Congenital Skeletal Anomalies Research Articles

Chronic diaphragmatic hernia and axial skeletal anomalies in a cat – Case report

Diaphragmatic hernia and congenital anomalies of the axial skeleton are alterations frequently identified in domestic cats. The objective of this case report was to present the electrocardiographic, radiographic, and tomographic findings observed in a 5-year-old neutered domestic shorthair cat, with skeletal malformations simultaneously with chronic diaphragmatic hernia. The cat lived well until he was 10-years old, when he developed progressive respiratory compromise leading to death. To our knowledge, occurrence of combined diaphragmatic hernia and congenital skeletal anomalies in domestic cats is very rare.

Protective effect of quercetin on fetal development and congenital skeletal anomalies against exposure of pregnant Wistar rats to crude oil vapor.

Epidemiological evidence indicates a relationship between maternal exposure to crude oil vapors (COV) during pregnancy and adverse pregnancy outcomes. Quercetin (QUE) is a plant flavonoid with purported antioxidant and anti-inflammatory effects, which has been shown to prevent birth defects. This study was aimed to investigate the protective role of QUE on fetal development and congenital skeletal anomalies caused by exposure of pregnant rats to COV. Twenty-four pregnant Wistar rats were randomly categorized into four groups of control, COV, COV + QUE, and QUE (50 mg/kg). The inhalation method was used to expose pregnant rats to COV from day 0 to 20 of pregnancy, and QUE was administered orally during this period. On day 20 of gestation, the animals were anesthetized and a laparotomy was performed, and then the weight and crown rump length (CRL) of the fetuses were determined. Skeletal stereomicroscopic evaluations of fetuses were performed using Alcian blue/Alizarin red staining method, and the expression of osteogenesis-related genes (Runx2 and BMP-4) was evaluated using qPCR. This study showed that prenatal exposure to COV significantly reduced fetal weight and CRL, and expression of Runx2 and BMP-4 genes. Moreover, COV significantly increased the incidence of congenital skeletal anomalies such as cleft palate, spina bifida and non-ossification of the fetal bones. However, administration of QUE with exposure to COV improved fetal bone development and reduced congenital skeletal anomalies. QUE can ameliorate the teratogenic effects of prenatal exposure to COV by increasing the expression of osteogenesis-related genes.

Repeated clinical case of fetal congenital malformation in a family with hereditary short-rib thoracic dysplasia type 3

The article shows the genetic causes of recurrent fetal malformations on the example of a clinical case of hereditary short-rib thoracic dysplasia type 3.
 Congenital malformations of the fetus are most often sporadic; however, in rare cases, this pathology can recur in one married couple, and the formation of congenital anomalies during subsequent pregnancy can both have general syndromes and affect various systems and organs.
 Short-rib thoracic dysplasia type 3 is a rare genetic disorder with autosomal recessive inheritance. Patients for whom the carriage of pathogenic alleles in genes associated with congenital skeletal anomalies has been confirmed require a detailed clinical examination. Such married couples want expert-level medical genetic counseling with performing additional genetic tests, if necessary. This may clarify the diagnosis, which will determine further tactics for preparing the couple for the next pregnancy on their own or using assisted reproductive technology programs and / or surrogate motherhood.

Atresia Ani (Imperforated Anus) in Calves: Clinical, Surgical and Pathological Aspects

