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Nail-Patella Syndrome

, MB ChB, FRCP, DRCOG, MD, , MD, PhD, and , PhD.

Author Information

Initial Posting: ; Last Update: October 15, 2020.

Estimated reading time: 26 minutes

Summary

Clinical characteristics.

Nail-patella syndrome (NPS) (previously referred to as Fong's disease), encompasses the classic clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns. Nail changes are the most constant feature of NPS. 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 patellae may be small, irregularly shaped, or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. Renal involvement, first manifest as proteinuria with or without hematuria, occurs in 30%-50% of affected individuals; end-stage renal disease occurs up to 15% of affected individuals. Primary open-angle glaucoma and ocular hypertension occur at increased frequency and at a younger age than in the general population.

Diagnosis/testing.

The diagnosis of nail-patella syndrome is established in a proband with suggestive findings and/or a heterozygous pathogenic variant in LMX1B identified by molecular genetic testing

Management.

Treatment of manifestations: Orthopedic problems may be helped by analgesics, physiotherapy, splinting, bracing, or surgery; MRI of joints to identify abnormal anatomy is important prior to surgery so that appropriate surgical treatment can be planned in advance; ACE inhibitors to control blood pressure and possibly to slow progression of proteinuria; renal transplantation as needed; standard treatment for decreased bone mineral density, hypertension, constipation/inflammatory bowel disease, glaucoma, epilepsy, and dental anomalies.

Surveillance: At least annually: monitoring of blood pressure for hypertension; assessment of urinalysis and first-morning urine albumin:creatinine ratio for renal disease; screening for glaucoma (as soon as a child is compliant). Dental examination at least every six months and DEXA scan as needed.

Agents/circumstances to avoid: Chronic use of NSAIDs because of the detrimental effect on kidney function.

Pregnancy management: The risk of developing preeclampsia may be increased in pregnant women with NPS; hence, frequent urinalysis and blood pressure measurement is recommended during pregnancy. For women taking an ACE inhibitor, transitioning to an alternative treatment ideally prior to pregnancy, or at least as soon as pregnancy is recognized, is recommended to avoid potential adverse effects of ACE inhibitors on the developing fetus.

Genetic counseling.

Nail-patella syndrome is inherited in an autosomal dominant manner. Eighty-eight percent of individuals with NPS have an affected parent; 12% of affected individuals have a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting NPS. Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant in the family has been identified.

Diagnosis

Formal clinical diagnostic criteria for nail-patella syndrome (NPS) have not been published, although iliac horns (bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis) are considered pathognomonic.

Suggestive Findings

Nail-patella syndrome (NPS) should be suspected in individuals with the following clinical and radiologic findings.

Clinical findings

  • Nail changes (see Figure 1), including nails that are:
    • Absent, hypoplastic, or dystrophic
    • Ridged longitudinally or horizontally
    • Pitted
    • Discolored
    • Separated into two halves by a longitudinal cleft or ridge of skin
    • Thin or (less often) thickened
    • Limited to triangular lunules (lunulae), a characteristic feature of NPS
  • Abnormal and unstable patella
    • Small, irregularly shaped or absent patella as assessed by palpation or radiographs
    • Recurrent subluxation or dislocation of the patella by history and/or physical exam
  • Limitation of extension, pronation, and supination at the elbow; cubitus valgus; and antecubital pterygia
Figure 1. . Typical presentation of thumb nails (a) and fingernails (b) in nail-patella syndrome.

Figure 1.

Typical presentation of thumb nails (a) and fingernails (b) in nail-patella syndrome. The arrow points to the index finger. Note decrease in severity of nail involvement from second to fifth finger and lack of creases over the distal interphalangeal joints. (more...)

Radiologic findings

  • Absent or hypoplastic patella that may be malpositioned
    Note: Patella ossification centers appear on radiographs between ages three and six years.
  • Dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle
  • Iliac horns (bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis), which are considered pathognomonic of NPS (See Figure 2.)
Figure 2.

Figure 2.

