Nail-Patella Syndrome

At a glance

Rare genetic disorder usually apparent at birth or during infancy. It is characterized by dysplasia of the fingernails and toenails, aplasia or hypoplasia of the patellae, webbing of skin at the elbow(s), and abnormal bilateral projections of the iliac superior crest. Other features include glaucoma (open-angle glaucoma) and “cloverleaf-shaped iris” (Lester iris). Approximately 30 to 40% of patients may also develop nephropathy, which is usually apparent during childhood or later in life.

Synonyms

Hereditary Osteo-Onycho-Dysplasia; HOOD Syndrome; Turner-Kieser Syndrome; Fong Disease.

Incidence

Unknown but estimated at 1:50,000 live births. Both sexes are affected equally. No racial predilection. Individuals of any age can be affected.

History

First reported clinically by Chatelain in 1820, whereas its hereditary nature was defined by Little in 1897.

Genetic inheritance

Autosomal dominant with variable expressivity and a high degree of penetrance.

Pathophysiology

The Nail-Patella is due to mutations of the LMX1B gene at chromosome 9q33.3-q34.1. This gene encodes a transcription factor which regulates target gene expression in dorsoventral pattern formation in the limbs, for differentiation of the anterior portions of the eyes, for development of certain neuron populations in the central nervous system, and for the differentiation and maintenance of podocytes in the kidneys.

Diagnosis

Classical tetrad of nail and elbow dysplasia, patellar aplasia or hypoplasia, and iliac horns. Other features commonly observed include ophthalmologic (open-angle glaucoma, cloverleaf dark pigmentation of the iris, micro and sclerocornea, and cataracts) and renal pathology. Electron microscopy shows characteristic ultrastructural changes in the glomerulus where many collagen fibrils are present in the thickened basement membranes and in mesangial matrix of otherwise normal glomeruli; this process is also known as collagenation of glomerular basement membrane. Radiologic examination of the pelvis and elbows differentiates this disorder from other causes of micronychia during childhood.

Clinical aspects

Nail deformities are recognized at birth and do not progress: nails are hypoplastic, discolored, and have poorly formed lunulae and/or splitting, most commonly of the thumbnail. Skeletal involvement usually presents with knee dislocation, pain, or gait disturbance. Hypoplasia of first ribs, malformed sternum, spina bifida, dislocation of the head of radius, scoliosis is also seen. Both elbow and knee dysplasia may lead to permanent restrictive deformities (incomplete extension). Cloverleaf pigmentation of the inner margin of the iris in 50% of patients. Nephropathy is commonly presented as proteinuria (50% of patients). The majority of patients with renal involvement have no associated mortality; however, in approximately 20%, slow progression to renal failure occurs between 5 and 25 years. Associated systemic abnormalities include cleft lip and palate, mental retardation, sensorineural hearing loss, hypoplasia or aplasia of some muscles (pectoralis minor, triceps, quadriceps), cataract, ...