Background: Anal atresia is a congenital malformation, which often affects calves, and is related to the imperforation of the membrane that separates the endoderm of the posterior intestine from the ectodermal anal membrane. It is commonly associated with other congenital malformations and skeletal anomalies. The clinical signs generally appear in the first days of the animal's life, due to a retention of feces. The diagnosis is clinical and is based on observation, anamnesis and a physical examination of the animal. The only viable treatment is surgical. This paper aims to report 6 cases of anal atresia in bovine calves, 4 males and 2 females that were successfully treated surgically. Cases: This work reports 6 cases of anal atresia in 4 male calves and 2 female calves. Three presented total atresia (type II), one partial (type I) and in both female calves, anal atresia and rectovaginal fistula (type IV) were observed. The animals were all of undefined race. Five of the cases were from northern Tocantins, 4 males and 1 female (anal atresia with rectovaginal fistula), and 1 female (anal atresia with rectovaginal fistula) was from Valença, RJ. All animals were born active, by eutocic/natural birth, and assumed a quadrupedal position followed by the first feeding as normal. They were aged between 2 days and 6 months, and had a clinical history of abdominal distention and difficulty or inability defecating, and the females both also had a rectovaginal fistula, all cases compatible with anal atresia. Based on the patient's history and clinical examination, surgical treatment for anal reconstruction was decided upon. Postoperative treatment consisted of enrofloxacin [2.5 mg/kg - intramuscularly (IM), once daily (SID), for 5 days] and fluxinin meglumine [1.1 mg/kg - IM, SID, for 3 days] ; as well as a healing ointment which was applied to the area of the surgical wound, every 12 h, for 7 days. There were no trans-surgical complications. The animals showed progressive recovery after anal reconstruction and the stitches were removed in all cases on the 10th postoperative day, with no postoperative complications and no recurrence of any clinical signs from that moment on.Discussion: The study of congenital and hereditary changes enables the identification of their origins, can help prevent new cases and, some of them, are open to economically viable treatment and/or correction that can improve the well-being of the animal and prevent economic losses due to death or animal sacrifice, as reported in the present study. Anal atresia is the most common congenital defect of the lower gastrointestinal tract in calves, being an isolated abnormality, or associated with other malformations, especially of the distal spinal column such as the absence of a tail (perosumus acaudato), as one of the animals in this study. The clinical signs and physical examination are sufficient to establish the diagnosis, as demonstrated in this report, which is usually made in newborn animals, due to the lack or difficulty in defecation associated with no anal orifice and/or swelling in the perineal region. The treatment of choice for anal atresia is surgical, in order to construct an anal neo-orifice and thus avoid endotoxemic shock as well as providing relief and well-being for the animals. As observed in this study, when anal atresia is diagnosed early, and surgical treatment is properly instituted, the prognosis is favorable. The surgery is considered of low complexity, quick and it can be carried out in the field. Thus, from a commercial point of view, considering the costs of the procedures and the value of the calf at the end of weaning, such treatments are beneficial to the owners. In addition, the surgical treatment is essential for animal health and welfare in cases of anal atresia.Keywords: cattle, congenital defects, hereditary pathology, perosomus acaudato, surgery.

Integrated Bioinformatics Analysis Reveals Potential Pathway Biomarkers and Their Interactions for Clubfoot

BackgroundCongenital talipes equinovarus (clubfoot), one of the most regular pediatric congenital skeletal anomalies, seriously affects the normal growth and development of about 1 in 1000 newborns. Although it has been investigated widely, the etiology and pathogenesis of clubfoot are still controversial.Material/Methodsg: Profiler, NetworkAnalyst and WebGestalt were used to probe the enriched signaling pathways by using the Gene Ontology (GO), Human Phenotype Ontology (HP), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome (REAC), and WikiPathways (WP) databases. Large numbers of enriched signaling pathways were identified using the integrated bioinformatics enrichment analyses.ResultsApoptosis or programmed cell death (PCD), disease, muscle contraction, metabolism, and immune system were the top functions. Embryo or organ morphogenesis and development, cell or muscle contraction, and apoptosis were the top biological processes, and cell/muscle contraction and apoptosis were the top molecular functions using enriched GO terms analysis. There were a large number of complex interactions in the genes, enriched pathways, and transcription factor (TF)-miRNA co-regulatory networks. Transcription factors such as FOXN3, GLI3, HOX, and NCOR2 family regulated the gene expression of APAF1, BCL2, BID, CASP, MTHFR, and TPM family.ConclusionsThe results of bioinformatics enrichment analysis not only supported the previously proposed hypotheses, e.g., extracellular matrix (ECM) abnormality, fetal movement reducing, genetic abnormality, muscle abnormality, neurological abnormality, skeletal abnormality and vascular abnormality, but also indicated that cellular or immune responses to external stimulus, molecular transport and metabolism may be new etiological mechanisms in clubfoot.

