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1.  Osteochondritis dissecans and Osgood Schlatter disease in a family with Stickler syndrome 
Stickler syndrome is among the most common autosomal dominant connective tissue disorders but is often unrecognised and therefore not diagnosed by clinicians. Despite much speculation, the cause of osteochondrosis in general and osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) in particular remain unclear. Etiological understanding is essential. We describe a pair of family subjects presented with OCD and OSS as a symptom complex rather than a diagnosis.
Detailed clinical and radiographic examinations were undertaken with emphasis on the role of MRI imaging. Magnetic resonance imaging may allow early prediction of articular lesion healing potential in patients with Stickler syndrome.
The phenotype of Stickler syndrome can be diverse and therefore misleading. The expectation that the full clinical criteria of any given genetic disorder such as Stickler syndrome will always be present can easily lead to an underestimation of these serious inheritable disorders. We report here two family subjects, a male proband and his aunt (paternal sister), both presented with the major features of Stickler syndrome. Tall stature with marfanoid habitus, astigmatism/congenital vitreous abnormality and submucus cleft palate/cleft uvula, and enlarged painful joints with early onset osteoarthritis. Osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) were the predominating joint abnormalities.
We observed that the nature of the articular and physeal abnormalities was consistent with a localised manifestation of a more generalised epiphyseal dysplasia affecting the weight-bearing joints. In these two patients, OCD and OSS appeared to be the predominant pathologic musculoskeletal consequences of an underlying Stickler's syndrome. It is empirical to consider generalised epiphyseal dysplasia as a major underlying causation that might drastically affect the weight-bearing joints.
PMCID: PMC2645398  PMID: 19193224
2.  Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping 
Human genetics  2009;126(4):589-602.
We report four new patients with a submicroscopic deletion in 15q24 manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features. These clinical features are shared with six recently reported patients with a 15q24 microdeletion, supporting the notion that this is a recognizable syndrome. We describe a case of an ~2.6 Mb microduplication involving a portion of the minimal deletion critical region in a 15-year-old male with short stature, mild mental retardation, attention deficit hyperactivity disorder, Asperger syndrome, decreased joint mobility, digital abnormalities, and characteristic facial features. Some of these features are shared with a recently reported case with a 15q24 microduplication involving the minimal deletion critical region. We also report two siblings and their mother with duplication adjacent and distal to this region exhibiting mild developmental delay, hypotonia, tapering fingers, characteristic facial features, and prominent ears. The deletion and duplication breakpoints were mapped by array comparative genomic hybridization and the genomic structure in 15q24 was analyzed further. Surprisingly, in addition to the previously recognized three low-copy repeat clusters (BP1, BP2, and BP3), we identified two other paralogous low-copy repeat clusters that likely mediated the formation of alternative sized 15q24 genomic rearrangements via non-allelic homologous recombination.
PMCID: PMC3669685  PMID: 19557438
3.  A complex microdeletion 17q12 phenotype in a patient with recurrent de novo membranous nephropathy 
BMC Nephrology  2012;13:27.
Microdeletions on chromosome 17q12 cause of diverse spectrum of disorders and have only recently been identified as a rare cause of Mayer-Rokitansky-Kuester-Hauser-Syndrome (MRKH), which is characterized by uterus aplasia ± partial/complete vaginal aplasia in females with a regular karyotype. For the first time we report about a patient with a 17q12 microdeletion who is affected by MRKH in combination with a vascular and soft tissue disorder. Repeatedly she suffered from kidney transplant failure caused by consuming membranous nephropathy.
Case presentation
A 38-year-old female patient had been diagnosed with right kidney aplasia, left kidney dysplasia and significantly impaired renal function during infancy. Aged 16 she had to start hemodialysis. Three years later she received her first kidney transplant. Only then she was diagnosed with MRKH. The kidney transplant was lost due to consuming nephrotic syndrome caused by de novo membranous nephropathy, as was a second kidney transplant years later. In addition, a hyperelasticity syndrome affects the patient with congenital joint laxity, kyphoscoliosis, bilateral hip dysplasia, persistent hypermobility of both elbows, knees and hips. Her clinical picture resembles a combination of traits of a hypermobile and a vascular form of Ehlers-Danlos-Syndrome, but no mutations in the COL3A1 gene was underlying. Instead, array-based comparative genomic hybridisation (CGH) detected a heterozygous 1.43 Mb deletion on chromosome 17q12 encompassing the two renal developmental genes HNF1β and LHX1.
