De novo enhancer deletion of LMX1B produces a mild nail-patella clinical phenotype.

Critical genes involved in embryonic development are often transcription factors, regulating many downstream genes. LMX1B is a homeobox gene that is involved in formation of the limbs, eyes and kidneys, heterozygous loss-of-function sequence variants and deletions cause Nail-Patella syndrome. Most of the reported variants are localised within the gene's coding sequence, however, approximately 5%-10% of affected individuals do not have a pathogenic variant identified within this region. In this study, we present a family with four affected individuals across two generations with a deletion spanning a conserved upstream LMX1B-binding sequence. This deletion is de novo in the mother of three affected children. Furthermore, in this family, the manifestations appear limited to the nails and limbs, and therefore may reflect an attenuated phenotype of the classic Nail-Patella phenotype that includes ophthalmological and renal manifestations.

Nail-patella syndrome with nephropathy in a de novo LMX1B mutation: triangular lunula of the thumb and lack of finger creases as clues.

Nail-patella syndrome (NPS) is an autosomal dominant disease caused mostly by mutations in the LMX1B gene and is characterized by hypoplastic nails, hypoplastic patella, elbow deformities, glaucoma, and nephropathy, sometimes leading to kidney failure. The combination and the severity of symptoms vary greatly from patient to patient. Because a kidney biopsy may show nonspecific findings, patients with nephropathy alone may not be diagnosed without undergoing genetic testing. We examined the case of a 6-year-old girl with persistent high proteinuria who was not diagnosed by kidney biopsy but had a diagnosis of a de novo mutation in the LMX1B gene following genetic testing. Retrospectively, only the thumbs showed triangular lunulae, while the third and fourth fingers lacked skin creases over the distal interphalangeal joints, which is subtle but characteristic of NPS. Notifying pediatric nephrologists of these findings can help avoid unnecessary kidney biopsies and lead to early detection of the disease.

The first presentation of a case of nail-patella syndrome newly diagnosed at the onset of rheumatoid arthritis: a case report.

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA). CASE PRESENTATION: A 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission. CONCLUSIONS: We have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations.

Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene.

BACKGROUND: In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction. OBJECTIVE: To demonstrate linkage and to identify the underlying genetic cause of disease. METHODS: Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed. RESULTS: Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS. CONCLUSIONS: Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.

Myelin bodies in LMX1B-associated nephropathy: potential for misdiagnosis.

BACKGROUND: Myelin figures, or zebra bodies, seen on electron microscopy were historically considered pathognomonic of Fabry disease, a rare lysosomal storage disorder caused by alpha-galactosidase A deficiency and associated with X-linked recessive mode of inheritance. More recently, iatrogenic phospholipidosis has emerged as an important alternate cause of myelin figures in the kidney. METHODS: We report two families with autosomal dominant nephropathy presenting with proteinuria and microscopic hematuria, and the kidney biopsies were notable for the presence of myelin figures and zebra bodies. RESULTS: Laboratory and genetic work-up for Fabry disease was negative. Genetic testing in both families revealed the same heterozygous missense mutation in LMX1B (C.737G>A, p.Arg246Gln). LMX1B mutations are known to cause nail-patella syndrome, featuring dysplastic nails and patella with or without nephropathy, as well as isolated LMX1B-associated nephropathy in the absence of extrarenal manifestations. CONCLUSIONS: LMX1B mutation-associated nephropathy should be considered in hereditary cases of proteinuria and/or hematuria, even in the absence of unique glomerular basement membrane changes indicative of nail-patella syndrome. In addition, LMX1B mutation should be included in the differential diagnosis of myelin figures and zebra bodies on kidney biopsy, so as to avoid a misdiagnosis.

A novel mutation in LMX1B gene in a newborn with nail-patella syndrome: Clinical and dermoscopic findings.

We report on a 3-month-old female patient presenting with bilateral anonychia of the thumbnails and hyponychia of the index nails. Clinico-dermoscopic examination revealed triangular lunulae in all fingernails. Sequence analysis of LMX1B gene identified a novel heterozygous de novo mutation within exon 2, pathogenetic for a nail-patella syndrome.