PIN1 is a new therapeutic target of craniosynostosis.

Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis–trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/− mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/− mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.

A new case of de novo chromosome 19p13.12 deletion in an Omani girl with multiple congenital anomalies: a first case report from Oman

Background: This report provides a molecular cytogenetic characterization of an Omani girl with 19p13.12 microdeletion and compares her clinical features of global developmental delay (GDD) and multiple congenital anomalies with the gene mutations and disorders associated with this locus. Case Presentation: The 4-year-old Omani girl presented to the National Genetic Center with the following clinical features: GDD, hypotonia, multiple congenital anomalies, facial dysmorphism, and skeletal anomalies. Array comparative genomic hybridization (CGH) identified a 1.913 Mb de novo microdeletion in the patient within 19p13.12. The deletion includes 53 genes, of which 35 are Online Mendelian Inheritance in Man (OMIM) genes. The deleted region includes NFIX (OMIM #164005), CACNA1A (OMIM # 601011) and NACC1 (OMIM # 610672) genes which are previously reported to be associated with the presented clinical features. Conclusion: 19p13.12 microdeletion syndrome is a rare condition for which only one prenatal and 5 postnatal cases have been reported previously. This case of 19p13.12 microdeletion syndrome is the first case to be reported in Oman as well as in the Gulf Cooperation Council countries (GCC) and in the Middle East and North Africa (MENA).

Inherited Unbalanced Chromosome from Parent with Balanced Translocation: A Case Report and Review of Literature

Reciprocal translocations are common, and the translocation heterozygote (carrier) may have a risk to have a child who would be mentally and physically abnormal due to a segmental aneusomy. The carriers of balanced translocation mostly do not have recognizable phenotypic expression, however, they can produce unbalanced chromosome, which is transmitted to next generation through fertilization of gametes carrying the derivative chromosome. We describe a 4-year-old boy with partial 10q trisomy and distal 13qmonosomy. The patient presented with delayed milestones, dysmorphic face, congenital heart defect, renal and skeletal anomalies. The conventional cytogenetic analysis showed a 46,XY, add(13q) karyotype. The child inherited the unbalanced chromosome from mother who was a carrier of balanced reciprocal translocation,t(10;13)(p24.2;q33.1). The phenotype observed in our patient resulted from the combination of those defects described in the isolated dup(10q) and distal del(13q) syndromes but predominantly resembles the children with distal trisomy 10q syndrome. Our finding are in concordance with the literature and supports the importance of critical regions like 10q24 and 13q32 for the phenotypic expression of distal 10q trisomy syndrome and distal 13q trisomy syndrome respectively.

Common skeletal features in rare diseases: New links between ciliopathies and FGF-related syndromes.

Congenital skeletal anomalies are rare disorders, with a subset affecting both the cranial and appendicular skeleton. Two categories, craniosynostosis syndromes and chondrodysplasias, frequently result from aberrant regulation of the fibroblast growth factor (FGF) signaling pathway. Our recent work has implicated FGF signaling in a third category: ciliopathic skeletal dysplasias. In this work, we have used mouse mutants in two ciliopathy genes, Fuzzy (Fuz) and orofacial digital syndrome-1 (Ofd-1), to demonstrate increase in Fgf8 gene expression during critical stages of embryogenesis. While the mechanisms underlying FGF dysregulation differ in the different syndromes, our data raise the possibility that convergence on FGF signal transduction may underlie a wide range of skeletal anomalies. Here, we provide additional evidence of the skeletal phenotypes from the Fuz mouse model and highlight similarities between human ciliopathies and FGF-related syndromes.