Deletions of HNF1β have recently drawn significant attention in pediatric nephrology as an important cause of prenatally hyperechogenic kidneys, renal aplasia and renal hypodysplasia. In contrast, membranous nephropathy represents an often-unaccounted cause of nephrotic syndrome in the adult population. A causative connection between theses two conditions has never been postulated, but is suggestive enough in this case to hypothesize it.
PMCID: PMC3412739  PMID: 22583611
Microdeletion 17q12 syndrome; Mayer-Rokitansky-Kuester-Hauser-Syndrome membranous nephropathy; Nephrotic syndrome; HNF1β; LHX1
4.  AB042. Therapies for the bone in mucopolysaccharidoses 
Annals of Translational Medicine  2015;3(Suppl 2):AB042.
Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to: (I) stenosis of the upper cervical region; (II) restrictive small lung; (III) hip dysplasia; (IV) restriction of joint movement; and (V) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs.
PMCID: PMC4563430
Mucopolysaccharidoses (MPS); enzyme replacement therapy (ERT); hematopoietic stem cell transplantation (HSCT); gene therapy; anti-inflammatory drug
5.  Therapies for the bone in mucopolysaccharidoses 
Molecular genetics and metabolism  2014;114(2):94-109.
Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required.
Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life.
This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs.
PMCID: PMC4312706  PMID: 25537451
mucopolysaccharidoses; skeletal dysplasia; enzyme replacement therapy; gene therapy; hematopoietic stem cell transplantation; anti-inflammatory drug
6.  Ehlers Danlos Syndrome: An Unusual Presentation You Need to Know about 
Case Reports in Pediatrics  2013;2013:764659.
The Ehlers Danlos syndromes (EDS) comprise a group of connective tissue disorders characterized by tissue fragility of the skin, ligaments, blood vessels and internal organs. Variable degrees of clinical severity and organ involvement are due to the molecular and biochemical heterogeneity of this group of disorders and have led to classification into well-characterized subtypes that are extending with the discovery of new genes and overlapping syndrome. Types include classical EDS (EDS I/II), hypermobility EDS (EDS III), vascular EDS (EDS IV), kyphoscoliosis EDS (EDS VI), arthrochalasia (EDS VIIA, B) and Dermatospraxis (EDS VIIC). Even to the well trained professional, the diagnosis of EDS remains a challenge due to overlapping symptoms and cases can remain without a well-defined classification. Life altering complications of this group of disorders include vascular and hollow organ rupture and ligamentous laxity leading to chronic dislocation with ensuing pain and long term disability. Patients initially present to the general practitioner who is expected to recognize the symptoms of EDS and to proceed with appropriate referral for definitive diagnosis and management to prevent devastating complications. In this paper, we describe a male with classical EDS complicated by devastating vascular and orthopedic events.
PMCID: PMC3670523  PMID: 23762718
7.  Phenotypic plasticity to light and nutrient availability alters functional trait ranking across eight perennial grassland species 
AoB Plants  2015;7:plv029.
Functional traits are often used as species-specific means in trait-based predictions of ecosystem processes, assuming that interspecific differences are greater than intraspecific trait variation. We grew eight perennial grassland species representing two functional groups (grasses vs. forbs) and growth statures (small vs. tall) under different light and nutrient availability. The strength of trait variation in response to resource availability differed among functional groups and growth statures in many aboveground traits, while being more consistent in belowground traits. Our results, showing the dependency of trait-based species ranking on environmental conditions, limit the applicability of species-specific mean trait values in ecological studies.
Functional traits are often used as species-specific mean trait values in comparative plant ecology or trait-based predictions of ecosystem processes, assuming that interspecific differences are greater than intraspecific trait variation and that trait-based ranking of species is consistent across environments. Although this assumption is increasingly challenged, there is a lack of knowledge regarding to what degree the extent of intraspecific trait variation in response to varying environmental conditions depends on the considered traits and the characteristics of the studied species to evaluate the consequences for trait-based species ranking. We studied functional traits of eight perennial grassland species classified into different functional groups (forbs vs. grasses) and varying in their inherent growth stature (tall vs. small) in a common garden experiment with different environments crossing three levels of nutrient availability and three levels of light availability over 4 months of treatment applications. Grasses and forbs differed in almost all above- and belowground traits, while trait differences related to growth stature were generally small. The traits showing the strongest responses to resource availability were similarly for grasses and forbs those associated with allocation and resource uptake. The strength of trait variation in response to varying resource availability differed among functional groups (grasses > forbs) and species of varying growth stature (small-statured > tall-statured species) in many aboveground traits, but only to a lower extent in belowground traits. These differential responses altered trait-based species ranking in many aboveground traits, such as specific leaf area, tissue nitrogen and carbon concentrations and above-belowground allocation (leaf area ratio and root : shoot ratio) at varying resource supply, while trait-based species ranking was more consistent in belowground traits. Our study shows that species grouping according to functional traits is valid, but trait-based species ranking depends on environmental conditions, thus limiting the applicability of species-specific mean trait values in ecological studies.
