INTRODUCTION
The nail-patella syndrome (NPS) or osteo-onychodysplasia is an autosomal dominant disorder characterized by hypoplastic or absent patella, dystrophic fingernails and toenails, and dysplasia of elbows and iliac horns. Renal involvement is variable.
INCIDENCE
The estimated incidence of NPS is 22 per million. The disease has been reported in patients all around the world.
It has been calculated that, for a parent with the NPS whose family has nephropathy, the risk of having a child with nephropathy is 24 percent and the risk of having a child who will progress to end-stage renal disease is 7 percent.
GENETICS
NPS is due to mutations of the LMX1B gene located at the distal end of the long arm of chromosome 9. LMX1B is a transcription factor of the LIM-homeodomain type that plays an important role for limb and renal development in vertebrates.
Studies in homozygous knock-out mice and in vitro assays demonstrated that LMX1B is a regulatory transcription factor that plays a role in glomerular development. It binds to sequences near and helps control the transcription of multiple genes integral for proper glomerular basement membrane formation and/or glomerular podocyte differentiation and function.
The following genes have been reported as target genes for LMX1B:
- COL4A4 and COL4A3 — LMXIB binds to the putative enhancer sequence of COL4A4, the gene for alpha-4 chain of collagen type IV. In addition, there is decreased expression of alpha-3 chain (gene product of COL4A3) and alpha-4 chain of collagen type IV collagen homozygous knock-out mouse for LMX1B. However, expression of both these proteins is normal in renal biopsies of patients with NPS. Mutations in type IV genes cause Alport syndrome and thin basement membrane nephropathy.
- The expression of both NPHS2, which encodes podocin, and the CD2AP gene is reduced in the homozygous LMX1B knock-out mouse , but not in humans with NPS. Podocin and CD2AP are expressed at the slit diaphragm, and mutations of both these genes are associated with glomerular disease. Although its role in NPS is unknown, mutations in the podocin gene, called NPHS2, cause familial nephrotic syndrome and may be responsible for a large number of cases of apparently sporadic steroid-resistant focal segmental glomerulosclerosis. Although not clearly causative, mutations in the gene for CD2AP were described in two patients with primary FSGS.
As noted above, findings in vitro and animal models are not necessarily equivalent to those observed in humans. As an example, although NPS is an autosomal dominant disease in humans, only mice homozygous for LMX1B deficiency display characteristic renal abnormalities. In vitro experiments suggest that the NPS phenotype results from haploinsufficiency rather than a dominant-negative effect.
It has also been suggested that there may be two allelic mutations of the gene, one responsible for the NPS without nephropathy and one responsible for the NPS with nephropathy.
Nevertheless, these findings unify the glomerular and genetic abnormalities noted in several diseases: NPS, Alport syndrome, and some inherited causes of the nephrotic syndrome.
EXTRARENAL MANIFESTATIONS OF NAIL-PATELLA SYNDROME
Nail abnormalities are present in 80 to 90 percent of patients and are observed at birth. The nails may be absent but are more often hypoplastic or dysplastic. Abnormalities predominate on the fingernails, particularly the thumb and index finger, whereas the toenails are often normal. The lesions are bilateral and symmetrical and include discoloration, longitudinal pterygion, splitting, and triangular lunulae.
Abnormalities of the knees and elbows are found in almost all patients. The patella may be absent or hypoplastic, often with fragmentation, causing lateral slippage during knee flexion. Complications such as arthritis, arthrosis, and knee effusion, may lead to knee pain.
Elbow symptoms are also commonly seen. The radial heads are typically hypoplastic, leading to subluxation. The distal ends of the humerus are also hypoplastic and posterior processes result in limitations of extension, pronation, and supination of the forearm.
Iliac horns, observed in 30 to 70 percent of the patients, are pathognomonic radiologic features of the disease. They consist of symmetrical bone formations arising from the antero-superior iliac crest. They are asymptomatic and may be detected on clinical examination. Other bone anomalies, affecting the feet and the ankles, may be seen and scoliosis been described.
Additional clinical features have been described. These include gastrointestinal abnormalities, such as symptoms similar to those of irritable bowel, and vasomotor symptoms.
RENAL MANIFESTATIONS OF NAIL-PATELLA SYNDROME
Renal symptoms are present in approximately one-half of the patients with the NPS. Females and males are equally affected. The degree of renal involvement varies between families and also within single families. The most frequent symptoms are proteinuria, sometimes with nephrotic syndrome, hematuria, and hypertension. Urine concentrating ability may be impaired.
Histology
Light microscopy shows normal or nearly normal glomeruli in patients with normal renal function. In comparison, patients with heavy proteinuria and/or impaired renal function may show basement membrane thickening and nonspecific lesions of focal segmental glomerulosclerosis. Immunofluorescence microscopy is negative or shows nonspecific segmental deposits of IgM and C3 in the sclerotic areas.
Electron microscopy shows a pathognomonic and constant lesion of the glomerular basement membrane (GBM). The lesion consists of irregular and lucent rarefactions within the lamina densa, containing clusters of cross-banded collagen fibrils. These abnormalities may also be found in the mesangial matrix, but the tubular basement membranes are not affected. The clusters of fibrils are clearly demonstrated by staining with uranyl acetate and phosphotungstic acid. They may be observed within segments of thickened GBM or along the entire GBM.
Immunohistochemical studies have shown an irregular mesangiocapillary localization of type III collagen and an abnormal distribution of type VI collagen. These findings are compatible with an abnormal composition of the basement membranes, which could be responsible for the renal and extrarenal manifestations.
Although the collagen fibrils are a constant feature of NPS, they are also found in patients without clinical evidence of renal involvement. Furthermore, there is no correlation between the severity of the ultrastructural lesions and the clinical manifestations. Similar collagen accumulation in the GBM has been described in patients with a familial progressive glomerulopathy that is not associated with nail or bone involvement. It is not known if this disorder is related to the NPS.
CLINICAL COURSE OF NAIL-PATELLA SYNDROME
End-stage renal disease develops in approximately 30 percent of cases at a mean age of 33 ± 18 years. The evolution of the renal disease is extremely variable, suggesting that nongenetic factors may be involved in the rapid deterioration of renal function observed in some patients. As an example, superimposed nephritis has been described in this disorder including anti-GBM antibody disease, membranous nephropathy, IgA nephropathy, and necrotizing vasculitis. It is not known if these disorders occur with increased frequency in NPS.
TREATMENT OF NAIL-PATELLA SYNDROME
There is no specific therapy available in NPS. The GBM lesions do not recur after renal transplantation and these patients do not develop anti-GBM antibodies, a finding that is occasionally seen in hereditary nephritis.
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