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A female infant is described with a lethal short rib syndrome, similar to a form of short rib-polydactyly syndrome but without polydactyly. It is felt that this infant has the same condition as that described by Beemer et al.
Maternal diabetes has an established aetiological link with developmental abnormalities, and the prevalence of major congenital malformations in the offspring of affected women is approximately 4-8%, compared to the general population risk of about 3%. Hallucal polydactyly, particularly with an unusual proximal placement of the extra digit, has been reported as a distinctive anomaly in diabetic embryopathy. We report on a child of a diabetic mother with this unusual form of hallucal polydactyly, together with other skeletal anomalies, confirming that this malformation is a useful clinical marker for the diagnosis of diabetic embryopathy.
Short rib-polydactyly syndrome (SRPS; types I-IV) is an autosomal recessive, lethal skeletal dysplasia characterized by short-limb dysplasia, narrow thorax, and polydactyly. This syndrome is invariable and can be detected by 2-trimester ultrasound. The underlying gene has not been discovered yet. We report a case of SRPS subtype III Verma-Naumoff-Le Marec that was sonographically detected at 20 weeks' gestation and compare prenatal ultrasound with postmortem findings from pathology and radiology. Since the risk of recurrence is 25%, early ultrasound for consecutive pregnancies was advised and performed at 11+6 weeks' gestation in the following pregnancy without any findings. Ultrasound diagnosis in this rare case of SRPS is a valuable tool for identification and early management, since there are no specific biochemical or histopathological markers for this syndrome. Radiological and pathological findings confirmed SRPS type III and assisted in the differential diagnosis of the subtype.
Short-rib-polydactyly syndrome represents a group of rare, autosomal recessive, lethal skeletal dysplasias characterized by hypoplastic thorax, short ribs, short limbs, polydactyly, and visceral abnormalities. We describe an affected fetus from a high-risk family presenting with increased nuchal translucency at 13 weeks of pregnancy. The diagnosis was established in the 2nd trimester.
In 1978, Temtamy and McKusick classified isolated, non-syndromic polydactyly and syndactyly, using a logical anatomical approach, into five distinct types for each group. Since then, there have been considerable advances in the molecular embryology of the developing limb bud. These include the proposal that retinoic acid and/or related retinoids are the morphogens responsible for the morphogenetic gradient giving rise to anterior-posterior pattern formation of the limb bud, the suggestion that the HOX4 complex and other homeotic genes may also be involved in patterning, and a greater understanding of other mechanisms such as programmed cell death in the shaping of the final hand and foot. This paper briefly reviews the molecular embryology of limb development and outlines the 'end-organ responsiveness' of the limbs to a variety of single-gene mutations. An alternative classification of syndactylies and polydactylies is suggested. It is still too early to match specific defects to individual genes with precision, and it is obvious that many important developmental genes remain to be identified; nevertheless, it is envisaged that clues from molecular embryological studies will become increasingly more useful.
Correct development of the limb is dependent on coordination between three distinct signaling centers. Recently, fibroblast growth factor-4 has been identified as a crucial determinant of AER function, which directs limb bud outgrowth, and Sonic hedgehog has been identified as a signaling molecule that mediates ZPA function, which specifies anterior-posterior patterning in the developing limb bud. In addition, Shh and FGF-4 reciprocally reinforce each other's expression via a positive feedback loop, providing a molecular basis for the coordination of limb bud outgrowth and anterior-posterior patterning. The mechanisms by which these signaling centers come to occupy their normal positions in the posterior limb bud during development are not understood. Here we identify and characterize Alx-4, a gene that encodes a paired-type homeodomain protein. Alx-4 is expressed in several populations of mesenchymal cells, including mesenchymal cells in the anterior limb bud, and mice homozygous for targeted disruption of the Alx-4 gene have multiple abnormalities, including preaxial polydactyly. The polydactyly is associated with the formation of an ectopic anterior ZPA, as indicated by anterior expression of Sonic hedgehog, HoxD13 and fibroblast growth factor-4. The expression of other candidate regulators of anterior-posterior positional information in the limb bud, including HoxB8 and Gli3, is not altered in Alx-4 mutant embryos. By chromosomal mapping experiments, Alx-4 is tightly linked to Strong's luxoid, a polydactylous mouse mutant. The results identify Alx-4 as a determinant of anterior-posterior positional identity in the limb and a component of a regulatory program that restricts ZPA formation to the posterior limb bud mesenchyme.