PMCID: PMC4417138  PMID: 25818071
Above- and belowground traits; forbs; functional groups; functional traits; grasses; growth stature; light; nutrients; trait variation
8.  A microfibril assembly assay identifies different mechanisms of dominance underlying Marfan syndrome, stiff skin syndrome and acromelic dysplasias 
Human Molecular Genetics  2015;24(15):4454-4463.
Fibrillin-1 is the major component of the 10–12 nm diameter extracellular matrix microfibrils. The majority of mutations affecting the human fibrillin-1 gene, FBN1, result in Marfan syndrome (MFS), a common connective tissue disorder characterised by tall stature, ocular and cardiovascular defects. Recently, stiff skin syndrome (SSS) and a group of syndromes known collectively as the acromelic dysplasias, which typically result in short stature, skin thickening and joint stiffness, have been linked to FBN1 mutations that affect specific domains of the fibrillin-1 protein. Despite their apparent phenotypic differences, dysregulation of transforming growth factor β (TGFβ) is a common factor in all of these disorders. Using a newly developed assay to track the secretion and incorporation of full-length, GFP-tagged fibrillin-1 into the extracellular matrix, we investigated whether or not there were differences in the secretion and microfibril assembly profiles of fibrillin-1 variants containing substitutions associated with MFS, SSS or the acromelic dysplasias. We show that substitutions in fibrillin-1 domains TB4 and TB5 that cause SSS and the acromelic dysplasias do not prevent fibrillin-1 from being secreted or assembled into microfibrils, whereas MFS-associated substitutions in these domains result in a loss of recombinant protein in the culture medium and no association with microfibrils. These results suggest fundamental differences in the dominant pathogenic mechanisms underlying MFS, SSS and the acromelic dysplasias, which give rise to TGFβ dysregulation associated with these diseases.
PMCID: PMC4492404  PMID: 25979247
9.  Morquio A Syndrome: Diagnosis and Current and Future Therapies 
Morquio A syndrome is an autosomal recessive disorder, one of 50 lysosomal storage diseases (LSDs), and is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Deficiency of this enzyme causes specific glycosaminoglycan (GAG) accumulation: keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The majority of KS is produced in the cartilage, therefore, the undegraded substrates accumulate mainly in cartilage and in its extracelluar matrix (ECM), causing direct leads to direct impact on cartilage and bone development and leading to the resultant systemic skeletal spondyloepiphyseal dysplasia. Chondrogenesis, the earliest phase of skeletal formation that leads to cartilage and bone formation is controlled by cellular interactions with the ECM, growth and differentiation factors and other molecules that affect signaling pathways and transcription factors in a temporal-spatial manner. In Morquio A patients, in early childhood or even at birth, the cartilage is disrupted presumably as a result of abnormal chondrogenesis and/or endochondral ossification. The unique clinical features are characterized by a marked short stature, odontoid hypoplasia, protrusion of the chest, kyphoscoliosis, platyspondyly, coxa valga, abnormal gait, and laxity of joints.
In spite of many descriptions of the unique clinical manifestations, diagnosis delay still occurs. The pathogenesis of systemic skeletal dysplasia in Morquio A syndrome remains an enigmatic challenge. In this review article, screening, diagnosis, pathogenesis and current and future therapies of Morquio A are discussed.
PMCID: PMC4259875  PMID: 25345096
mucopolysaccharidosis IVA; enzyme assay; keratan sulfate; tandem mass spectrometry; GALNS; enzyme replacement therapy; bone marrow transplantation; pathogenesis; Morquio tissue repository bank
10.  Evidence for anticipation in Beckwith–Wiedemann syndrome 
European Journal of Human Genetics  2013;21(12):1344-1348.
