Polydactyly with triphalangeal thumbs, brachydactyly, camptodactyly, congenital dislocation of the patellas, short stature and borderline intelligence.
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Abnormalities, Multiple↗
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Teratogenic mechanisms of longitudinal deficiency and cleft hand.
In order to better understand the teratogenic mechanisms of congenital defects of the digits, we analyzed clinical cases and induced similar types of congenital hand anomalies in rat fetuses by oral administration of busulfan. In clinical cases, radial and ulnar deficiencies had common characteristic features. We induced radial and ulnar deficiencies in rat fetuses with the same drug. Radial and ulnar deficiencies induced in rats have similar clinical manifestations and these anomalies might be caused by the same teratogenic mechanism. Then, the formation of the digital rays was examined histologically. The results of histological examination suggested that these deficiencies were not caused by localized damage of the limb bud. They also suggested that the cause of missing digits in longitudinal deficiency is closely related to a deficit of mesenchymal cells in the limb bud. Cleft hand is considered to be one of the types of longitudinal deficiency. However, several investigators have suggested that the abnormal induction of finger rays in the process of formation of fingers induced central polydactyly, osseous syndactyly and also cleft hand. X-rays of the clinical cases and skeletal changes of the anomalies induced in rats appear to demonstrate that cleft hand formation proceeds from osseous syndactyly and central polydactyly. The results of our experimental study show that the critical periods of central polydactyly, osseous syndactyly and cleft hand are the same. They also suggest that central polydactyly, syndactyly and cleft hand might be induced when the same teratogenic factor acts on embryos at the same developmental stage in the human being. Because they have a similar causation, cleft hand, syndactyly and central polydactyly should be classified into the same entity, that is, abnormal induction of digital rays. Based on these clinical and experimental studies, we modified the Swanson classification. In our modified classification, typical cleft hand, syndactyly and polydactyly are included in the same category of abnormal induction of digital rays as the fourth new category.
Animals↗
Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1).
To address the prevalence of congenital bone malformations in neurofibromatosis type 1 (Nf1; compared with Nf1 bone anomalies and tumors), we studied the Nf1 population of 135 children (70 boys, 65 girls) seen at the neurofibromatosis clinic, University of Catania, Italy, in the period 1990 through 1996. Twelve (8.8%) of the 135 children had congenital bone malformations: unilateral or bilateral postaxial polydactyly type A (n = 1) and type B (n = 1), bilateral postaxial polydactyly type A in association with preaxial polydactyly type 1 (n = 1) and bilateral preaxial polydactyly (n = 1); clynodactyly (n = 1); multiple segmentation anomalies of the vertebrae (n = 6), and complex costovertebral anomalies (n = 1). We found a higher frequency of polydactyly (2.9%) in comparison to that in the general population (0.014-0.12%) and in our national (0.027%) and regional (0.066%) population, and a higher frequency of vertebral (5.1%) and costovertebral (0.7%) malformations. This is the first study to state the overall prevalence of congenital bone malformations in an Nf1 population. Interestingly, polydactyly (postaxial type) and Nf1 was previously reported only once.
Adolescent↗
Cleft hands with six metacarpals.
PURPOSE: The purpose of this study was to identify children with cleft hands whose radiographs showed metacarpal polydactyly with 6 metacarpals to support the hypothesis that cleft hand develops not as a result of a longitudinal failure of formation but through a process of central polydactyly and osseous syndactyly. METHODS: We screened the hand radiographs of all children with a transverse or longitudinal deficiency of the upper limb and identified 8 children with cleft hands containing 6 metacarpals. RESULTS: Six cleft hands had a missing middle finger and consisted of a thumb and index finger separated from the ring and small fingers by a V-shaped central cleft. Two children had a more severe form of cleft hand with absence of both the index and middle fingers but presence of 6 metacarpals. CONCLUSIONS: These 8 cleft hands containing 6 metacarpals showed progression of polydactyly of the middle finger and osseous syndactyly between the 2 middle finger metacarpals and the adjacent index and ring finger metacarpals. This contradicts a longitudinal failure of formation mechanism and supports the alternative hypothesis that cleft hand, polydactyly, and syndactyly develop through a similar teratogenic mechanism. The 2 cleft hands that had more severe suppression of the index and middle fingers yet had 6 metacarpal polydactyly provided confirmatory evidence that both typical cleft hands and the more severe manifestations of cleft hand with absence of multiple digits develop through a similar failure of induction mechanism.
