- Patrick Niaudet, MD
Patrick Niaudet, MD
- Section Editor — Pediatric Nephrology
- Professor of Pediatrics
- Hôpital Necker-Enfants Malades, Paris, France
- Section Editors
- Tej K Mattoo, MD, DCH, FRCP
Tej K Mattoo, MD, DCH, FRCP
- Section Editor — Pediatric Nephrology
- Professor of Pediatrics
- Wayne State University School of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
The nail-patella syndrome (NPS, MIM #161200) or hereditary osteo-onychodysplasia (HOOD syndrome) is a rare autosomal dominant disorder. It is characterized by limb and pelvic skeletal abnormalities (eg, hypoplastic or absent patella, dysplasia of elbows, including pterygia, and iliac horns), nail and distal digital abnormalities, and renal disease.
The clinical manifestations, diagnosis, and management of children with NPS will be reviewed here.
The estimated incidence of NPS is 1 per 50,000 [1,2]. The disease has been reported in patients all around the world.
PATHOGENESIS AND LMX1B GENE MUTATIONS
NPS is an autosomal dominant disorder with full gene penetrance but variability of expression even within families [3,4].
Approximately 85 percent of families with NPS present with mutations of the LMX1B gene located at the distal end of the long arm of chromosome 9 [5-7]. LMX1B is a transcription factor of the LIM-homeodomain type that plays an important role for limb and renal development in vertebrates; however, it is expressed lifelong within the podocyte and it is essential for the maintenance the structured actin cytoskeleton in podocytes . More than 140 heterozygous mutations in LMX1B have been reported, including missense, splicing, deletions, and nonsense mutations. Most mutations result in protein truncation [3,7,9-11]. The identification of entire LMX1B deletions confirms that haploinsufficiency is the principal pathogenetic mechanism of NPS . Studies in homozygous knock-out mice and in vitro assays demonstrated that LMX1B protein expressed in glomerular podocytes helps control the transcription of multiple genes integral for proper glomerular basement membrane (GBM) formation, and/or glomerular podocyte differentiation and function during the early stages of renal development [5,13-16]. Putative target genes include COL4A3 and COLA4, genes for alpha-4 chains of collagen type IV [13,14], and NPHS2 and CD2AP genes, which encode podocyte proteins [14,15]. (See "Clinical manifestations, diagnosis and treatment of hereditary nephritis (Alport syndrome)" and "Steroid-resistant idiopathic nephrotic syndrome in children", section on 'NPHS2 mutations' and "Steroid-resistant idiopathic nephrotic syndrome in children", section on 'Other genes'.)
- Dombros N, Katz A. Nail patella-like renal lesions in the absence of skeletal abnormalities. Am J Kidney Dis 1982; 1:237.
- Levy M, Feingold J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 2000; 58:925.
- Bongers EM, Huysmans FT, Levtchenko E, et al. Genotype-phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. Eur J Hum Genet 2005; 13:935.
- Sweeney E, Fryer A, Mountford R, et al. Nail patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet 2003; 40:153.
- Chen H, Lun Y, Ovchinnikov D, et al. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet 1998; 19:51.
- Vollrath D, Jaramillo-Babb VL, Clough MV, et al. Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome. Hum Mol Genet 1998; 7:1091.
- Hamlington JD, Jones C, McIntosh I. Twenty-two novel LMX1B mutations identified in nail patella syndrome (NPS) patients. Hum Mutat 2001; 18:458.
- Burghardt T, Kastner J, Suleiman H, et al. LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys. J Am Soc Nephrol 2013; 24:1830.
- Dreyer SD, Zhou G, Baldini A, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet 1998; 19:47.
- Knoers NV, Bongers EM, van Beersum SE, et al. Nail-patella syndrome: identification of mutations in the LMX1B gene in Dutch families. J Am Soc Nephrol 2000; 11:1762.
- McIntosh I, Dreyer SD, Clough MV, et al. Mutation analysis of LMX1B gene in nail-patella syndrome patients. Am J Hum Genet 1998; 63:1651.
