Genetics of Nail-Patella Syndrome 

Updated: Mar 24, 2016
Author: Julie Hoover-Fong, MD, PhD, FACMG; Chief Editor: Maria Descartes, MD 



Nail-patella syndrome (NPS; OMIM 161200) is an autosomal dominant condition characterized by the classical clinical tetrad of nail dysplasia, patellar aplasia-hypoplasia, elbow arthrodysplasia, and iliac horns. The nails may be absent, hypoplastic, or dystrophic with ridges, pits, and/or triangular lunulae. See the image below.

Nail of a patient the nail-patella syndrome. Nail of a patient the nail-patella syndrome.

Typically, nail anomalies are symmetric; the thumbs are most severely affected, and severity decreases progressing toward the fifth digit. The patella may be absent, small, or irregularly shaped. Dislocation in a superior and lateral direction is common if patellae are present. Elbow anomalies may include decreased extension, pronation, supination, and/or pterygia. Patellae and elbow anomalies may be asymmetric. The iliac horns are bony prominences that project posterolaterally from the iliac bones. Although rarely palpable, they are radiographically visible in most patients with nail-patella syndrome.[1]

Proteinuria with or without hematuria occurs in 30-50% of affected individuals, but progresses to end-stage renal disease in approximately 5% of patients.[2] Ocular hypertension and open-angle glaucoma is more common in younger patients than in the general population.[3] The third documented chromosomal linkage identified in humans was between the nail-patella syndrome locus and the ABO blood group on chromosome 9.[4] LMX1B, located at 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 nail-patella syndrome.[5, 6]


Although the joint anomalies in nail-patella syndrome may limit range of motion (ROM), the associated glaucoma and nephropathy may be the most serious complication. Asymptomatic proteinuria may persist for years; however, end-stage renal failure occurs in less than 5%.

Mutations in the homeodomain of LMX1B versus LIM-A or LIM-B may be associated with proteinuria. However, further investigation of a larger population of patients with nail-patella syndrome (ideally sporadic) is needed to determine if this genotype-phenotype correlation is valid outside large pedigrees of nail-patella syndrome, which may be simultaneously segregating nephropathy-related genes.



United States

Nail-patella syndrome has been recognized for more than 100 years. It has an estimated prevalence of 1 per 50,000 live births.


Nail-patella syndrome has been described in multiple populations.


The severity of clinical features and manifestations cannot be predicted. Orthopedic problems may be treated with analgesics, physical therapy, bracing, and/or surgery. With concurrent renal disease, nonsteroidal anti-inflammatory drugs (NSAIDs) must be used cautiously to avoid worsening renal function. If orthopedic surgery is planned, MRI prior to surgery is recommended because joint structures (ie, ligament, tendon and muscle insertions, vessel locations) are typically distorted in patients with nail-patella syndrome.

Renal disease that manifests as proteinuria with or without hematuria occurs in 30-50% of patients, but progression to end-stage renal disease occurs in less than 5%. Hypertension and renal disease are treated as in the general population, with recognition that ACE inhibitors have been shown to slow progression of proteinuria in nail-patella syndrome. Patients who have undergone renal transplantation usually have good results. Glaucoma should also be treated as in the general population, but with increased surveillance in all patients with nail-patella syndrome (eg, annual ophthalmologic examination with glaucoma screening).


No race predilection has been reported.


Males and females are equally affected.


Prenatal diagnosis based on ultrasonography detection of iliac horns is reported; talipes may also be detected on antenatal ultrasonography. Nail anomalies and contractures of the knees or elbows may be noted at birth. Abnormal patellae are often noted in early childhood. Renal disease may occur at any age. When present, the onset of glaucoma or ocular hypertension is usually in adulthood but at an earlier age than in the general population. Other disease manifestations span all ages.




See the list below:

  • Family history: Collect a full 3 generation pedigree to detect family history of autosomal dominant nail-patella syndrome (NPS). Currently, 88% of affected individuals have a positive family history of nail-patella syndrome. Nail-patella syndrome is fully penetrant, but significant interfamilial and intrafamilial variability is noted.

  • Nail/digit anomalies: Nail anomalies are present at birth.

  • Knees: Recurrent patellar dislocations, deformity of knee joint, and knee pain are noted.

  • Elbows: Elbow pain, decreased flexion, pronation, and supination are reported.

  • Back pain: This is common in nail-patella syndrome; underlying spinal problems such as spondylolisthesis may be observed.

  • Renal disease: Proteinuria, hypertension, and/or decreased renal function may be observed in patients with nail-patella syndrome. End-stage renal disease is relatively rare and is reported in approximately 5% of patients.

  • Preeclampsia: This condition is more common in patients with nail-patella syndrome than in the general population.

  • Ophthalmology: Ocular hypertension or open-angle glaucoma may be observed.