Iliac horns (arrows) in an individual with nail-patella syndrome

Family history is consistent with an autosomal dominant inheritance pattern. Note: Absence of a known family history of NPS does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of nail-patella syndrome is established in a proband with suggestive findings and/or a heterozygous pathogenic variant in LMX1B identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of nail-patella syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of nail-patella syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of LMX1B is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

A multigene panel that includes LMX1B and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. This may be especially useful if renal disease or glaucoma is the predominant presenting feature, as large multigene genetic testing panels for these disease groups are available. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this condition, a multigene panel that includes deletion/duplication analysis is recommended.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of nail-patella syndrome has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene is likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Additional Testing Considerations for NPS

If targeted genetic testing or exome sequencing are not diagnostic, but NPS is clinically suspected and a dominant inheritance pattern is observed, karyotype may be considered. Chromosome translocations disrupting LMX1B have also been reported but represent a rare pathogenic mechanism [Duba et al 1998, Silahtaroglu et al 1999, Midro et al 2004].

Table 1.

Molecular Genetic Testing Used in Nail-Patella Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
LMX1B Sequence analysis 385% 4
Gene-targeted deletion/duplication analysis 510% 6
KaryotypeRare 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Proportion of affected individuals with pathogenic variants identified by sequence analysis of exons 2-6 [Clough et al 1999, Sweeney et al 2003, Harita et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

Clinical Characteristics

Clinical Description

The classic clinical tetrad of nail-patella syndrome (NPS) involves changes in the nails, knees, and elbows and the presence of iliac horns (see Diagnosis). Many other features may be seen in NPS, including renal disease and glaucoma [Sweeney et al 2003]. 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. Though the skeleton is affected in NPS, affected individuals are of average stature.

To date, more than 170 pathogenic variants in LMX1B have been reported in individuals identified to have nail-patella syndrome [Lichter et al 1997, Bongers et al 2002, Sweeney et al 2003, Dunston et al 2005, Lemley 2009, López-Arvizu et al 2011, Boyer et al 2013, Ghoumid et al 2016, Harita et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Select Features of Nail-Patella Syndrome

Feature% of Persons with FeatureComment
Nail changes96%-98%The thumb nail is most severely affected; the ulnar side of each nail is more severely affected [Sweeney et al 2003, Ghoumid et al 2016].
Digital changes~90%
Knee involvement74% Sweeney et al [2003]
Elbow involvement70% Sweeney et al [2003]
Illiac horns on radiographs70%-76%Pathognomonic for NPS [Tigchelaar et al 2015, Ghoumid et al 2016]
Tight Achilles tendonsUnknown prevalence, likely secondary to knee pterygiumMay contribute to talipes equinovarus and to-walking
ArthrogryposisDepending on classification of arthrogryposis, ≤75% Sabir et al [2020]
↓ bone mineral densityUnknown prevalence from limited data, but documented Towers et al [2005]
Renal involvement30%-50% Tigchelaar et al [2015]
Ophthalmologic involvement10%-25%Most often presenting as proteinuria, w/or w/o hematuria
Gastrointestinal involvement~30%Incl constipation or irritable bowel syndrome
↓ sensation to pain & temperature in hands & feet~25%Sweeney et al [2003], Dunston et al [2005], López-Arvizu et al [2011]
Seizures~6%
End-stage renal failureRare to 15%Price et al [2018], Harita et al [2020]
Vascular anomaliesRareUnclear if this is a rare co-occurrence or part of NPS

NPS = nail-patella syndrome

Nail changes are the most constant 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 fifth toenail that is affected.

Digital changes. 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 also be seen.

Knee abnormalities. Symptoms include pain, instability, locking, clicking, patella dislocation, and inability to straighten the knee joint. Knee involvement may also be associated with poor development of the vastus medialis muscle.

  • Patellae:
    • Findings may be asymmetric.
    • The patellae may be small, irregularly shaped, or absent.
    • 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.
  • Flexion contractures of the knees may occur due to tight hamstring muscles
  • Osteochondritis dissecans, synovial plicae, and absence of the anterior cruciate ligament may also occur.
  • Early degenerative arthritis is common.

Elbow involvement can include:

  • Limitation of extension, pronation, and supination at the elbow
  • Cubitus valgus
  • Antecubital pterygia

Affected individuals may experience dislocation of the radial head, usually posteriorly. Elbow involvement may be asymmetric.

Illiac horns are considered pathognomonic of NPS [Sweeney et al 2003].

  • Pelvic x-ray is usually necessary for their detection (Figure 2).
  • Although large horns may be palpable, they are typically asymptomatic.
  • Iliac horns may be seen on third-trimester ultrasound scanning [Feingold et al 1998], on x-ray at birth, and by bone scan [Goshen et al 2000].
  • In children, iliac horns may have an epiphysis at the apex.

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.

