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Nail-patella syndrome

Nail-patella syndrome
Literature review current through: Jan 2024.
This topic last updated: Apr 10, 2023.

INTRODUCTION — The nail-patella syndrome (NPS, MIM #161200) or hereditary osteo-onychodysplasia (HOOD syndrome) is a rare autosomal dominant disorder. It is characterized by limb and pelvic skeletal abnormalities (eg, hypoplastic or absent patella, dysplasia of elbows, including pterygia, and iliac horns), nail and distal digital abnormalities, and kidney disease.

The clinical manifestations, diagnosis, and management of children with NPS will be reviewed here.

INCIDENCE — The estimated incidence of NPS is 1 per 50,000 [1,2]. The disease has been reported in patients all around the world.

PATHOGENESIS AND LMX1B GENE MUTATIONS — NPS is an autosomal dominant disorder with full gene penetrance but variability of expression even within families [3,4].

Approximately 85 percent of families with NPS present with mutations of the LMX1B gene located at the distal end of the long arm of chromosome 9 [5-7]. LMX1B is a transcription factor of the LIM-homeodomain type that plays an important role for limb and kidney development in vertebrates; however, it is expressed lifelong within the podocyte and it is essential for the maintenance the structured actin cytoskeleton in podocytes [8]. More than 180 heterozygous mutations in LMX1B have been reported, including missense, splicing, deletions, and nonsense mutations [9]. Most mutations result in protein truncation [3,7,10-12]. The identification of entire LMX1B deletions confirms that haploinsufficiency is the principal pathogenetic mechanism of NPS [13]. Studies in homozygous knock-out mice and in vitro assays demonstrated that LMX1B protein expressed in glomerular podocytes helps control the transcription of multiple genes integral for proper glomerular basement membrane (GBM) formation, and/or glomerular podocyte differentiation and function during the early stages of kidney development [5,14-17]. Putative target genes include COL4A3 and COLA4, genes for alpha-4 chains of collagen type IV [14,15], and NPHS2 and CD2AP genes, which encode podocyte proteins [15,16]. (See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)".)

In addition, there are case reports of LMX1B mutation (R246 or R249 missense mutations) associated with familial focal segmental glomerulosclerosis (FSGS), but without any other clinical features of NPS [18-20]. A heterozygous A278V mutation was also reported in a child with steroid-resistant nephrotic syndrome and a lack of ossification of the proximal radial epiphysis but without nail or other bone anomalies associated with NPS [21]. (See "Focal segmental glomerulosclerosis: Genetic causes".)

A study of 55 families with NPS reported that LMX1B mutations were not found in 9 percent of the families, suggesting that mutation in other genes may be involved [22]. A loss-of-function mutation in WIF1, which is involved in mesoderm segmentation, was identified in a family with a dominantly inherited nail-patella-like disorder who tested negative for LMX1B mutation [23].

CLINICAL MANIFESTATIONS

Overview — NPS is classically characterized by limb and pelvic skeletal abnormalities (eg, hypoplastic or absent patella, dysplasia of elbows and iliac horns), nail and distal digital abnormalities, and kidney disease. However, information from two large cases series demonstrated additional clinical manifestations including sensorineural hearing loss and ophthalmological disease [3,4]. Data were obtained from comprehensive evaluation of 126 patients from 44 families recruited from genetic departments in Great Britain [4], and 106 patients from 22 unrelated families and 10 sporadic subjects [3].

The following clinical manifestations of NPS and relative frequency for the major findings are based on the results from these two large cohorts [3,4]:

Nail and distal digital abnormalities (100 percent)

Limb and pelvic abnormalities (almost 100 percent)

Kidney disease (30 to 40 percent)

Other findings:

Sensorineural hearing loss

Ophthalmologic disease (eg, glaucoma)

Gastrointestinal involvement

Vasomotor problems

Other neurologic and orthopedic manifestations

Nail and digital abnormalities — Almost all patients with NPS have nail and/or distal digital abnormalities [3,4]. These findings are typically bilateral and symmetrical, and may be observed at birth [3,4]. Toenails are usually less frequently involved than fingernails and have less severe abnormalities. If the toenails are involved, it is often the little toenail that is most affected. Thumbnails are the most severely affected of the fingernails and the severity tends to decrease towards the little finger (picture 1). For each individual fingernail, the ulnar side is more severely affected.

