eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Nail-Patella Syndrome

Author: Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine
Coauthor(s): Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine
Contributor Information and Disclosures

Updated: Feb 13, 2007

Introduction

Background

Nail-patella syndrome (NPS; OMIM 161200) is a well-known autosomal dominant condition characterized by nail dysplasia, patellar aplasia-hypoplasia, arthrodysplasia of the elbows, iliac horns, and nephropathy. Recent reports indicate that open-angle glaucoma (OAG) may also cosegregate with NPS. One of the first chromosomal linkages identified in humans is between the NPS locus and the ABO blood group on chromosome 9. LMX1B, located on band 9q34.1, is an LIM-homeodomain transcription factor required for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Heterozygous loss-of-function mutations in LMX1B cause NPS.

Pathophysiology

Although the joint anomalies in NPS may limit range of motion (ROM), the associated nephropathy may be the most serious complication. Asymptomatic proteinuria may persist for years; however, end-stage renal failure has been reported.

Frequency

United States

NPS has been studied for more than 100 years. It has a prevalence of 1 per 50,000 live births.

Mortality/Morbidity

The age of onset and degree of severity cannot be predicted. Patients are at risk for nephropathy that resembles glomerulonephritis. This occurs in 30-55% of cases, and renal failure is the leading cause of death. Proteinuria is the first clinical symptom, and some cases progress to end-stage renal disease (ESRD), which requires transplantation. Although many patients are asymptomatic until the early adult years, proteinuria may develop before age 2 years.

Research has revealed that the location of the LMXB1 mutation may play a role in the frequency and severity of proteinuria. If the mutation is located in the homeodomain, proteinuria is more frequent and more severe.

Race

No race predilection has been reported.

Sex

Males and females are equally affected.

Age

Prenatal diagnosis based on ultrasonography findings is reported; however, the associated clinical findings span all ages.

Clinical

History

  • Proteinuria: This is the first sign of renal involvement. The patient may remain asymptomatic or eventually develop ESRD.
  • Hypoplastic nails: Absence of the thumbnail is the most common nail pattern. Other nails may be less fragile.
  • Knee abnormalities: Some patients report recurrent dislocation or arthritis, which may necessitate patellar replacement.
  • Limited ROM in the elbows
  • Decreased pronation or supination of the elbows, appearing unilaterally or bilaterally
  • Hypoplastic radial head

Physical

  • Renal symptoms: These symptoms range from proteinuria to nephrotic syndrome.
  • Nephropathy (resembles glomerulonephritis)
    • Prevalence ranges from 30-55%, and renal failure is the leading cause of death.
    • Patients present with proteinuria as the first clinical symptom.
    • Some patients eventually develop ESRD and require transplantation.
  • Open-angle glaucoma
    • Strong evidence supports that OAG is a pleiotropic effect of the NPS1 gene.
    • Age at diagnosis ranges from birth to late adulthood.
    • Optic nerve and visual field damage can be prevented with early diagnosis and treatment of elevated intraocular pressure.
  • Patellar abnormalities
    • Skeletal deformities include patellar absence or hypoplasia, which may decrease flexion.
    • Osteoarthritis, osteoarthrosis, and knee effusions are associated complications; however, disability is not a major concern.
  • Dysplastic nails
    • Although absent or dysplastic nails are the most common nail findings, nonspecific changes include discoloration, longitudinal ridging, and poorly formed lunulae.
    • Nails are progressively less affected toward the fifth digit.
  • Iliac horns: These symmetrical, bilateral, central-posterior, iliac processes are asymptomatic and vary from a small dimple to a well-marked spur.
  • Elbow arthrodysplasia
    • Clinical manifestations include an increased carrying angle and limited supination and pronation.
    • On radiographs, the head of the radius is underdeveloped and posteriorly displaced.

Causes

  • The LMX1B gene plays a central role in limb dorsoventral patterning and patterning of the nails, patella, and long bones during development.
  • Human fetal and adult kidneys show a high level of LMX1B expression, thereby suggesting a critical function for this gene during kidney development.
  • The loss of function in one allele of this gene is the most likely cause of nephropathy, dysplastic nails, and hypoplastic patella manifesting in nail-patella syndrome.

More on Nail-Patella Syndrome

Overview: Nail-Patella Syndrome
Differential Diagnoses & Workup: Nail-Patella Syndrome
Treatment & Medication: Nail-Patella Syndrome
Follow-up: Nail-Patella Syndrome
References
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References

  1. Azouz EM, Kozlowski K. Small patella syndrome: a bone dysplasia to recognize and differentiate from the nail-patella syndrome. Pediatr Radiol. May 1997;27(5):432-5. [Medline].

