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PubMedDate not supplied

Gait analysis and muscle strength in children with surgically treated clubfeet.

Twenty-three children who had unilateral surgery for idiopathic clubfeet underwent gait analysis and isokinetic muscle-strength testing at an average of 10 years after surgical release. Ankle sagittal-plane kinematics were disturbed in 20 clubfeet. Fifteen children had an internal foot-progression angle. Genu valgum and knee hyperextension were common. Plantarflexion power was decreased by 23% on the side of surgery (p = 0.00005). Quadriceps weakness (defined as a decrease in strength >10% of the nonoperated-on limb's strength) was seen in nine of 22 operated-on limbs and hamstring weakness in eight of 22. Gastrocsoleus weakness exceeded 10% in 16 of 21 clubfeet. Average weakness of the gastrocsoleus was 27% (p < 0.05). Ten-year analysis of children treated with clubfoot releases revealed disturbances in ankle motion and strength. Loss of plantarflexion power and gastrocsoleus strength can be predicted by Achilles tendon lengthening. Knee kinematic abnormalities and weakness also were seen. These abnormalities produce functional difficulties in gait and may lead to degenerative changes later.

Child, Preschool↗
PubMed1997

Skeletal anomalies and deformities in patients with deletions of 22q11.

Skeletal anomalies in patients with a 22q11.2 deletion are reported infrequently. We report the skeletal findings in 108 patients with a 22q11.2 deletion, of whom 37 (36%) had a skeletal anomaly. Twenty-two patients (20%) had anomalies of the limbs, 7 of the upper limb, including preaxial or postaxial polydactyly. An anomaly of the lower limb was found in 16 patients, including postaxial polydactyly, clubfoot, severely overfolded toes, and 2-3 toe cutaneous syndactyly. Chest films of 63 patients were examined; 30% of them had abnormal findings, most commonly supernumerary ribs (17%) or a "butterfly" vertebral body (11%). Hypoplastic vertebrae, hemivertebrae, and vertebral coronal clefts were also noted. Thus, skeletal anomalies are not uncommon in patients with a 22q11.2 deletion and may occur more frequently than recognized previously.

Adolescent↗
PubMed1991

Paternal occupation and congenital anomalies in offspring.

This paper presents the results of an exploratory case-control study of paternal occupation as a risk factor for birth defects in offspring. With the use of a population-based registry in British Columbia, 14,415 liveborn children with birth defects were identified for the period, 1952-1973. Two controls were matched to each case by using the birth files of British Columbia. Paternal occupation was obtained from the birth certificate. The analysis included 20 birth defect categories. Paternal occupations found to be associated with an increased odds ratio (OR) of birth defects include janitors [hydrocephalus (OR = 5.04), ventricular septal defects (OR = 2.45), other heart defects (OR = 2.35)], forestry and logging workers [congenital cataract (OR = 2.28), atrial septal defects (OR = 2.03), syndactyly (OR = 2.03)], painters [spina bifida (OR = 3.21), patent ductus arteriosus (OR = 2.34), cleft palate (OR = 3.36)], printers [atresia of the urethra (OR = 4.50), clubfoot (OR = 2.18)], and plywood mill workers [patent ductus arteriosus (OR = 2.52), pyloric stenosis (OR = 4.12), dislocated hip (OR = 2.71)]. This study has several limitations and the results must be viewed with caution. Nonetheless, the study provides new leads for further evaluation of the role of father's occupation in the etiology of birth defects.

British Columbia↗
PubMed2001

Type I diabetes mellitus in a patient with chromosome 22q11.2 deletion syndrome.

We describe a patient with type I diabetes, clinical findings consistent with velocardiofacial syndrome, and a chromosome 22q11.2 deletion. A nine-year-old boy presented with a history of polyuria, polydipsia, weight loss, hyperglycemia, ketosis, serum insulin antibodies, and a low C-peptide level. He had distinctive facial features, learning disabilities, short stature, and a history of glottic web and clubfoot. Although a normal karyotype was obtained, fluorescence in situ hybridization (FISH) revealed a submicroscopic deletion in the DiGeorge/velocardiofacial syndrome critical region at 22q11.2. His maternal half-brother also carried a chromosome 22q11.2 deletion. His mother has similar facial features and hypoparathyroidism. Autoimmune problems associated with chromosome 22q11.2 deletions have been reported. We suggest that the defects in immune regulation due to T-cell deficiency in chromosome 22q11.2 deletion syndrome may predispose to autoimmune disorders, including type I diabetes mellitus.