Low-dose fetal CT for evaluation of severe congenital skeletal anomalies: preliminary experience

Congenital skeletal abnormalities compose a heterogeneous and complex group of conditions that affect bone growth and development and result in various anomalies in shape and size of the skeleton. Prenatal sonographic diagnosis of these anomalies is challenging because of the relative rarity of each skeletal dysplasia, the multitude of differential diagnoses encountered when the bony abnormalities are identified, lack of precise molecular diagnosis and the fact that many of these disorders have overlapping features and marked phenotypic variability. The following review is a preliminary summary of our experience at the Children's Hospital of Philadelphia (CHOP) using low-dose fetal CT in the evaluation of severe fetal osseous abnormalities.

Fibrodysplasia ossificans progressiva without characteristic skeletal anomalies

Fibrodysplasia ossificans progressiva (FOP) is a rare but extremely disabling genetic disease of the skeletal system. This disease is characterized by progression of heterotopic ossification within skeletal muscles, ligaments and tendons. Most patients with FOP are misdiagnosed early in life before the appearance of heterotopic ossification and undergo diagnostic procedures such as biopsy that can cause lifelong disability. Almost all of the patients have some peculiar congenital anomalies, including short great toes, hallux valgus, short thumbs and hypoplasia of digital phalanges. These congenital defects support the diagnosis of FOP, but are not constantly observed in the totality of patients. If necessary, genetic studies can be performed to confirm the diagnosis. Once diagnosed, patients should be advised in order to avoid unnecessary traumas, surgical procedures, biopsies, intramuscular injections and vaccinations. Here, we describe a patient with FOP without characteristic congenital skeletal anomalies.

Basal cell nevus syndrome: clinical and genetic diagnosis

Basal cell nevus syndrome (BCNS), also known as Gorlin-Goltz syndrome, comprises five main pathological features: nevoid basal cell carcinomas, keratocystic odontogenic tumors, congenital skeletal anomalies, calcification of the falx cerebri, and point skin depressions on the palms and/or soles. The disease exhibits a dominant autosomal hereditary trait, with implication of the human homologue of the Drosophila segment polarity Patched (PTCH) gene. BCNS is diagnosed on the basis of clinical and radiological criteria and can be confirmed by genetic study. The patient prognosis is very good, with normal life expectancy in most cases. The present study reports two cases of BCNS with the presence of maxillo-mandibular keratocystic odontogenic tumors. One case was diagnosed according to clinical criteria, while the other required genetic confirmation that revealed a germ line mutation in exon 17 (c.2868delC), not previously described in the databases, which was considered to be responsible for the disease.

Intrachromosomal duplications of 22q11 are not a common cause of isolated coloboma and coloboma with other limited features of cat eye syndrome

Cateye syndrome(CES) is adevelopmental disorder with a variable pattern of congenital anomalies (OMIM #115470). CES is clinically characterized by uveoretinal coloboma, preauricular pits or tags, anal anomalies, total anomalous pulmonary venous return (TAPRV), or other congenital heart defects, renal malformations, craniofacial malformations, skeletal anomalies, and mental retardation. The variability of clinical manifestations is large, ranging from marginally affected individuals, to those with the full pattern of malformations and a lethal outcome [Berends et al., 2001; Rosias et al., 2001]. The majority of patients with CES carry a supernumerary bisatellited dicentric chromosome derived from chromosome 22 and described as dic(22) (pter!q11.2::q11.2!pter). This supernumerary chromosome results in the presence of four copies (tetrasomy) of 22p and proximal 22q11 in affected individuals. CES can also be caused by an interstitial duplication within 22q11, which produces three copies of the cat eye syndrome critical region (CESCR). This form of duplication has been less frequently described, possibly because the interstitial duplication may not always be visible by conventional cytogenetic or FISH analysis. Additionally, patients with only one extra copy of the CESCR might showevenmoreof a variablephenotype. They are likely to be mildly affected or to have only isolated features of CES [Taylor et al., 1977; Reiss et al., 1985; Knoll et al., 1995; Lindsay et al., 1995; Fujimoto and Lin, 1996]. Six patients with features of CES and interstitial duplications have been reported to date [reviewed in Meins et al., 2003]. Only a patient described by Meins et al. [2003] showed all the major symptoms of CES including coloboma, preauricular anomalies, heart defect, kidney malformation, and anal atresia. Although tetrasomy and especially trisomy for the CESCR does not always present with the classic CES phenotype, patients with limited and isolated features of the syndrome are not routinely tested for abnormalities in the 22q11 region. We hypothesized that some of these patients could carry small intrachromosomal duplications of the CESCR that are missed using current clinical testing methodologies. To test this hypothesis, we examined individuals with coloboma with or without other limited clinical features of CES for duplications involving the 22q11 critical region, knowing that uveoretinal coloboma represents a common feature of CES. Coloboma is present in 60% of the patients with supernumerary dic(22) chromosome [Rosias et al., 2001] and was detected in two out of six reported cases with an interstitial duplication of the CESCR. This eye defect has also been described in a patient with mosaic trisomy22 [Thomas et al., 2004]. Therefore, increased dosage of genes on chromosome 22 can disturb eye development and result in coloboma. Patients with ocular coloboma were referred to our research study by geneticists, genetic counselors, and ophthalmologists. Peripheral blood samples