Child↗
The significance of genetic factors for thalidomide teratogenicity in the Norway rat.
Thalidomide teratogenicity was tested on a model based on the system of congenic strains of the laboratory rat, including the mutant allele lx, which determines the polydactyly-luxate syndrome. The phenotypic expression of the allele lx changes according to the genetic background of the carrier and also according to factors of the external environment. On a hybrid genetic background LEW/BN the allele lx acts as recessive, and heterozygotes +/lx are unaffected. In a number of experiments it was proved, however, that these hybrids (LEW/BN, +/lx) had an increased sensitivity to the induction of limb malformations (polydactyly, tibial hemimelia, oligodactyly) by various teratogens. Thalidomide was administered on the 12th day of pregnancy by the intraperitoneal route in a mixture of Tween 20 with saline (1:3) in doses of 25, 50 and 200 mg/kg to females with genetic background LEW that were purposely mated with males of the BN or BN.lx strains. The produced progeny had genotypes LEW/BN, +/+ or LEW/BN, +/lx. In offsprings that had in the genotype the mutant allele lx in a heterozygous condition (+/lx) preaxial polydactyly of hind limbs developed after all the thalidomide doses tested. This malformation occurred in 17 out of 18 litters, altogether in 97 out of 162 foetuses +/lx, i.e. in 59.9%. In the progeny without the mutant allele (genotype +/+) polydactyly did not develop in any of the 108 cases. Control foetuses +/+ the mothers of which had been administered only Tween 20 with saline remained unaffected, while in control foetuses +/lx polydactyly developed in 8.1% (3 cases). The result demonstrates thalidomide teratogenicity in the laboratory rat where it has not been proved unambiguously so far. The teratogenic effect is the outcome of the interaction of thalidomide with the mutant allele lx. At the same time there is emphasized the importance of the genotype of the experimental animals in the testing of teratogens.
Animals↗
Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci.
Bardet-Biedl syndrome (BBS) is an autosomal-recessive disorder of mental retardation, obesity, retinal dystrophy, polydactyly, and hypogenitalism. Renal and cardiac abnormalities are also frequent in this disorder. Previous clinical suggestions of heterogeneity of BBS were confirmed recently by the identification of four different chromosome loci linked to the disease. In this study we compared clinical manifestations of the syndrome in patients from 3 unrelated, extended Arab-Bedouin kindreds which were used for the linkage mapping of the BBS loci to chromosomes 3, 15, and 16. The observed differences included the limb distribution of the postaxial polydactyly and the extent and age-association of obesity. It appears that the chromosome 3 locus is associated with polydactyly of all four limbs, while polydactyly of the chromosome 15 type is mostly confined to the hands. On the other hand, the chromosome 15 type is associated with early-onset morbid obesity, while the chromosome 16 type appears to present the "leanest" form of BBS. Future cloning of the various BB genes will contribute to the understanding of the molecular basis of limb development and to the identification of human obesity-related genes.
Adolescent↗
Sonic hedgehog: restricted expression and limb dysmorphologies.