Classical Beckwith–Wiedemann syndrome (BWS) was diagnosed in two sisters and their male cousin. The children's mothers and a third sister were tall statured (178, 185 and 187 cm) and one had mild BWS features as a child. Their parents had average heights of 173 cm (mother) and 180 cm (father). This second generation tall stature and third generation BWS correlated with increased methylation of the maternal H19/IGF2-locus. The results were obtained by bisulphite treatment and subclone Sanger sequencing or next generation sequencing to quantitate the degree of CpG-methylation on three locations: the H19 promoter region and two CTCF binding sites in the H19 imprinting control region (ICR1), specifically in ICR1 repeats B1 and B7. Upon ICR1 copy number analysis and sequencing, the same maternal point variant NCBI36:11:g.1979595T>C that had been described previously as a cause of BWS in three brothers, was found. As expected, this point variant was on the paternal allele in the non-affected grandmother. This nucleotide variant has been shown to affect OCTamer-binding transcription factor-4 (OCT4) binding, which may be necessary for maintaining the unmethylated state of the maternal allele. Our data extend these findings by showing that the OCT4 binding site mutation caused incomplete switching from paternal to maternal ICR1 methylation imprint, and that upon further maternal transmission, methylation of the incompletely demethylated variant ICR1 allele was further increased. This suggests that maternal and paternal ICR1 alleles are treated differentially in the female germline, and only the paternal allele appears to be capable of demethylation.
PMCID: PMC3831082  PMID: 23572028
Beckwith–Wiedemann syndrome; anticipation; imprinting; H19; IGF2
11.  Current and emerging treatments and surgical interventions for Morquio A syndrome: a review 
Patients with mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) have accumulation of the glycosaminoglycans, keratan sulfate, and chondroitin-6-sulfate, in bone and cartilage, causing systemic spondyloepiphyseal dysplasia. Features include lumbar gibbus, pectus carinatum, faring of the rib cage, marked short stature, cervical instability and stenosis, kyphoscoliosis, genu valgum, and laxity of joints. Generally, MPS IVA patients are wheelchair-bound as teenagers and do not survive beyond the second or third decade of life as a result of severe bone dysplasia, causing restrictive lung disease and airway narrowing, increasing potential for pneumonia and apnea; stenosis and instability of the upper cervical region; high risk during anesthesia administration due to narrowed airway as well as thoracoabdominal dysfunction; and surgical complications. Patients often need multiple surgical procedures, including cervical decompression and fusion, hip reconstruction and replacement, and femoral or tibial osteotomy, throughout their lifetime. Current measures to intervene in disease progression are largely palliative, and improved therapies are urgently needed. A clinical trial for enzyme replacement therapy (ERT) and an investigational trial for hematopoietic stem cell transplantation (HSCT) are underway. Whether sufficient enzyme will be delivered effectively to bone, especially cartilage (avascular region) to prevent the devastating skeletal dysplasias remains unclear. This review provides an overview of historical aspects of studies on MPS IVA, including clinical manifestations and pathogenesis of MPS IVA, orthopedic surgical interventions, and anesthetic care. It also describes perspectives on potential ERT, HSCT, and gene therapy.
PMCID: PMC4020877  PMID: 24839594
mucopolysaccharidosis IVA; keratan sulfate; GALNS; enzyme replacement therapy; gene therapy; hematopoietic stem cell transplantation
12.  XYY syndrome: a 13-year-old boy with tall stature 
When evaluating the underlying causes of tall stature, it is important to differentiate pathologic tall stature from familial tall stature. Various pathologic conditions leading to adult tall stature include excess growth hormone secretion, Marfan syndrome, androgen or estrogen deficiency, testicular feminization, and sex chromosome anomaly, such as Klinefelter syndrome and XYY syndrome. Men with 47,XYY syndrome can exhibit multiple phenotypes. A 13-year-old boy visited the hospital for evaluation of tall stature. The boy had no other physical abnormalities except tall stature. All biochemical and imaging studies were within the normal ranges. He was diagnosed with XYY syndrome in this chromosome study. When evaluating men with tall stature, XYY syndrome should be ruled out.
PMCID: PMC4623347  PMID: 26512355
Growth disorders; Sex chromosome disorders; 47,XYY syndrome
13.  Turner syndrome presented with tall stature due to overdosage of the SHOX gene 
Turner syndrome is one of the most common chromosomal disorders. It is caused by numerical or structural abnormalities of the X chromosome and results in short stature and gonadal dysgenesis. The short stature arises from haploinsufficiency of the SHOX gene, whereas overdosage contributes to tall stature. This report describes the first Korean case of Turner syndrome with tall stature caused by SHOX overdosage. The patient presented with primary amenorrhea and hypergonadotropic hypogonadism at the age of 17 years. Estrogen replacement therapy was initiated at that time. She displayed tall stature from childhood, with normal growth velocity, and reached a final height of 190 cm (standard deviation score, 4.3) at the age of 30 years. Her karyotype was 46,X, psu idic(X)(q21.2), representing partial monosomy of Xq and partial trisomy of Xp. Analysis by multiplex ligation-dependent probe amplification detected a duplication at Xp22.3-Xp22.2, encompassing the PPP2R3 gene near the 5'-end of the SHOX gene through the FANCD gene at Xp22.2.
