Nail patella syndrome

○　Overview

• Overview
  Nail-patella syndrome is a hereditary disease characterized by four main features: absent or hypoplastic nails, absent or hypoplastic patella, skeletal deformities involving elbow joints, and iliac horns. Patients often develop nephropathy, with some progressing to end-stage kidney disease. Mutations in the LMX1B gene are responsible for the disease.
  Some mutation in the LMX1B gene also cause nail-patella-like renal disease (NPLRD) or focal segmental glomerulosclerosis, which does not accompany nail, patellar, elbow or iliac changes. These patients are diagnosed as LMX1B-associated nephropathy.
• Cause
  The cause of nail-patella syndrome is mutations in the LMX1B gene. In most cases (almost 90%) of this syndrome，a mutation in the LMX1B gene is identified. So far, more than 130 mutations have been reported.
  Mutations in LMX1B gene are also identified in some cases of NPLRD. Furthermore, with the advancement of next generation sequence technology, mutations in the LMX1B gene is being found in some patients with focal segmental glomerulosclerosis or steroid resistant nephrotic syndrome. Nephropathy is thought to be attributed to glomerular epithelial cell dysfunction by LMX1B mutations.
• Symptoms
  （１）Nail-patella syndrome
  Symptoms include absent or hypoplastic nails, absent or hypoplastic patella, skeletal deformity of elbow joints, and iliac horns. However, only one or some of these symptoms may be apparent. In patients with this syndrome, glaucoma or increased intraocular pressure are observed more often and at a younger age than the general population.
  Some patients develop concurrent nephropathy. The symptoms or signs range from mild abnormal urinalysis (asymptomatic proteinuria or hematuria) to massive proteiuria or nephrotic syndrome with edema. Regarding prognosis of nephropathy, most affected individuals only manifest with an accelerated age-related loss of filtration function, while only a minority of individuals progress to ESRD. A decrease in kidney function is predominantly seen in patients with severe proteinuria.
  While there are no specific histological findings at the light microscope level, electron microscopic analysis may demonstrate an irregular thicking of the glomerular basement membrane or moth-eaten appearance and the deposition of type III collagen in the lamina densa of glomerular basement membrane.
  （２）LMX1B-associated nephropathy
  Patients with LMX1B-associated nephropathy carry a mutation in LMX1B, and present with nephropathy (proteinuria or hematuria or renal dysfunction), but do not have extrarenal complications. In some patients, electron microscopic findings are similar to the kidney disease of nail-patella syndrome. Kidney disease can progress with age, and end-stage kidney disease may occur during childhood or adulthood.
• Treatment
  There is no specific treatment for nail, knee, or elbow abnormalities in nail-patella syndrome. Some patients may require surgical treatment for joint symptoms or glaucoma.
  For nephropathy, there is no specific treatment targeting LMX1B. However, treatment for chronic kidney disease may apply in some individuals, depending on kidney function. To prevent presumable damage to glomeruli (especially glomerular epithelial cells), treatment with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, is considered. Patients progressing to end-stage kidney disease require dialysis or kidney transplantation.
• Prognosis
  Nephropathy is a significant threat to quality of life. The reported incidence of kidney involvement varies from 35% to 50%, and it is often noticed during childhood. Among these patients, 10% to 30% progress to end-stage kidney disease.

＜Diagnostic criteria＞
（１）Diagnostic criteria for nail-patella syndrome

Ａ．Primary criterion:

Nail hypoplasia or dysplasia
(It is often present in the fingers, prominently on the thumb side. If it is present in the toes, the condition is more prominent in the little toe side. Severity varies from complete absence to hypoplasia. In some individuals, minor abnormality such as triangular lanulae, spoon nail, discoloration, or splits are the only feature. The condition is often observed from birth. The mild abnormalities can be easily missed.)

Ｂ．Secondary criteria:

• Patellar aplasia/hypoplasia
• Elbow deformities
• Iliac horns

Ｃ．Genetic testing

Heterozygous mutation in the LMXIB gene

Ｄ．Differential diagnosis

All the following differential diagnoses are excluded

• Meier-Gorlin syndrome (OMIM224690)
• Genitopatellar syndrome (OMIM606170)
• DOOR syndrome (OMIM220500)
• Mosaic trisomy 8
• Coffin Siris syndrome (OMIM135900)/BOD syndrome (OMIM113477)
• RAPADILINO syndrome (OMIM266280)

Ｅ．Referential criteria:

• Family history of nail-patella syndrome
• Kidney impairment (hematuria, proteinuria, or renal disfunction)
• Characteristic electron microscopic findings of the glomerular basement membrane
  (Kidney biopsy is considered in patients with kidney impairment, but it is not essential for diagnosis of nephropathy of this disease. Characteristic histopathological findings are thickening or a moth-eaten appearance of the glomerular basement membrane. The deposition of type III collagen fibers can observed in the lamina densa in the thickened glomerular basement membrane or in the mesangial matrix. Fibril clusters in glomerular basement membrane can be stained with phosphotungstic acid, tannic acid, or uranyl acetate/lead citrate staining.)

＜Diagnostic category＞

Definite: (A) + （at least one criterion of B or C) + (D)(exclude differential diseases in D)

（２）Diagnostic criteria for LMX1B-associated nephropathy

Ａ．Primary criterion:

• Kidney impairment
  (hematuria (1+ or more by dipstick), proteinuria (urinary protein greater than or equal to 0.15g/gCr)，or renal dysfunction (eGFR < 90 mL/min/1.73 m2))
• Diagnostic criteria for nail-patella syndrome are not met

Ｂ．Secondary criteria:

Characteristic electron microscopic findings of the glomerular basement membrane
(Kidney biopsy is considered in patients with kidney impairment, but it is not essential for diagnosis of nephropathy of this disease. Characteristic histopathological findings are thickening or a moth-eaten appearance of the glomerular basement membrane. The deposition of type III collagen fibers can observed in the lamina densa in the thickened glomerular basement membrane or in the mesangial matrix. Fibril clusters in glomerular basement membrane can be stained with phosphotungstic acid, tannic acid, or uranyl acetate/lead citrate staining.)

Ｃ．Genetic testing

Heterozygous mutation in the LMXIB gene
(Genetic testing for the LMXIB gene mutation is considered for patients with abnormal urinary findings or renal dysfunction whose kidney biopsy demonstrates characteristic findings of the glomerular basement membrane by electron microscopy, or who have family history of kidney disease consistent with autosomal dominant inheritance.)

＜Diagnostic category＞

Definite: (Both criteria of A) + (at least one criterion of B or C)
Cases with other causes for kidney impairment (morphological abnormalities of kidney, or kidney diseases due to other known gene abnormalities, other than LMXIB gene) should be excluded.

＜Severity classification＞

Cases are categorized as “severe” by the Chronic Kidney Disease
Severity Classification (categorized as “Red” in the chart below) or by urinary protein/creatinine ratio greater or equal to 0.5g/gCr regardless of kidney function.

*Points to be considered when applying the diagnostic criteria and the severity classification

• When not specified in the diagnostic criteria, diagnosis can be made based on clinical symptoms, laboratory findings etc. observed at any time. (As long as clinical symptoms, etc. are consistent with the clinical course or the disease and can be confirmed.)
• Severity classification after the initiation of treatment should be based on the worst condition, as judged by the physician in the last 6 months of treatment under appropriate medical management
• If patients in whom the severities of symptoms do not meet the criteria need to continue high-cost medical care, they are entitled to financial assistance for medical expenses.

*The diagnostic criteria was developed by a research group supported by Health and Labour Sciences Research Grant (H26-015).