Arthrogryposis. Though contractures of the elbows, knees, and calcaneovarus/calcaneovalgus are recognized in individuals with NPS, the term "arthrogryposis" is not often used in the clinical description of this condition.

  • Sabir et al [2020] noted "arthrogryposis" as the presenting feature of an affected individual who underwent whole-exome sequencing.
  • Due to limitations of phenotype search terms associated with established gene variants, LMX1B and NPS were not considered.
  • By definition, arthrogryposis refers to multiple congenital, usually non-progressive joint contractures involving more than one joint; therefore, many people with NPS may be considered to have arthrogryposis (suggested by Sabir et al [2020] to be present in as many as 75% of individuals with NPS).

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 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 tends 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 is present in 30%-50% of individuals with NPS. Variable rates of end-stage renal disease (ESRD) have been described as high as 15% by Lemley [2009], 5% by Sweeney et al [2003], and more recently, less than 5% by Harita et al [2020].
    • 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 during (or be exacerbated by) pregnancy.
    • Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESRD.
    • Steroids may not be effective in the treatment of proteinuria in individuals with NPS [Nakata et al 2017, Harita et al 2020]. See Genetic Steroid-Resistant Nephrotic Syndrome Overview, Clinical Characteristics.
    • 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 but the presence and severity of proteinuria appears to be predictive of progression [Harita et al 2020]. In individuals with ESRD, renal transplantation may be considered and typically has a favorable outcome (see Management, Treatment of Manifestations).
    • Nephritis may also occur in NPS.
  • Ultrastructural (electron microscopic) renal abnormalities are the most specific histologic changes seen in individuals with 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 [Lichter et al 1997, Sweeney et al 2003, Ghoumid et al 2016].
  • Congenital and normal-tension glaucoma have also been reported in individuals with NPS [Lichter et al 1997].
  • 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 [Sweeney et al 2003].

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 [Dunston et al 2005]. 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, 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 [Sweeney et al 2003].

Dental problems. Dental problems may include weak, crumbling teeth and thin dental enamel [Sweeney et al 2003].

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 [Sweeney et al 2003].

Vascular anomalies. There are limited reports of vascular anomalies in individuals with NPS, including internal carotid artery aplasia [Kraus et al 2020] and spontaneous coronary artery dissection [Nizamuddin et al 2015, Kaadan et al 2018]. The prevalence of vascular issues in a large population of individuals with NPS and the function of LMX1B in vessel formation must be studied further to determine if these findings are rare coincidental occurrences or part of the NPS phenotype. At this point, it is too early to know if this is part of the NPS phenotype.

Genotype-Phenotype Correlations

The majority (~80%) of pathogenic variants in LMX1B are found in the LIM domains.

Renal manifestations. Bongers el al [2005] suggested that individuals with a pathogenic variant in LMX1B in the LMX1 homeodomain showed significantly more frequent and higher values of proteinuria compared to those with pathogenic variants in the LIM domains. This observation is supported by Harita et al [2020] in a cohort of Japanese individuals with NPS. Thus far, it is not possible to predict progression of renal manifestations to end-stage renal disease based on genotype alone due to inter-individual variability. However the presence and severity of proteinuria appear to correlate with progression of renal disease.

Non-renal manifestations. No clear genotype-phenotype association is apparent for extrarenal manifestations of NPS.

Nomenclature

Nail-patella syndrome is the most accepted term but has the disadvantage of implying that nail and patellar dysplasia are the most important features. Hereditary onycho-osteodysplasia (HOOD) may be more accurate, but is rarely used. Perhaps hereditary onycho-osteodysplasia with nephropathy and glaucoma would be the best term.

The terms Fong's disease and Turner syndrome have also been used.

  • Captain EE Fong described the presence of unusual horn-like anomalies on the posterior aspect of the iliac bones in a woman undergoing an intravenous pyelogram. Fong published the description in 1946 and although he did not associate the anomaly with nail-patella syndrome, his name was connected to this condition [Fong 1946].
  • Turner* and Keiser published earlier descriptions of the iliac horns in individuals with nail-patella syndrome in 1933 and 1939, respectively.
    *Note: Referring to JW Turner and not HH Turner, who described the phenotype associated with a 45,X karyotype

Prevalence

The prevalence of NPS has been roughly estimated at 1:50,000 but may be higher because of undiagnosed individuals with a mild phenotype.

Differential Diagnosis

Table 3a.