Abnormalities, Multiple↗
PubMed1977

Poland syndrome in British Columbia: incidence and reproductive experience of affected persons.

Patients with Poland syndrome were ascertained through the British Columbia Health Surveillance Registry, through hospital records, and through practicing plastic and orthopedic surgeons. Of 44 patients who were ascertained, 28 had family histories taken and were examined. Physical findings were: absence of the sternal head of the pectoralis major in all patients, symbrachydactyly in most patients, and infrequent other associations such as ipsilateral undescended testis, Möbius syndrome, clubfoot, and submucous cleft palate. Family histories were "negative" in all cases. The 8 affected adults had 24 reportedly normal children. Mean paternal age was significantly higher than the paternal age in the population. The incidence was 1/32,000 livebirths in British Columbia. It was concluded that in the British Columbia population the syndrome is usually a sporadic event.

Adult↗
PubMed1988

Prenatal sonographic diagnosis of Pena-Shokeir syndrome type I, or fetal akinesia deformation sequence.

We report on a familial case of Pena-Shokeir syndrome type I (fetal akinesia deformation sequence) born to healthy parents. The antenatal ultrasound diagnosis was based on hydramnios, restricted limb movements, decreased fetal chest movements, small chest, arthrogryposis, clubfoot, fixed extension of knees, fixed flexion of elbows, camptodactyly, kyphosis of thoracic spine, cryptorchidism, and small muscle bulk. Thymic hyperplasia was noted at autopsy.

Abnormalities, Multiple↗
PubMed2003

Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families.

CDMP-1, a cartilage-specific member of the TGFss superfamily of secreted signaling molecules, plays a key role in chondrogenesis, growth and patterning of the developing vertebrate skeleton. Homozygous CDMP-1 mutations cause Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia and DuPan syndrome in humans, as well as brachypodism in mice, while heterozygous mutations cause brachydactyly type C (BDC). We present clinical and radiographic data from three unrelated families in which 12 members share the same heterozygous CDMP-1 mutation, an insertion (insG206), resulting in a frameshift predicted to cause functional haploinsufficiency. Although eight mutation carriers display BDC, four have normal hands and feet, confirming nonpenetrance of BDC with CDMP-1 mutations. In addition, several carriers have other skeletal abnormalities, including severe bilateral vertical talus (in two), developmental hip dysplasia (in one), and short stature (in two, who are otherwise unaffected). Premature vertebral end-plate disease was observed in four mutation carriers and was associated with spondylolysis and spondylolisthesis in three of these. Axial skeletal involvement has not been previously reported in association with CDMP-1 mutations. This finding is consistent with CDMP-1 expression in human hypertrophic chondrocytes, which are present in the ring epiphyses of vertebral end plates. Phenotypic variation in BDC has previously been attributed either to locus heterogeneity or to the varied functional effects of different CDMP-1 mutations. The remarkable range of phenotypes caused by this identical CDMP-1 mutation in these families emphasizes the crucial role of genetic background, stochastic variation and/or environmental factors in modifying the observed phenotype. Our findings illustrate that nonpenetrance for the typical features of BDC can be appreciable and that atypical skeletal features that have been reported in some patients with BDC (i.e., clubfoot, short stature, spondylolysis) may also result from CDMP-1 mutation.

Bone Diseases↗
PubMed2003

Identity by descent and candidate gene mapping of Richieri-Costa and Pereira syndrome.

The Richieri-Costa-Pereira syndrome is a rare autosomal recessive disorder characterized by short stature, Robin sequence, cleft mandible, pre/postaxial anomalies and clubfoot. Of 15 families reported with this disorder 14 are from Brazil suggesting a founder effect. We studied 15 families using identity-by-descent as a hypothesis to attempt gene localization We have examined through linkage analysis 497 polymorphic-markers and also performed direct sequencing of exons for 10 candidate genes selected on the basis of their expression in the developing mandible and limb. No evidence for allele sharing at any locus tested or mutations in candidate genes was found. Additional higher resolution mapping, new families and other candidate genes might improve future chances of gene identification.

Body Height↗
PubMed2003

Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign.

