Patella Syndrome Research Articles

A microdeletion of chromosome 9q33.3 encompasses the entire LMX1B gene in a Chinese family with nail patella syndrome.

Nail patella syndrome (NPS) is an autosomal dominant disorder characterized by nail malformations, patellar apoplasia, or patellar hypoplasia. Mutations within the LMX1B gene are found in 85% of families with NPS; thus, this gene has been characterized as the causative gene of NPS. In this study, we identified a heterozygous microdeletion of the entire LMX1B gene using multiplex ligation-dependent probe amplification (MLPA) in a Chinese family with NPS. The determination of the deletion breakpoints by Illumina genome-wide DNA analysis beadchip showed that the deletion was located in chromosome 9q33.3 and spanned about 0.66 Mb in size. This heterozygous deletion provides strong evidence for haploinsufficiency as the pathogenic mechanism of NPS.

GE-13 * A NOVEL ASSOCIATION OF PRIMARY CNS GERMINOMA IN A PATIENT WITH NAIL PATELLA SYNDROME

Nail patella syndrome (NPS) is an autosomal dominant disorder with a prevalence of 1/50,000 characterized by developmental abnormalities of the nails, knees and elbows, as well as renal dysplasia and open angle glaucoma. NPS is caused by a mutation in the LMX1B gene, a transcription factor involved in ventral/dorsal patterning of the vertebrate limb. While malignancy is rare in patients with NPS, Ewing's sarcoma and colon cancer have been reported. Additionally, NPS has been described in a 5 generation family with neurofibromatosis type 1. We report a novel association of NPS with primary CNS germinoma. A 22-year-old male presented with a two-month history of diabetes insipidus (DI) and headaches. Physical examination revealed partial Parinaud's syndrome, dystrophic nails and surgical repair of left hypoplastic patella. Because the family history revealed numerous maternal family members with dystrophic nails and hypoplastic patellae, we subsequently made a formal clinical diagnosis of NPS. Contrast enhanced MRI of the brain revealed an enhancing cystic pineal mass and a Chiari I malformation; serum and CSF alpha-fetoprotein and beta-human chorionic gonadotropin were negative. Biopsy of the pineal mass was consistent with pure germinoma for which the patient received external beam radiation therapy via intensity modulated radiation therapy (IMRT) as follows: 1) 2520 cGy to the craniospinal axis; 2) 5040 cGy to the pineal region; 3) and 4620 cGy to the suprasellar region (for presumed tumor in the posterior pituitary given the history of DI). He remains in remission 9 years post-treatment. For the NPS, the patient declined referral to genetics due to insurance concerns but he and his family have been referred to appropriate services for screening of other abnormalities associated with the syndrome. This case report suggests that LMX1B may play a role in the development of CNS germinoma.

Medial capsule reefing in patellar instability.

The efficacy of medial capsule reefing in the treatment of patellar instability is well documented. Aim of the present study was to prospectively evaluate the outcomes of an all-arthroscopic medial capsule reefing technique in young patients with painful patella syndrome and potential patellar instability. Thirty patients with painful patellar syndrome and potential patellar instability having undergone a minimum of 6 months of intensive rehabilitation were enrolled in the present study. All subjects were evaluated with physical examination, clinical and functional outcomes and complete imaging study. All patients were reviewed at an intermediate follow-up of 72 months. Average Kujala score improved from 72.9±15.0 to 88.4±7.6 (p<0.0001), average Larsen score from 15.0±2.5 to 17.2±2.2 (p<0.002), average Lysholm from 63.8±16.7 to 87.9±11.7 (p<0.0001) and average Fulkerson score from 69.5±21.5 to 90.8±9.8 (p<0.0001). No intraoperative or postoperative complications were recorded. Ninety per cent of patients were very satisfied or satisfied with their functional result. Twenty-eight patients were reviewed at the final follow-up, 120 months after surgery. Average Kujala was 87.7±8.8 (p<0.0001), average Larsen was 16.8±2.7 (p<0.01), average Lysholm was 87.6±14.3 (p<0.0001), and average Fulkerson was 87.2±13.9 (p<0.0001). Almost 86% of patients were very satisfied or satisfied with their result. However, slight deterioration of the outcomes over time was observed. At the final follow-up, the outcomes of all-arthroscopic technique were significantly improved from preoperative values; however, they were slightly inferior at the 72 months follow-up. This slight deterioration of the outcomes may be the consequence of the reduction in physical activities. Case series, Level IV.