The following nail and distal digital changes are observed in NPS [4]:

Nail hypoplasia.

Nail dystrophic changes, including discoloration, abnormal ridging and splitting, and triangular lunulae, a pathognomic finding (picture 2). The lunula is the visible root of the nail that normally is a crescent-shaped, whitish area at the nail bed, rather than the triangular shape (apex away from the base) observed in close to 80 to 90 percent of patients with NPS.

Distal digital changes are observed in almost all patients. The most common finding is the loss of the creases in the skin overlying the distal interphalangeal joint (picture 3). Other findings include flexion and hyperextension abnormalities of the proximal and distal interphalangeal joints, and swan-neck abnormalities of the fingers (picture 1 and figure 1).

Limb and pelvic abnormalities — Limb and pelvic abnormalities are observed in almost all patients. They include [3,4]:

Patellar abnormalities – Almost all patients have either patellar aplasia (image 1) or hypoplasia, which may be asymmetrical [24]. In patients with patellar hypoplasia, recurrent subluxation or dislocation of the patella causes lateral slippage during knee flexion [4,25,26]. In one large case series of 124 patients, three-quarters of the cohort reported knee symptoms including pain, knee instability, locking of the knee, inability to straighten the knee joint, and patellar dislocation.

Elbow abnormalities – Almost all patients with NPS have elbow abnormalities, including posterior subluxation of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle. Elbow abnormalities may be asymmetrical. Symptoms and findings due to these deformities include pain, limited elbow extension, limited pronation and supination, cubitus valgus (increased carrying angle of the arm), and pterygia (webbing of the elbow).

Leg and arm abnormalities – Almost all patients exhibit underdevelopment of arm and leg proximal musculature and hyperextensibility of large joints (eg, hip).

Iliac horns are bilateral symmetrical bone formations arising from the antero-superior iliac crest that project posteriorly and laterally (image 2). Iliac horns are pathognomonic asymptomatic radiologic features of NPS, and are present in 70 to 80 percent of patients. Large horns may be detected by palpation on clinical examination. Iliac horns may also be detected by prenatal ultrasound [27].

Ankle and feet abnormalities – Ankle and feet deformities include talipes equinovarus (clubfoot), calcaneovalgus (hyperdorsiflexion of the foot with abduction of the forefoot), pes planus (flat foot), and tight Achilles tendon.

Adults with NPS have a bone-mineral density that is 8 to 20 percent lower than controls, which is associated with an increase in the prevalence of fractures and scoliosis [28].

Orthopedic surgeons most experienced with NPS generally discourage any attempts at orthopedic "repair" of limb and pelvic abnormalities due to the profound defect in the baseline structures. When an orthopedic intervention is planned, it is important to determine if there are any abnormal bone or soft tissue abnormalities that could be affected by the procedure. For example, in patients with elbow pterygia, the neurovascular bundle may be superficial and within the confines of the webbing [4]. In addition, patients with NPS often have abnormal joint anatomy, which is important to determine prior to surgical intervention so that the appropriate intervention can be used [29].

Kidney manifestations — Kidney disease (30 to 40 percent) varies among affected families and within single families [3,4]. Because the underlying pathology is a defect in the glomerular basement membrane (GBM), patients with kidney involvement initially present with microalbuminuria and proteinuria. Proteinuria may present at any age or be intermittent, and is more prevalent during pregnancy. Microscopic hematuria is also common.

