NEPHROLOGY - CASE REPORT

Renal involvement in nail-patella syndrome: reportof three cases

Puneet Sood Æ Maria C. Rojas Æ Zvi Talor

Received: 25 November 2008 / Accepted: 3 March 2009 / Published online: 19 March 2009

� Springer Science+Business Media, B.V. 2009

Nail-patella syndrome (NPS) or hereditary onycho-

osteodysplasia (HOOD) was originally described in

1820 by Chatelian, a patient with a triad of abnormal

nails, elbows, and knees. The first report describing the

family cluster of the disease was published in 1969 by

Beals and Eckhardt [1]. Case reports in the literature

regarding the nephropathy observed in NPS are varied,

including minimal change disease [2], recurrent uri-

nary tract infections, nephrolithiasis vesicoureteral

reflux, renal hypoplasia/atrophy, PAN-type vasculitis

[3], and Goodpasture’s syndrome [4].

Here we report three cases with their respective

pedigrees followed at our institution with evidence of

different types of renal manifestations.

Case 1

A 38-year-old white female presented to our clinic

with proteinuria, microscopic hematuria, and hyper-

tension. The patient was diagnosed with nail-patella

syndrome 8 years prior to our evaluation. Upon

initial presentation, she had chronic knee pain, absent

patella, and dystrophic nails. Family history was

negative for NPS or any known renal disease.

Pertinent physical exam revealed a blood pressure

of 140/95, systolic ejection murmur 1/6, absent

patella bilaterally, and dystrophic nails. Respiratory,

abdominal, CVS and neurological exams were

otherwise unremarkable. Pertinent laboratory data

on initial evaluation included BUN 12 mg/dl, creat-

inine 0.7 mg/dl, estimated GFR by MDRD formula

was 96 ml/min, serum albumin 4.5. Urinanalysis and

dipstick showed 3? protein and microscopic hema-

turia. A 24-h urine protein was 2.36 g/24 h. Serum

serologies including ANA, ANCA, complement lev-

els, and hepatitis panel were all negative. The patient

had stable renal function and was treated with ACEi

up until 2 months prior to planned pregnancy. The

patient was followed for 18 months and was last seen

at 24 weeks of gestation, with stable renal function

and 24 h urine protein of 800 mg. There was no

hematuria. The patient was lost to follow-up after her

visit at 24 weeks of gestation.

P

Case 2

A 58-year-old white female was seen in our clinic

after an episode of painless hematuria. The patient

P. Sood (&) � M. C. Rojas � Z. Talor

Division of Nephrology, Hypertension and Transplant,

University of Florida, PO Box 100224, Gainesville, FL

32610-0224, USA

e-mail: puneet.sood@medicine.ufl.edu

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Int Urol Nephrol (2010) 42:499–502

DOI 10.1007/s11255-009-9557-6

had previously been diagnosed with NPS. Her past

medical history was remarkable for deep venous

thrombosis of the right lower extremity, basal cell

carcinoma status post resection, and dyslipidemia.

Family history was positive for NPS in her father,

paternal grandfather, and four of her children.

Pertinent findings on physical exam were a blood

pressure of 150/78, dystrophic nails, absent patella

bilaterally, 1? lower extremity edema bilaterally, and

subluxation of the elbows. Pertinent laboratory data

on initial evaluation was a BUN 11 mg/dl, creatinine

0.8 mg/dl, albumin 4.3 g/dl, estimated 24-h protein

excretion based on a spot urine protein, and creatinine

ratio was 0.10 g. Urinalysis showed specific gravity

of 1.014, negative protein, and 23 RBC. Renal

ultrasound showed a right kidney of 11.2 cm and a

left kidney of 11.4 cm and no hydronephrosis or

structural lesion to explain the hematuria. The patient

has been followed for 2 years without any further

episodes of gross hematuria and has had a stable

baseline renal function and no proteinuria.

P

Case 3

A 27-year-old white female with a history of nail-

patella syndrome, grade IV vesicoureteral reflux,

status post left ureteral reimplantation in 1992, recur-

rent urinary tract infections, and non-nephrotic range

proteinuria. The patient was part of a large kindred of

NPS from her mother’s side. The patient was evaluated

in the adult nephrology clinic at 34 weeks of gestation.