A novel small deletion of LMX1B in a large Chinese family with nail-patella syndrome.

BACKGROUND: Nail-patella syndrome (NPS) is an autosomal dominant developmental disorder most commonly characterized by dyplasia of nail or patella, the radial head or the humeral head hypoplasia, and, frequently ocular abnormalities and renal disease. It is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes LIM homeodomain transcription factor and is essential for regulating the dorsal limb fate. METHODS: A five generation pedigree was recruited. Genomic DNA was extracted from the peripheral blood samples. Mutation detection was performed by Sanger sequencing the LMX1B gene. In silico functional annotation of the variant was performed using the in silico predictors SIFT, PolyPhen-2 and Mutation Taster. RESULTS: A novel heterozygous small deletion within exon 4 of LMX1B, c.712_714delTTC, was identified in a rare five-generation NPS pedigree. The mutation resulted in a deletion of the conserved amino acid phenylalanine at codon 238 (p.Phe238del), which located in the homeodomain of LMX1B may abolish DNA binding with the molecule. Conformational prediction showed that the variation could transform the helical structure comprising p.Phe234, p.Lys235, p.Ala236, and p.Ser237. CONCLUSION: We identified a novel NPS-causing LMX1B mutation and expanded the spectrum of mutations in the LMX1B gene. The c.712_714delTTC mutation may affect the quaternary structure of LMX1B, which is essential for the specification of dorsal limb fate at both zeugopodal and autopodal levels, leading to typical NPS.

Difficulties adapting to Nail-Patella syndrome: A qualitative study of patients' perspectives.

Nail-Patella syndrome (NPS) is a genetic disorder generating physical malformations and, in approximately one in three cases, ocular and renal damage. The present research aimed to deeply understand patients' subjective experience with NPS, particularly the aspects of the syndrome that affect patients' adaptation and to propose interventions that can improve genetic and psychological counseling and help patients cope with their condition. Semi-structured interviews of nine people diagnosed with NPS were analyzed using interpretative phenomenological analysis. Results highlighted attempts to look like a person without disabilities by hiding malformations and not telling the truth about symptoms' genetic origin because of patients' poor self-esteem, negative self-cognition, and social isolation experienced from childhood to adulthood. Difficulties of adaptation to physical limits and pain were also identified. The majority of participants who were not diagnosed at birth tended to consider physical symptoms as "birth malformations" without imagining other potential implications until receiving a diagnosis. Despite the diagnosis, the majority continued to minimize the potential complications by considering NPS as a "physical difference" and not adhering to medical surveillance.

LMX1B-Associated Nephropathy With Type III Collagen Deposition in the Glomerular and Tubular Basement Membranes.

Variants in the LMX1B gene cause nail-patella syndrome, a rare autosomal dominant disorder characterized by dysplasia of nails, patella and elbow abnormalities, iliac "horns," and glaucoma. We describe an adult man with nephrotic syndrome and no systemic manifestations of nail-patella syndrome at the time of his initial kidney biopsy. His kidney biopsy was initially interpreted as a form of segmental sclerosis with unusual fibrillar deposits. At the time of consideration for kidney transplantation, a family history was notable for end-stage renal disease in 3 generations. Subsequent reanalysis of the initial biopsy showed infiltration of the lamina densa by type III collagen fibrils, and molecular studies identified a pathogenic variant in one allele of LMX1B (a guanine to adenine substitution at nucleoide 737 of the coding sequence [c.737G>A], predicted to result in an arginine to glutamine substitution at amino acid 246 [p.Arg246Gln]). This variant has been described previously in multiple unrelated families who presented with autosomal dominant nephropathy without nail and patellar abnormalities.

Nail-patella syndrome.