  • Neurology: Attention deficit disorder with and without hyperactivity (ADHD) may be more common in adults with nail-patella syndrome and does not exhibit the same increased male prevalence as in the general population.[7] Major depressive symptoms may also be part of the syndrome. A significant proportion of patients exhibit decreased sensitivity to pain and temperature in the extremities. Signs and symptoms of chronic fatigue may be present due to maldevelopment of the serotonergic system.

  • GI problems: Constipation and irritable bowel syndrome are more common in patients with nail-patella syndrome than in the general population.


Pes planus is seen in majority of patients with nail-patella syndrome. These patients also tend to have an overall typically thin body habitus, and they have difficulty gaining weight. Other findings on physical examination may include the following:

  • Nail/digit anomalies: Nails may be absent, hypoplasia, or dystrophic; triangular lunulae may be the sole nail anomaly. Typically, the thumb is most severely affected, with possible decreasing severity progressing to the fifth digit. Decreased creases over the distal interphalangeal (DIP) joints are noted.

  • Patellar anomalies: Patellae may be absent or hypoplastic. Dislocation in the superior and lateral direction is common. Pain is also common and osteoarthritis may be present.

  • Iliac horns: These bony prominences are typically asymptomatic and may be palpable on the posterolateral iliac bones. If not palpable, they are often detected using radiography. They are present in about 70% of patients and are pathognomonic of nail-patella syndrome.

  • Elbow anomalies: Decreased flexion, supination, and pronation are noted. The radius may be hypoplastic and posteriorly placed. Skin webbing (pterygia) may be present.

  • Renal disease: Proteinuria with or without hematuria may be present in 30-50% of patients. This progresses to end-stage renal disease in approximately 5%. No evidence suggests that renal transplantation has different outcome in patients with nail-patella syndrome than in the general population.

  • Open-angle glaucoma: Optic nerve and visual field damage can be prevented with early detection of elevated intraocular pressure and appropriate treatment.

  • Lester sign: A hyperpigmented, irregular ring in the iris may be noted.


See the list below:

  • The LMX1B gene is a transcription factor involved in the dorsoventral patterning of vertebrate limbs (including patterning of the nails, digits, elbows and patellae), the differentiation and function of kidney podocytes, development of the anterior eye structures, and the CNS.

  • The loss of function of one allele of LMX1B is the only known cause of nail-patella syndrome.



Differential Diagnoses

  • Genitopatellar syndrome

  • Meier-Gorlin syndrome

  • Patellar aplasia-hypoplasia

  • Radial and patellar aplasia/hypoplasia, cleft or high arched palate, infantile diarrhea and dislocated joints, little size and limb malformations, long slender nose and normal intelligence (RAPADILINO) syndrome

  • Small patella syndrome (ischiopatellar dysplasia, Scott-Taor syndrome)



Laboratory Studies

See the list below:

  • Annual screening urinalysis with microscopy is indicated in patients with nail-patella syndrome (NPS) to evaluate for proteinuria and hematuria. A urine protein-to-creatinine ratio or albumin-to-creatinine ratio is also indicated.

  • Annual blood pressure measurements and annual BUN and creatinine level assessments are indicated.

  • Consider 24-hour urine collection to quantitate protein and creatinine excretion if above screening results are abnormal.

  • LMX1B sequencing is diagnostic in the majority of patients.[8, 9, 10] LMX1B mutations in exons 2-6 can be found via DNA sequencing in 80-85% of patients with nail-patella syndrome and an additional 5% can be picked up with deletion and duplication analysis. Once a mutation is found, other family members can have targeted testing.

Imaging Studies

See the list below:

  • Radiography may reveal iliac horns, hypoplastic patellae or abnormal radial heads.

  • If joint surgery planned, conduct MRI of that joint to identify abnormal tendon, ligament, and/or muscle insertions and vessel distribution prior to surgery. Anatomy of joints in patients with nail-patella syndrome is typically abnormal.

Other Tests

See the list below:

  • Perform annual dilated ophthalmologic examination including slit-lamp quantification of intraocular pressure and visual fields.

  • Consider dual energy x-ray absorptiometry (DEXA) scanning to evaluate bone mineral content and density as surrogate indicator of bone strength. Bone mineral density is decreased by 8-20% in the hips of patients with nail-patella syndrome, and increased fractures have been reported.


See the list below:

  • Renal biopsy may be indicated after referral to nephrologist for evaluation of progressive renal insufficiency, proteinuria, and hypertension in nail-patella syndrome.

  • 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 and the presence of collagen-like fibrils within the basement membrane, which cannot be seen with light microscopy. These appearances are pathognomonic.

Histologic Findings

See the list below:

  • 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.

  • Histological features are present even in patients without clinically evident renal involvement.



Medical Care

ACE inhibitors for proteinuria, hypertension, or both are indicated in patients with nail-patella syndrome (NPS). Consultation with a nephrologist may permit implementation of prophylactic treatment with ACE inhibitors.

