Nail-Patella Syndrome (Hereditary osteo-onychodysplasia (HOOD), Fong disease, Turner-Kieser syndrome, Osterreicher-Turner Syndrome)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Nail patella syndrome is transmitted in an autosomal dominant fashion, so a careful family history may identify other affected individuals. Nail patella syndrome classically will involve the nails, knees, elbows, and patients will demonstrate the presence of iliac horns. The kidneys and eyes can also be affected. There is variability between family members as to the severity of the disease. Iliac horns are considered to be a pathognomonic finding, and are identified on x-ray studies. Overall, patients with the Nail Patella syndrome are thin, and have difficulty putting on weight despite an adequate food intake. Some female patients have demonstrated poor breast development.

Characteristic findings on physical examination

Abnormal nails are the most constant feature of nail patella syndrome. The nail changes are most often bilateral and are symmetrical. Although the most characteristic finding seen in the nails is that of a triangular lunula (Figure 1), many other nail dystrophies have been described. These include nails which are absent, hypoplastic, have horizontal or longitudinal ridges, pitted, thickened or thinned nails, and nail described as separated into two halves by a longitudinal cleft.

Figure 1.

Multiple fingernails demonstrate triangular lunulae, characteristic of nail patella syndrome. Photo courtesy of Dr. William James

Each nail is more severely affected on the ulnar side. The thumbnails are the most severely affected. The severity of nail changes tends to decrease towards the 5th finger. In a study of 123 patients with nail patella syndrome by Sweeney et al, 98% had nail changes. Triangular lunulae were seen in 88% of patients.

Onychodystrophy of the toenails is less intense and less frequent than the changes seen in the fingernails. In the study by Sweeney et al, 67% of nail patella patients demonstrated toenail changes. The most common toenail finding was a small and dystrophic 5th toenail. Other affected toenails have been described as thickened, discolored, thin, dystrophic, and hypoplastic.

An interesting finding in this study was that 96% of nail patella patients had loss of the creases in the skin overlying the distal interphalangeal joints of the fingers. This sign showed the same gradient of involvement as was seen in the nails. There was often an associated reduction in flexion of the affected joints. “Swan-neck” deformities can be seen in the fingers.

The patella of patients with Nail Patella syndrome can be absent, small, irregularly shaped, or asymetrically developed. A common finding is recurrent subluxation or dislocation of the patella. Patients can describe knee instability. X-ray studies can be helpful in defining patella abnormalities (Figure 2).

Figure 2.

An x-ray demonstrates absence of the patella, as can be seen in the nail patella Syndrome. (Courtesy of William James, MD)

Onychodystrophy is more prominent and more frequent on the fingernails as compared to the toenails. When the toenails are affected, the 5th digit is most often affected and demonstrates a small and dystrophic nail. Other toenail findings reported in the nail patella syndrome include thickened, discolored, hypoplastic, and otherwise dystrophic nails. Nail changes can be observed at birth.

The elbows in Nail Patella syndrome can demonstrate a limited range of movement, and elbow contractures may be present. Typical radiologic findings include dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle.

A characteristic occular finding is the presence of the Lester’s sign of the iris, which consists of an area of darker pigmentation around the central part of the iris, which presents in a cloverleaf or flower shape. It is most prominent in patients with blue eyes. In the study by Sweeney et al, Lester’s sign was observed in 54% of nail patella patients. Lester’s sign was usually present bilaterally. Lester’s sign can be seen in the general population at a substantially lower frequency, and is not considered a pathognomonic feature of nail patella syndrome.

The forehead can be high, and resemble a male pattern hairline, when seen in women.

Expected results of diagnostic studies

Genetic testing should demonstrate a mutation in the LMX1B gene.

Renal changes can be detected by electron microscopy, and include irregular thickening of the glomerular basement membrane, with a “moth eaten” appearance, as well as collagen-like fibers in the basement membrane and mesangial matrix. Dental issues include weak, crumbling teeth and thin dental enamel. Dental problems were reported in 23% of nail patella patients in the study by Sweeney et al.

Diagnosis confirmation

The differential diagnosis for nail patella syndrome would include other genetic syndromes that most prominently affect the knees and nails. For a patient presenting to a dermatologist, the differential diagnosis should focus on those syndromes that include nail findings. Other syndromes to consider with nail changes include DOOR syndrome (Deafness, Onychodystrophy, Osteodystrophy, and Mental Retardation), Trisomy 8 mosaicism (absent or hypoplastic patellae, limited elbow supination, abnormal nails, learning difficulties, facial dysmorphism, progressive joint restriction), Coffin-Siris syndrome (diminished or absent fifth fingernails and toenails, shortened fifth fingers and toes, hypotonia, joint laxity, mental retardation, craniofacial abnormalities with coarse facial features, can also have small patellae) and Senior syndrome/Brachymorphism Onychodysplasia Dysphalangism syndrome (BOD) (hypoplastic fifth digits with abnormal phalanges and tiny nails, facial dysmorphism, short stature, mild intellectual impairment).