Mutations that affect vertebrate limb development provide insight into pattern formation, evolutionary biology and human birth defects. Patterning of the limb axes depends on several interacting signaling centers; one of these, the zone of polarizing activity (ZPA), comprises a group of mesenchymal cells along the posterior aspect of the limb bud that express sonic hedgehog (Shh) and plays a key role in patterning the anterior-posterior (AP) axis. The mechanisms by which the ZPA and Shh expression are confined to the posterior aspect of the limb bud mesenchyme are not well understood. The polydactylous mouse mutant Strong's luxoid (lst) exhibits an ectopic anterior ZPA and expression of Shh that results in the formation of extra anterior digits. Here we describe a new chlorambucil-induced deletion allele, lstAlb, that uncovers the lst locus. Integration of the lst genetic and physical maps suggested the mouse Aristaless-like4 (Alx4) gene, which encodes a paired-type homeodomain protein that plays a role in limb patterning, as a strong molecular candidate for the Strong's luxoid gene. In genetic crosses, the three lst mutant alleles fail to complement an Alx4 gene-targeted allele. Molecular and biochemical characterization of the three lst alleles reveal mutations of the Alx4 gene that result in loss of function. Alx4 haploinsufficiency and the importance of strain-specific modifiers leading to polydactyly are indicative of a critical threshold requirement for Alx4 in a genetic program operating to restrict polarizing activity and Shh expression in the anterior mesenchyme of the limb bud, and suggest that mutations in Alx4 may also underlie human polydactyly.
Patterning of the vertebrate limb along the anterior-posterior axis is controlled by the zone of polarizing activity (ZPA) located at the posterior limb margin. One of the vertebrate Hh family members, Shh, has been shown to be able to mediate the function of the ZPA. Several naturally occurring mouse mutations with the phenotype of preaxial polydactyly exhibit ectopic Shh expression at the anterior limb margin. In this study, we report the molecular characterization of a spontaneous mouse mutation, Doublefoot (Dbf). Dbf is a dominant mutation which maps to chromosome 1. Heterozygous and homozygous embryos display a severe polydactyly with 6 to 8 digits on each limb. We show here that Shh is expressed normally in Dbf mutants. In contrast, a second Hh family member, Indian hedgehog (Ihh) which maps close to Dbf, is ectopically expressed in the distal limb bud. Ectopic Ihh expression in the distal and anterior limb bud results in the ectopic activation of several genes associated with anterior-posterior and proximal-distal patterning (Fgf4, Hoxd13, Bmp2). In addition, specific components in the Hedgehog pathway are either ectopically activated (Ptc, Ptc-2, Gli1) or repressed (Gli2). We propose that misexpression of Ihh, and not a novel Smoothened ligand as recently suggested (Hayes et al., 1998), is responsible for the Dbf phenotype. We consider that Ihh has a similar activity to Shh when expressed in the early Shh-responsive limb bud. To determine whether Dbf maps to the Ihh locus, which is also on chromosome 1, we performed an interspecific backcross. These results demonstrate that Dbf and Ihh are genetically separated by approximately 1.3 centimorgans, suggesting that Dbf mutation may cause an exceptionally long-range disruption of Ihh regulation. Although this leads to ectopic activation of Ihh, normal expression of Ihh in the cartilaginous elements is retained.
Short Rib Polydactyly Syndrome (SRPS) is a group of rare congenital disorders characterized by polydactyly, short limbs, and short ribs. Infants with type I SRPS (Majewski syndrome) may exhibit dysgenesis of the larynx, which is manifested by epiglottic hypoplasia. Photographic documentation of laryngeal findings obtained at autopsy in an affected infant is provided. To our knowledge, such photographic documentation has not been previously published. Normal laryngeal development is reviewed, based on the Carnegie system of staging. The developmental errors leading to SRPS are thought to occur at 33 to 48 days of fetal life (Carnegie stages 15 through 19).
A prospective screening program of 11,161 newborns identified twenty-one infants who had postaxial type-B polydactyly (a prevalence of one in 531 live births). Sixteen infants (76 per cent) had bilateral postaxial type-B polydactyly. Eighteen infants (86 per cent) had a family history of the anomaly. The racial prevalence was one in 143 live births of black infants and one in 1339 live births of white infants. The duplicated small fingers were treated in the newborn nursery with suture ligation at the base of the pedicle. One infant had a second procedure to remove a blackened digit that remained firmly attached one month after the initial treatment. No other complications occurred. Fifteen patients (twenty-eight fingers) were reexamined at an average age of twenty months (range, twelve to thirty-seven months). Twelve fingers (43 per cent) had a residual bump, with an average diameter of two millimeters (range, one to six millimeters). Despite the residual bumps, all of the parents were satisfied with the cosmetic result.
Short rib-polydactyly syndrome (SRPS) is a group of lethal skeletal dysplasia of an autosomal recessive inheritance characterized by markedly narrow ribs, micromelia, and multiple anomalies of major organs. We report a case of type IV SRPS with uncommon associations of polydactyly and bilateral polycystic kidneys, in a 28 week old female fetus. She was born dead to a 28 year old mother, showing a hydropic change, narrow thorax, and shortened limbs with postaxial heptasyndactyly of both hands and feet. Radiologic examination revealed short horizontal ribs, curved short tubular limb bones, small ilia and scapula, and a mild vertebral abnormality. Postmortem examination disclosed pulmonary hypoplasia, pancreatic cysts, hepatic fibrosis, and left persistent superior vena cava. In addition this case had bilateral huge polycystic renal dysplasia that was seldom described in any type of SRPS. Histologic sections of the vertebrae disclosed abnormal enchondral ossification with irregular and retarded hypertrophic zone.
