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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.  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
5.  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
6.  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
7.  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
8.  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.
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  A new variant of spondylometaphyseal dysplasia with autosomal dominant mode of inheritance. 
Journal of Medical Genetics  1982;19(2):104-109.
Clinical and radiographic evaluation of an infant boy and his father revealed findings suggesting a new variant of spondylometaphyseal dysplasia with an apparently autosomal dominant mode of inheritance. The main clinical findings included short stature and marked ligamentous laxity in the infant. X-ray findings included severe and peculiar multiple metaphyseal involvement and striking vertebral undermineralisation in the infant, and platyspondyly in the father. However, all the epiphyses were normal. Laboratory studies were essentially normal except for an extremely raised serum alkaline phosphatase in the infant. The uniqueness of these findings suggests a new variant of the spondylometaphyseal dysplasias, distinct from the cases described initially by Kozlowski et al and subsequent investigators.
PMCID: PMC1048838  PMID: 7077620
19.  Mucopolysaccharidosis type VI in a Miniature Poodle-type dog caused by a deletion in the arylsulphatase B gene 
New Zealand Veterinary Journal  2012;60(3):183-188.
To investigate and characterise an inborn error of metabolism in a dog with skeletal and ocular abnormalities.
A 2.5-year-old small male Miniature Poodle-like dog was presented with gross joint laxity and bilateral corneal opacities. Clinical examination was augmented by routine haematology, serum chemistry, radiographs, pathology, enzymology and molecular genetic studies. Euthanasia was requested when the dog was 3 years of age because of progressively decreasing quality of life.
Radiology revealed generalised epiphyseal dysplasia, malformed vertebral bodies, luxation/subluxation of appendicular and lumbosacral joints with hypoplasia of the odontoid process and hyoid apparatus. These clinical and radiographic findings, together with a positive urinary Berry spot test for mucopolysaccharides, and metachromatic granules in leucocytes, were indicative of a mucopolysaccharidosis (MPS), a lysosomal storage disease. Histological lesions included vacuolation of stromal cells of the cornea, fibroblasts, chondrocytes, macrophages and renal cells. The brain was essentially normal except for moderate secondary Wallerian-type degeneration in motor and sensory tracts of the hind brain. Dermatan sulphateuria was present and enzymology revealed negligible activity of N-acetylgalactosamine-4-sulphatase, also known as arylsulphatase B, in cultured fibroblasts and liver tissue. A novel homozygous 22 base pair (bp) deletion in exon 1 of this enzyme’s gene was identified (c.103_124del), which caused a frame-shift and subsequent premature stop codon. The “Wisdom pure breed-mixed breed” test reported the dog as a cross between a Miniature and Toy Poodle.
The clinicopathological features are similar to those of MPS type VI as previously described in dogs, cats and other species, and this clinical diagnosis was confirmed by enzymology and molecular genetic studies. This is an autosomal recessively inherited lysosomal storage disease.
The prevalence of MPS VI in Miniature or Toy Poodles in New Zealand and elsewhere is currently unknown. Due to the congenital nature of the disorder, malformed pups may be subject to euthanasia without investigation and the potential genetic problem in the breed may not be fully recognised. The establishment of a molecular genetic test now permits screening for this mutation as a basis to an informed breeding policy.
PMCID: PMC3401909  PMID: 22329490
Lysosomal storage disease; mucopolysaccharidosis; Arylsulphatase B; Miniature/Toy Poodle; mutation
20.  Ehlers-Danlos syndrome 
Indian Dermatology Online Journal  2014;5(Suppl 1):S68-S70.
Ehlers-Danlos syndrome (EDS) is a generalized disorder of one element of connective tissue manifesting clinically by fragility and hyperelasticity of the skin and joint laxity. It is a hereditary disorder, the inheritance being usually autosomal dominant with low penetrance. Autosomal recessive and X-linked recessive varieties are also known. First described by Hippocrates in 4th century B.C., the various clinical types with variable penetrance have been described lately. The number of cases EDS reported in the literature is very meagre. With the available information only about six publications of classic EDS in siblings had been reported in Indian literature.
PMCID: PMC4252965  PMID: 25506578
Cigarette paper scarring; Gorlin's sign; Reverse Namaskar sign
21.  Assessment of the relationship between joint laxity and migration of the hip in children with Down syndrome 
The aim of this cross-sectional cohort study is to describe the incidence of joint laxity and the correlation between joint laxity and radiological migration of the hip in children with Down syndrome.
Sixty-five children (2–19 years) with Down’s syndrome were examined for joint laxity. For each subject, laxity scores for joints were carried out with the Bulbena method. Plane pelvic radiographs were used to determine the migration of the hip, according to Reimer’s migration index.