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene result in a family of skeletal dysplasias, which comprise lethal (achondrogenesis type 1B and atelosteogenesis type 2) and non-lethal conditions (diastrophic dysplasia and recessive multiple epiphyseal dysplasia (rMED)). The most frequent mutation is R279W, which in a homozygous state results in rMED with bilateral clubfoot, MED, and "double layered" patella. We describe three patients with rMED caused by a previously unreported homozygous mutation in the DTDST gene. The three patients (from two families) were born to healthy, non-consanguineous parents. All developed signs of hip dysplasia in early childhood and two had episodes of recurrent patella dislocation. Two underwent bilateral total hip replacements at ages 13 and 14 years. The feet, external ears, and palate were normal. Stature was normal in all cases. Radiographs showed dysplastic femoral heads, mild generalized epiphyseal dysplasia, abnormal patella ossification, and normal hands and feet. Direct sequence analysis of genomic DNA demonstrated a homozygous 1984T > A (C653S) change in the DTDST gene in all patients. The clinically normal parents were heterozygous for the change. This is the first description of a homozygous C653S mutation of the DTDST gene. Hip dysplasia and patella hypermobility dominates the otherwise mild phenotype. These patients further expand the range of causative mutations in the DTD skeletal dysplasia family.

Adolescent↗
PubMed2026

Moebius-Plus Phenotype With Positive RCEM Episignature May Indicate Broader Embryologic Malformation Spectrum Detectable by Methylation Profiling.

Moebius syndrome (OMIM #157900) is a rare congenital cranial dysinnervation disorder characterized by abducens (CN VI) and facial (CN VII) nerve palsies with variable craniofacial and limb anomalies. Despite advances in genomic testing, the majority of patients remain genetically unexplained. Episignature testing, which detects syndrome-specific DNA methylation patterns, has emerged as a complementary diagnostic tool for conditions with shared developmental mechanisms. We describe an 8-month-old male born prematurely with bilateral clubfoot, craniofacial dysmorphism, feeding difficulty requiring gastrostomy tube placement, and respiratory failure requiring tracheostomy. Neuroimaging demonstrated absence of bilateral abducens and facial nerves with pontocerebellar hypoplasia, supporting a clinical diagnosis of Moebius syndrome. Extensive genetic evaluation, including genome sequencing and targeted testing for hypotonia and hypoventilation syndromes, was nondiagnostic. Episignature analysis revealed a moderately positive methylation signature consistent with a recurrent constellation of embryonic malformation (RCEM), concordant with two of three previously validated RCEM classifier models. To our knowledge, this is the first report of a patient with a positive RCEM episignature and Moebius syndrome, suggesting a common embryologic pathway. Episignature testing may represent a valuable diagnostic tool in patients with Moebius syndrome and related craniofacial-limb malformation spectra when conventional genomic testing is unrevealing.

RCEM↗
PubMed2002

Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay.

Desmosterol (cholesta-5,24-dien-3beta-ol) is a minor sterol that forms as an intermediate in the cholesterol biosynthetic pathway when the 24-unsaturated sterol bond is reduced as the last step rather than earlier in the conversion of lanosterol to cholesterol. In 1998, FitzPatrick et al. reported a premature infant who died shortly after birth and had marked tissue elevations of desmosterol and a strikingly abnormal phenotype. We describe here the first living patient with desmosterolosis and show biochemical evidence in plasma and cultured lymphoblasts for an autosomal recessive deficiency of 24-dehydrocholesterol reductase (DHCR24). The infant has severe microcephaly, agenesis of the corpus callosum, downslanting palpebral fissures, micrognathia, submucous cleft palate, clubfoot, and a persistent patent ductus arteriosus. Plasma sterol quantification in the patient at age 2 years demonstrated a normal cholesterol level, but a 100-fold increased level of desmosterol (60 mcg/ml; nl 0.5 +/- 0.3 mcg/ml (SD)) suggesting deficient activity of 24-dehydrocholesterol (desmosterol) reductase (DHCR24). Both parents had mildly increased levels of desmosterol in plasma (mother: 1.4 mcg/ml; father: 1.8 mcg/ml), consistent with heterozygosity for DHCR24 deficiency. Analysis of sterol metabolism in cultured transformed lymphoblasts showed a 100-fold increased level of desmosterol and a moderately decreased level of cholesterol in the patient's cells and a 10-fold elevation of desmosterol in the mother's cells. At the age of 3.5 years, the patient stands but does not walk, uses a 5-word vocabulary, and lacks any major medical problems. This unique patient broadens the spectrum of inborn errors of cholesterol biosynthesis and suggests additional candidate clinical phenotypes associated with abnormal cholesterol metabolism.

Abnormalities, Multiple↗
PubMed2003

Developmental skeletal anomalies.

