Kent A. Reinker

Etiology of Idiopathic Scoliosis: Current Trends in Research*

Current population studies characterize idiopathic scoliosis as a single-gene disorder that follows the patterns of mendelian genetics, including variable penetrance and heterogeneity. The role of melatonin and calmodulin in the development of idiopathic scoliosis is likely secondary, with indirect effects on growth mechanisms. Reported abnormalities of connective tissue, skeletal muscle, platelets, the spinal column, and the rib cage are all thought to be secondary to the deformity itself. Although no consistent neurological abnormalities have been identified in patients with idiopathic scoliosis, it is possible that a defect in processing by the central nervous system affects the growing spine. The true etiology of idiopathic scoliosis remains unknown; however, it appears to be multifactorial.

Bone Resorption in Syndromes of the Ras/MAPK Pathway

Stevenson DA, Schwarz EL, Carey JC, Viskochil DH, Hanson H, Bauer S, Cindy Weng H‐Y, Greene T, Reinker K, Swensen J, Chan RJ, Yang F‐C, Senbanjo L, Yang Z, Mao R, Pasquali M. Bone resorption in syndromes of the Ras/MAPK pathway.

Attempted limb lengthenings beyond twenty percent of the initial bone length: results and complications.

In response to historic guidelines suggesting limits to the amount of limb lengthening, we report the results and complications of those patients in whom the initial goal of lengthening exceeded 20% of the initial segment length. Thirty-one patients underwent a total of 35 attempted lengthenings with a mean follow-up of 38.6 months. Limb-length discrepancy was the primary indication in all but one case. With an average goal of 35% of the original bone length, we achieved a mean gain of 33%. Lengthening to within 2.5 cm was achieved in 31 (89%) of 35 cases, and significantly more successful with goals extending < or =55% of the initial bone length (p<0.05). Treatment times extended a mean of 8.7 months with a healing index of 37 days/cm. By Paleys classification scheme, all had problems, in addition to an average of 1.3 obstacles and 0.9 complications per segment lengthened. In 23 patients with extended follow-up, good to excellent results were achieved in 78%, and were significantly more successful with goals < or =55% (< or =0.05).

Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines.

Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in this group, most notably Noonan syndrome and Costello syndrome. CFC is genetically heterogeneous and caused by gene mutations in the Ras/mitogen-activated protein kinase pathway. The major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. It is essential that this condition be differentiated from other RASopathies, as a correct diagnosis is important for appropriate medical management and determining recurrence risk. Children and adults with CFC require multidisciplinary care from specialists, and the need for comprehensive management has been apparent to families and health care professionals caring for affected individuals. To address this need, CFC International, a nonprofit family support organization that provides a forum for information, support, and facilitation of research in basic medical and social issues affecting individuals with CFC, organized a consensus conference. Experts in multiple medical specialties provided clinical management guidelines for pediatricians and other care providers. These guidelines will assist in an accurate diagnosis of individuals with CFC, provide best practice recommendations, and facilitate long-term medical care.

Early diagnosis and treatment of hinge abduction in Legg-Perthes disease

A review of 106 cases of Legg-Perthes disease disclosed 26 in whom a particularly poor radiographic appearance was seen. Hinge abduction was detected in 19 of these patients and was suspected but not proven in the remainder. Hinge abduction was found to occur early in the course of Legg-Perthes, and hinging frequently occurred about an unossified portion of femoral head, making detection difficult. Failure of movement of the lateral corner of the epiphysis under the edge of the acetabulum on an internally rotated and abducted radiograph is prima facie evidence of hinge abduction. Confirmation is easily obtained by arthrography. Hinging must be relieved if guidance of femoral head growth by the healthy acetabulum is to be possible. Both clinical and radiographic outcomes were worse in patients with unrelieved hinge abduction. Relief of hinging can frequently be accomplished by traction, and containment can then be maintained by appropriate surgery.

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function.

Tetrasomy 18p: report of the molecular and clinical findings of 43 individuals.

