been mapped to the terminal portion of 9q (9q34) and is closely linked to the ABO locus, the red cell adenylate kinase locus (AK-11, and the argininosuccinate synthetase locus (AS)[Ferguson-Smith et al, 19761.The renal changes in the NPS are well described [del Pozo and Lapp, 1970; Bennett et al., 1973;Morita et al., 1973; Gubler et al., 1980; Angelov et al., 1981; Browning et al., 19881 and are summarized in Table I. Only 40% of patients have proteinuria, and not all manifest the renal abnormalities. When clinical manifestations and renal disease are present, light microscopy shows increased amounts of mesangial matrix, either diffuse or segmental, particularly in the hilar region. Cell proliferation may be absent in the mesangium, although in some cases [del Pozo et al., 1970; Browning et al., 19881 the mesangium is hypercellular. The glomerular basement membrane is generally thickened. The thickening varies from glomerulus to glomerulus and even from tuft to tuft in a single glomerulus [Morita et al., 19731.Both visceral and parietal epithelial cells may be slightly increased in size. The basement membrane of Bowman’s capsule is usually thickened. Immunofluorescencestudies are not consistently positive for a specific substance. In one reported case IgM was positive 3 + [Browninget al., 19881, whereas in other cases, IgG, IgA, c3, and Clq were positive [Bennett et al., 19731. Some had completely negative immunofluorescence [Bennett et al., 19731. On electron microscopic examination, the epithelial cells may show focal fusion of foot processes [Ben-Bassat et al., 1971;Angelov et al., 19811and a few lipid droplets [Morita et al., 19731. There is an increase in electron density of the cytoplasm near the basement membrane. The basement membrane is generally thickened in an irregular fashion [Morita et al., 19731. Large numbers of electron-lucent areas are present within the electrondense areas in the thickened spaces [Morita et al., 1973; Angelov et al., 19811. Endothelial cells are slightly swollen with focal loss offenestration. Mesangial matrix

Nail-Patella Syndrome


Fig. 4. Electron microscopy showing increased mesangial matrix with deposits (arrows), within the mesangium and in a subendothelial location. x 13,200.

TABLE I. Nail-Patella Syndrome: Renal Lesions Light microscopy Thickening and irregularity of the glomerular capillary wall

Thickening of the basement membrane and increase mesangial matrix, demonstrable by PAS and methenamine silver stain Slowly progressive segmental sclerosis and obsolescence with tubular atrophy, cortical fibrosis, and chronic neDhritis.

Immunofluorescence Focal deposits of IgM and complement, presumably nonspecific findings shared by other types of glomerular disease

Ultrastructure Thickening of the glomerular basement membrane. Deposition of collagen fibers in the glomerular basement membrane and appearance of electronlucent zones Collagen fibers in the mesangial matrix (occasionally)

is usually increased in amount with electron-lucent basement membrane. Fibrils characteristic of collagen areas giving a moth-eaten appearance. This is in con- are seen in the electron-lucent areas in the basement trast to the electron-dense deposits within the mes- membrane and mesangial matrix. In our case, the changes were similar to those noted angial matrix and is similar t o the changes seen in the


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Fig. 5. Electron microscopy showing numerous intramembranous subendothelial and mesangial electron dense deposits (arrows). Capillary walls are irregularly thickened due to the numerous deposits. x 33,000.

above with the exception that no electron-lucent areas or collagen deposits were identified in the basement membrane of mesangium, although electron dense material was seen. Perhaps the electron-dense deposits precede collagen deposition, and collagen would have become apparent as the lesion progressed. In our patient, fibrin was the only protein found by immunofluorescence in the glomerular capillary walls and mesangium. We hypothesize that fibrinogen deposition in utero may ultimately lead to glomerular fibrosis and intrabasement membrane collagen deposition as seen in adult renal lesion of the NPS.

REFERENCES Angelov A, Boykinov B, DragievM (1981):Electronmicroscope study of renal lesions in nail-patella syndrome. Folia Medica 23:41-46. Ben-Bassat M, Cohen L, Rosenfeld J (1971):The glomerular basement membrane in the nail-patella syndrome. Arch Path 92:350-355. Bennett WM, Musgrave J E , Campbell RA, Elliot D, Cox R, Brooks RE,

Lovrien EW, Beak RK, Porter GA (1973):The nephropathy of the nail-patella syndrome: clinicopathologic analysis of 11 kindred. Am J Med 53:304-319. Browning MC, Weidner N, Lorenz WB (1988):Renal histopathology of the nail-patella syndrome in a two-year-old boy. Clinical Nephrology 29:210-213. del Pozo E, Lapp H (1970):Ultrastructure of the kidney in the nephropathy of the nail-patella syndrome. Amer J Clin Path 54:845-851. Dombros N, Katz A (1982): Nail-patella-like renal lesions in the absence of skeletal abnormalities. Am J Kidney Dis 1:237-240. Ferguson-Smith NA, Aitken DA, Turleau C, de Grouchy J (1976): Localization of the human ABO: Np-1:AK-1 linkage group by regional assignment of AK-1 to 9q34. Hum Genet 34:35-43. Gubler MC, Levy M, Naizot C, Habib R (1980): Glomerular basement membrane changes in hereditary glomerular diseases. Renal physiol 3:405-413. Loomer RL (1985): Shoulder girdle dysplasia associated with nailpatella syndrome. Clin Orthopo 238:112-116. Morita T, Laughlin LO, Kawano K, Kimmerstiel P, Suzuki Y, Churg J (1973): Nail-patella syndrome: light and electron microscopic studies of the kidney. Arch Intern Med 131:271-277.

Nail-patella syndrome in a spontaneously aborted 18-week fetus: ultrastructural and immunofluorescent study of the kidneys.

Nail-patella syndrome (NPS), hereditary onycho-osteodysplasia, is an autosomal dominant disorder of nail dystrophy, patellar absence or hypoplasia, in...
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