The pathognomonic symptoms of patients with nail-patella syndrome are their small or absent patellae and dysplastic or absent finger- and toenails. Many of the patients suffer from renal symptoms which also affect their prognosis. In 1998, mutations in the gene encoding the transcription factor LMX1B were identified as underlying this autosomal-dominant disease. The LMX1B gene is expressed in a variety of tissues, and the symptoms are reflected nicely by its expression pattern. LMX1B is essential for dorso-ventral pattern formation in the limbs, for differentiation of the anterior portions of the eyes, for development of certain neuron populations in the central nervous system, and for the differentiation and maintenance of podocytes. Accordingly, kidney biopsies of patients with nail-patella syndrome show an altered podocyte structure and defects in the glomerular basement membrane. Recent evidence suggests that LMX1B regulates genes which encode proteins associated with the actin cytoskeleton.

Spectrum of LMX1B mutations: from nail-patella syndrome to isolated nephropathy.

Nail-patella syndrome (NPS) is an autosomal-dominant disease caused by LMX1B mutations and is characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Renal involvement is the major determinant of the prognosis for NPS. Patients often present with varying degrees of proteinuria or hematuria, and can occasionally progress to chronic renal failure. Recent genetic analysis has found that some mutations in the homeodomain of LMX1B cause isolated nephropathy without nail, patellar or skeletal abnormality (LMX1B-associated nephropathy). The classic term "nail-patella syndrome" would not represent disease conditions in these cases. This review provides an overview of NPS, and highlights the molecular genetics of NPS nephropathy and LMX1B-associated nephropathy. Our current understanding of LMX1B function in the pathogenesis of NPS and LMX1B-associated nephropathy is also presented, and its downstream regulatory networks discussed. This recent progress provides insights that help to define potential targeted therapeutic strategies for LMX1B-associated diseases.

Steroid-resistant nephrotic syndrome as the initial presentation of nail-patella syndrome: a case of a de novo LMX1B mutation.

BACKGROUND: Nail-patella syndrome (NPS) is an autosomal dominant disorder caused by mutations in the LMX1B gene and is characterized by nail dysplasia, skeletal abnormalities, and nephropathy. We herein report a case of steroid-resistant nephrotic syndrome (SRNS) prior to overt orthopedic symptoms in a patient with NPS. CASE PRESENTATION: A 24-year-old woman presented to our hospital with knee pain. She had poorly developed nails, hypoplastic patellas, dislocation of the elbows, and iliac horns in the pelvis. At the age of 7, she developed nephrotic syndrome and was diagnosed with primary focal segmental glomerulosclerosis by renal biopsy. She received long-term corticosteroid therapy with no obvious response. Her clinical course and orthopedic manifestations indicated NPS, and a genetic analysis showed a de novo mutation in the LMX1B gene (c.819 + 1G > A). Nephropathy in this case was considered to be associated with NPS. Therefore, we discontinued corticosteroids without the exacerbation of nephrotic syndrome. CONCLUSIONS: Patients with NPS may develop nephrotic syndrome prior to overt orthopedic symptoms and only show non-specific findings in renal biopsy at an early stage of NPS nephropathy. Hereditary nephrotic syndrome, often presenting as childhood-onset SRNS, may also be difficult to diagnose in patients with the following conditions: renal symptoms prior to overt extrarenal symptoms, de novo mutations, and non-specific findings in renal biopsy. Therefore, in the management of SRNS in children, we need to reconsider the possibility of hereditary diseases such as NPS even without a family history.

Management of patellar problems in skeletally mature patients with nail-patella syndrome.

PURPOSE: Nail-patella syndrome (NPS) or hereditary onychoosteodysplasia is a rare autosomal dominant disease, characterized by a tetrad of findings, which include fingernail abnormalities, hypoplasia of the patellae, radial head dislocation and prominent iliac horns. Most of the literature on the treatment of patellar problems in NPS concerns paediatric patients, and there is no standard treatment algorithm for adult patients. METHODS: We reviewed the charts of skeletally mature patients with NPS who presented to our clinic. We reviewed the presenting complaints, the physical examination findings and the radiographic imaging. RESULTS: We identified seven skeletally mature patients with NPS who presented with patellofemoral complaints. Their symptoms were instability, pain, or a combination of the two. Examination and imaging revealed a wide range of severity but included patellar instability and patellar arthritis. In our series, milder forms of the disease were treated with non-operative measures, but the majority of our patients required surgery including medial patellofemoral ligament reconstruction, tibial tuberosity transposition, patellofemoral and total knee arthroplasty. At midterm follow-up, most patients had good results. CONCLUSION: Nail-patella syndrome has a wide range of presentations and severity in skeletally mature patients. Knee surgeons should be familiar with the spectrum of clinical presentation and the range of treatment options available in order to provide optimum treatment for patients with this disorder. LEVEL OF EVIDENCE: IV.

