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Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular and skeletal abnormalities resembling Marfan syndrome, including a predisposition for pathologic fracture. LDS is caused by heterozygous mutations in the genes encoding transforming growth factor-β (TGF-β) type 1 and type 2 receptors. In this study, we characterized the skeletal phenotype of mice carrying a mutation in the TGF-β type 2 receptor associated with severe LDS in humans. Cortical bone in LDS mice showed significantly reduced tissue area, bone area, and cortical thickness with increased eccentricity. However, no significant differences in trabecular bone volume were observed. Dynamic histomorphometry performed in calcein-labeled mice showed decreased mineral apposition rates in cortical and trabecular bone with normal numbers of osteoblasts and osteoclasts. Mechanical testing of femurs by three-point bending revealed reduced femoral strength and fracture resistance. In vitro, osteoblasts from LDS mice demonstrated increased mineralization with enhanced expression of osteoblast differentiation markers compared with control cells. These changes were associated with impaired TGF-β1-induced Smad2 and Erk1/2 phosphorylation and upregulated TGF-β1 ligand mRNA expression, compatible with G357W as a loss-of-function mutation in the TGF-β type 2 receptor. Paradoxically, phosphorylated Smad2/3 in cortical osteocytes measured by immunohistochemistry was increased relative to controls, possibly suggesting the cross-activation of TGF-β-related receptors. The skeletal phenotype observed in the LDS mouse closely resembles the principal structural features of bone in humans with LDS and establishes this mouse as a valid in vivo model for further investigation of TGF-β receptor signaling in bone.

Loeys-Dietz syndrome is a recently recognized connective tissue disorder with widespread systemic involvement. Little is known about its skeletal phenotype. Our goal was to investigate the risk of fracture and incidence of low bone mineral density in patients with Loeys-Dietz syndrome. We performed a cross-sectional, descriptive, survey-based study with subsequent chart review from July 2011 to April 2012. Fifty-seven patients (26 men, 31 women) with Loeys-Dietz syndrome confirmed by genetic testing completed the survey (average age, 25.3 years; range, 0.9-79.6 years). There were a total of 51 fractures (33 patients): 35 fractures in the upper extremities, 14 in the lower extremities, and two in the spine. Fourteen patients (24.6%) reported two or more fractures. There was a 50% risk of fracture by age 14 years. The incidence of any fracture in this cohort was 3.86 per 100 person-years. Seventeen patients had dual-energy X-ray absorptiometry scans available for review, 11 (64.7%) of whom had at least one fracture. Thirteen included lumbar spine absorptiometry reports; eight (61.5%) indicated low or very low bone mineral density. In the left hip, ten of 14 participants (71.4%) had low or very low bone mineral density. In the left femoral neck, nine of 13 participants (69.2%) had low or very low bone mineral density. The lowest Z- and T-scores were not associated with an increased number of fractures. Patients with Loeys-Dietz syndrome have a high risk of fracture and a high incidence of low bone mineral density.

Clinical studies indicate that as a group, osteogenesis imperfecta (OI) subjects are shorter than age- and sex-matched controls. Not only somatic growth, but also cellular growth appears to be impaired, and these may be related to defects in extracellular matrix common to this disorder. We have investigated the growth characteristics of dermal fibroblasts and trabecular osteoblasts isolated from patients with OI and control subjects of various ages. Cell growth curves and cell doubling times were determined by measuring cell number using crystal violet dye binding. Growth curves were modeled by a modified logistic function, the three parameters of which are markers for biologically relevant growth parameters: the plateau value or upper asymptote, which reflects the maximum cell density upon confluence; the maximal growth rate (microM); and the lag time. Both normal human fibroblasts and osteoblasts showed an age-dependent decrease in microM. Normal fibroblasts exhibited no age-dependence to their upper asymptote or lag time. Fibroblasts derived from patients with OI did not have significantly different upper asymptote values microM, or lag times when compared with normal fibroblasts. Normal osteoblasts had a decrease in upper asymptote, decrease in microM, but a relatively constant lag time with increasing age. In contrast, OI osteoblast microM was decreased relative to that of normal subjects. For osteoblasts from OI patients, decreased microM appeared unrelated to the age of the subject, whereas OI fibroblasts did exhibit an age-dependent decrease in microM. The percentage of collagenase-digestible protein (a measure of collagen synthesis) produced by normal human fibroblasts correlated well with microM. Treating normal human osteoblasts with the proline analogue 3,4-dehydroproline, which destabilizes collagen triple helix formation and alters collagen synthesis, secretion, and turnover, also decreased microM. A dose response to varying concentrations of 3,4-dehydroproline was observed for normal human bone cell microM. These data suggest a link between type I collagen synthesis and cellular proliferation.

