SMOC1 is essential for ocular and limb development in humans and mice

Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice.     

Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome

HOXD13, the homeobox-containing gene located at the most 5' end of the HOXD cluster, plays a critical role in limb development. It has been shown that mutations in human HOXD13 can give rise to limb malformations, with variable expressivity and a wide spectrum of clinical manifestations. Polyalanine expansions in HOXD13 cause synpolydactyly, whereas amino acid substitutions in the homeodomain are associated with brachydactyly types D and E. We describe two large Han Chinese families with different limb malformations, one with syndactyly type V and the other with limb features overlapping brachydactyly types A4, D, and E and mild syndactyly of toes 2 and 3. Two-point linkage analysis showed LOD scores >3 (theta =0) for markers within and/or flanking the HOXD13 locus in both families. In the family with syndactyly type V, we identified a missense mutation in the HOXD13 homeodomain, c.950A-->G (p.Q317R), which leads to substitution of the highly conserved glutamine that is important for DNA-binding specificity and affinity. In the family with complex brachydactyly and syndactyly, we detected a deletion of 21 bp in the imperfect GCN (where N denotes A, C, G, or T) triplet-containing exon 1 of HOXD13, which results in a polyalanine contraction of seven residues. Moreover, we found that the mutant HOXD13 with the p.Q317R substitution was unable to transactivate the human EPHA7 promoter. Molecular modeling data supported these experimental results. The calculated interactions energies were in agreement with the measured changes of the activity. Our data established the link between HOXD13 and two additional limb phenotypes--syndactyly type V and brachydactyly type A4--and demonstrated that a polyalanine contraction in HOXD13, most likely, led to other digital anomalies but not to synpolydactyly. We suggest the term "HOXD13 limb morphopathies" for the spectrum of limb disorders caused by HOXD13 mutations.     

Localization of a gene for syndactyly type 1 to chromosome 2q34-q36

Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. After exclusion of a candidate region previously identified for syndactyly type 2 (synpolydactyly), we performed a genomewide linkage analysis in a large German pedigree. We found evidence for linkage of SD1 to polymorphic markers on chromosome 2q34-q36, with a maximum LOD score of 12.40 for marker D2S301. Key recombination events in affected individuals defined a 9.4-cM region between markers D2S2319 and D2S344. The identification of the responsible gene will give further insights into the molecular basis of limb development.     

X-Chromosomally inherited split-hand/split-foot anomaly in a Pakistani kindred

Summary A Pakistani kindred comprising seven generations and 36 members with the split-hand/split-foot anomaly is described. The full expression of the trait, monodactylous or split hand and split foot, mainly of the lobster-claw type, was present in 33 males and 3 females. Other females showed a distinctly milder expression of the trait, usually in the form of partial syndactyly, metacarpal and phalangeal hypoplasia, and malformation. The distribution of the affected members in the pedigree is compatible with X-chromosomal inheritance. Hemizygous males and presumably homozygous females exhibit the typical split-hand/split-foot anomaly, whereas only a part of the obligatory heterozygous females show the milder expression. There were no associated anomalies, such as ectodermal dysplasia, cleft lip/palate, macular degeneration, malformations of the long bones or internal organs, and overt mental retardation.     

A simple method for characterising syndactyly in clinical practice

Non-syndromic syndactyly is a heterogeneous group of limb malformations involving webbing of fingers and/or toes. There are at least nine non-syndromic types described in the literature. For the clinician and the genetic counsellor not having gathered experience with this malformation, it is rather tedious to identify the correct subtype for the patient's phenotype. We therefore present a protocol for clinical use, which visualises the malformation in a graphical way and thereby simplifies typing. In addition, this protocol provides a simple documentation system for reporting clinical data for new syndactyly families. It might encourage clinicians to report families that are still unclassifed and thus, helping to extend and improve the existing classification system.     

Deletions in HOXD13 segregate with an identical,novel foot malformation in two unrelated families.

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation consisting of 3/4 syndactyly in the hands and 4/5 syndactyly in the feet, with digit duplication in the syndactylous web. The condition recently has been found to result from different-sized expansions of an amino-terminal polyalanine tract in HOXD13. We report a novel type of mutation in HOXD13, associated in some cases with features of classic SPD and in all cases with a novel foot phenotype. In two unrelated families, each with a different intragenic deletion in HOXD13, all mutation carriers have a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well. This phenotype has not been reported in any mice with genetic modifications of the HoxD gene cluster. The two different deletions affect the first exon and the homeobox, respectively, in each case producing frameshifts followed by a long stretch of novel sequence and a premature stop codon. Although the affected genes may encode proteins that exert a dominant negative or novel effect, they are most likely to act as null alleles. Either possibility has interesting implications for the role of HOXD13 in human autopod development.     