In this study, 26 out of 65 children with Down’s syndrome (40 %) were diagnosed with general joint laxity. On the radiographs of the hips we found a mean Reimer’s Migration Index of 5.2 % for all the subjects. Children with general joint laxity showed a lower Reimer’s Migration Index (2.1 %). No significant correlation was found between general joint laxity and migration of the hip.
This study showed no relationship between joint laxity and migration of the hip in children with Down’s syndrome. This implicates that we were not able to prove that joint laxity is the major factor in developing hip migration in children with Down’s syndrome.
PMCID: PMC3468730  PMID: 24082952
Down’s syndrome; Children; Joint laxity; Hip dysplasia; Migration of the hip
22.  A new manual method for assessing elbow valgus laxity 
A screening of ulnar collateral ligament insufficiency is required for overhead throwers, since secondary pathologic changes result from an increased elbow valgus laxity. We developed a new manual method for assessing elbow valgus laxity and investigated the reliability of this method and its correlation with ultrasonographic assessment.
We defined elbow valgus laxity as the difference between the shoulder external rotation angle (ER angle) measured with the elbow in 90 degrees flexion and that measured with the elbow in extension because ER angle measured with the elbow in 90 degrees flexion includes elbow valgus laxity and ER angle with the elbow in extension does not include it. ER angle measurement with the elbow in extension involved the use of a custom arm holder. Three examiners each measured elbow valgus laxity by the new method in 5 healthy volunteers. Intraobserver and interobserver reliability was evaluated by calculating the intraclass correlation coefficient. We then assessed 19 high-school baseball players with no complaints of shoulder or elbow pain. Elbow ultrasonography was performed with a 10-MHz linear transducer with the elbow in 90 degrees flexion, and the forearm in the neutral position, and the width of the medial joint space at the level of the anterior bundle was measured. Elbow valgus laxity assessed by ultrasonography was defined as the difference between the medial joint space width with gravity stress and that without gravity stress. Increased elbow valgus laxity assessed by both our method and ultrasonography was defined as the difference between the laxity of the elbow on the throwing side and that on the contralateral side. Pearson's correlation coefficient (r) was calculated to evaluate the relationship between increased elbow valgus laxity obtained by our manual method and that by ultrasonography.
Intraobserver reliability ranged from 0.92 to 0.98, and interobserver reliability was 0.70. The increased elbow valgus laxity assessed by our method was significantly correlated with that assessed by ultrasonographic assessment (P = 0.019, r = 0.53).
Elbow valgus laxity can be assessed by our method. This method may be useful for screening for insufficiency of the ulnar collateral ligament.
PMCID: PMC3327632  PMID: 22429865
23.  Computer-aided preoperative planning in knee osteotomy. 
It has been demonstrated that osteoarthritis (OA) is activity related and may worsen when joint contact stress becomes excessive due to overloading. Hence, joint alignment and loading are considered to be the key biomechanical determinants for OA. The initiation of pathologic changes in the knee has been described by the mechanism termed, "vicious cycle" in which joint axial malalignment creates excessive stresses to the localized joint cartilage/subchondral bone regions and the surrounding soft tissue which in turn produces more laxity and joint deformity and thus repeats the cyclic degradation mechanism. If this degenerative cycle can be broken with joint alignment surgery such as osteotomy, a procedure to realign the knee joint and thus redistribute joint forces applied to each compartment, performed properly and at the appropriate time, the osteoarthritic disease process can be decelerated and even reversed. The main goals of this paper are to emphasize the importance of accurate preoperative planning for osteotomy in order to properly correct joint alignment, and to justify the application of an existing computer program, OASIS (Osteotomy Analysis and Simulation Software) using plain radiographs to perform appropriate surgical planning. Normal subjects and knee osteotomy patients were studied to establish a database for the purpose of establishing the utility and efficacy of the presently proposed concept. We wish to rationalize knee osteotomy as a preferred and cost-effective treatment for patients with early symptoms of OA in the knee. This paper presents a new concept of preoperative planning for knee osteotomy based on the underlying etiology of the disease and biomechanical viewpoint with strong emphasis on surgical treatment rationales. The established principles in this paper can be applied to other joints of the body and will help implement preventive measures and other non-surgical means to manage patients with axial malalignment or early degenerative changes.
PMCID: PMC2329085  PMID: 7634043
24.  Finger joint laxity, number of previous pregnancies and pregnancy induced back pain in a cohort study 
General joint hypermobility is estimated to affect about 10% of the population and is a prerequisite of heritable connective tissue disorders where fragile connective tissue is a prominent feature. Pregnancy induced back pain is common whereas about 10% of women still have disabling pain several years after childbirth. The pathogenesis of the pain condition is uncertain, although several risk factors are suggested including general joint hypermobility. In the present study, the possible association of peripheral joint mobility in early pregnancy on the incidence of back pain with onset during pregnancy and persisting after childbirth was explored.
