Treating Congenital Proximal Interphalangeal Joint Contracture.

The management of congenital proximal interphalangeal joint deformity, also known as camptodactyly, is challenging. There are numerous theories on the cause of this abnormal finger posture, leading to variations in classification, definition, and treatment approaches. This article assesses the previous literature and provides clarity and guidance for the practical treatment of camptodactyly.

Frame shift mutations of the ZMPSTE24 gene in two siblings with restrictive dermopathy.

Restrictive dermopathy (RD) is a rare lethal autosomal recessive genodermatosis, characterized by abnormally rigid skin with prominent superficial vasculature, erosions and epidermal hyperkeratosis, dysplastic clavicles, joint contractures, mouth fixed in the 'O' position, small pinched nose, and neonatal death. Mutations of ZMPSTE24 and LMNA genes are reported as the causes of RD, with those of ZMPSTE24 being more prevalent. Here, we report on a familial c.50delA (p.Lys17Serfs*21) mutation of the ZMPSTE24 gene, causing RD in two siblings.

Hereditary inclusion-body myopathies.

The term hereditary inclusion-body myopathies (HIBMs) defines a group of rare muscle disorders with autosomal recessive or dominant inheritance and presence of muscle fibers with rimmed vacuoles and collection of cytoplasmic or nuclear 15-21 nm diameter tubulofilaments as revealed by muscle biopsy. The most common form of HIBM is due to mutations of the GNE gene that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. This results in abnormal sialylation of glycoproteins that possibly leads to muscle fiber degeneration. Mutations of the valosin containing protein are instead responsible for hereditary inclusion-body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD), with these three phenotypic features having a variable penetrance. IBMPFD probably represents a disorder of abnormal cellular trafficking of proteins and maturation of the autophagosome. HIBM with congenital joint contractures and external ophthalmoplegia is due to mutations of the Myosin Heavy Chain IIa gene that exerts a pathogenic effect through interference with filament assembly or functional defects in ATPase activity. This review illustrates the clinical and pathologic characteristics of HIBMs and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness.

Hereditary myosin myopathies are characterized by variable clinical features. Inclusion body myopathy 3 (IBM-3) is an autosomal dominant disease associated with a missense mutation (E706K) in the myosin heavy chain IIa gene. Adult patients experience progressive muscle weakness. Biopsies reveal dystrophic changes, rimmed vacuoles with cytoplasmic inclusions, and focal disorganization of myofilaments. We constructed a transgene encoding E706K myosin and expressed it in Drosophila (E701K) indirect flight and jump muscles to establish a novel homozygous organism with homogeneous populations of fast IBM-3 myosin and muscle fibers. Flight and jump abilities were severely reduced in homozygotes. ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin. Light scattering experiments and electron microscopy revealed that mutant myosin heads bear a dramatic propensity to collapse and aggregate. Thus E706K (E701K) myosin appears far more labile than wild-type myosin. Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments. Our Drosophila model reveals the unambiguous consequences of the IBM-3 lesion on fast muscle myosin and fibers. The abnormalities observed in myosin function and muscle ultrastructure likely contribute to muscle weakness observed in our flies and patients.

From neurodevelopment to neurodegeneration: the interaction of neurofibromin and valosin-containing protein/p97 in regulation of dendritic spine formation.