PMCID: PMC4504991  PMID: 26191517
Turner syndrome; SHOX protein; Gonadal dysgenesis
14.  Metacarpal index in Marfan's syndrome and in constitutional tall stature. 
Archives of Disease in Childhood  1994;70(2):149-150.
The metacarpal index (MCI) in 54 children with constitutional tall stature was mean (SD) 8.65 (0.8) and in 55 with Marfan's syndrome 9.15 (0.9). Indices in both groups showed arachnodactyly and differed from those found in normal individuals (< 7.9). Because the MCI is a poor discriminator patients with tall stature or clinical signs of arachnodactyly should be examined for additional signs of Marfan's syndrome or other hereditary disorders of connective tissue.
PMCID: PMC1029724  PMID: 8129443
15.  Sequential Sectioning of the Ulnar Collateral Ligament of the Elbow in Cadaveric Arms with Ulnohumeral Laxity Assessed by Dynamic Ultrasonography 
Orthopaedic Journal of Sports Medicine  2013;1(4 Suppl):2325967113S00016.
Injury of the ulnar collateral ligament (UCL), whether acute or chronic, is potentially career-threatening for elite overhead throwing athletes. Dynamic ultrasound (DUS) allows for rapid, cost-effective, non-invasive, and non-radiating evaluation of the UCL and elbow joint both at rest and with applied stress. The purpose of this study was to determine the amount of cadaveric elbow valgus laxity with sequential UCL sectioning using DUS. Our objective was to quantify which portions of the UCL must be injured to cause the varying levels of laxity seen clinically on DUS testing. No prior study has used DUS to quantify valgus joint laxity with sequential cadaveric UCL sectioning. It was hypothesized that the change in laxity due to release of the anterior band of the UCL would be greater than that seen when the posterior and transverse bands were cut.
Twelve cadaveric elbows were dissected free of skin and subcutaneous tissue by an experienced orthopaedic surgeon. Baseline DUS at rest and with applied valgus stress was then performed by an experienced ultrasonographer. Sequential sectioning of the medial elbow soft-tissue stabilizing structures was then carried out with valgus stress applied to the joint at each sectioning interval utilizing a standardized device (Telos, Marburg, Germany). First the transverse band of the UCL was released, followed by the posterior band, then the anterior bundle of the anterior band, the remaining posterior bundle of the anterior band, and finally the complete flexor pronator mass.
Mean ulnohumeral laxity in millimeters with 95% CIs was calculated for each step of the sequence. The deltas between each step of the dissection were also calculated with means and 95% CIs. Mean baseline laxity of the unstressed ulnohumeral joint at rest was 3.2 mm (CI, 2.2-4.2); with the addition of valgus stress, mean laxity was 4.7 mm (CI, 3.5-6.0). When the transverse band was cut, ulnohumeral laxity increased to a mean of 5.5 mm (CI, 4.0-7.0). With release of the posterior band, mean laxity was 6.4 mm (CI, 4.3-8.5). When the anterior bundle of the anterior band of the UCL was cut, mean ulnohumeral laxity was 8.4 mm (CI, 5.7-11.0) and when the entire anterior band was released, mean laxity was 10.9 mm (CI, 7.8-14.0). Complete release of the flexor pronator muscle mass resulted in mean ulnohumeral laxity of 15.5 mm (CI, 12.9-18.1). The largest deltas were observed with release of the anterior bundle of the anterior band (2.0 mm; CI, 1.0-3.0), the entire anterior band (2.6 mm; CI, 1.3-3.8), and flexor pronator mass (4.6 mm; CI, 1.3-3.8). Release of the transverse and posterior bands of the UCL resulted in deltas of 0.74 mm (CI, 0.1-1.3) and 0.9 mm (CI, 0.3-1.5) respectively.
DUS allows for rapid, cost-effective, non-invasive, non-radiating evaluation of the elbow joint and UCL both at rest and with applied valgus stress. Previous studies have indicated that DUS can identify abnormalities of the UCL associated with chronic degeneration and ligamentous injury including thickening of the anterior band of the UCL as well as hypoechoic foci/calcifications. The results of the current cadaveric study suggest that different changes in clinical laxity are seen on DUS with injury of particular bands of the UCL. Early identification and localization of injury to a particular band of the UCL may allow more appropriate selection of patients who will benefit from operative treatment.