Combined TSC1 and LMX1B mutations in a single patient

Tuberous sclerosis complex (TSC) and nail-patella syndrome (NPS) are autosomal dominant pleiotropic disorders with full penetrance that can both involve kidneys. TSC1 and NPS genes are located on chromosome 9q3. In a large family with the two disorders with two novel frameshift TSC1 and LMX1B mutations, we describe the phenotypes. The father, who has both disorders, has passed on TSC to three of his children, NPS to another three, and both TSC and NPS to one child. Patients carrying both mutations appear to show an additive phenotype and no obvious epistatic effects. The segregation of two dominant disorders in this family poses a challenge for genetic counseling and indicates the importance of a careful clinical and molecular evaluation for accurate risk assessment.

Tbx4 interacts with the short stature homeobox gene Shox2 in limb development

The short stature homeodomain transcription factors SHOX and SHOX2 play key roles in limb formation. To gain more insight into genes regulated by Shox2 during limb development, we analyzed expression profiles of WT and Shox2-/- mouse embryonic limbs and identified the T-Box transcription factor Tbx4 as a potential downstream target. Tbx4 is known to exert essential functions in skeletal and muscular hindlimb development. In humans, haploinsufficiency of TBX4 causes small patella syndrome, a skeletal dysplasia characterized by anomalies of the knee, pelvis, and foot. Here, we demonstrate an inhibitory regulatory effect of Shox2 on Tbx4 specifically in the forelimbs. We also show that Tbx4 activates Shox2 expression in fore- and hindlimbs, suggesting Shox2 as a feedback modulator of Tbx4. Using EMSA studies, we find that Tbx4/TBX4 is able to bind to distinct T-box binding sites within the mouse and human Shox2/SHOX2 promoter. Our data identifies Tbx4 as a novel transcriptional activator of Shox2 during murine fore- and hindlimb development. Tbx4 is also regulated by Shox2 specifically in the forelimb bud possibly via a feedback mechanism. These data extend our understanding of the role and regulation of Tbx4 and Shox2 in limb development and limb associated diseases.

Medial and Lateral Retinaculum Plasty for Congenital Patellar Dislocation due to Small Patella Syndrome

The objective of this study was to explore the clinical effect of medial and lateral retinaculum plasty for congenital patellar dislocation due to small patella syndrome. Twelve patients with congenital patellar dislocation due to small patella syndrome treated at the authors' hospital between January 2005 and February 2010 were enrolled in the study. The study group comprised 4 men (4 knees) and 8 women (8 knees) with an average age of 10.58±6.91 years. All patients underwent medial and lateral retinaculum plasty. Clinical evaluation included the number of patellar redislocations, patellar apprehension sign, Kujala score, subjective questionnaire score, and patella lateral shift and patellar tilt angle measured using a cross-sectional computed tomography scan. All patients were followed up, and the shortest follow-up time was 2 years. Kujala scores improved from 49.20±6.20 preoperatively to 80.10±5.80 postoperatively. Subjective questionnaire scores indicated that the excellent and good rate was 75%. In addition, a significant difference existed in the patellar tilt angle and patella lateral shift between pre- and postoperative results (P<.05). Medial and lateral retinaculum plasty for patients with congenital patellar dislocation due to small patella syndrome can be effective to correct the tracking of the patellofemoral joint and improve knee function.

LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy

Nail-patella syndrome (NPS) is a rare autosomal-dominant disorder caused by LMX1B mutation. In patients with the renal lesions typical of NPS without skeletal or nail findings, it is described as nail-patella-like renal disease (NPLRD). However, the pathogenesis of NPLRD is largely unknown. A 6-year-old girl with microscopic haematuria and mild proteinuria was diagnosed with NPLRD because of an aberrantly thickened glomerular basement membrane (GBM) and deposition of Type III collagen in the GBM observed by electron microscopy. Immunohistological analyses of podocyte protein expression were performed on biopsy tissues. Sequence analysis of LMX1B was performed, and the functional consequences of the detected mutation were analysed by luciferase reporter assay. When analysing molecules that are important for podocyte development, maintenance and maturation, CD2AP expression was found to be altered in the podocytes. A novel LMX1B missense mutation (R246Q) was identified. Functional analyses revealed partial but significant impairment of R246Q transcriptional activity. However, no dominant-negative effect of R246Q was detected, which suggests that NPLRD is caused by LMX1B haploinsufficiency. This is the first report on LMX1B mutation identified in a patient with NPLRD. Residual transcriptional activity would account for normality of the nails and patella in this case. Genetic and pathological analyses of additional cases would clarify the role of LMX1B in glomerulopathy without systemic symptoms, which, together with nephropathy in NPS, can be designated as 'LMX1B nephropathy'.

A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome

The phenotypic similarities have been demonstrated between non-lethal campomelic dysplasia (CD) and small patella syndrome (SPS), in which different genetic defects have been identified. We report on a familial case of skeletal dysplasia with overlapping phenotype of mild CD and SPS, including defective ischio-pubic ossification, elongated femoral neck, hypoplastic patellae, and increased space between the first and the second toes (sandal gap). Direct sequencing analysis demonstrated a novel missense mutation (p.H169Q) within the coding region of the SOX9 gene and negative for TBX4 mutations. Functional analysis of the p.H169Q mutant revealed reduced but not fully abolished transactivation capacity of the mutated protein. Retained residual SOX9 function might contribute to an extremely mild CD phenotype in the present cases. © 2013 Wiley Periodicals, Inc.

TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension

BackgroundChildhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene,...

Genitopatellar syndrome

Genitopatellar syndrome is one of the syndromes described in the last decade. It is characterized by agenesis of the corpus callosum, absent or hypoplastic patellae, extremity contractures, skeletal anomalies, urogenital anomalies, and facial dysmorphic features. While writing this report, only 15 cases have been reported in the literature. The etiology, clinical features, management, and natural history of this syndrome are not yet well established. Past reports in the literature have not been able to identify the exact genetic etiology but it somewhat coincides with nail patella syndrome and short patella syndrome. We would like to introduce this terminology to the orthopedic community and highlight the clinical features of the genitopatellar syndrome. To the best of our knowledge, this is a single case report with the longest follow-up of 11 years in the literature.

A ganglion of the patellar tendon in patellar tendon-lateral femoral condyle friction syndrome

Intratendinous ganglia are rare. We report the case of a sedentary woman with chronic mechanical anterolateral pain of the knee and an extensive ganglion of the patellar tendon as indicated on magnetic resonance (MR) and ultrasound (US) examinations. There was evidence of a high-riding patella, patellar malalignment and patellar tendon-lateral femoral condyle friction syndrome with significantly close contact between the patellar tendon and the lateral facet of the femoral trochlea. The ultrasound-guided aspiration of the ganglion enabled a localized injection of an anti-inflammatory drug (cortivazol) and the cytopathological examination of the fluid, which confirmed the diagnosis. Clinical improvement was maintained with knee rehabilitation and was satisfactory at follow-up after 1year. To our knowledge, we report the first case of a ganglion of the patellar tendon subsequent to patellar tendon-lateral femoral condyle friction syndrome. We found that this case was illustrative of mucoid degeneration in connective tissue due to chronic repetitive microtraumas. Additionally, this case provided the opportunity to discuss the management of this condition in a sedentary individual with a high-riding patella and patellar malalignment.