Both Neurofibromatosis type I (NF1) and inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) are autosomal dominant genetic disorders. These two diseases are fully penetrant but with high heterogeneity in phenotypes, suggesting the involvement of genetic modifiers in modulating patients' phenotypes. Although NF1 is recognized as a developmental disorder and IBMPFD is associated with degeneration of multiple tissues, a recent study discovered the direct protein interaction between neurofibromin, the protein product of the NF1 gene, and VCP/p97, encoded by the causative gene of IBMPFD. Both NF1 and VCP/p97 are critical for dendritic spine formation, which provides the cellular mechanism explaining the cognitive deficits and dementia found in patients. Moreover, disruption of the interaction between neurofibromin and VCP impairs dendritic spinogenesis. Neurofibromin likely influences multiple downstream pathways to control dendritic spinogenesis. One is to activate the protein kinase A pathway to initiate dendritic spine formation; another is to regulate the synaptic distribution of VCP and control the activity of VCP in dendritic spinogenesis. Since neurofibromin and VCP/p97 also regulate cell growth and bone metabolism, the understanding of neurofibromin and VCP/p97 in neurons may be applied to study of cancer and bone. Statin treatment rescues the spine defects caused by VCP deficiency, suggesting the potential role of statin in clinical treatment for these two diseases.

Another VCP interactor: NF is enough.

Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. How missense mutations in this abundant, ubiquitously expressed, multifunctional protein lead to the degeneration of disparate tissues is unclear. VCP participates in diverse cellular functions by associating with an expanding collection of substrates and cofactors that dictate its functionality. In this issue of the JCI, Wang and colleagues have further expanded the VCP interactome by identifying neurofibromin-1 (NF1) as a novel VCP interactor in the CNS. IBMPFD-associated mutations disrupt binding of VCP to NF1, resulting in reduced synaptogenesis. Thus, aberrant interactions between VCP and NF1 may explain the dementia phenotype and cognitive delay observed in patients with IBMPFD and neurofibromatosis type 1.

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density.

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spinogenesis. The functions of neurofibromin and VCP in spinogenesis were shown to correlate with the learning disability and dementia phenotypes seen in patients with IBMPFD. Consistent with the previous finding that treatment with a statin rescues behavioral defects in Nf1(+/-) mice and providing further support for our hypothesis that there is crosstalk between neurofibromin and VCP, statin exposure neutralized the effect of VCP knockdown on spinogenesis in cultured hippocampal neurons. The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.

Unusual and recently described cutaneous atrophic disorders.

Cutaneous atrophic conditions are typically caused by changes in the dermis or subcutaneous tissue, sometimes consisting of the loss of a single fiber type. Since a significant decrease of subepidermal tissue is necessary for these lesions to be macroscopically atrophic, many conditions may not be appreciated as atrophy in the clinical setting. Clinicians should be familiar with the common or classic disorders causing cutaneous atrophy; however, there are a few new or rarely described atrophic conditions which are more difficult to identify and may not be atrophic clinically. This paper serves to describe the salient clinical and histological features of these new or rare disorders.

Reconstruction of the first web in congenital thumb anomalies.

Reconstruction of the first web is an important technique for thumb adduction contracture accompanying congenital anomalies. Our previous cases have been reviewed here to evaluate and compare the indications, results, and problems for these two techniques. The angle formed by the first and second metacarpals (first-second metacarpal angle; 1-2 MCA) on the anterio-posterior (AP) view of the hand, with the thumb in maximum radial abduction, was measured from X-ray. There were 37 patients (43 hands: 27 males, ten females). The average age at the time of surgery was 6.6 years (range, two to 22 years). The five-flap Z-plasty was performed on 20 hands. The spinner flap was performed on 23 hands. The Spinner flap is indicated when contractures are severe or when the preoperative 1-2 MCA is <20°. The five-flap Z-plasty is indicated when contractures are mild or when the preoperative 1-2 MCA is ≥20°.

An unusual amniotic rupture sequence with thoracoabdominal restricting band, low-set posterior hairline, and trapezius contracture.

Amniotic rupture sequence is associated with defects of variable severity and at different sites. Analysis of the literature reveals difficulties in the classification, which, in addition to uncertainties surrounding its causes, make diagnosis of unusual presentations rather difficult. We present an unusual case of a thoracoabdominal restrictive band from the umbilicus to a low-set posterior hairline with severe trapezius contracture, sternoclavicular dislocation, and no associated craniofacial or limb abnormalities. Amnion rupture sequence with adhesion band seems to be the most probable cause of this rare combination of anomalies.