Sonic hedgehog, SHH, is required for patterning the limb. The array of skeletal elements that compose the hands and feet, and the ordered arrangement of these bones to form the pattern of fingers and toes are dependent on SHH. The mechanism of action of SHH in the limb is not fully understood; however, an aspect that appears to be important is the localized, asymmetric expression of Shh. Shh is expressed in the posterior margin of the limb bud in a region defined as the zone of polarizing activity (ZPA). Analysis of mouse mutants which have polydactyly (extra toes) shows that asymmetric expression of Shh is lost due to the appearance of an ectopic domain of expression in the anterior limb margin. One such polydactylous mouse mutant, sasquatch (Ssq), maps to the corresponding chromosomal region of the human condition pre-axial polydactyly (PPD) and thus represents a model for this condition. The mutation responsible for Ssq is located 1 Mb away from the Shh gene; however, the mutation disrupts a long-range cis-acting regulator of Shh expression. By inference, human pre-axial polydactyly results from a similar disruption of Shh expression. Other human congenital abnormalities also map near the pre-axial polydactyly locus, suggesting a major chromosomal region for limb dysmorphologies. The distinct phenotypes range from loss of all bones of the hands and feet to syndactyly of the soft tissue and fusion of the digits. We discuss the role played by Shh expression in mouse mutant phenotypes and the human limb dysmorphologies.
Embryonic Induction↗
Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome.
Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.
Abnormalities, Multiple↗
A novel acropectoral syndrome maps to chromosome 7q36.
F syndrome (acropectorovertebral syndrome) is a dominantly inherited skeletal dysplasia affecting the hands, feet, sternum, and lumbosacral spine, which has previously been described in only two families. Here we report a six generation Turkish family with a related but distinct dominantly inherited acropectoral syndrome. All 22 affected subjects have soft tissue syndactyly of all fingers and all toes and 14 also have preaxial polydactyly of the hands and/or feet. In addition, 14 have a prominent upper sternum and/or a blind ending, inverted U shaped sinus in the anterior chest wall. Linkage studies and haplotype analysis carried out in 16 affected and nine unaffected members of this family showed that the underlying locus maps to a 6.4 cM interval on chromosome 7q36, between EN2 and D7S2423, a region to which a locus for preaxial polydactyly and triphalangeal thumb-polysyndactyly has previously been mapped. Our findings expand the range of phenotypes associated with this locus to include total soft tissue syndactyly and sternal deformity, and suggest that F syndrome may be another manifestation of the same genetic entity. In mice, ectopic expression of the gene Sonic hedgehog (Shh) in limb buds and lateral plate mesoderm during development causes preaxial polydactyly and sternal defects respectively, suggesting that misregulation of SHH may underlie the unusual combination of abnormalities in this family. A recently proposed candidate gene for 7q36 linked preaxial polydactyly is LMBR1, encoding a novel transmembrane receptor which may be an upstream regulator of SHH.
Abnormalities, Multiple↗
Canadian Bardet-Biedl syndrome family reduces the critical region of BBS3 (3p) and presents with a variable phenotype.
There are at least five distinct Bardet-Biedl syndrome (BBS) loci, four of which have been mapped: 11q (BBS1), 16q (BBS2), 3p (BBS3), and 15q (BBS4). A comparative study of the three Arab-Bedouin kindreds used to map the BBS2, BBS3, and BBS4 loci suggests that the variability in the number and severity of clinical manifestations, particularly the pattern of polydactyly, reflects chromosome-specific subtypes of BBS [Carmi et al., 1995a; Am J Med Genet 59:199-203]. We describe a Newfoundland kindred of northern European descent and confirm the initial finding of a BBS locus on chromosome 3. However, the "BBS3 phenotype," which includes polydactyly of all four limbs and a progression to morbid obesity, was not observed. Rather, four of the five BBS patients in this family had polydactyly restricted to their feet. The obesity in these patients was reversible with caloric restriction and/or exercise. Mental retardation has been considered a major symptom of BBS. However, formal IQ testing shows that these patients are of average intelligence. Haplotype analysis reduces the BBS3 critical region to a 6-cM interval between D3S1595-D3S1753.
Adult↗
Laurin-Sandrow syndrome with additional associated manifestations.
