A 54-year-old man was referred to the genetic clinic with familial nail dysplasia in September 2012 (Fig 1). On further questioning, he reported recurrent knee pain due to patellar dislocation. There was no elbow involvement or renal problem. A skeletal survey was performed in view of his skeletal complaint (Fig 2). His family history was significant: his paternal grandfather, father, and two of his paternal uncles also had nail dysplasia and knee problems, but had undergone no formal medical assessment. What is the diagnosis?

The combination of nail dysplasia, patella hypoplasia, and iliac horn led to the clinical diagnosis of nail-patella syndrome (NPS). This syndrome is also known as Fong disease or hereditary osteo-onychodysplasia. Multiple organ systems are affected including the nails, the eyes, the kidneys, and the skeleton. The clinical presentation of NPS can be highly heterogeneous and is summarised in the Table.1 2 It is a rare autosomal dominant disease with a prevalence of about 1 in 50 000 newborn.1 It is highly penetrant but with significant intra- and inter-familial variability in expression.

The diagnosis of NPS is usually based on clinical findings. It is straightforward when the classic tetrad of abnormal nails, elbows, knees, and iliac horns are present. Nonetheless molecular genetic testing should be considered when the diagnosis is in doubt, or when prenatal or pre-implantation diagnosis is desired. The LMX1B gene is the only gene known to be associated with NPS. Sequence analysis would identify the LMX1B gene mutation in 85% of cases of NPS.

LMX1B gene sequencing was performed for this patient (Fig 3) and revealed a missense mutation LMX1B NM_002316.3}:c.[175T>C];[=];LMX1B{NP _002307.2}:p.[Cys59Arg];[=]. This changed the 59th amino acid from cysteine to arginine in the LIM-A domain of the LMX1B protein. It was located in an evolutionarily highly conserved region and has been reported in the literature to be associated with NPS. Therefore, it was considered to be pathogenic.3

To date, more than 150 mutations of the LMX1B gene have been reported, but no clear genotype-phenotype correlation has been demonstrated. LMX1B has been demonstrated in animal models to be involved in multiple developmental functions including dorso-ventral patterning of the limb bud, and cellular differentiation in the kidney. Nonetheless the exact pathogenesis of NPS has not been elucidated.4

Upon initial diagnosis, comprehensive renal, orthopaedic, and ophthalmological assessments are essential. The renal manifestation strongly affects the long-term prognosis. Kidney involvement occurs in 30% to 50% of patients, but kidney failure only occurs in 3% to 5%.2 Since nephropathy may not develop until later in life, prospective monitoring is essential for all NPS patients. Primary open-angle glaucoma or ocular hypertension occurs in 10% of NPS patients so regular eye surveillance is also warranted. Nail-patella syndrome is an autosomal dominant disorder with a 50% chance of occurrence in offspring, thus genetic counselling is essential (Box2). Genetic testing of other at-risk family members, and prenatal and pre-implantation genetic diagnoses are possible only if the disease-causing mutation is known in the index patient.

1. Bongers EM, Gubler MC, Knoers NV. Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol 2002;17:703-12. Crossref

2. Sweeney E, Fryer A, Mountford R, Green A, McIntosh I. Nail-patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet 2003;40:153-62. Crossref

3. Clough MV, Hamlington JD, McIntosh I. Restricted distribution of loss-of-function mutations within the LMX1B genes of nail-patella syndrome patients. Hum Mutat 1999;14:459-65. Crossref

4. Chen H, Lun Y, Ovchinnikov D, et al. Limb and kidney defects in LMX1B mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet 1998;19:51-5. Crossref