Panhypopituitary insufficiency in a patient with clinical diagnosis of Chitayat-Hall syndrome.

We report an 8-year-old proband with severe motor and intellectual disability presenting a variety of dysmorphic features such as microcephaly, prominent glabella (ridged metopic suture) and congenital distal limb contractures. As well as panhypopituitary insufficiency, brain defects, e.g. agenesis of corpus callosum, colpocephaly, and pachygyria as well as strabismus and tracheo-laryngeal hypoplasia, were diagnosed. Genetic examination revealed a normal karyotype and excluded Wolf-Hirschhorn syndrome and subtelomeric deletions. Chitayat-Hall syndrome was diagnosed based on clinical traits.

Fetal akinesia deformation sequence with delayed skeletal muscle maturation and polymicrogyria: evidence for a hypoxic/ischemic pathogenesis.

Multiple congenital contractures, also known as fetal akinesia deformation sequence (FADS) and related terms, result from decreased fetal movement. The underlying etiologies are diverse and include central nervous system (CNS) dysgeneses and primary myopathies. Persistent central nuclei or the presence of myotubes is often regarded as evidence of a primary myopathic etiology; however, these findings are also associated with impaired fetal innervation. We report 7 fetuses, estimated gestational age 20 to 23 weeks, with persistent myotubular morphology, a change that could be (mis)interpreted as a primary myopathy. In 4 of the patients, CNS histology showed hypoxic/ischemic injury, polymicrogyria, mineralized neurons, and microinfarcts with or without loss of anterior horn neurons. FADS cases with polymicrogyria have frequently been interpreted as a consequence of a primary brain malformation. Only a few descriptions of FADS associate polymicrogyria with CNS hypoxic/ischemic injury, however, and do not describe skeletal muscle maturation delay. We hypothesize that this combination of neural and muscular pathology is an under-recognized pattern in FADS, which results from diffuse hypoxic/ischemic injury involving the brain and spinal cord during early to middle gestation.

Treatment of popliteal pterygium using an Ilizarov external fixator.

Popliteal pterygium syndrome is a rare congenital disorder that consists of popliteal webs and craniofacial, genitourinary and extremity anomalies. Only moderate successful surgical excision of the fibrotic band within the popliteal web has been reported because the nerves and vessels in the affected site are short and displaced into the web and they are attached to adjacent tissues. We performed hamstring tenotomy on the ischial tuberosity, tenotomy of the flexor hallucis longus and Z-lengthening of the Achilles tendon on the ankle in our patient, and this was followed by gradual correction using an Ilizarov external fixator. Full extension of the knee joint was achieved at the ninth postoperative week. However, some recurrence of flexion contracture was noted at two years follow-up. Gradual soft tissue lengthening with an Ilizarov external fixator can be one of the optimal procedures when excision of a fibrous band and Z-plasty are not possible due to severe adhesion of the nerves and vessels into a fibrotic band. However, a cautious approach is recommended when considering the high risk of recurrence.

Popliteal pterygium knee contracture: treatment with the Ilizarov technique.

INTRODUCTION: Various treatment options are in use to address severe knee flexion contractures in children. Their success depends on an adequate selection of the proper one applying to each individual anatomical situation. HYPOTHESIS: Applied to limb deformity, the Ilizarov technique combines progressive correction, to joint structures flexibility restitution in case of severe knee flexion contracture. We review a continuous series of popliteal pterygium syndrome patients managed with this technique. PATIENTS AND METHODS: Medical records of eight children (11 knees), consecutively treated between 1986 and 2007, were reviewed. Knee flexion ranged from 40 to 120 degrees. Contracture (> 90 degrees) was extremely severe in 10 cases. Progressive correction was gained by Ilizarov external fixation. Complications during and following articular chain distraction-lengthening were noted. Follow-up ranged from 1 to 21 years. RESULTS: Surgical realignment was rendered particularly complex by the popliteal cutaneous band itself, partly responsible of the joint stiffness and sciatic nerve shortening. Deformities were corrected by the Ilizarov technique. Complete extension was obtained in all cases. In six cases, flexion contracture reccurrence required to repeat the correction, using the same technique, at a mean interval of 3-4 years. During follow-up, four evolutive partial posterior tibial dislocations and one complete dislocation were diagnosed, all associated with recurrence of the flexion contracture. LEVEL OF EVIDENCE: Level IV. Therapeutic Study.

