Genetics of Nail-Patella Syndrome

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

Background

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]

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Pathophysiology

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.

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Epidemiology

Frequency

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.

International

Nail-patella syndrome has been described in multiple populations.

Mortality/Morbidity

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).

Race

No race predilection has been reported.

Sex

Males and females are equally affected.

Age

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.

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