Short rib-polydactyly syndromes (SRPS) are a heterogeneous group of recessively inherited lethal skeletal dysplasias. Four types have been recognised. However, overlap in the clinical and radiological features of the four types has led to difficulties in distinguishing between them. The congenital infection-like syndrome is an autosomal recessive syndrome characterised by mental retardation, microcephaly, seizures, and intracranial calcifications. We report a complex consanguineous family of Baluchi origin in whom short rib-polydactyly type III and congenital infection-like syndrome are segregating. Four children inherited SRPS III, one inherited congenital infection-like syndrome, and one inherited both. Although the radiological features in all the children with SRPS in this report were typical of type III, there was overlap in the clinical features with the other types of SRP syndromes. Furthermore, the child who inherited both SRPS III and congenital infection-like syndrome had CNS malformations in addition to periventricular calcification. CNS malformations have been described in SRPS types II and IV but not type III. This report further highlights the overlap between the different types of SRP syndrome. Moreover, it draws attention to the importance of considering the possibility of two recessive syndromes in the same child in complex consanguineous families when features overlap two syndromes.
In this report we describe a 17 weeks old female fetus with a lumbosacral meningocoele, multicystic renal dysplasia (Potter type IIb) and postaxial polydactyly type A at the left hand and left foot. There was no hepatic fibrosis. Although multicystic renal dysplasia and postaxial polydactyly are often present in the Meckel syndrome, a lumbosacral neural tube defect is not a typical finding in this syndrome.
A female German Holstein twin calf showed polydactyly in both front limbs and in one of the hind limbs. In three limbs an additional medial toe was seen. No malformations of the limbs were present in the male twin partner and four maternal half sibs. The analysis of the pedigree revealed that the affected calf had common ancestors. The coefficient of inbreeding of the affected calf was 1.312%. As a monogenic or digenic inheritance was suspected in similar cases, it may be probable that the polydactyly observed here has a genetic background.
We describe a newborn with multiple congenital anomalies consistent with an oro-facio-digital syndrome (OFDS). These are a group of inherited syndromes that have in common anomalies of the tongue (bifid or lobulated tongue with hamartomas), the face (median cleft lip) and the digits (brachydactyly, polydactyly, clinodactyly and/or syndactyly). OFDS has been classified into 11 types. The case described in this paper had manifestations overlapping with OFDS II (Mohr) and OFDS IV (Mohr-Majewski) and OFDS VI (Varadi). We propose that the present patient has a new variation of the OFDS due to the co-existence of the very atypical combination of polydactyly, cerebellar hypoplasia, hypothalamic hamartoma and classical facial findings of OFDS.
The short rib polydactyly syndromes (SRP) are lethal neonatal skeletal dysplasias with a narrow chest, short limbs, and other abnormalities. Type II (Majewski) short rib polydactyly can be distinguished from the Type I/III (Saldino-Noonan) type on the basis of radiographic and histologic changes. Our previous transmission electron microscopic studies suggested unusual patterns of cartilage calcification in these syndromes. We evaluate calcification in the present study using scanning electron microscopy and quantitative morphometry of calcification regions digested to expose calcospherite nodules (calcification nodules), distinctive morphologic structures which form during cartilage calcification. Mean calcospherite area of the Majewski Type II SRP (3.5 +/- 0.24 x 10(-6) mm2 (3) (mean +/- sem (n) did not differ from normal control means (3.1 +/- 0.5 x 10(-6) mm2, (3)). The mean area for Type I/III, however, was significantly larger than both the control and Type II means (8.9 +/- 1.16 x 10(-6) mm2 (7), p = .001). This difference in calcospherite size adds a further differentiating feature between these two dysplasias.
The present studies assessed reproductive capacity of hereditary polydactyly(pd/pd) female rats that had genetically caused polydactyly in both fore- and hindlimbs. During an 8- or 10-day period of vaginal estrous cycle observation, persistent estrus was found in 30 to 39% of the pd/pd females. Although mating indices were comparable between polydactylous (pd/pd) and phenotypically normal (pd/+ or +/+) females, fertility indices were significantly decreased in pd/pd females. All impregnated pd/pd females delivered normally but had a significant decrease in the numbers of corpora lutea and pups delivered as compared with pd/+ or +/+ females. Examination of oviductal ova at 2 days after copulation revealed ovulation in only 75% of the pd/pd females and also a slight decrease in the numbers of ovulatory corpora lutea and oviductal ova in these females. In the nonovulating persistent estrus pd/pd females, the ovaries were polycystic. These results demonstrate a reduction in reproductive ability of pd/pd females.
We analyzed dermatoglyphic patterns of patients with pre- and postaxial polydactylies. It was found that (i) an additional finger was always accompanied by the respective digital triradius, radiants and the main line, and (ii) in postaxial polydactylies a circular pattern of epidermal ridges around the 6th finger and a 2nd additional triradius are formed. On this basis it is suggested that the palmar main lines, radiants and digital triradii serve as marker structures and borders in the process of differentiation of digital morphogenetic fields out of a unitary field organized in a fashion described by a polar coordinate system model.