Previously, she had been followed by pediatric

nephrology. Pertinent physical examination revealed

blood pressure of 110/60, dysmorphic nails, absent

patella bilaterally, pregnant abdominal exam, 2? pedal

edema bilaterally. Pertinent laboratory data included a

BUN 23 mg/dl, serum creatinine 0.7 mg/dl, albumin

2.7 g/dl. Twenty-four-hour urine collection revealed

proteinuria of 2.7 g/24 h. Renal ultrasound showed a

right kidney of 9.7 cm, left kidney size of 9.1 cm,

cortical scarring, and mild left hydronephrosis. She

had renal scarring of the left kidney on a dim-

ercaptosuccinic acid (DMSA) scan. No intervention

was done for proteinuria because of the patient’s

pregnant status. The patient was seen once more at

6 weeks after her uneventful pregnancy outcome. She

was found to have a proteinuria of 8 g based on a spot

urine exam. She did not have any dysmorphic RBCs on

her urianalysis and her blood pressure was in the

normal range. A renal biopsy was contemplated but the

patient was lost to follow-up after that visit.

P

Discussion

Nail-patella syndrome is a rare autosomal-dominant

pleiotropic genetic disorder with a prevalence of

1/500,000 and a high degree of penetrance but

variable expression [5]. The genetic abnormality

has been identified as a loss of function mutation in

LMX1B, and a transcription factor belonging to the

LIM homeodomain family localized in the long arm

of chromosome 9 (9q34) [6]. This transcription factor

is involved in the normal dorso-ventral patterning of

the limbs and normal development of glomerular

basement membrane in the kidney [7]. There is a

suggested role for LMX1B in the regulation of

collagen IV expression and in the transcriptional

regulation of podocyte specification and differentia-

tion [7]. Homozygous LMX1B knockout mice lack

patella and suffer from podocyte damage.

500 Int Urol Nephrol (2010) 42:499–502

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Phenotypic characteristics of the NPS include

hypoplastic or absent patella, dystrophic fingernails

and toenails, dysplasia of the elbows, iliac horns,

hyperpigmentation of pupillary margins, heterochro-

mic iris with clover leaf deformity, microcornea,

glaucoma, and skin laxity [8]. Renal manifestations

of NPS were initially described by Hawkins and

Smith in 1950 with four of 21 affected individuals

showing clinical features of chronic glomerulone-

phritis [9]. Renal involvement in cases has been

reported as ranging from 25 to 60% and manifests as

proteinuria, microscopic hematuria, and hypertension

[8]. Proteinuria may present at any time from birth

onwards and may be intermittent. In a retrospective

study of 123 cases of NPS reported in the literature

by Meyrier et al., 60% of patients presented with

non-nephrotic range proteinuria. The proteinuria may

remain asymptomatic, remit spontaneously, or may

progress to nephrotic syndrome in less than 20% of

the patients [8, 10, 11]. In this study, 15% of the

patients progressed to ESRD. The severity of renal

impairment varies significantly among patients [8].

The presence of hematuria in NPS has been described

in 10–20% of patients [5, 7, 8]. Renal presentation

may occur for the first time during pregnancy. In the

study cohort of Meyrier et al., the incidence of pre-

eclampsia was found to be 29% as compared to 2–5%

described in pregnancies in general population [12].

In a cohort of eight Dutch affected families, seven

different mutations were identified. There was a high

incidence of renal disease in one of the families, with

the nephropathy sparing some family members and

with different spectrum of the severity of disease in

others [13]. To date, there is no correlation between

genotypic and phenotypic expression of the disease.

There are no specific light microscopy or immuno-

fluorescence features of NPS. Electron microscopy

shows irregular thickening of the glomerular basement

membrane with electron lucent areas, the so-called

‘‘moth-eaten appearance’’. Other histopathology find-

ings include podocyte foot process effacement,

fibrillary inclusions in the GBM, and diffuse hydropic

degeneration of tubular epithelium. The fibrils have

been identified as type III collagen [14].

There is no specific therapy for the renal involve-

ment in NPS. The use of RAAS blocking agents in

various settings of proteinuria has been discussed and

debated [15, 16]. We found a single case report of

successful treatment of proteinuria with combined

ACEi and ARB treatment for 2 years in a 7-year-old

pediatric patient with NPS [17]. Successful renal

transplantation has been reported [17, 18]. A case of

successful cadaveric renal transplant from a donor

with nail-patella syndrome has been reported in the

literature [18]. Genetic counseling is recommended

since it is an autosomal-dominant disease.

In summary, we present here three patients with

nail-patella syndrome, two of them with non-nephro-

tic range proteinuria, and one with microscopic

hematuria along with their respective pedigree anal-

ysis. Since some of these patients can end up with

loss of kidney function, regular clinical follow-up is

important.

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