A genetic and molecular revolution is taking place in medicine today. Led by the Human Genome Project, genetic information and concepts are changing the way diseases are defined, diagnoses are made, and treatment strategies are developed. The profound implications of actually understanding the molecular abnormalities of many clinical problems are affecting virtually all medical and surgical disciplines. The ability to apply knowledge gleaned from the laboratory is our best hope for developing strategies to modify the pathologic effects of genes (by drug therapy), repair genes (gene therapy), and restore lost or affected tissues (tissue engineering). Instead of an empiric trial-and-error approach to therapy, it may become feasible to tailor treatment to the specific molecular malfunction. In this review we have chosen to emphasize a few selected musculoskeletal disorders, including skeletal dysplasias, spinal deformities, developmental dislocation of the hip, and idiopathic clubfoot. The logical extension of our understanding of the molecular players in many of these disorders is to establish precisely what the products of the affected genes do during skeletal development, and how mutations disturb these functions to produce the characteristic phenotype. Despite the many hypotheses generated from the work in human genetics, and the knowledge that has been gained from animal models, there remains a relatively poor understanding of how these genes interfere with skeletal development. Unraveling these mysteries and defining them in molecular and cellular terms will be the challenges for the near future.

Bone Diseases, Developmental↗
PubMedDate not supplied

Prenatal diagnosis of pentalogy of Cantrell in three cases, two with craniorachischisis.

In this report, we describe 3 cases of pentalogy of Cantrell diagnosed prenatally with sonography. All 3 fetuses had an omphalocele and ectopia cordis; 2 of them also had craniorachischisis, in which the open cranial defect (anencephaly or exencephaly) is continuous with the completely open spine (spinal dysraphism). The association of the pentalogy of Cantrell with exencephaly is rare, and to our knowledge, the association of this syndrome with craniorachischisis has not been reported previously. In addition, 2 of our cases had clubfoot, and 1 of them also had clubhand, neither of which has been reported previously in association with the pentalogy of Cantrell. Finally, polyhydramnios, which occurred in 2 of our cases, has been reported to occur in association with that syndrome in only 1 previous case. We believe that sonographers should be aware that these anomalies may occur simultaneously with the classic anomalies of the pentalogy of Cantrell.

Abdominal Wall↗
PubMed1987

Effect of peripheral nerve on limb development.

The effect of peripheral nerve on limb growth and maturation has received little attention after the limb differentiation stage. This study used an amphibian model (Rana pipiens) to examine the effect of temporary denervation on the development of limb muscle and bone tissues. Quantitative microscopic techniques were employed to evaluate bone and muscle size and cellularity between denervated and control limbs. A 15% decrease in tibial length and a 17% decrease in cross-sectional area were found in the temporarily denervated limbs as compared with the control limbs during the growing period studied. A 26% increase in tibial osteocyte density was found in the denervated limbs, although total osteocyte number was the same. The same differences were found on comparing less and more mature limbs from normal animals. Gastrocnemius muscle from temporarily denervated limbs had a 46% lesser cross-sectional surface area and a 66% greater muscle fiber density as compared with control limbs. Total muscle fiber number was the same. Similar findings were observed comparing limbs of different maturities from normal unoperated animals. This study suggests that the absence of peripheral nerves decreases the rate of bone maturation, which effect may be responsible for the diminished size of denervated limbs. This work demonstrates a model for regional growth disturbances that may aid in understanding such disorders as idiopathic leg length discrepancy, hemihypertrophy, clubfoot, and the limb deformities created by paralytic diseases.

Animals↗
PubMed1989

Effect of denervation on limb growth.

This study used Rana pipiens tadpoles to assess the effect of complete and partial sciatic denervation on tibial bone growth and foot growth. Complete sciatic denervation was performed in R. pipiens at Stages XIV, XVII, and XX and they were killed at Stages XVII, XX, and XXIV. Partial denervation consisted of peroneal or tibial nerve sectioning at Stages XVII and XX with killing at Stages XX and XXIV. Analysis of experimental animals and controls consisted of (a) quantitative axon counts, (b) tibial length, (c) midtibial cross-sectional area, (d) midtibial cortical thickness, (e) midtibial cartilage anlage cross-sectional area, (f) foot silhouette area, and (g) osteocyte number and osteocyte density. Both complete and partial denervation resulted in significant effects on bone and foot growth: (a) decreased bone length, (b) decreased cross-sectional bone area without cortical thinning, (c) increased cartilage anlage cross-sectional area, and (d) decreased foot size. This experiment demonstrated a trophic effect of nerve on bone growth and development and foot growth. The mechanism of this action is unknown but the data suggests a slowed rate of maturation in denervated bones. The possibility exists that defective peripheral nerve-limb tissue interactions may cause human deformities such as idiopathic clubfoot and idiopathic limb length discrepancy.