Although there are no longitudinal data that provide information on the long-term kidney prognosis, there is limited evidence that patients with NPS have an accelerated loss of kidney function that is twice the normal rate of deterioration in unaffected individuals [30]. Some patients with proteinuria will develop nephrotic syndrome and infrequently (1 to 5 percent of all patients) progress to kidney failure (KF) [3,4]. Impairment of kidney function, and in a small minority of patients, KF, is thought to be due to progressive thickening and disorganization of the GBM. Patients with chronic and/or end-stage kidney disease are reported to have LMXIB mutations mainly located to a short region of the LMX1B homeodomain and to the N-terminal region of the LIM domain [31]. In addition, specific LMX1B mutations (p.R246P, p.R246Q, p.R249Q missense mutation) have been associated with familial focal segmental glomerulosclerosis (FSGS), but without any other clinical features of NPS [18,20]. (See 'Pathogenesis and LMX1B gene mutations' above.)

Histopathologic findings from kidney biopsy — NPS is distinguished from other diseases associated with proteinuria by the electron microscopic pathognomic finding of irregular and lucent rarefactions containing clusters of cross-banded collagen fibrils within the lamina densa of the GBM (image 3) [32-35]. These abnormalities may also be found in the mesangial matrix, but the tubular basement membranes are not affected. The clusters of fibrils are clearly demonstrated by staining with uranyl acetate and phosphotungstic acid. They may be observed within segments of thickened GBM or along the entire GBM. Although the collagen fibrils are a constant feature of NPS, they are also found in patients without clinical evidence of kidney involvement [36]. Other lesions such as podocyte myelin figures and zebra bodies observed in patients with p.R246Q LMX1B mutation are most commonly associated with Fabry disease (see "Fabry disease: Kidney manifestations", section on 'Pathology'), and may lead to misdiagnosis [37]. Furthermore, there is no correlation between the severity of the ultrastructural lesions at diagnosis and the clinical kidney manifestations [31].

In contrast, light microscopy and immunofluorescence microscopy are normal or demonstrate nonspecific changes. In patients with heavy proteinuria and/or impaired kidney function, light microscopy may show GBM thickening and nonspecific lesions of FSGS (image 4), and immunofluorescence microscopy may show nonspecific segmental deposits of immunoglobulin M (IgM) and complement component 3 (C3) in the sclerotic areas.

Other findings

Sensorineural hearing loss — In one case series of 106 patients, sensorineural hearing loss was observed in 11 of 24 patients from four of six families who underwent audiometric testing [3]. As a result, the overall prevalence of hearing loss is unclear. In this study, bilateral involvement was observed in one-third of the cases with hearing impairment. The mean age of detection was 46.7 years (range 17.5 to 69.2 years). Unaffected family members had normal hearing.

Ophthalmological disease — Both open-angle glaucoma and ocular hypertension have been observed in patients with NPS [3,4,38]. However, there is considerable variability in the reported prevalence of these two disorders from 16 to 35 percent [3,4]. Approximately half of affected patients have hyperpigmentation of the central part of the iris, called Lester's sign [39].

Gastrointestinal involvement — In one case series, one-third of patients reported gastrointestinal symptoms that included symptoms of irritable bowel syndrome (characterized by alternating constipation and diarrhea accompanied with cramping abdominal pain) and constipation requiring intervention [4].

Vasomotor symptoms — In one case series, 12 of 22 patients who were queried reported symptoms related to poor peripheral circulation (cold hands and feet even in warm weather) [4].

Other orthopedic findings — In one study, back pain was reported in half of the cohort, which may be associated with the increased incidence of lumbar lordosis seen in patients with NPS [4]. There was also an increased risk of mild scoliosis, other spinal abnormalities, and pectus excavatum.

Other neurologic findings — Reduced sensitivity to pain and temperature in the hands and feet of patients with NPS has been reported [4]. Complaints of intermittent tingling, numbness, and burning without any precipitant have also been elicited. In addition, both attention deficient hyperactivity disorder (ADHD) and mood disorders have been reported to be associated with NPS [40].

DIAGNOSIS — The clinical diagnosis of NPS is based on the presence of classical physical and radiologic findings [29,30]. (See 'Clinical manifestations' above.)