Dialysis and/or renal transplant may be indicated in as many as 5% of patients who have renal involvement that progresses to end-stage renal disease.

Physical therapy, bracing, and analgesics may be needed for joint pain. Caution is necessary in using analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) because renal disease may also be part of this condition.

Surgical Care

Renal transplantation has proven successful in patients with nail-patella syndrome who develop end-stage renal disease.

Patella realignment surgery may help in cases of recurrent dislocation. Joint replacement may be beneficial in cases of severe osteoarthritis of the knee or elbow.

Excision of the radial head should only be undertaken after careful consideration and only for pain relief as range of movement is not usual improved significantly by surgery.

MRI is necessary to reveal the abnormal muscle and nerve insertions that may complicate orthopedic procedures.

A study by Tigchelaar et al found that although surgical treatment for patellofemoral instability appeared to produce unfavorable results in patients with nail-patella syndrome, patients tended to have a good opinion of the outcome. Those who underwent the surgery had lower postoperative Knee Injury and Osteoarthritis Outcome Scores and Kujala knee scores than did patients who did not undergo surgery. Nonetheless, the surgery patients had pain improvement in 87% of knees and functional improvement in 30%; patient satisfaction with surgery reached 61%.[11]


See the list below:

  • Geneticist

  • Orthopaedist

  • Ophthalmologist

  • Nephrologist


See the list below:

  • No dietary restrictions are necessary unless hypertension or nephrotic syndrome develop.


See the list below:

  • Joint abnormalities and pain may limit physical activity.



Medication Summary

ACE inhibitors should be used to treat proteinuria, hypertension, or both in nail-patella syndrome (NPS). Consultation with a nephrologist may permit implementation of prophylactic treatment with ACE inhibitor medication prior to overt proteinuria or hypertension.

Vitamin D analogs, thiazides, and prednisone are effective in alleviating the complicating symptoms of nephrotic syndrome and end-stage renal failure (ESRF) in nail-patella syndrome as in all patients with ESRF.[12]

Vitamin D Analog

Class Summary

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

Calcitriol (Rocaltrol)

Increases calcium levels by promoting absorption of calcium in intestines and retention in kidneys. The beneficial effects of vitamin D replacement in renal osteodystrophy appear to result from correction of hypocalcemia and secondary hyperparathyroidism.

Thiazide diuretics

Class Summary

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

Hydrochlorothiazide (Hydro-Diuril, Microzide)

Inhibits reabsorption of sodium in distal tubules, increasing excretion of sodium, water, and potassium and hydrogen ions.


Class Summary

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

Prednisone (Deltasone, Orasone)

Acts as an anti-inflammatory agent and immunosuppressant.

Dose depends on specific disease entity being treated; in situations of less severity, lower doses generally suffice, whereas, in selected patients, higher initial doses may be required; initial dosage should be maintained or adjusted prn.

Alternate day therapy (ADT) PO is a corticosteroid-dosing regimen in which twice the usual daily dose of corticoid is administered every other morning.

The purpose of this mode of therapy is to provide the patient who requires long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children.

Angiotensin-converting Enzyme (ace) Inhibitor

Class Summary

ACE inhibitors are preferred for treating hypertension and proteinuria associated with nail-patella syndrome.

Captopril (Capoten)

Captopril is an example of an ACE inhibitor used off-label for hypertension and proteinuria in neonates, infants, and children. Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.



Further Outpatient Care

See the list below:

  • Annual renal function screening with urinalysis, blood testing for BUN and creatinine levels, and blood pressure assessment is indicated.

  • Annual ophthalmological evaluation is indicated for detection of glaucoma.

  • Orthopedic consultations are indicated as needed.

Further Inpatient Care

See the list below:

  • Admit patients with nail-patella syndrome (NPS) for testing and renal transplantation if end-stage renal disease is progressive.

  • If the patient has severe joint problems, surgery such as joint replacement or patellar realignment may be required.

Inpatient & Outpatient Medications

See the list below:

  • ACE inhibitors should be used to treat proteinuria and/or hypertension in nail-patella syndrome. Consultation with a nephrologist may permit implementation of prophylactic treatment with ACE inhibitor medication prior to overt proteinuria or hypertension.

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


See the list below:

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


See the list below:

  • Glaucoma

  • Osteoarthritis

  • Nephrotic syndrome

  • ESRF


See the list below:

  • Approximately 30-55% of patients with nail-patella syndrome develop nephropathy, which may lead to ESRF in about 5% of patients.

  • Prognosis after renal transplantation is good.

Patient Education

See the list below:

  • Genetic counseling is recommended because the risk of having affected offspring is 50%. Prenatal diagnosis using molecular analysis is possible but because of the marked intrafamilial variability, the severity of the condition in an affected child cannot be predicted.

  • Stress the importance of regular assessment of renal function to the patient.

  • The patient should receive annual glaucoma checks.