- Bongers EM, de Wijs IJ, Marcelis C, et al. Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man. Eur J Hum Genet 2008; 16:1240.
- Morello R, Zhou G, Dreyer SD, et al. Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome. Nat Genet 2001; 27:205.
- Miner JH, Morello R, Andrews KL, et al. Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation. J Clin Invest 2002; 109:1065.
- Rohr C, Prestel J, Heidet L, et al. The LIM-homeodomain transcription factor Lmx1b plays a crucial role in podocytes. J Clin Invest 2002; 109:1073.
- Dunston JA, Hamlington JD, Zaveri J, et al. The human LMX1B gene: transcription unit, promoter, and pathogenic mutations. Genomics 2004; 84:565.
- Boyer O, Woerner S, Yang F, et al. LMX1B mutations cause hereditary FSGS without extrarenal involvement. J Am Soc Nephrol 2013; 24:1216.
- Isojima T, Harita Y, Furuyama M, et al. LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy. Nephrol Dial Transplant 2014; 29:81.
- Edwards N, Rice SJ, Raman S, et al. A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'. Clin Kidney J 2015; 8:113.
- Giglio S, Provenzano A, Mazzinghi B, et al. Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression. J Am Soc Nephrol 2015; 26:230.
- Ghoumid J, Petit F, Holder-Espinasse M, et al. Nail-Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity. Eur J Hum Genet 2016; 24:44.
- Tigchelaar S, Rooy Jd, Hannink G, et al. Radiological characteristics of the knee joint in nail patella syndrome. Bone Joint J 2016; 98-B:483.
- Guidera KJ, Satterwhite Y, Ogden JA, et al. Nail patella syndrome: a review of 44 orthopaedic patients. J Pediatr Orthop 1991; 11:737.
- Lippacher S, Mueller-Rossberg E, Reichel H, Nelitz M. Correction of malformative patellar instability in patients with nail-patella syndrome: a case report and review of the literature. Orthop Traumatol Surg Res 2013; 99:749.
- Feingold M, Itzchak Y, Goodman RM. Ultrasound prenatal diagnosis of the Nail-Patella syndrome. Prenat Diagn 1998; 18:854.
- National Center for Biotechnology Information (NCBI) Gene Reviews. Nail-Patella syndrome. www.ncbi.nlm.nih.gov/books/NBK1132/#nail-ps.Resources (Accessed on October 23, 2014).
- Lemley KV. Kidney disease in nail-patella syndrome. Pediatr Nephrol 2009; 24:2345.
- Del Pozo E, Lapp H. Ultrastructure of the kidney in the nephropathy of the nail--patella syndrome. Am J Clin Pathol 1970; 54:845.
- Hoyer JR, Michael AF, Vernier RL. Renal disease in nail-patella syndrome: clinical and morphologic studies. Kidney Int 1972; 2:231.
- Sabnis SG, Antonovych TT, Argy WP, et al. Nail-patella syndrome. Clin Nephrol 1980; 14:148.
- Bennett WM, Musgrave JE, Campbell RA, et al. The nephropathy of the nail-patella syndrome. Clinicopathologic analysis of 11 kindred. Am J Med 1973; 54:304.
- López-Arvizu C, Sparrow EP, Strube MJ, et al. Increased symptoms of attention deficit hyperactivity disorder and major depressive disorder symptoms in Nail-patella syndrome: potential association with LMX1B loss-of-function. Am J Med Genet B Neuropsychiatr Genet 2011; 156B:59.
- PATHOGENESIS AND LMX1B GENE MUTATIONS
- CLINICAL MANIFESTATIONS
- Nail and digital abnormalities
- Limb and pelvic abnormalities
- Renal manifestations
- - Histopathologic findings from renal biopsy
- Other findings
- - Sensorineural hearing loss
- - Ophthalmological disease
- - Gastrointestinal involvement
- - Vasomotor symptoms
- - Other orthopedic findings
- - Other neurologic findings
- Molecular genetic testing
- Renal biopsy
- DIFFERENTIAL DIAGNOSIS
- EVALUATION FOLLOWING INITIAL DIAGNOSIS
- SUMMARY AND RECOMMENDATIONS