LMX1B‐Regulated Nephrogenesis: A Role for Proteoglycans

Lmx1b is a transcription factor necessary for kidney development. In humans, haploinsufficiency causes Nail Patella Syndrome frequently with chronic renal failure. In Lmx1b knockout mice, glomerular basement membrane formation is impaired, blocking filtration, urine production and long term survival. The mechanisms used by Lmx1b to direct basement membrane formation remain unclear. Recent microarray studies in the limb have implicated the proteoglycans Keratocan, Lumican, and Decorin (KLD) as downstream targets of Lmx1b. We hypothesized that Lmx1b might also regulate the KLD proteoglycans during kidney development.To determine the role of Lmx1b in regulating the KLD proteoglycans, we compared the expression patterns of Lmx1b, Podocin, Keratocan, Lumican, and Decorin in the developing chicken kidney using whole mount in situ hybridization.We found that Keratocan expression localized to nephric tubules and collecting ducts, Lumican expression was associated with nephric tubules, and Decorin expression surrounded Bowman's capsules and nephric tubules. Correspondingly, Lmx1b is expressed in Bowman's capsule and in nephric tubules. Thus, the expression of Decorin complements the expression of Lmx1b.Our data suggests Decorin is a target of Lmx1b regulation during nephrogenesis. Further research is needed to determine the functional role of KLD proteoglycans in kidney development.Grant Funding Source: Departmental

A hypoplastic patella fracture in nail patella syndrome: a case report

IntroductionNail patella syndrome is a rare autosomal dominant hereditary condition, with an incidence of 22 per million in the United Kingdom. The syndrome’s most common features include iliac horns, hypoplastic patella and nail dysplasia.Case presentationWe report the case of a 26-year-old Caucasian man with nail patella syndrome who sustained a fracture of his right hypoplastic patella after a fall. His right knee became swollen and he was unable to extend against gravity immediately post fall. Radiographs revealed a fracture of the lower pole of his right patella with associated complete disruption of the extensor mechanism of the knee. He underwent operative fixation and his post operative course was uneventful. He was further treated post operatively with a full knee cast and graded immobilization. At six months he had regained the full range of motion at the knee joint.ConclusionsTo the best of our knowledge, this is the only case report in the literature describing a patella fracture in an individual with nail patella syndrome. We hypothesize that given the extent of pre-existing knee joint impairment in these individuals, functional outcome may be inferior, suggesting the need for more frequent follow-up.

The use of human embryonic kidney (HEK 293) cells to enhance characterization of the LMX1B pathway

LMX1B is a homeodomain transcription factor critical to kidney development and glomerular filtration. In humans, LMX1B haploinsufficiency causes a condition known as Nail Patella syndrome (NPS). Individuals with NPS typically have under developed nails, absent patellae, and impaired kidney function. In &lt;I/&gt;Lmx1b knockout mice, the absence of Lmx1b function disrupts glomerular filtration and abates urine production. The molecules targeted by LMX1B that regulate glomerular development and function, however, are poorly characterized. Immortalized human embryonic kidney (HEK 293) cells provide a potential tool for high‐throughput identification of LMX1B targets and an &lt;I/&gt;in vitro system for dissecting the functional role of targets. Thus, we characterized the known LMX1B pathway in HEK 293 cells and evaluated sites of LMX1B binding. We demonstrate the expression of &lt;I/&gt;LMX1B and its renal targets, &lt;I/&gt;COLLAGEN 4 ALPHA 4 and &lt;I/&gt;PODICIN in HEK 293 cells by RT‐PCR. Protein expression of LMX1B was verified by western blot analysis. In addition, using Chromatin immunoprecipitation we determined that LMX1B binds to regulatory sequences associated with both target genes. Further characterization of the LMX1B pathway in HEK 293 cells is underway and will likely enhance the identification of relevant downstream targets and the molecular cascade that regulates glomerular development and function.Grant Funding Source: (NICHD) HD 39421