PMCID: PMC4588929
16.  Skeletal Dysplasia, Global Developmental Delay, and Multiple Congenital Anomalies in a 5 year-old boy– Report of the Second Family with B3GAT3 mutation and Expansion of the Phenotype 
As a major component of the extracellular matrix, proteoglycans influence the mechanical properties of connective tissue and play an important role in cell-cell and cell-matrix interactions. Genetic defects of proteoglycan biosynthesis lead to multi-system disorders, often most prominently affecting the skeletal system and skin. Specific deficiencies in the enzymes involved in the biosynthesis of the linkage region between the core of the proteoglycan protein and its glycosaminoglycan side chains are known as linkeropathies. We report on a patient from a second family with a homozygous c.830 G>A (p.Arg277Gln) mutation in the B3GAT3 gene. The clinical features expand the previously reported phenotype of B3GAT3 mutations and of linkeropathies in general. This patient has short stature, facial dysmorphisms, skeletal findings, joint laxity, and cardiac manifestations similar to those previously associated with B3GAT3 mutations. However, he also has developmental delay, a visual refractory defect, dental defects, pectus carinatum, and skin abnormalities that have only been associated with linkeropathies caused by mutations in B4GALT6 and B4GALT7. He has bilateral inguinal hernias and atlanto-axial as well as atlanto-occipital instability that have not been previously associated with B3GAT3 mutations. We provide a detailed clinical report and a comparative overview of the phenotypic features of the linkeropathies caused by mutations in B3GAT3, B4GALT6 and B4GALT7.
PMCID: PMC4384644  PMID: 24668659
B3GAT3; proteoglycan disorder; linkeropathy; Larsen-like syndrome
17.  Chronic Neck Pain: Making the Connection Between Capsular Ligament Laxity and Cervical Instability 
The use of conventional modalities for chronic neck pain remains debatable, primarily because most treatments have had limited success. We conducted a review of the literature published up to December 2013 on the diagnostic and treatment modalities of disorders related to chronic neck pain and concluded that, despite providing temporary relief of symptoms, these treatments do not address the specific problems of healing and are not likely to offer long-term cures. The objectives of this narrative review are to provide an overview of chronic neck pain as it relates to cervical instability, to describe the anatomical features of the cervical spine and the impact of capsular ligament laxity, to discuss the disorders causing chronic neck pain and their current treatments, and lastly, to present prolotherapy as a viable treatment option that heals injured ligaments, restores stability to the spine, and resolves chronic neck pain.
The capsular ligaments are the main stabilizing structures of the facet joints in the cervical spine and have been implicated as a major source of chronic neck pain. Chronic neck pain often reflects a state of instability in the cervical spine and is a symptom common to a number of conditions described herein, including disc herniation, cervical spondylosis, whiplash injury and whiplash associated disorder, postconcussion syndrome, vertebrobasilar insufficiency, and Barré-Liéou syndrome.
When the capsular ligaments are injured, they become elongated and exhibit laxity, which causes excessive movement of the cervical vertebrae. In the upper cervical spine (C0-C2), this can cause a number of other symptoms including, but not limited to, nerve irritation and vertebrobasilar insufficiency with associated vertigo, tinnitus, dizziness, facial pain, arm pain, and migraine headaches. In the lower cervical spine (C3-C7), this can cause muscle spasms, crepitation, and/or paresthesia in addition to chronic neck pain. In either case, the presence of excessive motion between two adjacent cervical vertebrae and these associated symptoms is described as cervical instability.
Therefore, we propose that in many cases of chronic neck pain, the cause may be underlying joint instability due to capsular ligament laxity. Currently, curative treatment options for this type of cervical instability are inconclusive and inadequate. Based on clinical studies and experience with patients who have visited our chronic pain clinic with complaints of chronic neck pain, we contend that prolotherapy offers a potentially curative treatment option for chronic neck pain related to capsular ligament laxity and underlying cervical instability.
PMCID: PMC4200875  PMID: 25328557
Atlanto-axial joint; Barré- Liéou syndrome; C1-C2 facet joint; capsular ligament laxity; cervical instability; cervical radiculopathy; chronic neck pain; facet joints; post-concussion syndrome; prolotherapy; spondylosis; vertebrobasilar insufficiency; whiplash.
18.  Further delineation of Nevo syndrome. 
Journal of Medical Genetics  1997;34(5):366-370.