Absent or dystrophic nails including triangular lunulae (a pathognomonic finding) (picture 2 and picture 1)

Absent or hypoplastic patella, which may require radiographic confirmation

Elbow abnormalities (limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia)

Iliac horns, a pathognomonic finding, demonstrated on pelvic radiograph are found in 70 percent of patients (image 2)

Because of the variability in phenotypic expression, genetic testing should be considered in patients in whom a diagnosis of NPS is suspected.

Molecular genetic testing — In cases where the diagnosis remains uncertain, molecular genetic testing to detect a mutation of the LMX1B gene can be used to confirm the diagnosis. Gene testing for LMX1B mutations is commercially available. The National Center for Biotechnology Information (NCBI) Genetic Testing Registry lists commercial and academic laboratories throughout the world that offer molecular genetic testing for NPS.

Kidney biopsy — Renal biopsy is not necessary if the diagnosis is confirmed by genetic testing. There is no clear relationship between the clinical course and renal histopathology [30], and findings on kidney biopsy do not alter the clinical management.

DIFFERENTIAL DIAGNOSIS — Kidney biopsy is not necessary if the diagnosis is confirmed by genetic testing. There is no clear relationship between the clinical course and kidney histopathology [4,29]. However, NPS is distinguished from these other disorders by the characteristic combination of both patellar and nail abnormalities. In addition, the pathognomic findings of iliac horns and/or triangular lunulae differentiate NPS from any other condition.

Disorders with patellar abnormalities include small patella syndrome (ischiopatellar dysplasia, coxo-podo-patellar syndrome, Scott-Taor syndrome), patella aplasia-hypoplasia, familial recurrent dislocation of the patella, Meier-Gorlin syndrome (absent patella, microtia, short stature, and characteristic facial appearance), genitopatellar syndrome (patellar, genital, and renal abnormalities; microcephaly; and intellectual disability), and RADADILINO syndrome (radial defects, absent or hypoplastic patellae, dislocated joints, short stature, cleft palate, and facial dysmorphism).

Disorders with nail abnormalities include DOOR syndrome (nail, digital, renal, and ophthalmological abnormalities; bilateral ptosis; and Dandy-Walker malformation), Trisomy 8 mosaicism, and Senior syndrome (small nails, short stature, characteristic facial appearance, and mild intellectual impairment).

Coffin-Siris syndrome has both nail and patellar abnormalities, but is also associated with intellectual disability and coarse facial features.

EVALUATION FOLLOWING INITIAL DIAGNOSIS — Once the diagnosis of nail-patella syndrome (NPS) is made, the following evaluation is recommended to determine the extent of the disease [29]:

History and physical examination to detect any orthopedic problems, and identify any gastrointestinal, neurologic, or vasomotor abnormalities.

Assessment to detect kidney involvement includes blood pressure measurement, urinalysis, and measurement of a urine protein to creatinine ratio of a sample of urine from the first morning void. (See 'Kidney manifestations' above.)

Ophthalmological examination to detect glaucoma or ocular hypertension.

MANAGEMENT — There is no specific therapy for NPS. Management is directed towards identifying and treating complications, and involves a multidisciplinary team [3,4,29]. In our practice, we use the following approach:

Monitoring for the following long-term complications:

Kidney disease − Annual measurement of blood pressure (BP) and urine protein to creatinine ratio on a sample from a first morning void. However, it may be challenging to obtain adequate BP measurement in patients with limb abnormalities.

Eye disease – Ophthalmologic screening every two years that includes measurement of intraocular pressure, examination of the optic disc, and assessment of visual fields.

Orthopedic management includes analgesics, physiotherapy, splinting, bracing, or surgery. If at all possible, orthopedic intervention should only be performed by surgeons who have expertise in treating patients with NPS. Prior to surgery or intensive physiotherapy, identifying any bony or soft tissue abnormality by magnetic resonance imaging that would impact the choice of intervention is recommended.

Management of glaucoma, hearing loss, and gastrointestinal complaints for patients with NPS is the same as for individuals of the general population with these disorders.

Kidney disease – For patients with nephropathy, our management approach includes the following:

For patients with documented proteinuria/albuminuria, we provide either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). This suggestion is based on data that angiotensin antagonism reduces protein excretion and slows kidney disease progression in other nondiabetic, proteinuric, glomerular diseases [30]. (See "Steroid-resistant nephrotic syndrome in children: Management".)

