Clinical Vignette

1 Abstract

Nail patella syndrome is a rare autosomal dominant disorder characterized by nail dysplasia, absent or hypoplastic patella, abnormality of the elbows and presence of iliac horns. Here, we report a case of a one-and-half-year-old girl with nail patella syndrome. Mutation analysis of the patient revealed a known de novo pathogenic variant, c.668G>A (p.R223Q) in exon 4 of the LMX1B gene.

2 Introduction

Nail patella syndrome (NPS) (OMIM 161200) is characterized by absent or hypoplastic, split or ridged and discolored nails, small and irregular or absent or dislocated patellae, elbow deformity that limits the movements of pronation or supination and the presence of bilateral iliac horns. Additional features like nephropathy and glaucoma are observed within the disease spectrum. The prevalence of this condition is about 1 in 50,000 individuals. Haplo-insufficiency of LMX1B (OMIM 602575) due to the presence of pathogenic variants is known to cause this condition. LMX1B encodes an LIM homeobox transcription factor 1 beta, which is a member of LIM-homeodomain family. This transcription factor is essential for the dorsoventral patterning of the limbs, normal development of the kidney, eyes and dopaminergic and serotonergic neurons. In this article, we report a patient with NPS due to a known variant in LMX1B.

3 Case report

The patient was a one-and- half-year-old girl. She was the only child born to a non-consanguineous couple at term with no antenatal or neonatal complications. She had first presented at 19 days of age, with a left club foot deformity and bilateral dislocation of knee-caps. On examination she had prominent forehead, depressed nasal bridge, and dystrophic nails with longitudinal ridges (Fig 1 A-C). Ultrasound examination of both knees showed small patellae with bilateral dislocation. Radiologic examination of both hips showed bilateral iliac horns (Fig 1 D-G). Rest of the systemic examination was normal.

At two months of age, Achilles tenotomy was done in view of left congenital talipes equinovarus (CTEV). Diagnosis of nail patella syndrome was made on clinical and radiological grounds. Follow-up at 8 months of age showed normal developmental milestones and her length was 66cm (normal). Her renal function tests and ophthalmologic evaluations were within normal limits. The study has the approval of institutional ethics committee and written informed consent was taken from the patient. We performed Sanger sequencing of LMX1B which revealed a known pathogenic variant c.668G>A (p.R223Q) in exon 4. Sequence analysis of parents did not reveal this variant suggesting the de novo occurrence of the mutation (Fig 1 H-J).

4 Discussion

Clinically, the classical presentation of NPS involves changes in nails, knees, elbows and presence of iliac horns. However, the severity of the disease varies extremely within individuals of the same family also. Many families may remain undiagnosed because of the mild phenotype. As multiple systems are involved in NPS, there may be a predominance of disease in one system whereas others may be minimally affected. The spectrum of orthopedic afflictions includes ‘swan necking’ of index finger, patellar abnormalities (dysplasia, small patellae), tight hamstring muscles and congenital talipes equinovarus (CTEV). Pinette et al., reported a case of prenatal diagnosis of NPS by identifying skeletal dysplastic changes (absence of left patella and severe malrotation of left foot) in an anomaly scan establishing the importance of a targeted anomaly scan in afflicted families. Renal impairment complicates 40% cases of NPS. Primary open angle glaucoma and ocular hypertension are common ophthalmologic findings. Hence, annual screening for nephropathy (blood pressure monitoring, urinalysis and urine albumin/ creatinine ratio) and for glaucoma form part of NPS patient care. In the present study, the patient had three of the classic tetrad of features typical of NPS. However, there were no signs of elbow deformity, nephropathy, and glaucoma which have been reported as consistent features of this condition and she would require annual surveillance for the same.

More than 400 cases with NPS have been reported so far all over the world and more than 140 pathogenic variants have been identified in patients with NPS. Different types of mutations including missense, nonsense, frameshift, and splice site mutation, as well as partial and whole gene mutations have been identified in LMX1B. In majority of the cases (88%) the variants are inherited from a parent in an autosomal dominant manner and in some cases (12%) the mutation arises de novo. LMX1B regulates expression of genes encoding alpha 3 and alpha 4 chains of collagen IV, interstitial type III collagen, podocin and CD2AP that form slit pore membrane connecting podocytes. The pathogenic variant identified in this study is found in the mutation hotspot of LMX1B which spans exons 2-6. Missense mutations are found to be most commonly present at the mutation hotspot. Therefore, the diagnostic strategy would be to analyze the mutation hotspot. If no pathogenic variants are found, then deletion/duplication analysis is considered.

Identification of LMX1B pathogenic variants supports the role of this gene in the causation of NPS and reinforces the importance of molecular genetic testing as part of prenatal counseling for families with affected individuals.

References