Nail Patella syndrome




Nail-patella syndrome 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.

Nail-patella syndrome has been recognized for more than 100 years. It has an estimated prevalence of 1 per 50,000 live births (US). Males and females are equally affected.


The classic clinical tetrad of nail-patella syndrome (NPS) involves changes in the nails, knees, and elbows, and the presence of iliac horns. Many other features may be seen in NPS, and involvement of other body systems such as the kidneys and eyes is well documented. The clinical manifestations are extremely variable in both frequency and severity, with inter- and intrafamilial variability. Individuals may be severely affected by one aspect of NPS but have much milder or no manifestations elsewhere. Males and females are affected equally. Although the diagnosis may be made at birth, it is common for families to remain undiagnosed for several generations despite having been seen by doctors from a variety of disciplines. 

Digital changes. In NPS, a reduction in flexion of the distal interphalangeal (DIP) joints is associated with loss of the creases in the skin overlying the dorsal surface of the DIP joints of the fingers. The gradient of severity is the same as seen in the nails; therefore, the index fingers are the most affected. Hyperextension of the proximal interphalangeal (PIP) joints with flexion of the DIP joints (resulting in "swan-necking") and fifth finger clinodactyly may be seen.

Knee involvement. In addition to the previously mentioned patellar abnormalities, tight hamstring muscles may cause flexion contractures of the knees. There may also be osteochondritis dissecans, synovial plicae, and absence of the anterior cruciate ligament. Early degenerative arthritis is common. Symptoms associated with knee abnormalities in NPS include pain, instability, locking, clicking, patella dislocation, and inability to straighten the knee joint.

Involvement of the ankles and feet. Talipes equinovarus, calcaneovarus, calcaneovalgus, equinovalgus, and hyperdorsiflexion of the foot may occur. Tight Achilles tendons are common, contributing to talipes equinovarus and to toe-walking. Pes planus is common.

Spinal and chest wall problems. Back pain occurs in half of individuals with NPS. There may be an increased lumbar lordosis, scoliosis (usually mild), spondylolisthesis, spondylolysis, or pectus excavatum.

Osteoporosis. Bone mineral density (BMD) is reduced by 8%-20% in the hips of individuals with NPS. An increased rate of fractures has also been reported.

General appearance. A lean body habitus may be associated with NPS and affected individuals often have difficulty putting on weight (particularly muscle) despite adequate dietary intake and exercise. In particular, muscle mass in the upper arms and upper legs tend to be decreased. The tendency to be very lean is most evident in adolescents and young adults and becomes less apparent after middle age.

Increased lumbar lordosis may make the buttocks appear prominent.

The high forehead and hairline, particularly at the temples, resembles a receding male pattern hairline when seen in women.

Renal involvement. Renal involvement occurs in 30%-50% of individuals with NPS; end-stage renal disease (ESRD) occurs in approximately 5%.

 The first sign of renal involvement is usually proteinuria, with or without hematuria. Proteinuria may present at any age from birth onwards and may be intermittent. Renal problems may present, or be exacerbated, during pregnancy. Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESRD. Progression to renal failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified. Nephritis may also occur in NPS.

 Ultrastructural (electron microscopic) renal abnormalities are the most specific histologic changes seen in NPS and include irregular thickening of the glomerular basement membrane with electron-lucent areas giving a mottled "moth-eaten" appearance, and the presence of collagen-like fibers within the basement membrane and the mesangial matrix.

Ophthalmologic findings. Primary open-angle glaucoma and ocular hypertension occur at increased frequency in NPS and at a younger age than in the general population. Congenital and normal-tension glaucoma have been reported in individuals with NPS.

Iris pigmentary changes (termed Lester's sign) consisting of a zone of darker pigmentation shaped like a cloverleaf or flower around the central part of the iris are seen frequently.

Gastrointestinal involvement. One third of individuals with NPS have problems with constipation (often from birth) or irritable bowel syndrome.

Neurologic problems. Many individuals with NPS exhibit reduced sensation to pain and temperature in the hands and feet, most likely because of the inability of Aδ and C fibers to connect with interneurons in the dorsal spinal cord. Some affected individuals report intermittent numbness, tingling, and burning sensations in the hands and feet, with no obvious precipitant. Rarely, these symptoms may be secondary to local orthopedic problems or neurologic compromise from the spine or cervical ribs. In most cases, however, the paresthesia follows a glove and stocking pattern rather than the distribution of a particular dermatome or peripheral nerve.

Epilepsy was reported in 6% of affected individuals in one large study.

Vasomotor problems. Some individuals have symptoms of a poor peripheral circulation, such as very cold hands and feet, even in warm weather. Some may be diagnosed with Raynaud's phenomenon.

Dental problems. Dental problems may include weak, crumbling teeth and thin dental enamel.


The NPS is caused by a mutation in the LMX1B gene, located at 9q34.1. It 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.

The NPS is inherited in an autosomal dominant pattern – one defect copy of the gene is sufficient to cause the disease. 


Nail-patella syndrome is inherited in an autosomal dominant manner. Eighty-eight percent of individuals with NPS have an affected parent. Twelve percent of affected individuals have a de novo mutation. The offspring of an affected individual are at a 50% risk of inheriting NPS. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family has been identified.


The diagnosis of nail-patella syndrome is based on clinical findings. Diagnosis of nail-patella syndrome (NPS) should be suspected in individuals with:

Nail changes. Nail changes are the most constant feature of NPS (98%). Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The nail changes may be limited to triangular lunules (lunulae), a characteristic feature of NPS. 