Twenty-five Tc/tw5 and 12 control mice were killed at different ages and radiographically and histologically examined. In addition, histochemical analysis was performed on muscles from four mutant and one control mouse. All Tc/tw5 mice were tailless and had a fluid-filled lumbar myelomeningocele. Radiographically, most animals had six instead of 10 lumbosacral vertebrae. Vertebral anomalies were common. The spinal cord was grossly abnormal: at the level of the plaque, it was replaced by patches of neural tissue intermingled with connective tissue and muscle. Affected skeletal muscles had small myofibers with centrally placed nuclei consistent with arrest of development at the myotubular stage secondary to denervation in early embryonic life. Abnormal nerves were smaller and had fewer axons. Tc/tw5 mice show features of neural tube and notochord dysplasia. These mutant mice may be useful as animal models of lumbosacral agenesis and myelomeningocele.

SUMMARY Roberts/pseudothalidomide syndrome is a rare autosomal recessive disorder, involving growth and mental retardation, midline craniofacial abnormalities and tetraphocomelia. Cytogenetic studies have confirmed reproducible chromosomal abnormalities throughout the syndrome's wide range of clinical presentations. A family with two affected siblings is presented. One child was stillborn; the other, though severely affected by all of the physical characteristics of this disorder, has developed normally both at school and in his social-personal skills. This report supports the idea that Roberts syndrome and pseudothalidomide syndrome are the same condition, and emphasizes that normal intelligence and positive social-personal adjustment are possible, even with all of the stigmata of Roberts syndrome. Aggressive medical intervention is suggested, as well as forthright parental counselling when discussing the possible outcome for these patients. RESUME Syndrome pseudothalidomide/Roberts et intelligence normale: approche diagnostique et therapeutique Le syndrome pseudothalidomide/Roberts est un trouble autosomal recessif rare, comprenant un defaut de croissance, un retard mental, des anomalies cranio-faciales de la ligne mediane et une tetra phacomelie. Les etudes cytogenetiques ont confirme l'existence d'anomalies chromosomiques reproductibles au travers des expressions cliniques variees du syndrome. Une famille avec deux membres d'une meme fratrie atteints est presente. Un enfant etait mort-ne; l'autre, bien que gravement atteint dans toutes les caracteristiques physiques du syndrome, avait presente un developpement normal a l'ecole et dans les aptitudes d'autonomie sociale. Ces donnees suggerent que le syndrome de Roberts et celui pseudothalidomide traduisent une entite commune, soulignent qu'une intelligence normale et lautonomie sociale sont possibles, meme lorsque sont presents tous les stigmates du syndrome de Roberts. Une intervention medicate tres active est suggeree, aussi bien comme conseil genetique qu'en discussion du pronostic fonctionnel chez les enfants atteints. ZUSAMMENFASSUNG Roberts/Pseudothalidomid Syndrom und normale Intelligenz: Ansatze zur Diagnose und Behandlung Das Roberts/Pseudothalidomid Syndrome ist eine seltene autosomal rezessive Erkrankung mit Wachstumsverzogerung und geistiger Retardierung, kraniofazialen Mittelliniendefekten und Tetraphokomelie. Zytogenetische Studie haben fur das gesamte klinische Spektrum des Syndroms reproduzierbare chromosomale Veranderungen bestatigt. Es wird eine Familie mit zwei betroffenen Kindern vorgestallt. Ein Kind wurde tot geboren, das andere hat sich trotz aller fur diese Erkrankung charakteristischen korperlichen Misbildungen, sowohl in der Schule, als auch im sozial-personlichen Bereich normal entwickelt. Dieser Bericht stutzt die Auffassung, das das Roberts- und das Thalidomid Syndrom identisch sind und unterstreicht, das normale Intelligenz und gute sozialpersonliche Eingliederung auch mit all den Stigmata des Roberts Syndroms moglich sind. Es wird empfohlen, medizinisch alles zu tun und die Eltern offen zu beraten, wenn es um die Zukunftschancen fur diese Patienten geht. RESUMEN Sindrome de Roberts/pseudotalidominico e inteligencia normal: aproximacion a su diagnostico y manejo El sindrome de Roberts/pseudotalidominico es una rara alteracion autosomica recesiva, que da lugar a un retraso mental y del crecimiento, anomalias craneofaciales de la linea media y tetrafocomelia. Los estudios citogeneticos han confirmado que hay anomalias cromosomicas reproducibles en tadas los formas clinicas de presencacion del sindrome. Se presenta una familia con dos hermanos afectados. Un nino nacio muerto, mientras que el otro, aunque afectado por todas las caracteristicas fisca de la enfermedad, se habia desarrollado normalmente en la escuela y por lo que hace a sus habilidades personales. Este trabajo apoya la idea de que el sindrome de Roberts y el sindrome de la pseudotalidominico son la misma enfermedad y pone de relieve la posibilidad de una inteligencia normal y una adaptacion social-personal positiva, incluso con todos lo estigmas del sindrome de Roberts. Se sugiere una intervencion medica agresiva, asi como un consejo abierto a los padres al discuter el posible futuro de estos pacierites.

