Nail-Patella Syndrome 

Updated: Feb 19, 2019
Author: Anna Choczaj-Kukula, MD, PhD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Nail-patella syndrome (NPS), also known as hereditary osteo-onychodysplasia (HOOD), is an uncommon genetically determined disease that involves organs of both ectodermal and mesodermal origin. Chatelain described NPS in 1820, and Little first documented its hereditary nature in 1897.[1] See the image below.

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

Pathophysiology

Nail-patella syndrome (NPS) is inherited as an autosomal dominant trait with a high degree of penetrance but variable expression. Autosomal recessive mode of inheritance has also been reported[2] ; 88% of individuals with NPS have an affected parent.[3] The responsible gene was described by Dreyer et al in 1998.[4] The protein encoded by LMX1B is responsible for the normal dorsoventral patterning of the limb, morphogenesis of the glomerular basement membrane and anterior segment of the eye.[5, 6, 7] Heterozygous variants in LMX1B are responsible for NPS, and it has been postulated that the variable expressivity is due to the interaction of LMX1B with other developmental genes.[8]

Numerous studies have demonstrated that the NPS locus is linked to that of the ABO blood group[9] and the enzyme adenylate kinase.[10] The NPS locus has been linked to the locus of the alpha1 chain of type 5 collagen. LMX1B is involved in the regulation of collagen IV expression and in the transcriptional regulation of podocyte specification and differentiation[11] (LMX1B regulates genes, which encode proteins associated with the actin cytoskeleton important for podocyte function).[12] At present, no evidence for a correlation between the presence and severity of the clinical anomalies and the LMX1B genotype has been found.[13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 3, 26, 27, 28, 29, 30, 31, 32] A hypothesis of genetic heterogenicity was raised by Ghoumid et al, with 38 different LMX1B variants or deletions identified.[33] More recently, missense mutations in the homeodomain of LMX1B have been identified to cause a kidney-limited phenotype of NPS without extrarenal manifestations.[34, 35] Pathogenic mutations in the LMXB1 gene explain approximately 95% of NPS cases, with 5% of cases remaining unexplained. Mutation of WiF1, involved in mesoderm segmentation, was reported as a suspected cause of NPS in a family negative for the LMX1B mutation.[36]

The diagnostic tetrad includes fingernail dysplasia, absent or hypoplastic patellae, presence of posterior conical iliac horns, and deformation or luxation (ie. hypoplasia) of the radial heads. The clinical manifestations are extremely variable in both frequency and severity, with interfamilial and intrafamilial variability.[37] Kidney disease (focal segmental glomerulosclerosis) and glaucoma are now recognized as part of the syndrome.[38] The most serious complication associated with NPS is nephropathy.[39, 40]

A postulated cause of the progressive renal disease is secondary immune damage to the altered glomerular basement membrane. Curtis et al described a series of patients with NPS who had immune complex nephropathy and altered collagen, and they remarked that the patients with NPS were indistinguishable from patients with Goodpasture disease.[41]

Numerous other skeletal and eye anomalies are also described in patients with NPS.

Etiology

The mechanisms underlying the different manifestations and severity of the symptoms in nail-patella syndrome (NPS) remain uncertain.

NPS is known to be an autosomal dominant hereditary disease affecting development of the limbs, kidneys, and eyes. A genetic abnormality is believed to lead to altered connective-tissue metabolism with widespread structural defects in collagen.

Abnormal collagen type 3 deposition in the glomeruli probably causes the nephropathy associated with NPS.[42, 43]

Epidemiology

Frequency

The prevalence is estimated to be 1 case in 50,000 live births.

Race

No clear racial predominance is recognized.

Sex

Both sexes are equally affected.

Age

No preferential age at onset has been reported; individuals of any age can be affected.

Prognosis

Prognosis is determined by the associated abnormalities, mainly nephropathy.[44] The incidence of nephropathy in nail-patella syndrome (NPS) is reported to be approximately 40% among patients with various degrees of dysfunction. Of these patients, 10% die of renal insufficiency.

Patient Education

Genetic counseling is recommended.

 

Presentation

History

The first symptom that usually causes the patient to seek medical care is knee pain, instability, or an inability to completely extend the knee joint.[45] The patellae may be hypoplastic or absent, and they are frequently dislocated.[46, 47, 48]

Limitation of elbow motion or subluxation of the radius often occurs as a result of hypoplasia of the radial head. Other joints tend to be hyperflexible.

Back pain occurs in 50% of individuals with NPS. An increased frequency of fractures has been reported as bone mineral density is reduced by 8-20% in the hips of patients with NPS.[37, 49]

Renal involvement may result in proteinuria, hematuria, and recurrent urinary tract infections.[50, 51]

Cutaneous manifestations are nail changes that involve mainly the thumbs and progressively decrease in severity in the second to fifth fingers. Loss of dorsal creases of the skin overlying the distal interphalangeal joints may be helpful as a diagnostic clue.[52]

Patients often report palmoplantar hyperhidrosis.[53]

Individuals with NPS may report peripheral neurological symptoms (numbness, tingling, or burning sensations in the hands and feet or decreased sensation to pain),[3, 18] vasomotor manifestations (cold sensation despite high temperature),[54] or gastrointestinal problems such as constipation or irritable bowel syndrome.