Medications that may be detrimental (eg, nonsteroidal antiinflammatory drugs) are avoided.

For patients with kidney failure (KF), kidney transplantation is the preferred renal replacement therapy. NPS does not reoccur after transplantation and patients do not develop antibodies to glomerular basement membrane (GBM) proteins, as is seen in patient with hereditary nephritis (Alport syndrome). (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)".)

Genetic counseling should be provided to all affected families. Families should be informed that NPS is an autosomal dominant disorder with variability of expression even within families.

SUMMARY AND RECOMMENDATIONS

Definition and pathogenesis – The nail-patella syndrome (NPS), or osteo-onychodysplasia, is an autosomal dominant disorder characterized by hypoplastic or absent patella, dystrophic fingernails and toenails, and dysplasia of elbows and iliac horns. NPS is due to mutations of the LMX1B gene, a transcription factor of the LIM-homeodomain type that plays an important role for limb and kidney development. (See 'Pathogenesis and LMX1B gene mutations' above.)

Manifestations – The major clinical manifestations and their relative frequency of NPS include:

Nail and distal digital abnormalities (100 percent) include nail hypoplasia (picture 1) and dystropic changes (discoloration, abnormal ridging and splitting, and triangular lunulae [pathognomic finding] (picture 2)), and distal digital changes include loss of the creases in the skin overlying the distal interphalangeal joint (picture 3), and flexion and extension abnormalities. (See 'Nail and digital abnormalities' above.)

Limb and pelvic abnormalities (100 percent) include patellar aplasia or hypoplasia (image 1), elbow abnormalities, and the pathognomic finding of iliac horns (80 percent) (image 2). (See 'Limb and pelvic abnormalities' above.)

Kidney disease (30 to 40 percent) initially presents with microalbuminuria and proteinuria. Some patients will progress to nephrosis and infrequently (1 to 5 percent of all patients) to kidney failure (KF). (See 'Kidney manifestations' above.)

Other manifestations include sensorineural hearing loss, ophthalmological disease (ie, glaucoma, and intraocular hypertension), gastrointestinal complaints, back pain, and vasomotor and distal neurological symptoms. (See 'Other findings' above.)

Diagnosis – The clinical diagnosis of NPS is based on the presence of classical physical and radiologic findings. These include nail abnormalities (eg, triangular lunulae), patellar hypoplasia or aplasia, elbow abnormalities, and the radiologic finding of iliac horns. In cases where the diagnosis remains uncertain, molecular genetic testing to detect a mutation of the LMX1B gene is usually used to confirm the diagnosis. Kidney biopsy is not warranted, as it is not typically needed to make the diagnosis. (See 'Diagnosis' above.)

Assessing extent of disease – Once the diagnosis of NPS is made, evaluation is recommended to determine the extent of the disease. This entails a comprehensive history and physical examination to detect orthopedic, gastrointestinal, neurologic, or vasomotor abnormalities; and screening for kidney and ophthalmologic disease. (See 'Evaluation following initial diagnosis' above.)

Management – There is no specific therapy for NPS. Management is directed towards identifying and treating complications. We suggest the following management approach for patients with NPS (Grade 2C):

Monitoring for the development of kidney disease (annual measurement of blood pressure and urine protein to creatinine ratio from a first morning void), and ophthalmologic screening every two years.

Orthopedic management consists of analgesics, physiotherapy, splinting, bracing, or surgery based on the specific condition.

Management of glaucoma, hearing loss, and gastrointestinal complaints for patients with NPS is the same as for individuals of the general population with these disorders.

For patients with nephropathy, we provide either angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) therapy to decrease protein excretion rate and to slow the progression of kidney disease.

For patients with KF, we recommend kidney transplantation as the preferred renal replacement therapy (Grade 1B). NPS does not recur after transplantation and there have been no reports of antibodies to glomerular basement membrane (GBM) proteins following transplantation.

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