eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
Nail-Patella Syndrome
Updated: Oct 20, 2009
Introduction
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.
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.
Proteinuria with or without hematuria occurs in 30-50% of affected individuals, but progresses to end-stage renal disease in approximately 5% of patients.1 Ocular hypertension and open-angle glaucoma is more common in younger patients than in the general population. The third documented chromosomal linkage identified in humans was between the nail-patella syndrome locus and the ABO blood group on chromosome 9. 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.2,3
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.
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.
Clinical
History
- 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. 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.
Physical
- 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.
Causes
- 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.
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| References |
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References
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Further Reading
Keywords
nail-patella syndrome, NPS, Fong disease, NPS 1, onycho-osteodysplasia, hereditary onycho-osteodysplasia disease, HOOD, Turner-Kieser syndrome, arthro-onychodysplasia, nephrotic syndrome, end-stage renal disease, ESRD, end-stage renal failure, ESRF, , proteinuria, spondylolisthesis, attention deficit disorder, ADD, attention deficit hyperactivity disorder, ADHD, constipation, irritable bowel syndrome, IBS, osteoarthritis, treatment, diagnosis