A Thai man with Laurin-Sandrow syndrome (LSS, MIM 135750), the ninth reported case, is described. He had an underdeveloped nasal bone, scar-like seams under the nose, large heads of mandibular condyles, and brachymesophalangy of toes as newly observed findings of the syndrome. He also had mental retardation. The patient had duplication of ulna, with triphalangeal thumbs, and polydactyly of one finger. The triphalangeal thumbs were non-opposable. Carpal bones were malformed. Mirror image polydactyly of the toes was present. There were nine toes on the right and eight on the left. Joint abnormalities were observed at his elbows, wrists, knees, ankles, fingers, and toes. Synostosis of severely malformed tarsal bones was noted. This appears to be the first case of LSS with anomalies not limited to the nose and limbs. The relationship between LSS, tibial hemimelia-polysyndactyly-triphalangeal thumbs syndrome, triphalangeal thumb-polysyndactyly syndrome, preaxial polydactyly types 2 and 3, and Haas-type syndactyly is discussed.
Abnormalities, Multiple↗
Hypothesis: hemimelia and the maintenance of pentadactyly?
The limbs of extant terrestrial vertebrates possess five or fewer digits, yet, polydactyly is accepted as being the ancestral state. Therefore, I propose a hypothesis to account for the maintenance of digital number at five or fewer digits, based on a selective disadvantage associated with polydactylous states in terrestrial vertebrates. This disadvantage is not associated with the polydactyly per se, but rather with the hemimelia which is a common feature of polydactylies in mammals. Hemimelia causes a twisting, or luxation, of the distal segment of the limb, which is due to a malformation of the radius/tibia of the limb. This defect results in the limb being held in an abnormal gait, which causes problems in the locomotion of the animal which would compromise their ability to flourish. Therefore, the abnormal gait and torsion of the limb caused by the hemimelia is acting as a stabilizing force to maintain the dactyly of the tetrapod limb with five or fewer digits.
Animals↗
Transvaginal ultrasonography and transabdominal embryoscopy in the first-trimester diagnosis of Smith-Lemli-Opitz syndrome, type II.
OBJECTIVE: Our goal was to demonstrate the efficacy of transabdominal embryoscopy in the first trimester of pregnancy. STUDY DESIGN: A patient at risk for Smith-Lemli-Opitz syndrome, type II, was referred for prenatal diagnosis at 11 weeks 5 days of gestation. RESULTS: A transvaginal ultrasonographic examination revealed the presence of a nuchal membrane and bilateral polydactyly. A transabdominal embryoscopy confirmed the diagnosis of polydactyly. The patient had an unremarkable postprocedure course before termination of pregnancy 5 days later. In a second pregnancy embryoscopy revealed a normal fetal hand despite a suggestion on transvaginal ultrasonography that there was polydactyly. On the basis of this information the patient elected to continue the pregnancy, and a normal baby was delivered at 35 weeks. CONCLUSION: This case validates the efficacy of noninvasive and invasive techniques, used adjunctively, in the first-trimester diagnosis of a lethal fetal condition composed of subtle phenotypic manifestations.
Abnormalities, Multiple↗
Correction of a deformed thumb by distraction of the phalanx.
We used distraction osteogenesis to correct six deformed thumbs in four patients ranging in age from 4 to 7 years. Two of the patients had Apert syndrome (syndromic craniosynostosis with symmetrical syndactyly) and two had polydactyly. We used a small fixator with a ball joint and successfully corrected the angular deformity after lengthening the proximal phalanx by distraction. This single inclusive procedure was extremely useful. We found the optimal distraction regimen for the digital phalanx was a one day waiting period and lengthening at 1 mm/day. The mean healing indexes were 37.2 days/cm (range 24.2 to 41.5) in those with Apert syndrome and 64.3 days/cm in those with polydactyly (62.5 and 66.0). Our results suggest that osteogenesis at the distraction site may be quicker in patients with Apert syndrome than in those with polydactyly.
Acrocephalosyndactylia↗
Maternal cigarette smoking during pregnancy increases the risk of having a child with a congenital digital anomaly.