Nevo syndrome is an autosomal recessive syndrome characterised by prenatal overgrowth, joint laxity, kyphosis, wrist drop, spindle shaped fingers, and volar oedema. Four children from two families have been reported previously. We report two further children from two unrelated Arab families from two different tribes. Both presented at birth with hypotonia, joint laxity, kyphosis, wrist drop, spindle shaped fingers, and volar oedema. Both have delayed motor development at the ages of 2 years 10 months and 3 months respectively. Cognitive development is normal in one, and the other case appears to be developing normally at 3 months of age. One has, in addition, a wide spinal canal on MRI of the spine indicating some degree of dural ectasia. This report brings the total number of children reported with this syndrome to six from four families; three of these families are Arab. This indicates that the gene for this syndrome is probably commoner in Arabs than in other populations.
PMCID: PMC1050942  PMID: 9152832
19.  Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency 
Journal of Clinical Investigation  2000;106(2):271-279.
Over 20 severely obese subjects in 11 independent kindreds have been reported to have pathogenic heterozygous mutations in the gene encoding the melanocortin 4 receptor (MC4R), making this the most common known monogenic cause of human obesity. To date, the detailed clinical phenotype of this dominantly inherited disorder has not been defined, and no homozygous subjects have been described. We determined the nucleotide sequence of the entire coding region of the MC4R gene in 243 subjects with severe, early-onset obesity. A novel two–base pair GT insertion in codon 279 was found in two unrelated subjects, and four novel missense mutations, N62S, R165Q, V253I, C271Y, and one mutation (T112M) reported previously were found in five subjects. N62S was found in homozygous form in five children with severe obesity from a consanguineous pedigree. All four heterozygous carriers were nonobese. Several features of the phenotype, e.g. hyperphagia, tendency toward tall stature, hyperinsulinemia, and preserved reproductive function, closely resemble those reported previously in Mc4r knock-out mice. In addition, a marked increase in bone mineral density was seen in all affected subjects. In transient transfection assays, the N62S mutant receptor showed a responsiveness to αMSH that was intermediate between the wild-type receptor and mutant receptors carrying nonsense and missense mutations associated with dominantly inherited obesity. Thus MC4R mutations result in a syndrome of hyperphagic obesity in humans that can present with either dominant or recessive patterns of inheritance.
PMCID: PMC314308  PMID: 10903343
20.  Somatic Overgrowth Predisposes to Seizures in Autism Spectrum Disorders 
PLoS ONE  2013;8(9):e75015.
Comorbidity of Autism Spectrum Disorders with seizures or abnormal EEG (Autism-Epilepsy Phenotype) suggests shared pathomechanisms, and might be a starting point to identify distinct populations within the clinical complexity of the autistic spectrum. In this study, we tried to assess whether distinct subgroups, having distinctive clinical hallmarks, emerge from this comorbid condition.
Two-hundred and six individuals with idiopathic Autism Spectrum Disorders were subgrouped into three experimental classes depending on the presence of seizures and EEG abnormalities. Neurobehavioral, electroclinical and auxological parameters were investigated to identify differences among groups and features which increase the risk of seizures. Our statistical analyses used ANOVA, post-hoc multiple comparisons, and the Chi-squared test to analyze continuous and categorical variables. A correspondence analysis was also used to decompose significant Chi-squared and reduce variables dimensions.
The high percentage of children with seizures (28.2% of our whole cohort) and EEG abnormalities (64.1%) confirmed that the prevalence of epilepsy in Autism Spectrum Disorders exceeds that of the general population. Seizures were associated with severe intellectual disability, and not with autism severity. Interestingly, tall stature (without macrocephaly) was significantly associated with EEG abnormalities or later onset seizures. However, isolated macrocephaly was equally distributed among groups or associated with early onset seizures when accompanied by tall stature.
Tall stature seems to be a phenotypic “biomarker” of susceptibility to EEG abnormalities or late epilepsy in Autism Spectrum Disorders and, when concurring with macrocephaly, predisposes to early onset seizures. Growth pattern might act as an endophenotypic marker in Autism-Epilepsy comorbidity, delineating distinct pathophysiological subtypes and addressing personalized diagnostic work-up and therapeutic approaches.
PMCID: PMC3781047  PMID: 24086423
21.  Identifying Multiplanar Knee Laxity Profiles and Associated Physical Characteristics 
Journal of Athletic Training  2012;47(2):159-169.
A single measure of knee laxity (ie, measurement of laxity in a single plane of motion) is probably inadequate to fully describe how knee joint laxity is associated with anterior cruciate ligament injury.
To characterize interparticipant differences in the absolute and relative magnitudes of multiplanar knee laxity (ie, sagittal, frontal, and transverse planes) and examine physical characteristics that may contribute to these differences.
Descriptive laboratory study.
University research laboratory.
Patients or Other Participants:
140 participants (90 women, 50 men).