Clinical and histological findings of autosomal dominant renal-limited disease with LMX1B mutation.

AIM: Mutations of LMX1B cause nail-patella syndrome, a rare autosomal dominant disorder. Recently, LMX1B R246Q heterozygous mutations were recognised in nephropathy without extrarenal manifestation. The aim of this study was to clarify characteristics of nephropathy caused by R246Q mutation. METHODS: Whole exome sequencing was performed on a large family with nonsyndromic autosomal dominant nephropathy without extrarenal manifestation. Clinical and histological findings of patients with LMX1B mutation were investigated. RESULTS: LMX1B R246Q heterozygous mutation was identified in five patients over three generations. Proteinuria or haematoproteinuria was recognized by urinary screening from all patients in childhood. Proteinuria gradually increased to nephrotic levels and renal function decreased in adolescence. Two patients progressed to end-stage renal disease in adulthood. Renal histology demonstrated minimal change in childhood and focal segmental glomerulosclerosis in adulthood. Using electron microscopy, focal collagen deposition could be detected in glomeruli even when a "moth-eaten appearance" was not apparent in the glomerular basement membrane. In addition, podocin expression in glomerular podocytes was significantly decreased, even in the early stages of disease progression. CONCLUSION: Comprehensive genetic analyses and collagen or tannic acid staining may be useful for diagnosis of LMX1B-associated nephropathy. While renal prognosis of R246Q may be worse than that of typical NPS nephropathy, signs of podocytopathy can be detected during the infantile period; thus, childhood urinary screening may facilitate early detection.

Identification of a novel LMX1B nonsense variant associated with congenital talipes equinovarus by prenatal exome sequencing: A case report.

BACKGROUND: Congenital talipes equinovarus (CTEV) is a rotational foot deformity that affects muscles, bones, connective tissue, and vascular or neurological tissues. The etiology of CTEV is complex and unclear, involving genetic and environmental factors. Nail-patella syndrome is an autosomal dominant disorder caused by variants of the LIM homeobox transcription factor 1 beta gene (LMX1B, OMIM:602575). LMX1B plays a key role in the development of dorsal limb structures, the kidneys, and the eyes, and variants in this gene may manifest as hypoplastic or absent patella, dystrophic nails, and elbow and iliac horn dysplasia; glomerulopathy; and adult-onset glaucoma, respectively. This study aimed to identify pathogenic variants in a fetus with isolated talipes equinovarus diagnosed by ultrasound in the second trimester, whose father exhibited dysplastic nails and congenital absence of bilateral patella. METHODS: Prenatal whole-exome sequencing (WES) of the fetus and parents was performed to identify the genetic variant responsible for the fetal ultrasound abnormality, followed by validation using Sanger sequencing. RESULTS: A novel heterozygous nonsense variant in exon 6 of LMX1B (c.844C>T, p.Gln282*) was identified in the fetus and the affected father but was not detected in any unaffected family members. This nonsense variant resulted in a premature termination codon at position 282, which may be responsible for the clinical phenotype through the loss of function of the gene product. CONCLUSIONS: Our study indicating that a fetus carrying a novel nonsense variant of LMX1B (c.844C>T, p.Gln282*) can exhibit isolated talipes equinovarus, which expands the LMX1B genotypic spectrum and is advantageous for genetic counseling.

ST-segment elevation myocardial infarction in Nail-Patella syndrome with anomalous coronary anatomy and aneurysms: a case report.