Physical Examination

Nail dysplasia and patellar hypoplasia are essential findings for diagnosis of nail-patella syndrome (NPS). Other diagnostic features are hypoplasia of the radial head and iliac prominences, which are known as iliac horns.[55, 56] Renal complications and ophthalmologic problems can accompany NPS.[57, 58]  It is important to examine the nails in children with skeletal dysplasias so a diagnosis of NPS is not missed.[59]

Nails

Nail changes are present in 98% of individuals with NPS and may be present since birth.[37, 52] Patients have different degrees of nail dysplasia, with almost all patients having bilateral and symmetric nail changes.[60, 61] The nails, especially those on the thumbs, are typically absent, may be hypoplastic, discolored, and separated by a cleft. Nail dysplasia, a typical feature, is more severe on the ulnar side than on the radial side, with the thumb most severely affected and improvement toward the fifth digit.[62, 61] The toenails are rarely involved; if dysplasia is present, it most frequently affects the little toenail.[37, 61, 63, 63]

Other nail abnormalities in patients with NPS include splitting, longitudinal crease, longitudinal fracture, pseudopterygium, longitudinal or horizontal ridging, pitting, koilonychia, poor lunula formation, and discoloration.[64, 65, 66]

In the absence of other nail changes, V-shaped triangular lunulae with a distal peak in the midline are pathognomonic for NPS.[67, 68] The presence of triangular lunulae has been suggested to be a good marker of medial nail damage (longitudinal crease, longitudinal fracture, and pseudo-pterygium).[65]

Bones and joints

Complaints related to the knee are reported in up to 74% of cases,[69] with symptoms of instability, pain, or a combination of both.[70] Patellar involvement is present in approximately 90% of patients; however, patellar aplasia occurs in only 20%. Isolated unilateral absent patella and contralateral small patella have been reported.[71] In instances in which the patellae are smaller or luxated, the knees may be unstable. Synovial band preventing the engagement of the patella into the trochlear groove has been described.[72]

The elbows may have limited motion (eg. limited pronation, supination, extension). Subluxation of the radial head may occur. Pterygia (webbing) may be present across the elbow. Arthrodysplasia of the elbows is reported in approximately 90% of patients.[13, 73]

General hyperextension of the joints can be present.

Exostoses arising from the posterior aspect of the iliac bones are present in as many as 80% of patients; this finding is considered pathognomonic for the syndrome[3] and can be observed by ultrasound scanning from the third trimester of pregnancy.[74] Iliac horns may be also seen on radiographs at birth, and by bone scan.[56]

Other reported bone changes include scoliosis, scapular hypoplasia, genu valgum, club feet, and the presence of cervical ribs.[75]

Kidneys[76, 77]

From 22-60% patients present with renal anomalies, which may result in only asymptomatic proteinuria.[78] Hematuria; nephrotic syndrome,[79, 80] which may develop prior to orthopedic symptoms[81] ; and progression to renal failure requiring dialysis or transplantation have been observed in approximately 10% of patients.[33, 51] NPS patients are often affected by glomerulonephritis.[82]

Pedal edema[83] and recurrent urinary tract infections can also be manifestations of renal involvement.

Isolated nephropathy cases without nail, patellar, or skeletal abnormality, caused by some mutations in the homeodomain of LMX1B, have been reported.[84, 85, 86, 87]

Eyes

Ocular manifestations may include variable degrees of intraocular hypertension, glaucoma, or normal tension glaucoma.[88, 89]

Hyperpigmentation of the pupillary margin of the iris, the Lester iris, occurs in 45% of patients with NPS. This can be a helpful diagnostic sign.

Other abnormalities, such as heterochromia of the iris with cloverleaf deformity, cataracts, microcornea, and glaucoma, have also been reported.[90]

Other

Skin laxity may be present. Webbing of the elbows and absent skin creases in the distal parts of the fingers are described in some patients.[91] A case of coexisting ectopic cilia and NPS in one patient has been described.[92]

Dysmorphic facial features have been described in children with NPS. A high forehead hairline, especially on the temples, may be seen in women.

One third of NPS patients have gastrointestinal involvement—constipation or irritable bowel syndrome.[3, 93]

Some studies suggest that NPS phenotype may be more extensive than previously recognized, including neurologic and neurobehavioral aspects. Patients with NPS are at increased risk of attention deficit-hyperactivity disorder (ADHD) and depressive disorder, which have been attributed to the LMX1B protein dysfunctions in the development of mesoencephalic dopaminergic signalling and the serotoninergic signalling system.[94]

Schizophrenia was reported in patients with NPS. Based on LMX1B expression in brain regions that are implicated in neuropsychiatric illness, and especially in the development of dopaminergic neurons, it has been hypothesized that schizophrenia may be part of the clinical spectrum of NPS.[95, 96]

Possible neurologic symptoms include diminished pain and temperature response, numbness, tingling, and burning sensation in hands and feet.[18]

A case of a child with NPS and a short stature and hypothyroidism has been reported.[97]

Complications

Renal involvement is the major determinant of the prognosis for nail-patella syndrome (NPS). Complications may arise because of associated abnormalities, especially in patients with renal involvement.[98] The most serious complication associated with NPS is nephropathy, which occurs in approximately 40% of patients; 10% of the patients die of renal insufficiency.