Main Outcome Measure(s):
Using cluster analysis, we grouped participants into distinct multiplanar knee laxity profiles based on the absolute and relative magnitudes of their anterior knee laxity (AKL), genu recurvatum (GR), and varusvalgus (VV) and internal-external rotation (IER) knee laxity. Using multinomial logistic regression, we then examined associations between the different laxity profile clusters and physical characteristics of sex, age, activity level, general joint laxity, body mass index, thigh strength, and 8 measures of lower extremity anatomical alignment.
Six clusters were identified: low (LOW), moderate (MOD) and high (HIGH) laxity overall and disproportionally higher VV/IER (MODVV/IER), GR (HIGHGR), and AKL (HIGHAKL) laxity. Once all other physical characteristics were accounted for, the LOW cluster was more likely to be older, with longer femur length. Clusters with greater magnitudes of VV and IER laxity were more likely to be younger and to have lower body mass index, smaller Q-angle, and shorter femur length (MOD, HIGH, MODVV/IER) and less thigh strength (HIGH). The HIGHGR cluster was more likely to be female and to have a smaller tibiofemoral angle and longer femur length. The HIGHAKL cluster was more likely to have greater hip anteversion and navicular drop.
The absolute and relative magnitudes of a person's multiplanar knee laxity are not always uniform across planes of motion and can be influenced by age, body composition, thigh strength, and structural alignment. Except in HIGHGR, sex was not a significant predictor of cluster membership once other physical characteristics were taken into account.
PMCID: PMC3418127  PMID: 22488281
hypermobility; anterior cruciate ligament injury risk factors; body composition; strength; lower extremity alignment; age; sex
22.  Combined Bentall and modified Ravitch procedures in a patient with Marfan syndrome 
Marfan syndrome is an inherited, connective-tissue disorder transmitted as an autosomal dominant trait. Cardinal features of the disorder include tall stature, ectopia lentis, mitral valve prolapse, aortic root dilatation, and aortic dissection. Pectus excavatum may exist as an isolated lesion or in association with a genetic syndrome such as Marfan syndrome. We report the successful management of a simultaneous correction of pectus excavatum and the underlying cardiovascular diseases.
PMCID: PMC3590552  PMID: 23493844
Aortic aneurysm; Marfan syndrome; pectus excavatum
23.  3-M syndrome associated with growth hormone deficiency: 18 year follow-up of a patient 
3-M syndrome is a rare autosomal recessive disorder that causes short stature, unusual facial features and skeletal abnormalities. Mutations in the CUL7, OBSL1 and CCDC8 genes could be responsible for 3-M syndrome.
Here we describe the growth and evolution of dismorphic features of an Italian boy with 3-M syndrome and growth hormone deficiency (GHD) from birth until adulthood. He was born full term with a very low birth weight (2400 g=−3.36 standard deviation score, SDS) and length (40.0 cm =−6.53 SDS). At birth he presented with a broad, fleshy nose with anteverted nostrils, thick and patulous lips, a square chin, curvilinear shaped eyebrows without synophrys, short thorax and long slender bones. Then, during childhood tall vertebral bodies, hip dislocation, transverse chest groove, winged scapulae and hyperextensible joints became more evident and the diagnosis of 3-M syndrome was made; this was also confirmed by the finding of a homozygous deletion in exon 18 of the CUL7 gene, which has not been previously described.
The patient also exhibited severe GHD (GH <5 ng/ml) and from the age of 18 months was treated with rhGH. Notwithstanding the early start of therapy and good compliance, his growth rate was always very low, except for the first two years of treatment and he achieved a final height of 132 cm (−6.42 SDS).
PMCID: PMC3608257  PMID: 23517720
3-M syndrome; Growth hormone deficiency; CUL-7 gene mutation
24.  Determination of the molecular basis of Marfan syndrome: a growth industry 
Journal of Clinical Investigation  2004;114(2):161-163.
Although it has been known for more than a decade that Marfan syndrome — a dominantly inherited connective tissue disorder characterized by tall stature, arachnodactyly, lens subluxation, and a high risk of aortic aneurysm and dissection — results from mutations in the FBN1 gene, which encodes fibrillin-1, the precise mechanism by which the pleiotropic phenotype is produced has been unclear. A report in this issue now proposes that loss of fibrillin-1 protein by any of several mechanisms and the subsequent effect on the pool of TGF-β may be more relevant in the development of Marfan syndrome than mechanisms previously proposed in a dominant-negative disease model. The model proposed in this issue demonstrates several strategies for clinical intervention.
PMCID: PMC449756  PMID: 15254580
25.  Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation 
The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal.
We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome.
Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients.
In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity.
PMCID: PMC3135503  PMID: 21699693

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