A cohort of 200 pregnant women recruited from antenatal health care clinics was assessed by questionnaire and clinical examination, including measurement of passive abduction of the left fourth finger, throughout pregnancy and at 13 weeks postpartum. Comparisons were made between women with and without back pain. Statistical tests used were χ2-test, t-test, Spearman correlation and multiple logistic regression.
In the cohort, the mean passive abduction angle of the left fourth finger increased from 40.1° in early pregnancy to 41.8° at the postpartum appointment. At the postpartum appointment, women in the back pain group had a significantly larger mean passive abduction angle of the left fourth finger of 4.4°, twice as many previous pregnancies and deliveries, and more than twice as frequent back pain in previous pregnancy, as compared with women with no persistent back pain. A similar pattern was displayed in late pregnancy. In a multiple regression analysis, the passive abduction angle of the left fourth finger in early pregnancy and the number of previous pregnancies were positively, significantly and independently associated to the incidence of back pain in late pregnancy and postpartum.
Finger joint laxity as a reflection of constitutional weakness of connective tissue and number of previous pregnancies were associated with the development of back pain induced in pregnancy and persisting after childbirth. These factors may provide a foundation for development of targeted prevention strategies, but this have to be confirmed in future research including measurement of general joint laxity.
PMCID: PMC4015760  PMID: 24507564
Finger joint laxity; Back pain; Pregnancy; Postpartum
25.  Severe Osteogenesis Imperfecta in Cyclophilin B–Deficient Mice 
PLoS Genetics  2009;5(12):e1000750.
Osteogenesis Imperfecta (OI) is a human syndrome characterized by exquisitely fragile bones due to osteoporosis. The majority of autosomal dominant OI cases result from point or splice site mutations in the type I collagen genes, which are thought to lead to aberrant osteoid within developing bones. OI also occurs in humans with homozygous mutations in Prolyl-3-Hydroxylase-1 (LEPRE1). Although P3H1 is known to hydroxylate a single residue (pro-986) in type I collagen chains, it is unclear how this modification acts to facilitate collagen fibril formation. P3H1 exists in a complex with CRTAP and the peptidyl-prolyl isomerase cyclophilin B (CypB), encoded by the Ppib gene. Mutations in CRTAP cause OI in mice and humans, through an unknown mechanism, while the role of CypB in this complex has been a complete mystery. To study the role of mammalian CypB, we generated mice lacking this protein. Early in life, Ppib-/- mice developed kyphosis and severe osteoporosis. Collagen fibrils in Ppib-/- mice had abnormal morphology, further consistent with an OI phenotype. In vitro studies revealed that in CypB–deficient fibroblasts, procollagen did not localize properly to the golgi. We found that levels of P3H1 were substantially reduced in Ppib-/- cells, while CRTAP was unaffected by loss of CypB. Conversely, knockdown of either P3H1 or CRTAP did not affect cellular levels of CypB, but prevented its interaction with collagen in vitro. Furthermore, knockdown of CRTAP also caused depletion of cellular P3H1. Consistent with these changes, post translational prolyl-3-hydroxylation of type I collagen by P3H1 was essentially absent in CypB–deficient cells and tissues from CypB–knockout mice. These data provide significant new mechanistic insight into the pathophysiology of OI and reveal how the members of the P3H1/CRTAP/CypB complex interact to direct proper formation of collagen and bone.
Author Summary
Osteogenesis Imperfecta (OI), also known as “brittle bone disease,” is an inherited condition with multiple defects in collagen-containing structures, including the bones, skin, and other connective tissues. Patients with OI suffer from short stature, scoliosis, thin skin, hearing loss, and, most notably, fragile bones that break with little or no trauma. Although many cases are due to dominantly inherited point mutations in the collagen genes, autosomal recessive forms have been described due to defects in the genes for Prolyl-3-Hydroxylase-1 (LEPRE1) and Cartilage-Associated Protein (CRTAP), proteins that modify newly synthesized procollagen. Some patients with OI do not have mutations in any of the known disease-related genes. Here, through the use of newly generated knockout mice, we identify the endoplasmic-reticulum resident prolyl-isomerase cyclophilin B (CypB) as a new autosomal recessive OI gene in mice. CypB, P3H1, and CRTAP were shown to have interrelated effects in maintaining their respective protein levels and ability to bind to collagen. These studies enhance our understanding about how collagen, the most abundant protein in the body, becomes properly assembled to form bones with adequate strength.
PMCID: PMC2777385  PMID: 19997487

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