- 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 nail-patella syndrome will be reviewed here.
The estimated incidence of nail-patella syndrome (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 due to mutations of the LMX1B gene located at the distal end of the long arm of chromosome 9 [3-5]. 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. More than 140 heterozygous mutations in LMX1B have been reported, including missense, splicing, deletions, and nonsense mutations [5-9]. Most mutations are located in the LIM domains. LMX1B gene mutations are fully penetrant, but there is variability of expression even within families [9,10]. In addition, there are case reports of LMX1B mutation (R246 missense mutation) associated with familial focal segmental glomerulosclerosis (FSGS), but without any other clinical features of NPS [11,12] (see "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", section on 'Other genes'). 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 [13-16]. LMX1B protein expressed in glomerular podocytes helps control the transcription of multiple genes integral for proper glomerular basement membrane formation, and/or glomerular podocyte differentiation and function during the early stages of renal development . 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'.)
Overview — Nail-patella syndrome (NPS) is classically characterized by limb and pelvic skeletal abnormalities (eg, hypoplastic or absent patella, dysplasia of elbows and iliac horns), nail and distal digital abnormalities, and renal disease. However, information from two large cases series demonstrated additional clinical manifestations including sensorineural hearing loss and ophthalmological disease [9,10]. Data were obtained from comprehensive evaluation of 126 patients from 44 families recruited from genetic departments in Great Britain , and 106 patients from 22 unrelated families and 10 sporadic subjects .
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- 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.
- 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.
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- 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.
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- 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.
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- 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