Genes of Interest in the Differential Diagnoses of Nail-Patella Syndrome

Gene(s)DisorderMOIFeatures of Differential Diagnosis Disorder
Overlapping w/NPSDistingusihing from NPS
ARID1A
ARID1B
SMARCA4
SMARCB1
SMARCE1
SOX11
Coffin-Siris syndrome AD
  • Absence or hypoplasia of nails & patellae
  • Elbow dislocation
  • Nail hypoplasia, usually affecting the little finger nails
  • Facial dysmorphism
CDC6
CDC45
CDT1
GMNN
MCM5
ORC1
ORC4
ORC6
Meier-Gorlin syndrome (OMIM PS224690)AR
AD
  • Absent patellae
  • Dislocation of radial head
  • Microtia
  • Markedly short stature
  • Delayed bone age
  • Characteristic facies
KAT6B Genitopatellar syndrome (See KAT6B Disorders.)AD
  • Absent patellae
  • Renal anomalies
  • Flexion deformities of knees & hips
  • Clubfoot
  • Hypoplasia of the ischia & iliac bones
  • Genital anomalies
  • Facial dysmorphism
  • Microcephaly
  • Intellectual disability
  • Structural (multicystic kidneys or hydronephrosis) (vs functional) abnormalities
  • Renal manifestations
RECQL4 RAPADILINO syndrome 1 (OMIM 266280)AR
  • Radial defects
  • Absent or hypoplastic patellae
  • Dislocated joints
  • Cleft palate
  • Facial dysmorphism
  • Short stature
  • Radial defects incl absent or hypoplastic thumbs & radii
TBC1D24 DOORS syndrome (See TBC1D24-Related Disorders.)ARAbsent or poorly formed nails
  • Long thumbs & big toes, often w/triphalangy
  • Other fingers & toes short due to absent or hypoplastic distal phalanx
  • Bilateral ptosis
  • Short broad nose w/broad nasal tip & large nostrils
  • Structural renal tract abnormalities
  • Cataracts
  • Optic atrophy
  • Dandy-Walker malformation
  • Seizures
TBX4 Small patella syndrome (ischiopatellar dysplasia, coxopodo-patellar syndrome) (OMIM 147891)AD
  • Small or absent patellae
  • Recurrent patella dislocations
  • Pelvic anomalies
  • Defective ossification at schiopubic junction
  • Ischial hypoplasia
  • Infra-acetabular "axe-cut" notch
  • No nail or elbow changes, renal involvement, or ocular involvement

Table 3b.

Chromosome Disorder and Hereditary Disorders of Unknown Genetic Cause in the Differential Diagnoses of Nail-Patella Syndrome

DisorderFeatures of Differential Diagnosis Disorder
Overlapping w/NPSDistinguishing from NPS
Brachymorphism-
onychodysplasia-
dysphalangism
syndrome (OMIM
113477)
Small nails
  • Characteristic facial appearance
  • Short stature
  • Mild intellectual impairment
Patella aplasia
hypoplasia (OMIM
168860)
Isolated aplasia OR hypoplasia of the patellaNo nail or elbow changes, renal involvement, or ocular involvement
Trisomy 8
mosaicism 1
  • Absent or hypoplastic patellae
  • Limited elbow supination
  • Abnormal nails
  • Significant learning difficulties
  • Variable facial dysmorphism
  • Camptodactyly & progressive joint restriction, usually of fingers & toes

NPS = nail-patella syndrome

1.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with nail-patella syndrome (NPS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Nail-Patella Syndrome

System/ConcernEvaluationComment
Musculoskeletal History & physical exam to detect orthopedic issues or concerns
  • If present, referral to orthopedist
  • Before surgery or intensive physiotherapy for orthopedic complaints; investigation via MRI for possible bone/soft tissue anatomic abnormalities
Consideration of formal quantification of BMD via DEXA 1, 2, 3As indicator of fracture propensity
Renal
  • Measurement of blood pressure
  • Urinalysis & urine albumin:creatinine ratio 4 on a first-morning urine specimen
To screen for renal disease; if abnormal, referral to nephrologist
Ophthalmologic Measurement of intraocular pressure, exam of optic disc, & assessment of visual fields 5
  • To detect glaucoma, incl normal-pressure glaucoma
  • To be completed as soon as child can cooperate w/exam
  • Referral to ophthalmologist
Gastrointestinal Assessment for signs & symptoms of constipation or irritable bowel syndromeConsider referral to gastroenterologist.
Neurologic Assessment for ↓ pain & temperature sensation in hands & feet
Assessment for signs & symptoms of epilepsyConsider referral to neurologist.
Dental Examination of teeth for weakness, crumbling, or thin enamelReferral to dentist; consider urgent referral if abnormalities noted.
Vasomotor Assessment of peripheral circulation
Genetic
counseling
By genetics professionals 6To inform patients & families re nature, MOI, & implications of NPS in order to facilitate medical & personal decision making
Family support/
resources
Assess:

BMD = bone mineral density; DEXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance

1.