Renal problems may occur or become exacerbated in pregnancy. In one study, 29% of pregnant women with NPS developed preeclampsia.[3]

 

DDx

Differential Diagnoses

 

Workup

Approach Considerations

A careful family history including pedigree should be obtained in all patients.[45, 99]

Laboratory Studies

Urinalysis

Assess the urine albumin-to-creatinine ratio on a first morning urine sample. If any abnormalities are detected, refer to a nephrologist. These tests should be performed annually in all NPS patients.[37]

Imaging Studies

Consider performing diagnostic imaging (radiography, CT scanning, MRI) to search for diagnostic and minor signs.[100] The distinct malformations of the knee in nail-patella syndrome (NPS) are recognizable on conventional radiographs.[101]

Dual-energy x-ray absorptiometry (DEXA) scanning should be considered in perimenopausal and postmenopausal females and older males with NPS.[37]

Diagnostic radiographic findings include the following[102, 103, 104] :

  • Hypoplastic patellae

  • Bilateral posterior iliac horns

  • Hypoplasia of the radial head or capitulum

The following findings are also reported:

  • Scapular hypoplasia

  • Scoliosis

  • Hypoplastic lateral humerus epicondyle

Other Tests

Urine test with an annual microalbuminuria/creatinuria ratio is recommended.

Annual ophthalmological assessment is advised. Blood pressure monitoring and glaucoma screening should be performed.[37]

Molecular genetic testing to identify a pathogenic variant in the LMX1B gene may be useful to confirm the diagnosis in cases of mild or atypical phenotype in the proband or at-risk family members.[105, 106] Comprehensive genetic analysis may be useful for diagnosis of LMX1B-associated nephropathy.[107]

Prenatal diagnosis by molecular analysis can be offered when the mutation is known in the family, and evaluation of at-risk fetuses by three-dimensional ultrasound scan can be helpful in identifying the extent of associated abnormalities.[108]

Procedures

In patients with proteinuria, percutaneous renal biopsy may be useful in evaluating renal involvement.

The features of nail-patella syndrome (NPS) nephropathy at light, immunofluorescence, and electron microscopy have been detailed,[17, 109] with an emphasis on the presence of characteristic ultrastructural collagen fibrils in the glomerular basement membrane.

Midline synovial septum completely subdividing the knee into medial and lateral compartments has been found during arthroscopy in patients with NPS.[110]

Histologic Findings

The literature includes descriptions of numerous histologic abnormalities in the kidneys of patients with nail-patella syndrome (NPS). These findings include chronic glomerulonephritis, focal glomerular necrosis, diffuse hydropic degeneration of the tubular epithelium, and localized basement membrane thickening with mild proliferation of the endothelial and epithelial cells.

 

Treatment

Approach Considerations

A careful family history should be obtained in all patients.

Medical Care

No treatment is available for the cutaneous findings of nail-patella syndrome (NPS), also known as hereditary osteo-onychodysplasia (HOOD).

Associated abnormalities require appropriate care from specialists.

ACE inhibitors are used to treat renal disease. Proesmans et al reported that enalapril at 1 mg/kg/d plus losartan at 1 mg/kg/d achieved complete remission of proteinuria in a young girl with NPS.[111] End-stage kidney disease patients can undergo transplantation, and the renal involvement does not recur in the transplanted kidney.[43]

Frequent urinalysis and blood pressure measurements are recommended in pregnant women with NPS.

Surgical Care

More than 90% of individuals with nail-patella syndrome (NPS) have patellar involvement resulting in a wide range of patellofemoral complaints.

Congenital permanent dislocation of the patella (CPDP) should be treated with surgical procedures.[112, 113] Preferably, orthopaedic correction should be performed when the patient is aged approximately 2-3 years to prevent secondary deformities and growth-related disability.

The aim of orthopedic surgery should be correction of the underlying pathology with resection of the synovial band and an additional realignment of the patella by recentering of the quadriceps muscle. Good clinical results have been reported.[72]

There have been reports of total knee arthroplasty in patients with NPS.[114, 115]

In mature patients, milder forms of the disease can be treated with nonoperative measures, but many affected adults require knee surgery, including patellofemoral ligament reconstruction, tibial tuberosity transposition, patellofemoral arthroplasty, and total knee arthroplasty.[45, 47]

Consultations

Consult an orthopedist, nephrologist, and ophthalmologist, as determined by the patient's history and physical examination findings. Also consult a genetic counselor.

Prevention

Genetic counseling is recommended because nail-patella syndrome (NPS) is an autosomal dominant disease.

Long-Term Monitoring

Periodic and prolonged follow up is recommended in all nail-patella syndrome (NPS) patients, with annual monitoring for hypertension and renal disease and screening for ocular hypertension and glaucoma.[59] Despite long periods of stable renal function, long-term follow-up care is essential in patients with NPS.