Nail-patella syndrome (Fong disease)

• Autosomal dominant, LMX1B (9q33.3), a LIM-homeodomain transcription factor
• Loss-of-function through haploinsufficiency; sequencing plus deletion analysis identifies a variant in roughly 85 to 95% of people meeting clinical criteria
• About 20% of cases are de novo
• Penetrance is essentially complete, but expressivity varies widely within a single family, so severity in a parent does not predict severity in a child
• Also called hereditary onycho-osteodysplasia (HOOD) and Fong disease, the latter after the iliac horns

The classic tetrad is nails, patellae, elbows, and iliac horns, in that order of frequency.

• Nail dysplasia (~98%): absent or hypoplastic nails, longitudinal ridging, splitting, koilonychia. Severity follows a radial-to-ulnar gradient, worst on the thumbs and decreasing toward the fifth digit. Triangular lunulae are effectively pathognomonic
• Patellar hypoplasia or aplasia (~90%): small, irregular, or absent patellae with recurrent lateral subluxation and dislocation, knee pain, and early degenerative change. The lateral femoral condyle is often hypoplastic
• Elbow dysplasia (~90%): limited extension, pronation, and supination; cubitus valgus; antecubital pterygia; radial head hypoplasia or posterior dislocation
• Iliac horns (~70%): bilateral conical exostoses projecting posteriorly from the iliac wings. Asymptomatic and visible only on imaging, but pathognomonic when present
• Nephropathy (30 to 50%): proteinuria, sometimes with microscopic hematuria, presenting from childhood through adulthood. Roughly 5 to 15% progress to end-stage kidney disease. This is the feature that determines long-term outcome
• Primary open-angle glaucoma and ocular hypertension: increased risk, with onset earlier than in the general population
• Less consistent: sensorineural hearing loss, constipation and irritable bowel symptoms, thin upper lip

• The clinical tetrad is usually sufficient; a pelvic radiograph for iliac horns is the cheapest confirmatory image and is often the finding that settles an uncertain case
• Molecular confirmation by LMX1B sequencing with deletion/duplication analysis
• If a kidney biopsy is done, electron microscopy shows irregular thickening of the glomerular basement membrane with electron-lucent "moth-eaten" areas containing fibrillar type III collagen. This is distinct from the lamellated, basket-weave splitting of Alport syndrome

Genotype-phenotype note: specific missense variants in the LMX1B homeodomain, most notably at the p.Arg246 residue, cause an isolated nephropathy with no nail, patellar, elbow, or iliac findings. A family with dominant proteinuric kidney disease and a normal skeletal exam can still be LMX1B-related, so the absence of the tetrad does not exclude the gene.

• Clouston syndrome and hypohidrotic ectodermal dysplasia: nail dystrophy with hair and sweat gland involvement, no patellar or iliac findings
• Alport syndrome: hereditary nephropathy with hearing loss and lenticonus, but normal nails and patellae and a different basement membrane ultrastructure
• Small patella syndrome (TBX4): patellar hypoplasia with pelvic anomalies but normal nails and no nephropathy. The cleanest discriminator is the nails
• Genitopatellar syndrome (KAT6B): absent patellae with intellectual disability, renal cysts, and genital anomalies

• Annual urine protein-to-creatinine ratio and blood pressure from the time of diagnosis, lifelong, including in people with mild skeletal findings. Refer to nephrology once proteinuria appears
• ACE inhibitor or angiotensin receptor blocker for proteinuria; kidney transplant outcomes are good and the disease does not recur in the graft
• Annual eye examination with intraocular pressure from adolescence
• Orthopedic and physical therapy management of patellar instability; bracing and quadriceps strengthening before considering realignment surgery
• Reproductive counseling: 50% recurrence for each pregnancy, with prenatal or preimplantation testing available once the familial variant is known