Thus far, the phenotype of tetrasomy 18p has been primarily delineated by published case series and reports. Findings reported in more than 25% of these cases include neonatal feeding problems, growth retardation, microcephaly, strabismus, muscle tone abnormalities, scoliosis/kyphosis, and variants on brain MRI. Developmental delays and cognitive impairment are universally present. The purpose of this study was to more fully describe tetrasomy 18p at both the genotypic and the phenotypic levels. Array CGH was performed on 43 samples from individuals with tetrasomy 18p diagnosed via routine karyotype. The medical records of 42 of these 43 individuals were reviewed. In order to gain additional phenotypic data, 31 individuals with tetrasomy 18p underwent a series of clinical evaluations at the Chromosome 18 Clinical Research Center. Results from the molecular analysis indicated that 42 of 43 samples analyzed had 4 copies of the entire p arm of chromosome 18; one individual was also trisomic for a section of proximal 18q. The results of the medical records review and clinical evaluations expand the phenotypic description of tetrasomy 18p to include neonatal jaundice and respiratory distress; recurrent otitis media; hearing loss; seizures; refractive errors; constipation and gastroesophageal reflux; cryptorchidism; heart defects; and foot anomalies. Additional findings identified in a small number of individuals include hernias, myelomeningocele, kidney defects, short stature, and failure to respond to growth hormone stimulation testing. Additionally, a profile of dysmorphic features is described. Lastly, a series of clinical evaluations to be considered for individuals with tetrasomy 18p is suggested.

Evidence That Smith-McCort Dysplasia and Dyggve-Melchior-Clausen Dysplasia Are Allelic Disorders That Result from Mutations in a Gene on Chromosome 18q12

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and a short trunk with a barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. We performed a genomewide scan in a consanguineous family from Guam and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined two-point LOD score of 3.04 at a recombination fraction of 0 for the marker at locus D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in two affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the defective gene. Analysis of three small, unrelated families with Dyggve-Melchior-Clausen syndrome, a radiographically identical disorder with the additional clinical finding of mental retardation, provided evidence of linkage to the same region, a result consistent with the hypothesis that the two disorders are allelic.

Can VEPTR® Control Progression of Early-onset Kyphoscoliosis?: A Cohort Study of VEPTR® Patients With Severe Kyphoscoliosis

BackgroundKyphoscoliosis is considered a relative contraindication to treatment with the Vertical Expandable Prosthetic Titanium Rib (VEPTR®; Synthes Inc, Paoli, PA). Nevertheless, patients do present with early-onset kyphoscoliosis and thoracic insufficiency syndrome, and no suitable alternative treatments are currently available. However, it is unclear whether VEPTR® is reasonable for treating patients with kyphoscoliosis.Questions/purposesWe determined whether VEPTR® controls progression in patients with kyphoscoliosis and, if so, what methods might be used to improve control of deformity progression in these patients.Patients and MethodsWe retrospectively reviewed 14 patients who had VEPTR® treatment of early-onset kyphoscoliosis. Degrees of kyphosis and scoliosis before, during, and after treatment were measured, and levels of instrumentation, thoracic dimensions, and complications were recorded. Minimum followup was 1.7 years (average, 5.8 years; range, 1.7–12.8 years).ResultsWhile scoliosis was stabilized, kyphosis increased a mean of 22° at last followup. Supple kyphosis became rigid during treatment. Proximal cradle cutout was a recurring problem. Distal anchors placed too proximally had inadequate lever arms to control kyphosis.ConclusionsProgression of kyphosis can be minimized during VEPTR® treatment by early extension of the construct to the second ribs bilaterally, distal extension of hybrid constructs to the pelvis, use of bilateral hybrid VEPTR® implants, and use of redesigned VEPTR® constructs that enhance fixation at the upper end. While our early results suggest these devices control progression of kyphosis, longer followup with more patients will be required to confirm the concept in these patients.Level of EvidenceLevel IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Peripheral muscle weakness in RASopathies

Introduction: RASopathies are a group of genetic conditions due to alterations of the Ras/MAPK pathway. Neurocutaneous findings are hallmark features of the RASopathies, but musculoskeletal abnormalities are also frequent. The objective was to evaluate handgrip strength in the RASopathies. Methods: Individuals with RASopathies (e.g., Noonan syndrome, Costello syndrome, cardio‐facio‐cutaneous [CFC] syndrome, and neurofibromatosis type 1 [NF1]) and healthy controls were evaluated. Two methods of handgrip strength were tested: GRIP‐D Takei Hand Grip Dynamometer and the Martin vigorimeter. A general linear model was fitted to compare average strength among the groups, controlling for confounders such as age, gender, height, and weight. Results: Takei dynamometer: handgrip strength was decreased in each of the syndromes compared with controls. Decreased handgrip strength compared with sibling controls was also seen with the Martin vigorimeter (P < 0.0001). Conclusions: Handgrip strength is decreased in the RASopathies. The etiology of the reduced muscle force is unknown, but likely multifactorial. Muscle Nerve 46: 394–399, 2012