Congenital flexion deformity of the long, ring, and little fingers with an aberrant origin of the flexor digitorum profundus: case report.

A case of congenital flexion deformity of the long, ring, and little fingers with an aberrant origin of the flexor digitorum profundus is described. The aberrant tendinous band originated from a bone prominence in the medial and anterior aspect of the proximal side of the ulna, which was confirmed in the operation. Resection of the aberrant origin could achieve only partial relief for the flexion contracture of the 3 fingers. Further muscle-sliding procedure was needed to achieve a thorough release.

[Clinical diagnosis and surgical treatment of congenital contractural arachnodactyly: analysis of 6 cases].

OBJECTIVE: To discuss the clinical diagnosis and surgical treatment of congenital contractural arachnodactyly (CCA). METHODS: The clinical data of 6 CCA patients, 1 male and 5 female, aged 7.5 (5-14) were analyzed. All cases had kyphoscoliosis, 2 in the thoracic segments and 4 in the thoracolumbar segments. The average scoliosis Cobb angle was 88.6 degrees (85 degrees-117 degrees). The average kyphosis Cobb angle was 93.6 degrees (75 degrees-123 degrees). All of the cases underwent internal fixation with pedicle screw and lamina hooks instrumentation, in which 4 cases underwent posterior Smith-Petersen osteotomy. The diagnosis was based on a constellation of clinical findings. The clinical manifestations included marfanoid habitus, flexion contractures of multiple joints (elbow, knee, hip, and finger), kyphoscoliosis, muscular hypoplasia, and abnormal pinnae ("crumpled" outer helices). Molecular genetic testing showed mutation in the fibrillin-2 (FBN2) gene encoding the extracellular matrix microfibril. Four cases were followed up for 6-9 months. RESULTS: After operation the average Cobb angle of the scoliosis and kyphosis were 37.6 degrees (35 degrees-52 degrees) and 38.6 degrees (28 degrees-54 degrees) immediately, with 62.3% and 68.7% curve correction respectively. Three cases got excellent synostosis of posterior lamina, 1 case underwent revision with lamina hook because the distal screw was loose and hurt the nerve root, and the other 2 cases lost follow-up. The patients' body appearance and pulmonary function were obviously improved. CONCLUSION: The characteristic clinical manifestation include severe and stiff kyphoscoliosis, difficult to correct , and enhanced Cobb angle, and pedicle dysplasia of vertebral pedicle leading to difficulty in installing screws. Smith-Petersen osteotomy is often necessary. CCA should be differentiated with Marfan syndrome (MFS), Stickler syndrome, Homocystinuria, and distal arthrogryposis, especially MFS.

Differential diagnosis of congenital muscular dystrophies.

Congenital muscular dystrophies (CMDs) are defined by signs of muscle weakness in the first 6 months of life with myopathic changes in muscle biopsy. The progress in the last decade has helped to make molecular and genetic diagnoses in the majority of patients fulfilling these criteria. In a number of patients a definite diagnosis cannot be reached and these individuals are often grouped together as "merosin positive" congenital muscular dystrophy. In the last 5 years, 25 patients referred for assessment as possible congenital muscular dystrophy have been found to have alternative diagnoses. This paper aims to highlight these conditions as the common differentials or more difficult to diagnoses to consider in patients presenting as CMD.