  2. Bennett WM, Musgrave JE, Campbell RA, et al. The nephropathy of the nail-patella syndrome. Clinicopathologic analysis of 11 kindred. Am J Med. Mar 1973;54(3):304-19. [Medline].

  3. 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. Aug 2005;13(8):935-46. [Medline].

  4. Browning MC, Weidner N, Lorentz WB Jr. Renal histopathology of the nail-patella syndrome in a two-year-old boy. Clin Nephrol. Apr 1988;29(4):210-3. [Medline].

  5. 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. May 1998;19(1):51-5. [Medline].

  6. Cormier-Daire V, Chauvet ML, Lyonnet S, et al. Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation. J Med Genet. Jul 2000;37(7):520-4. [Medline].

  7. Cottereill CP, Jacobs P. Hereditary Arthro-osteo-onchyodysplasia associated with iliac horns. Br J Clin Pract. 1961;15(11):933-941.

  8. Curtis JJ, Bhathena D, Leach RP, et al. Goodpasture''s syndrome in a patient with the Nail-Patella syndrome. Am J Med. Sep 1976;61(3):401-6. [Medline].

  9. Darlington D, Hawkins, CF. Nail patella syndrome with iliachorns and hereditary nephropathy: necropsy report and anatomical dissection. J Bone Joint Surg [Am]. Jan 1967;49B:164-74. [Medline].

  10. Dreyer SD, Zhou G, Baldini A, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet. May 1998;19(1):47-50. [Medline].

  11. Dunston JA, Hamlington JD, Zaveri J, et al. The human LMX1B gene: transcription unit, promoter, and pathogenic mutations. Genomics. Sep 2004;84(3):565-76. [Medline].

  12. Eisenberg KS, Potter DE, Bovill EG Jr. Osteo-onychodystrophy with nephropathy and renal osteodystrophy. A case report. J Bone Joint Surg [Am]. Sep 1972;54(6):1301-5. [Medline].

  13. Feingold M, Itzchak Y, Goodman RM. Ultrasound prenatal diagnosis of the Nail-Patella syndrome. Prenat Diagn. Aug 1998;18(8):854-6. [Medline].

  14. Fong EE. 'Iliac horns' (symmetrical bilateral central posterior iliac processes):a case report. Radiology. 1946;47:517-518.

  15. Galloway G, Vivian A. An ophthalmic screening protocol for nail-patella syndrome. J Pediatr Ophthalmol Strabismus. Jan-Feb 2003;40(1):51-3. [Medline].

  16. Leahy MS. The hereditary nephropathy of osteo-onychodysplasia. Nail-patella syndrome. Am J Dis Child. Sep 1966;112(3):237-41. [Medline].

  17. Looij BJ Jr, te Slaa RL, Hogewind BL, van de Kamp JJ. Genetic counselling in hereditary osteo-onychodysplasia (HOOD, nail- patella syndrome) with nephropathy. J Med Genet. Oct 1988;25(10):682-6. [Medline].

  18. McIntosh I, Clough MV, Gak E. Prenatal diagnosis of nail-patella syndrome [letter]. Prenat Diagn. Mar 1999;19(3):287-8. [Medline].

  19. Morita T, Laughlin LO, Kawano K, et al. Nail-Patella syndrome. Light and electron microscopic studies of the kidney. Arch Intern Med. Feb 1973;131(2):271-7. [Medline].

  20. Sabnis SG, Antonovych TT, Argy WP, et al. Nail-patella syndrome. Clinical Nephrology. Sep 1980;14(3):148-53. [Medline].

  21. Schulz-Butulis BA, Welch MD, Norton SA. Nail-patella syndrome. J Am Acad Dermatol. Dec 2003;49(6):1086-7. [Medline].

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Further Reading

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Keywords

nail-patella syndrome, NPS, Fong disease, NPS 1, onycho-osteodysplasia, Turner-Kieser syndrome, arthro-onychodysplasia, nephrotic syndrome, end-stage renal disease, ESRD, end-stage renal failure, LMX1B, NPS1, proteinuria

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Contributor Information and Disclosures

Author

Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine
Suzanne M Carter, MS is a member of the following medical societies: American Bar Association
Disclosure: Nothing to disclose.

Coauthor(s)

Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine
Susan J Gross, MD, FRCS(C), FACOG, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, American Society of Human Genetics, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Medical Editor

Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System
Leonard G Feld, MD, PhD, MMM is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Heart Association, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplant Surgeons, Eastern Society for Pediatric Research, International Society of Nephrology, Juvenile Diabetes Foundation International, National Kidney Foundation, Society for Experimental Biology and Medicine, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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