The National Marfan Foundation sponsored a symposium in August 2005 to review recent progress in the area of Marfan-related musculoskeletal research. Orthopaedic surgeons, molecular geneticists, medical geneticists, and pain specialists met to review a variety of topics. This report reviews and summarizes the proceedings of the symposium, with emphasis on future directions for study that were identified in the course of the meeting. Areas covered include clinical detection, diagnosis, growth, spine deformity, molecular mechanisms, dural ectasia, protrusio acetabuli, and pain in Marfan syndrome.

This study sought to examine the reliability and validity of three generic instruments for measuring the health of children with cerebral palsy (CP) and to compare them with a disease-specific measure, the Gross Motor Function Measure (GMFM). The Pediatric Evaluation and Disability Inventory (PEDI), the Pediatric Outcomes Data Collection Instrument (PODCI), and the Child Health Questionnaire (CHQ) were completed by the primary caregivers of 115 young children with spastic CP. The GMFM was administered to the children. The mean age of the sample was 5 years 8 months (range 3:1 to 10:4) and consisted of more males (58%) than females. The PEDI scales demonstrated higher internal consistency than the PODCI and CHQ scales. In comparison with the GMFM, the PODCI transfer and mobility scale (relative validity, 62%) and the PEDI mobility scale (relative validity, 53%) detected the most significant health differences between children with hemiplegia, diplegia, and quadriplegia. The PEDI social function scale detected the largest differences in cognitive function between children with an IQ of less than 70 compared with those with an IQ of 70 or greater. The reliability and validity of these different instruments varied significantly in this patient population.

Dural ectasia, an expansion of the dural sac surrounding the spinal cord, is one of the most common orthopedic manifestations of Marfan syndrome. The purpose of the present study was to characterize the clinical symptoms associated with dural ectasia in patients with Marfan syndrome and to understand the effects of symptomatic dural ectasia on the overall health of affected patients. Twenty-two volunteers aged 9-55 years with Marfan syndrome, and dural ectasia diagnosed by MRI or CT, filled out a "symptoms" questionnaire and completed an SF-36 health survey. Overall, It appears that the symptoms associated with dural ectasia have a marked impact on the overall health of patients with Marfan syndrome. Based on our findings, a "classic" picture of dural ectasia in the Marfan patient may consist of low back pain, headache, proximal leg pain, weakness and numbness above and below the knee, and genital/rectal pain. Symptoms, when present, are typically moderate to severe, occur several times per week (often daily), are commonly exacerbated by upright posture, and are not always relieved by recumbency.

Understanding the growth pattern in Marfan syndrome is important for prediction of expected growth, prevention of excessive growth by hormone therapy, timing of surgical epiphysiodesis for cessation of growth, and instituting brace treatment for scoliosis. In this study, we analyze growth patterns and generate growth charts for persons with Marfan syndrome. From the charts of 180 clinically diagnosed Marfan patients, longitudinal height and weight measurements were obtained. From this data, growth charts and growth velocity charts were generated for males and females. Skeletal maturation was studied by determining the Risser signs from the x-rays of 71 males and 56 females. From 22 female patients, age of menarche was available and retrieved either by reviewing the charts or contacting the patients. Mean length at birth was 53 ± 4.4 cm for males and 52.5 ± 3.5 cm for females. Mean final height was 191.3 ± 9 cm for males and 175.4 ± 8.2 cm for females. Mean birth weight was 3.51 ± 0.74 kg for males and 3.48 ± 0.68 kg for females. The puberty-associated peak in growth velocity was 2.4 years earlier than the gender-matched general population for males with Marfan syndrome and 2.2 years earlier for females. Age of menarche was 11.7 ± 2 years of age, which is also early compared to the general population. This study suggests that the growth spurt and pubertal skeletal maturation occur early in Marfan syndrome. The growth curves generated should help more accurately predict adult stature, as well as monitor progression toward it. © 2002 Wiley-Liss, Inc.