While these syndromes have abormal nails, nail patella syndrome may be separated by the presence of the characteristic triangular lunulae. Additionally, these other syndromes demonstrate other distinct features including distinctive facial dysmorphisms.

Who is at Risk for Developing this Disease?

Since nail patella Syndrome is transmitted in an autosomal dominant fashion, those with affected family members are at risk. The incidence of nail patella syndrome has been reported to be approximately 1 in 50,000. Some cases may go unrecognized because of a mild phenotype. Patients with spontaneous mutations have also been reported, so lack of a family history of the disorder should not exclude nail patella syndrome from consideration.

What is the Cause of the Disease?

The LMX1B gene is mutated in nail patella syndrome. This gene encodes the transcription factor LMX1B, which is involved in the normal development of the limb as well as the early formation of the glomerular basement membrane. It serves a fundamental role in pattern formation during verebrate limb development and developement of the kidney.

Systemic Implications and Complications

The most serious issue that can be lethal in nail patella syndrome is renal failure. The pathophysiology for this issue involves a defect in the glomerular basement membrane. The first sign of renal involvement is most commonly proteinuria, which can also occur with hematuria. The proteinuria can be present at birth, or later, and can also be intermittent. Pregnancy can cause the onset or worsening of renal dysfunction, and can be associated with pre-eclampsia.

In the study of 123 patients with the syndrome, the mean age that renal involvement was detected was 21.7 years, and renal failure occurred in 3% of patients. The course of renal dysfunction is variable, but it can progress to nephrotic syndrome, nephritis, and renal failure.

Glaucoma is a serious issue, and the most frequent type identified is open angle glaucoma. Ocular hypertension can also be seen.

Treatment Options

Interventions will depend on the severity of the different organ systems affected. Renal dysfunction has been treated by transplantation with success.

Optimal Therapeutic Approach for this Disease

From a dermatologic standpoint, the most important interventions would be to secure a diagnosis if not already made, and also to ensure that the patient is followed by appropriate specialists for the more serious systemic aspects of the disorder, including nephrology, opthomology, and orthopedics.

Patient Management

Patient managment should focus on monitoring and prevention of serious complications.

Refer to a nephrologist for annual screening for renal disease from birth. This should include blood pressure and urine analysis. Checking of a urine albumin:creatinine ratio on a first morning urine is preferable to urine analysis dipsticks since it is more sensitive, and corrects for concentration of the urine. Abnormalities should be referred to a nephrologist for follow-up. ACE inhibitors can be helpful in slowing the progression of proteinuria. Chronic use of nonsteroidal antiinflammatory drugs should be avoided because of their effect on kidney function.

Refer to opthalmology for routine screening for glaucoma, including measurement of intraocular pressure, examination of the optic disc, and assessment of visual fields. Normal pressure glaucoma may be present. This screening should be initiated as soon as a child is able to cooperate with the examination.

Screen blood pressure annually.

Before orthopedic abnormalities are treated, evaluation of the bone and soft tissue should be undertaken by magnetic resonance imaging (MRI).

Dental examination should be conducted at least every 6 months.

Genetic counseling should be offered.

Unusual Clinical Scenarios to Consider in Patient Management

There is variability in the severity of the findings within and between famlies, so patients may present with limited nail findings and a lack of history of systemic involvement. In cases with mild involvement, other family members may not know they are affected.

What is the Evidence?

Sweeny, E, Fryer, A, Mountford, R, Green, A, McIntosh, I. “Nail patella syndrome: a review of the phenotype aided by developmental biology”. J Med Genet. vol. 40(3). 2003. pp. 153-62. (In this study, 123 patients with nail patella syndrome were reviewed. The patients originated from 43 families. The study group consisted of 70 females and 53 males. Nail changes were seen in 98% of the patients. Triangular lunulae were seen in 88% of patients. In 38 of the 43 families which were studied, mutations in the LMX1B gene was identified. This article comprehensively examines and describes features of the nail patella syndrome.)

Bongers, E, Gubler, M, Knoers, N. “Nail-patella syndrome”. Overview on clinical and molecular findings. Pediatr Nephrol. vol. 17. 2002. pp. 703-12. (A comprehensive review of the clinical features of nail patella syndrome, with detailed analysis of clinical features, electron microscopic findings, and LMX1B function and mutation analysis.)

McIntosh, I, Dunston, J, Liu, L, Hoover-Fong, J, Sweeney, E. “Nail patella syndrome revisited: 50 Years after linkage”. Ann Hum Genetics. vol. 69. 2005. pp. 349-63. (A comprehensive review that focusus on the genetics of nail patella syndrome and the function of the LMX1B gene.)

Sweeney, E, Hoover-Fong, JE, McIntosh, I, Pagon, RA, Bird, TD, Dolan, CR, Stephens, K. “Nail-patella syndrome”. Gene Reviews [Internet]. 1993-2003 May 31. (An up-to-date, comprehensive description of nail patella syndrome that describes diagnostic features and patient management.)