AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Familial patella aplasia-hypoplasia syndrome
Genitopatellar syndrome
Small patella syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Conduct urinalysis, along with a microscopic analysis, to check for proteinuria and hematuria.
• Obtain a 24-hour urine collection to quantitate protein and creatinine excretion. A urine protein-to-creatinine ratio on a random sample is also acceptable (normal ratio <0.2).
• Evaluate the blood chemistry for plasma urea, BUN, and creatinine concentrations.

Imaging Studies

• Radiography findings reveal iliac horns and hypoplastic patella in adults.
• Conduct MRI to identify abnormal muscle insertions, which cannot be observed using radiography.
• Ultrasonography is indicated in young children for a better evaluation of the unossified patella.

Other Tests

• Some families have glaucoma that cosegregates with nail-patella syndrome (NPS).
• The following annual vision checks are important:
• • Visual acuity testing
  • Slit-lamp biomicroscopic examination
  • Intraocular pressure determination
  • Applanation
  • Gonioscopy
  • Ophthalmoscopy

Procedures

• Renal biopsy: Light microscopy reveals glomerulonephritis and basement membrane thickening; however, negative results do not rule out pathological processes in the kidney. Electron microscopy can reveal ultrastructural changes, such as irregularities and thickening of the basement membrane, which cannot be seen with light microscopy. This moth-eaten appearance is pathognomonic.

Histologic Findings

Increased lucency of the glomerular basement membrane resembles a moth-eaten appearance. A typical lesion consists of irregular basement membrane thickening, epithelial foot process fusion, and the presence of fibrillar collagenlike material within the basement.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Unless the patient presents with acute findings, perform the evaluation on an outpatient basis.
• Suggest knee replacement if the patient develops osteoarthritis in the knees.
• Dialysis and transplantation are necessary in patients who develop ESRD. Approximately 30-55% of patients have renal involvement.
• The use of diuretics in patients with nephrotic syndrome depends on the glomerular filtration rate. Any therapy for edema requires an assessment of intravascular volume status.

Surgical Care

• Renal transplantation has proven successful in patients with nail-patella syndrome (NPS) who develop ESRD.
• Avoid excision of the radial head to correct elbow arthrodysplasia. This excision forces the ulna into the wrist, creating a painful condition.
• MRI is necessary to reveal the abnormal muscle and nerve insertions that may complicate orthopedic procedures.

Consultations

• Dentist
• Geneticist
• Nephrologist
• Ophthalmologist
• Orthopedist
• Rheumatologist

Diet

• No dietary restrictions are necessary unless hypertension or nephrotic syndrome develop. At this time, a salt-free diet is appropriate.

Activity

• Joint abnormalities generally do not limit physical activity.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Vitamin D analogs, thiazides, and prednisone are effective in alleviating the symptoms of nephrotic syndrome and end-stage renal failure.

Drug Category: Vitamin D analog

Vitamin D is necessary to maintain the correct amount of calcium needed for strong bones and teeth and is needed throughout the body.

Drug Category: Thiazide diuretics

These agents are used to treat edema caused by renal dysfunction (eg, nephrotic syndrome, chronic renal failure).

Drug Category: Corticosteroids

These agents induce diuresis or remission of proteinuria in nephrotic syndrome.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit the patient for testing and renal transplantation.
• If the patient has severe osteoarthritis, knee replacement may be required.

Further Outpatient Care

• Monitor renal function.
• An ophthalmological evaluation is suggested for detection of glaucoma.
• Consider a dermatologic consultation.

In/Out Patient Meds

• Prednisone, vitamin D replacement, and thiazides are appropriate to manage nephrotic syndrome and end-stage renal failure.

Transfer

• Transfer may be required for further evaluation and renal transplantation.

Complications

• Glaucoma
• Osteoarthritis
• Nephrotic syndrome
• End-stage renal failure

Prognosis

• Approximately 30-55% of patients with nail-patella syndrome (NPS) develop nephropathy, which may lead to end-stage renal failure. However, the presence of nephropathy or renal failure does not increase the risk of the same complications in their children.
• A normal lifestyle, including procreation, is possible after renal transplantation; however, genetic counseling is recommended in patients with NPS.

Patient Education

• Genetic counseling is recommended because the risk of having affected offspring is 50%. Prenatal diagnosis using ultrasonography and molecular analysis is possible.
• Stress the importance of regular assessment of renal function to the patient.
• The patient should receive annual glaucoma checks.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize associated conditions such as glaucoma
• Failure to recommend genetic counseling

Special Concerns

• Nephropathy occurs in children as young as 2 years.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• 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].
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• 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].
• McIntosh I, Clough MV, Gak E. Prenatal diagnosis of nail-patella syndrome [letter]. Prenat Diagn. Mar 1999;19(3):287-8. [Medline].
• 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].
• Sabnis SG, Antonovych TT, Argy WP, et al. Nail-patella syndrome. Clinical Nephrology. Sep 1980;14(3):148-53. [Medline].
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Article Last Updated: Feb 13, 2007