Rhizomelic chondrodysplasia punctata (RCDP) is a rare peroxisomal disorder leading to multiple developmental malformations, including skeletal deformity. Specifically, involvement of the vertebral bodies has been described. Presented here is a case of a two-year-old female child with RCDP leading to advanced cervical stenosis as detected on magnetic resonance imaging (MRI) studies of the cervical spine. The practicing clinician should be aware of the possibility of cervical stenosis secondary to RCDP and its impact on the management of the patient with this rare disease process.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE • To apply the technique of pelvic osteotomy to a select group of adult female patients with exstrophy, in view of the low complication rate and acceptable success rate of the technique. PATIENTS AND METHODS • We applied this technique as an adjunct to uterovaginal suspension and abdominal wall repair after our prior success in treating patients with extreme pelvic diastasis. • Bilateral innominate (transverse) and vertical iliac osteotomies were done from an anterior approach and an external fixator was placed. The fixator and pelvic bones were gradually cranked together over a period of 2–3 weeks until the diastasis was less than 4 cm. • Then sacrocolpopexy was performed with revision of the abdominal wall and revision genitoplasty along with the placement of an intrasymphyseal titanium plate. RESULTS • Six patients presented with uterine/vaginal prolapse and concerns about the appearance of their abdominal wall and genitalia. Three patients had undergone uterine suspension before and one patient had had five prior attempts at suspension, which failed. The mean (range) age was 22.3 (18–26) years. • All the patients underwent staged reduction of pubic diastasis and sacrocolpopexy along with revision of the abdominal wall and in four cases revision genitoplasty was also performed. The mean (range) diastasis was 12.8 (8–18) cm and 2.8 (3–4) cm before and after staged reduction respectively. • Complications included transient femoral nerve palsy (two) and foot drop secondary to sciatic nerve stretch (one), which resolved with time. The symphyseal plate needed to be removed in three patients: secondary to persistent pain at the site (one), persistent discharge from the lower abdominal wound (one) and erosion into the anterior wall of the vagina (one). • At a mean (range) follow-up of 60.7 (2–137) months the cosmetic and functional outcome of the abdominal wall reconstruction and genitoplasty was good with all the patients being satisfied. Five patients are currently sexually active and none has had a recurrence of their prolapse. None has become pregnant yet. CONCLUSIONS • Although the morbidity of this procedure in the adult is not insignificant, it is a valuable adjunct to pelvic floor reconstruction in young women of childbearing age even in those who have had prior suspension procedures. • In addition, it allows the movement of lateral previously unoperated skin into the midline, allowing scar and skin replacement with healthier more vascularized tissue.

Objective To assess the role of osteotomy at the time of bladder neck reconstruction (BNR) for continence in classic bladder exstrophy, in which closure of the pelvic ring and reconstitution of the pelvic diaphragm may affect eventual continence. Patients and methods The results of using osteotomy at the time of BNR in 29 children were reviewed. The mean bladder capacity before BNR was 76 mL. The indications for osteotomy were a wide pubic diastasis and a soft intersymphyseal bar. After osteotomy, all children were maintained in external fixation and lower-extremity traction for 6–8 weeks. Results Complications of osteotomy were limited to a partial femoral nerve palsy (one patient) and delayed union of fragments (one patient). Complications of BNR included urethral stricture (five patients) and bladder calculi (six patients). Continence results were modest, with 11 of 29 children (38%) dry during the day (dry interval > 3 h) and eight of 29 (28%) dry at night. Eight children had daytime dry intervals of ≈3 h. The mean preoperative bladder capacity in children who were dry both day and night was 101 mL. Conclusions The preoperative bladder capacity remains a key determinant for the attainment of continence after BNR in the reconstruction of classic bladder exstrophy. Osteotomy allows pelvic closure and thus improves cosmesis of the mons and stabilizes the BNR in patients with a soft intersymphyseal bar, but seems to have no effect on continence when performed at the time of bladder neck plasty.