A case of ectopic cilia in nail–patella syndrome

Both ectopic cilia and nail-patella syndrome (NPS) are rare entities. To our knowledge we report the first case of the two anomalies coexisting in one patient. We present the case of a 2-year-old girl, with no other ophthalmic complication of NPS, who had an excellent cosmetic outcome and no lesion recurrence following surgical excision of ectopic cilia.

Nail patella syndrome: a rare cause of renal failure in a young adult

Nail Patella Syndrome (NPS) is a rare hereditary disease affecting multiple systems with predominant involvement of Kidney, Bones and Nails and Eyes. We report a case of NPS which presented as renal failure in a 22 year old male. The patient was admitted with decreased urine output and features of fluid overload and was being evaluated for renal failure. Physical examination revealed associated bony deformities which raised the suspicion of NPS as a possible etiology. This was confirmed by the radiological evaluation which showed the classical features of NPS. Though NPS is a rare clinical condition, physicians should complete knowledge about the components of NPS for appropriate diagnosis and for early detection of other systems involvement.

A 10-year-old with proteinuria and collagen fibers in glomerular basement membrane: questions

Light microscopy revealed normocellular glomeruli showing mild mesangial widening and focal mild basement membrane thickening on PAS stains (see fig. 1). Congo red stains were negative. Non-specific, faint deposits of IgG, IgM, IgA, C3, and C1q were seen along the capillary loops, not conforming to any diagnostic pattern. Ultrastructure revealed bundles of banded collagen in the focally vacuolated lamina densa (see fig. 2) as has been described in nail-patella syndrome (NPS). The foot processes were focally obliterated (see fig. 3). No electron dense deposits were seen. In view of the findings of the kidney biopsy, the patient was clinically and radiologically reassessed for all the features of nail-patella syndrome (NPS). Nails were unremarkable; the patient had normal patellae and no pelvic horns were seen radiologically. Other than mild pectus excavatum and bilateral in-turned fifth toes, there were no remarkable stigmata. Joint examination, especially of the elbows, was normal. In the absence of complete clinical, radiological, and laboratory data of the mother, it was not possible to exclude the possibility of nail–patella syndrome in her. Specific enquiry was, however, made about the clinical features of NPS in the deceased mother and this was not contributory.

Nail patella syndrome: a rare cause of renal failure in a young adult

Nail patella syndrome: a rare cause of renal failure in a young adult

Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Meier-Gorlin syndrome (ear, patella, short stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterised by absent/hypoplastic patellae and markedly small ears1-3. Both pre and post-natal growth are impaired in this disorder and although microcephaly is often evident, intellect is usually normal. We report here that this disorder shows marked locus heterogeneity and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.

Hand and Foot Abnormalities Associated with Genetic Diseases

The small bones and soft tissues of the hands and feet can be affected by systemic disorders, and frequently, the findings are quite unique and virtually diagnostic for some genetic or metabolic disorders. Photographs and imaging studies for the hands and feet are available in a digitized system, which has been approved by our hospital institutional review board. Examination of these and their description can establish a relationship with some degree of certainty to a series of highly variable and uncommon clinical disorders. Description of the clinical, physiologic and genetic characteristics, and illustrations of hand and foot abnormalities are provided for an array of diseases, including Ellis-van Creveld syndrome, fibrodysplasia ossificans progressiva, achondroplasia, Kniest dysplasia, pseudo- and pseudo-pseudohypoparathyroidism, acromegaly, nail-patella syndrome, Marfan's disease, cartilage-hair hypoplasia, and several forms of mucopolysaccharidosis. The findings support the concept that many genetic disorders can often be diagnosed by clinical and imaging examination of the patient's hands and feet.