- 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'.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
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- 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.
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- 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.
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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