A Complex Brain Malformation Syndrome with Rhombencephalosynapsis, Preaxial Hexadactyly plus Facial and Skull Anomalies

We report on a 15-year-old boy with epilepsy and mental retardation who had been repeatedly shunted since birth for hydrocephalus. This child showed at imaging an unusual, severe and complex brain malformation consisting of distorted gyral patterns with deeply infolded mantle in the parietal-lateral and posterior-temporal lobes, normal versus dysplastic cortex, unseparated thalami, thin white matter, collapsed ventricles, partial frontal corpus callosum agenesis, closely apposed superior and middle cerebral peduncles with narrow fourth ventricle, continuity of posterior cerebellum hemispheric foliar patterns across the midline, closely apposed cerebellar peduncles, asymmetrical hypogenesis of the vermis and herniation of the cerebellar hemispheric pattern up through the tentorial incisure. In addition, this boy had congenital skeletal and skin anomalies including pre-axial hexadactyly with thumb duplication, wide bone occipital lacunae (catlin mark) with partial occipital suture synostosis, cutis vertex rigirata and a tuft of hair in the outer region of the right eyebrow. Several of these cerebral and cerebellar abnormalities were suggestive of rhombencephalosynapsis. Nonetheless, many of these brain abnormalities are also recorded in Chiari type 2 malformation after operative shunting. To the best of our knowledge, however, this complex constellation of nervous system, skeletal and skin abnormalities has not been previously reported.

Skeletal anomalies in hyper-IgE recurrent infection syndrome (HIES, Job syndrome)

Rationale Hyper-IgE syndrome (HIES, Job syndrome) is characterized by a triad of elevated IgE, skin abscesses and cyst-forming pneumonia. Non-immunological characteristics of this syndrome (skeletal anomalies, scoliosis, retention of primary teeth, osteoporosis, pathologic fractures, characteristic facies and hyperextensibility) have been described in detail only recently. Some of these characteristics as well as the severe infectious complications may not be apparent until late childhood or adolescence. Our objective was to study the association of HIES with skeletal anomalies that are detectable in the early years. Methods We reviewed our data from 159 subjects in 49 families evaluated for possible HIES at the National Institutes of Health. Congenital skeletal anomalies were detected by radiological assessment of the skull, spine and long bones. Results HIES was diagnosed in 52 patients. Ten of these patients had not had either skin abscesses or a history of pneumonias by the time of diagnosis, but presented with the other components of this syndrome and/or a fully affected first degree relative. Seventeen of the 52 HIES patients (32%) had at least one congenital skeletal anomaly, in contrast to 5 of 107 (4.7%) subjects in whom HIES was not confirmed (p=0.002). Some of the observed skeletal anomalies were: craniosynostosis, hemivertebrae, short limbs, spina bifida, bifid rib and Blount's disease. Conclusions HIES patients have an increased incidence of congenital skeletal anomalies. Physicians should look for skeletal anomalies when considering HIES, especially in patients too young to have enough manifestations of HIES to make a definitive diagnosis.