Animals↗
PubMed2006

HOXD10 M319K mutation in a family with isolated congenital vertical talus.

Congenital vertical talus (CVT) is a primary dislocation of the talonavicular joint that often occurs in neuromusculoskeletal syndromes, but may also be seen as an isolated abnormality. Six families with isolated CVT were ascertained. DNA was isolated from 21 affected individuals and 17 unaffected individuals from these families, as well as from five sporadic patients with CVT. Variable expressivity was noted in three families, manifesting as clubfoot in three individuals. Genome-wide linkage analysis generated a maximum two-point logarithm of odds score on chromosome 2q with D2S1353 (Zmax = 1.43 at theta(max) = 0.1), 17 Mb from the HOXD gene cluster. DNA from one affected individual of each family was subjected to mutational analysis of the HOXD10 gene. A single missense mutation was identified (M319K, 956T > A) in the homeodomain recognition helix of the HOXD10 gene that segregated with disease in one large British family. This mutation was recently described in a family of Italian descent with CVT and Charcot-Marie-Tooth deformity HOXD10 gene mutations were not identified in any of the other families or sporadic patients with CVT, suggesting that genetic heterogeneity underlies this disorder.

Chromosomes, Human, Pair 2↗
PubMed2006

Postmortem evaluation of 220 prenatally diagnosed fetuses with neural tube defects: detection of associated anomalies in a Turkish population.

OBJECTIVES: The aim of this study is to represent the distribution of disorders resulting from neural tube defects (NTDs). MATERIALS AND METHODS: This study was conducted on 220 prenatally diagnosed cases with NTDs. Fetuses were evaluated by physical examination, anthropometric measurements, X-rays, and photographs after termination of pregnancy. Chromosome analysis and autopsy were performed for 37 fetuses (16.8%) with additional malformations. RESULTS: In 29 out of 37 fetuses (78.4%), additional malformations were detected by prenatal ultrasonography, whereas in eight cases postmortem evaluation produced additional findings that were not detected prenatally. Fourteen of 37 (37.8%) and 65 of 220 (29.5%) fetuses had clubfoot, which was mostly secondary to NTDs. There was no difference in sex distribution between isolated NTDs and the group with additional abnormalities and among the groups anencephaly and anencephaly + anomaly, encephalocele and encephalocele + anomaly, spina bifida and spina bifida + anomaly. There was only one case, a female fetus, with iniencephaly in this group. Anencephaly was more frequent in cases with isolated NTDs (48.1%) than in those with additional anomalies (27%). There was no difference for other groups of NTDs. The most frequent disorder was vertebral segmentation defects, which were detected in 11 out of 37 cases (29.7%). CONCLUSIONS: Evaluation of associated malformations and confirmation of ultrasound findings can be performed by postmortem examination and simple X-ray studies for exact diagnosis, which strongly affects decisions on further pregnancies as well as genetic counseling. This method is straightforward, inexpensive and effective.

Autopsy↗
PubMed2002

Prenatal sonographic diagnosis of the 49,XXXXY syndrome.

The 49,XXXXY syndrome is a rare sex chromosome anomaly with an approximate incidence of 1 in 85,000 male live births. The diagnosis is usually ascertained postnatally by the association of mental retardation, variable growth deficiency, Down syndrome-like facial dysmorphy, hypogenitalism and other malformations, especially involving the heart and skeleton. Prenatal diagnosis of the pentasomy 49,XXXXY is generally fortuitous and sonographic features have rarely been described in the literature. We report here on two cases of 49,XXXXY syndrome diagnosed prenatally because of sonographic abnormalities. In the first, amniocentesis was performed at 26 weeks' gestation for polyhydramnios, unilateral clubfoot and micropenis. In the second, a karyotype was carried out on chorionic villi at 13 weeks' gestation for cystic hygroma. These observations and the six previously reported cases demonstrate that cystic hygroma in first or second trimester of pregnancy may be associated with sex chromosome aneuploidy other than Turner syndrome. Moreover, they emphasize the importance of detailed sonographic examination in the second trimester, as small penis and abnormal posturing of the lower extremities are very suggestive of the 49,XXXXY syndrome.

Abnormalities, Multiple↗