BACKGROUND: The U.S. Natality database from 2001 and 2002 was used to investigate the relationship between maternal cigarette smoking during pregnancy and the risk of having a child with polydactyly, syndactyly, or adactyly. METHODS: The records of 6,839,854 live births were examined to identify 5171 newborns with isolated polydactyly, syndactyly, or adactyly and 10,342 controls with no congenital anomalies. RESULTS: Maternal cigarette use during pregnancy was associated with a significantly elevated risk of having a child with a congenital digital anomaly (unadjusted odds ratio, 1.33; 95 percent confidence interval, 1.21 to 1.47; p < 0.0001). Univariate analysis indicated that maternal marital status and medical risk factors (anemia, cardiac disease, lung disease, diabetes, hydramnios/oligohydramnios, pregnancy-associated hypertension, incompetent cervix, previous preterm or small-for-gestational-age infant, and rhesus factor sensitization) were potential confounding factors. After adjustment for these variables, the odds ratio remained significant (adjusted odds ratio, 1.31; 95 percent confidence interval, 1.18 to 1.45; p < 0.0001). Cigarette consumption per day was divided into four groups: no smoking, 1 to 10 cigarettes per day, 11 to 20 cigarettes per day, and 21 or more cigarettes per day. A statistically significant dose-response relationship was found when comparing each smoking category with the no-smoking reference group: 1.29 (95 percent confidence interval, 1.15 to 1.46), 1.38 (95 percent confidence interval, 1.12 to 1.71), and 1.78 (95 percent confidence interval, 0.97 to 3.26), respectively. Increased cigarette smoking during pregnancy resulted in an elevated risk of having a child with polydactyly, syndactyly, or adactyly. CONCLUSIONS: This is the largest study to date to investigate specifically the association between maternal cigarette smoking and the risk of having a newborn with a congenital digital anomaly. The elevated odds ratio for tobacco use and the significant trend in the dose-response relationship suggests smoking during pregnancy may be an important preventable risk factor for these common congenital differences.
Abnormalities, Multiple↗
Phenotypic analysis of triphalangeal thumb and associated hand malformations.
Triphalangeal thumb (TPT), a long, finger-like thumb with three phalanges instead of two, is regarded as a subtype of preaxial polydactyly. It can occur as a sporadic disorder, but is more often seen as a dominant familial trait. We describe four white Dutch families in which triphalangeal thumb has variable expression and is sometimes associated with preaxial extra rays, rudimentary postaxial polydactyly, cutaneous syndactyly of the hands, and, rarely, postaxial polydactyly and syndactyly of the feet. A comparison with similar familial conditions reported during the past 10 years is provided. The potential significance of linkage and molecular genetic analysis for better insight into the pathogenesis of complex hand malformations is discussed.
Adult↗
Pallister-Hall syndrome and McKusick-Kaufmann syndrome: one entity?
The Pallister-Hall syndrome is characterised by specific facial anomalies, postaxial polydactyly, imperforate anus, and brain anomalies including a diencephalic hamartoblastoma. The hallmarks of the McKusick-Kaufmann syndrome are hydrocolpos owing to vaginal atresia, postaxial polydactyly, imperforate anus, and congenital heart defects. We report a patient with the unique features of hydrocolpos, postaxial polydactyly, and hypothalamic hamartoblastoma and discuss the different aetiological considerations of both syndromes and implications for clinical management.
Abnormalities, Multiple↗
Genetic interaction of Gli3 and Alx4 during limb development.
The Gli3 and Alx4 transcriptional regulators are expressed in the anterior limb bud mesenchyme and their disruption in mice results in preaxial polydactyly. While the polydactylous phenotype of Alx4 deficient limb buds depends on SHH, the one of Gli3 deficient limb buds is completely independent of SHH signalling, suggesting that these genes act in parallel pathways. Analysis of limb buds lacking both Gli3 and Alx4 now shows that these two genes interact during limb skeletal morphogenesis. In addition to the defects in single mutants, the stylopod is severely malformed and the anterior element of the zeugopod is lost in double mutant limbs. However, limb bud patterning in Gli3-/-; Alx4-/- double mutant embryos is not affected more than in single mutants as the expression domains of key regulators remain the same. Most interestingly, the loss of the severe preaxial polydactyly characteristic of Gli3-/- limbs in double mutant embryos establishes that this type of polydactyly requires Alx4 function.
Animals↗