The prevalence of cervical and thoracic congenital skeletal abnormalities in basal cell naevus syndrome; a review of cervical and chest radiographs in 80 patients with BCNS.

The major clinical stigmata of basal cell naevus syndrome (BCNS) appear in adolescence and adult life but some occult skeletal abnormalities are congenital. BCNS is dominantly inherited and it would be useful to identify, as early in life as possible, which of the offspring of patients with BCNS are at risk of developing the syndrome. Radiographs of the neck and chest of 80 patients with BCNS diagnosed confidently on clinical criteria have been examined for abnormalities which were considered to be congenital skeletal anomalies. Congenital abnormalities of the cervical and thoracic spine, mainly spina bifida occulta, were found in 45%. Congenital abnormalities of ribs were found in 49% and of the shoulder(s) in 36%. Overall congenital abnormalities were shown on the neck or chest radiograph in 55 (69%) patients. The presence of one or more of these congenital abnormalities on the chest or neck radiograph of a child who is the offspring of a person with BCNS makes it extremely likely that the child also has BCNS. The absence of these features, and of any clinical features of BCNS, would suggest that the risk of the child developing BCNS has been reduced from the prior expectation of 50% to approximately half that (24%).

Ultrasonic appearances of the early changes in fibrodysplasia ossificans progressiva

Progressive heterotopic ossification and congenital skeletal anomalies characterize the very rare and relentless condition of fibrodysplasia ossificans progressiva (FOP) or myositis ossificans progressiva (MOP)(McKusick, 1972). These patients frequently present with subcutaneous masses which are often painful (Lindhout & Golding, 1985) and therefore ultrasound may be used in the initial investigation. We report a case of FOP presenting with recurrent soft-tissue swellings and demonstrate the ultrasonic appearances not previously documented in this condition. A 5-year-old boy first presented with a history of pain in his right knee following a minor injury. Radiographs showed an apparent simple exostosis arising from the medial side of the proximal tibial metaphysis (Fig. 1); no further investigations were performed at this time. He presented again several months later with a swelling in the subcutaneous tissues of the left anterior thigh and with pain on walking. No soft-tissue abnormality was identified on the radiographs. Ultrasonic examination using a Diasonics 5 MHz rotating transducer demonstrated an increase in the thickness of the soft tissues and a well defined hypoechoic lesion with an echogenic central region in the deep compartment of the anterior thigh (Fig. 2). When radiographs were repeated 3 months later ossification had taken place in this area (Fig. 3.). Further similar swellings developed in the para-vertebral tissues of the lumbar region and around the right scapula. Ultrasound now demonstrated separation of the normal muscular fasicular planes by echogenic material together with increase in the muscle size (Fig. 4).

MR Imaging of Early Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva is a rare disorder characterized by progressive heterotopic bone formation in connective tissue and muscle in association with congenital skeletal anomalies. The disease usually leads to extensive immobility and eventual disability. We report the magnetic resonance findings in a boy prior to ossification of his soft tissue masses.

A distinct dysmorphic syndrome with congenital glaucoma and probable autosomal recessive inheritance

Three sisters with congenital glaucoma, peculiar facies and mild skeletal anomalies are described. It is concluded that such an aggregate of anomalies probably corresponds to a 'new' autosomal recessive syndrome.

Congenital myopathy with cleft palate and increased susceptibility to malignant hyperthermia: King syndrome?

Six children of similar ethnic origin with congenital myopathy, cleft palate, malignant hyperthermia (or susceptibility to malignant hyperthermia), and skeletal anomalies are presented. The findings are remarkably consistent among our patients, 3 of whom were related. This syndrome is likely to be inherited as an autosomal recessive trait. Children with this disorder are likely to undergo surgery with general anesthesia for facial or skeletal deformities and should be recognized as predisposed to developing malignant hyperthermia.