Nail-Patella Syndrome

Excerpt

Clinical characteristics: Nail-patella syndrome (NPS) encompasses the classic clinical tetrad of nail abnormalities, abnormal and unstable patella with knee abnormalities, limited elbow mobility, and iliac horns on radiographs. Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The patellae may be small, irregularly shaped, or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. Kidney involvement, first manifest as proteinuria with or without hematuria, occurs in 30%-50% of affected individuals; end-stage kidney disease occurs in up to 15% of affected individuals. Primary open-angle glaucoma and ocular hypertension occur at increased frequency and at a younger age than in the general population.

Diagnosis/testing: The diagnosis of NPS is established in a proband with suggestive findings and/or a heterozygous pathogenic variant in LMX1B identified by molecular genetic testing.

Management: Treatment of manifestations: Orthopedic problems may be helped by analgesics, physical therapy, splinting, bracing, or surgery; MRI of joints to identify abnormal anatomy is important prior to surgery so that appropriate surgical treatment can be planned in advance; angiotensin-converting enzyme (ACE) inhibitors to control blood pressure and possibly to slow progression of proteinuria; kidney transplantation as needed; standard treatment for decreased bone mineral density, hypertension, constipation, inflammatory bowel disease, glaucoma, epilepsy, and dental anomalies; education regarding reduced pain and temperature sensation to avoid burns and injuries; social work and family support.

Surveillance: At least annually, assess orthopedic manifestations, measure blood pressure, perform urinalysis and first-morning urine albumin-to-creatinine ratio for kidney disease, assess for gastrointestinal and neurologic manifestations, and screen for glaucoma (as soon as child is able); dental examination at least every six months; and dual-energy x-ray absorptiometry scan as needed.

Agents/circumstances to avoid: Chronic use of nonsteroidal anti-inflammatory drugs because of the detrimental effect on kidney function.

Evaluation of relatives at risk: Molecular genetic testing of apparently asymptomatic older and younger at-risk relatives for the familial LMX1B pathogenic variant is appropriate in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance measures. If the familial pathogenic variant is not known, monitor kidney findings (i.e., blood pressure, urinalysis, and first-morning urine albumin-to-creatinine ratio) and screen for glaucoma.

Pregnancy management: The risk of developing preeclampsia may be increased in pregnant women with NPS; hence, frequent urinalysis and blood pressure measurement is recommended during pregnancy. For women taking an ACE inhibitor, transitioning to an alternative treatment ideally prior to pregnancy, or at least as soon as pregnancy is recognized, is recommended to avoid potential adverse effects of ACE inhibitors on the developing fetus.

Genetic counseling: NPS is inherited in an autosomal dominant manner. Eighty-eight percent of individuals diagnosed with NPS have an affected parent. Each child of an individual with NPS has a 50% chance of inheriting the causative pathogenic variant. The range and severity of manifestations may be extremely variable among affected family members. Once the LMX1B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.