Nail changes may be observed at birth and are most often bilateral and symmetric. The thumbnails are the most severely affected; the severity of the nail changes tends to decrease from the index finger toward the little finger. Each individual nail is usually more severely affected on its ulnar side. Dysplasia of the toenails is usually less marked and less frequent than that of the fingernails; if the toenails are involved, it is often the little toenail that is affected.

Knee involvement. The patellae may be small, irregularly shaped, or absent. Patella involvement may be asymmetric. Recurrent subluxation or dislocation of the patella is common in NPS and may be associated with poor development of the vastus medialis muscle. The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. Symptoms of knee involvement were apparent in 74% of cases in one study 

Elbow involvement. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Elbow abnormalities may be asymmetric. Typical radiologic findings include dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle. These abnormalities may result in dislocation of the radial head, usually posteriorly. Approximately 70% of individuals with NPS exhibit some degree of elbow involvement. 

Iliac horns. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. They are present in about 70% of individuals with NPS and are considered pathognomonic of NPS. Pelvic x-ray is usually necessary for their detection. Although large horns may be palpable, they are asymptomatic. Iliac horns may be seen on third-trimester ultrasound scanning, on x-ray at birth, and by bone scan. In children, iliac horns may have an epiphysis at the apex.

The diagnosis of nail-patella syndrome (NPS) is established in a proband with at least one but usually more than one of the manifestations listed above, with nail changes being present in 98%. In cases where the clinical diagnosis is uncertain the identification of a heterozygous pathogenic variant in LMX1B is diagnostic. LMX1B is the only gene in which pathogenic variants are known to cause NPS.


Approximately 30-55% of patients with nail-patella syndrome develop nephropathy, which may lead to end-stage renal failure (ESRF) in about 5% of patients. Prognosis after renal transplantation is good.

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


Hypertension and renal disease are treated as in the general population. When renal transplantation is necessary, results are usually favourable. ACE inhibitors are useful in slowing progression of proteinuria, but their use should be monitored carefully in children.

Orthopedic problems may be helped by analgesics, physiotherapy, splinting, bracing, or surgery. Because of the abnormal joint anatomy that may be present in individuals with NPS, MRI of joints to identify abnormal anatomy is important prior to surgery, so that appropriate surgical treatment can be planned in advance.

Treatment as in the general population for:

  • Glaucoma
  • Constipation
  • Dental problems
  • Surveillance

 Annual measurement of the following is appropriate: 

  • Measurement of blood pressure
  • Urinalysis
  • Urine albumin:creatinine ratio on a first-morning urine. If any abnormalities are detected, the individual should be referred to a nephrologist.
  • Screening for glaucoma from the time that a child is compliant with the examination
  • Dental examination is indicated at least every six months.

DEXA scanning frequency in adults is based on clinical symptoms, abnormalities detected on previous evaluations, and standard practice in peri- and post-menopausal females and older males.

Agents/Circumstances to Avoid

Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided because of their detrimental effect on kidney function.

Evaluation of Relatives at Risk

Early diagnosis of NPS in at-risk family members allows for ophthalmologic and renal screening, especially in individuals with mild-moderate skeletal involvement who may not otherwise come to clinical attention. Molecular genetic testing can be used if the pathogenic variant in the family is known; otherwise, monitor renal findings (i.e., blood pressure, urinalysis, and urine albumin:creatinine ratio on a first-morning urine) and screen for glaucoma.

Pregnancy Management

Renal problems may present during (or be exacerbated by) pregnancy and in one study 29% of pregnant women with NPS developed preeclampsia. Hence, frequent urinalysis and blood pressure measurement is recommended in pregnant women with NPS. Medication used to treat renal disease, such as ACE inhibitors, should be reviewed ideally prior to pregnancy, or at least as soon as pregnancy is recognized, so that transition to an alternative treatment can be considered in order to avoid potential adverse effects of ACE inhibitors on the developing fetus.




[3] Sweeney E, Fryer A, Mountford R, Green A, McIntosh I. Nail patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet. 2003;40:153–62.

[4] Feingold M, Itzchak Y, Goodman RM. Ultrasound prenatal diagnosis of the nail-patella syndrome. Prenat Diagn. 1998;18:854–6.

[5] Goshen E, Schwartz A, Zilka LR, Zwas ST. Bilateral accessory iliac horns: pathognomonic findings in nail-patella syndrome. Scintigraphic evidence on bone scan. Clin Nucl Med. 2000;25:476–7.

[6] Lichter PR, Richards JE, Downs CA, Stringham HM, Boehnke M, Farley FA. Cosegregation of open-angle glaucoma and the nail-patella syndrome. Am J Ophthalmol. 1997;124:506–15.

[7] Bongers EM, van Kampen A, van Bokhoven H, Knoers NV. Human syndromes with congenital patellar anomalies and the underlying gene defects. Clin Genet. 2005 Oct. 68(4):302-19.

[8] McIntosh I, Dunston JA, Liu L, Hoover-Fong JE, Sweeney E. Nail patella syndrome revisited: 50 years after linkage. Ann Hum Genet. 2005 Jul. 69(Pt 4):349-63.

[9] Dunston JA, Reimschisel T, Ding YQ, Sweeney E, Johnson RL, Chen ZF, McIntosh I. A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression. Eur J Hum Genet. 2005;13:330–5.