Background: Nail-Patella syndrome (NPS) is an autosomal-dominant pleiotropic condition characterized by pelvic and skeletal abnormalities and most commonly affecting a tetrad of nails, knees, elbows, and iliac horns, the iliac horns being pathognomonic for the condition. The most well-documented extra-skeletal manifestation is renal involvement with alteration in Type III collagen. No documented cases of NPS with anomalous coronary arteries or aneurysms, acute coronary occlusion, or successfully coronary interventions exist in the medical literature. Case summary: A 62-year-old female with a medical history significant for NPS diagnosed 50 years ago presented to the emergency department with a chief complaint of chest pain. She recently developed end-stage renal disease managed with peritoneal dialysis within the last year. Angiography revealed 100% right coronary artery occlusion with an anomalous take-off from the left circumflex artery. She demonstrated diffuse coronary aneurysms in the right coronary artery, mid-left anterior descending artery, and other epicardial vessels. Two drug-eluting stents were placed in overlapping fashion. Following careful apposition, the aneurysmal segment was successfully stented without complication. The patient was discharged without complication 2 days later. Discussion: Our case shows the first reported case of coronary vascular anomalies and successful coronary revascularization in a patient with NPS in the medical literature. Given the recently reported vascular anomalies and known collagen alterations seen in patients with the genetic disorder, clinicians should suspect further systemic vascular anomalies with their own unique therapeutic challenges when encountering patients with this rare genetic syndrome.

Radiological manifestations of nail-patella syndrome in a 56-year-old female: A case report.

Nail-patella syndrome (NPS) is a rare autosomal dominant pleiotropic disorder characterized by dysplasia of the nails, patellar aplasia or hypoplasia, iliac horns and dysplasia of the elbows. We present a case of a 56-year-old female presenting with bilateral knee pain, where initial radiographic findings of hypoplastic patellae prompted further investigation, revealing characteristic skeletal anomalies consistent with NPS. This case underscores the importance of recognizing radiological clues and conducting thorough clinical evaluation to diagnose rare genetic conditions such as NPS.

Evaluation of characteristics, associations and clinical course of isolated spontaneous renal artery dissection.

BACKGROUND: Spontaneous renal artery dissection (SRAD) is a rare entity of unknown etiology. We aimed to study the clinical course and outcomes and compare the characteristics of patients with SRAD with those of the general population. METHODS: All cases of isolated renal artery dissection diagnosed at the University of Michigan Hospitals between January 2000 and July 2012 were identified by the ICD-9 code. Cases were matched by age, gender and race with individuals from the 2009-2010 National Health and Nutrition Examination Survey (NHANES). Characteristics and awareness of comorbid conditions were compared. Information about the clinical course after diagnosis was retrieved from the case group to ascertain their outcomes. RESULTS: Overall, 17 patients with SRAD with a mean age of 38.6 years (SD = 8.3) were identified. Eleven patients were male and 14 were white. The most common presenting symptom was excruciating sudden-onset flank pain ipsilateral to the site of dissection. Fibromuscular dysplasia, Ehlers-Danlos and polyarteritis nodosa were present in 4, 4 and 1 patients, respectively. After adjusting in a multivariable model, the case group was more likely to report history of hypertension, cancer and connective tissue disorders (P < 0.001), and less likely to have obesity (BMI ≥30 kg/m(2)) compared with the general population. Supportive medical treatment, endovascular intervention and surgery were required in 8, 5 and 4 cases, respectively. After discharge from the hospital, hypertension was adequately controlled in all the patients but one. CONCLUSION: SRAD may be part of a syndrome having multi-organ involvement. With appropriate medical or surgical management, long-term clinical outcome appears favorable.

Dilated Cardiomyopathy and Nail-Patella Syndrome: A Case Report.

Nail-patella syndrome (NPS) is a rare genetic disorder with multiple skeletal deformities and a variety of extra-skeletal involvements. We present a 17-year-old male with a clinical tetrad of skeletal abnormalities, multiple bony deformities, advanced renal failure, hypothyroidism, and dilated cardiomyopathy. A clinical diagnosis of NPS was made, supported by radiographic findings, and corroborated by compatible renal biopsy results. There are very few published reports describing the association of dilated cardiomyopathy with this syndrome. A high index of suspicion is needed to make this diagnosis, given myriads of multi-systemic manifestations.