DEXA norms are readily available in most clinical settings for adults and may be pursued in all young adults (age >18 years) at least once.

2.

Pediatric DEXA norms are often less readily available, but may be obtained via local pediatric endocrinologist or machine manufacturer.

3.

No formal recommendations for DEXA scanning of pediatric patients exist at this time, but DEXA should be pursued if fractures or unexplained skeletal pain occurs with additional clinical evaluation.

4.

This test is a more sensitive measure of renal disease than urinalysis because it corrects for urine concentration.

5.

Any infant or young child found to have an abnormal or absent red reflex on eye examination by a primary care physician should be referred to an ophthalmologist immediately.

6.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with Nail-Patella Syndrome

Manifestation/
Concern
TreatmentConsiderations/Other
Joint symptoms 1 Analgesics, physiotherapy, splinting, &/or bracing
Anatomic joint
abnormalities 2
Standard treatment per orthopedist incl possible surgical correctionMRI of joints to identify abnormal anatomy prior to surgery so that appropriate surgical treatment can be planned in advance
↓ bone mineral
density 3
No established treatment specific to NPS; standard treatment per pediatric/adult endocrinologist
Hypertension Standard treatment per nephrologist
Mild-to-moderate
renal disease
Standard treatment per nephrologist
  • ACE inhibitors are useful in slowing progression of proteinuria, but their use should be monitored carefully in children.
  • Steroids may not be effective in treatment of proteinuria. 4
ESRD Renal replacement therapy w/consideration of renal transplantResults of renal transplant are usually favorable.
Constipation Standard treatment
Inflammatory bowel disease Standard treatment per gastroenterologist
Glaucoma Standard treatment per ophthalmologist
↓ pain & temperature sensation in hands
& feet
Provider & patient awareness of this deficit in daily life to avoid burns & other injuries.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 5
Dental anomalies Standard treatment per dentist
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Consider involvement in adaptive sports.

ASM = anti-seizure medication; ESRD = end-stage renal disease

1.

Including pain, instability, locking, clicking, dislocation, decreased range of motion (ROM) in the absence of anatomic abnormalities that limit ROM

2.

Due to anatomic differences that affect joint function (e.g., contractures, pterygia)

3.

Resulting in osteoporosis and/or frequent fractures

4.
5.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Surveillance

Table 6.

Recommended Surveillance for Individuals with Nail-Patella Syndrome

System/ConcernEvaluationFrequency
Hypertension Measurement of blood pressureAt least annually
Renal
  • Urinalysis 1
  • Urine albumin:creatinine ratio on a first-morning urine 1
Ophthalmologic Screening for signs & symptoms of glaucoma 2
Dental Exam by dentistAt least every 6 mos
Osteoporosis DEXA scan 3As needed 4

DEXA = dual-energy x-ray absorptiometry

1.

Referral to a nephrologist if any abnormalities are detected

2.

From the time that a child is compliant with the examination

3.

Age-adjust results for child.

4.

Frequency in adults is based on clinical symptoms, abnormalities detected on previous evaluations, and standard practice in peri- and postmenopausal females and older males.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance measures, particularly relating to ophthalmologic and renal manifestations. Evaluations can include:

  • Molecular genetic testing if the pathogenic variant in the family is known;
  • Monitoring renal findings (i.e., blood pressure, urinalysis, and urine albumin:creatinine ratio on a first-morning urine) and screening for glaucoma if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Renal problems may present during (or be exacerbated by) pregnancy. In one study 29% of pregnant women with NPS developed preeclampsia [Sweeney et al 2003]. Onset of nephrotic syndrome in pregnancy has also been described [Aboobacker et al 2018]. 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.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Nail-patella syndrome (NPS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Eighty-eight percent of individuals diagnosed with NPS have an affected parent [Sweeney et al 2003].
  • Twelve percent of individuals diagnosed with NPS have the disorder as the result of a de novo LMX1B pathogenic variant [Sweeney et al 2003].
  • If the proband appears to be the only affected family member (i.e., a simplex case) and has a known LMX1B pathogenic variant, molecular genetic testing is recommended for the parents of the proband. If the causative pathogenic variant is not known, physical examination of the parents is recommended; however, it is possible that mild manifestations of NPS may not be readily apparent.
  • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The family history of some individuals diagnosed with NPS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. NPS is fully penetrant in heterozygous individuals; however, the range and severity of manifestations may be extremely variable among affected family members.
  • If the proband has a known LMX1B pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or both parents are clinically unaffected, the recurrence risk to sibs appears to be low but greater than that of the general population because of the possibility of parental mosaicism [Marini et al 2010].

Offspring of a proband. Each child of an individual with NPS has a 50% chance of inheriting the causative pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the LMX1B pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Note: The clinical manifestations of NPS are variable and cannot be predicted based on family history or the presence of an LMX1B pathogenic variant identified on prenatal testing.

Ultrasound examination. Talipes equinovarus, other identifiable limb anomalies, or large iliac horns may be detected on fetal ultrasound examination in the third trimester of pregnancy.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Nail Patella Syndrome Worldwide
    Nail Patella Syndrome Worldwide is the official organization of the NPS Community.
    Email: info-npsw@npsw.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Nail-Patella Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
LMX1B 9q33​.3 LIM homeobox transcription factor 1-beta LMX1B database LMX1B LMX1B

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Nail-Patella Syndrome (View All in OMIM)

161200NAIL-PATELLA SYNDROME; NPS
602575LIM HOMEOBOX TRANSCRIPTION FACTOR 1, BETA; LMX1B

Molecular Pathogenesis

Nail-patella syndrome is caused by pathogenic loss-of-function variants in LMX1B, encoding a transcription factor which directs dorso-ventral patterning of limb development and the formation of the anterior eye and the podocytes of the kidneys. This explains the phenotypic features of knee and elbow manifestations (early embryologic state of lower extremities positioned dorsally), glaucoma, and renal disease associated with proteinuria. The role of the LMX1B protein product is less well understood in the cardiovascular and central nervous system, requiring further study.

The majority (~80%) of pathogenic variants in LMX1B are found in the LIM domains, with the rest in the homeodomain. There is variability in the phenotype between and within families, even with the same LMX1B pathogenic variant. For this reason, it is difficult to predict the disease severity based on the genotype. However, there appear to be more pathogenic variants in the homeodomain in individuals who have been described with renal disease (see Genotype-Phenotype Correlations).

Pathogenic missense variants within the homeodomain reduce or eliminate DNA binding [Dreyer et al 1998, McIntosh et al 1998, Dreyer et al 2000, Bongers et al 2002]. Pathogenic missense variants within the LIM domains are believed to affect the secondary structure of the zinc fingers [McIntosh et al 1998, Clough et al 1999].

Mechanism of disease causation. NPS is the result of heterozygous loss-of-function pathogenic variants within the gene encoding the transcription factor. Bongers et al [2005] suggested a potential mechanism of disease of dominant-negative effect on the normal gene product, but this has not been replicated in subsequent studies.

LMX1B-specific laboratory technical considerations. All amino acid substitutions that have been observed cause NPS [Dunston et al 2004]. Missense variants are concentrated within the homeodomain and the residues in the LIM domains essential for maintaining the zinc finger structures. A series of recurrent variants within the homeodomain account for approximately 30% of all LMX1B pathogenic variants [Clough et al 1999]. No pathogenic variants have been identified in the terminal third of the gene.

Chapter Notes

Author Notes

The Greenberg Center for Skeletal Dysplasias in the Department of Genetic Medicine at Johns Hopkins University provides the diagnostic workup and management for patients with all forms of genetic skeletal disorders, including nail-patella syndrome.

Website: www.hopkinsmedicine.org/institute-genetic-medicine/patient-care/genetics-clinics/about/greenberg-center-skeletal-dysplasia/

Acknowledgments

The authors would like to acknowledge the patients we have had the privilege to meet over the last decades through our clinical practice as well as patient support groups including Nail-Patella Syndrome Worldwide.

Revision History

  • 15 October 2020 (ma) Comprehensive update posted live
  • 13 November 2014 (me) Comprehensive update posted live
  • 28 July 2009 (me) Comprehensive update posted live
  • 26 July 2005 (me) Comprehensive update posted live
  • 31 May 2003 (me) Review posted live
  • 14 April 2003 (im) Original submission

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