Anophthalmos with limb anomalies (Waardenburg opththalmo-acromelic syndrome): report of a new Italian case with renal anomaly and review

Anophthalmos with limb anomalies (Waardenburg Opththalmo-Acromelic Syndrome) is a very rare autosomal recessive multiple congenital anomaly syndrome, first described by Waardenburg et al. in 1961 (MIM 206920). It is characterized by mono or more often bilateral anophthalmia/microphthalmia and foot malformations, which can be observed in 91% of the patients. The most common anomaly of the feet is the presence of four toes. The hands are affected bilaterally in 77% of the cases. The most characteristic anomaly is the synostosis of the fourth and fifth metacarpals. To date, 33 cases from 19 families have been reported. We present an Italian case of anophthalmia with limb anomalies and a renal malformation, which has never been described in the literature.     

A case of symbrachydactyly with oligodactyly

The term symbrachydactyly describes syndactyly accompanied by brachydactyly. Brachydactyly is seen in middle phalanges of both hands and feet and very short in length or absent. As for syndactyly it is a cutaneous type. It has always been observed unilaterally and sporadically. A familial type of this syndrome has also been reported. There have been many classifications of symbrachydactyly. Of these, Blauth classification is the most favored one. Yet these classifications have been inadequate to include many recently discovered other forms of symbrachydactyly. A three month old child was brought to the Istanbul University Genetic Research Center because of his abnormal hands and feet. He was the second child of a couple who had no kinship ties to each other. In the history of the family, there was no mention of any anomaly as such. There was a complete syndactyly involving the 3rd through the 5th fingers, partial syndactyly between the 2nd and 3rd, and the thumb was normal in the right hand. There was only one finger in the left hand. There was total syndactyly in four toes of the right foot with oligodactyly and absence of the big toe. The left foot had five toes with a complete syndactyly between the 2nd and the 3rd. Radiological observation indicated that the middle phalanges of both extremities were rudimentary or never developed. There was no osseous syndactyly. As observed in this case, oligodactylous type that is bilateral and involves both hands and feet together is very unusual. The purpose of this study is to present a rare case of this anomaly that requires a reassessment of symbrachydactyly and its traditional classifications.     

Use of magnetic resonance imaging for the evaluation of vascular malformations of the lower extremity

Vascular malformations are anatomically subdivided according to the predominant channel anomaly into either capillary, arterial, venous, lymphatic, or combinations. They can be further subdivided into high- or low-flow malformations. Any lesion that has an arterial component is considered a high-flow malformation. Once the diagnosis of a vascular malformation is made, it is of paramount importance to define not only the flow characteristics but also the full range of extension, because the prognosis and appropriate treatment vary substantially for each type of anomaly. The two most useful noninvasive imaging techniques for assessing vascular malformations are magnetic resonance imaging (MRI) and ultrasonography. The aim of this review is to give surgeons involved in treating patients with vascular malformations an opportunity to gain some background on MRI scans when assessing vascular malformations. Although MRI is a powerful modality for assessing vascular malformations, we will also discuss some of the limitations of MRI. We further suggest a diagnostic flow chart developed on the basis of MRI features designed to help determine the composition of a vascular birthmark when intervention is anticipated.     

Two unusual types of syndactyly in the same family; Cenani-Lenz type and "new" type versus severe type I syndactyly?

Cenani-Lenz syndactyly is a very rare syndrome where the syndactyly is totally disorganized with abnormal development of pattern formation of the hand. We report here an additional case of Cenani-Lenz syndactylism in a woman who has congenital cataract and an unusual type of duplication of big toes not described so far. She had a half cousin who had an unusual new type or severe type I syndactyly. It is not clear whether these two types of syndactyly present in this family may be coincidental or not.     

One more case of a severe lethal condition resembling the Smith-Lemli-Opitz, type II syndrome.

A male child with a lethal multiple congenital anomaly syndrome of facial dysmorphism, ambiguous genitalia, syndactyly and postaxial polydactyly is presented. He had findings consistent with the diagnosis of Smith-Lemli-Opitz type II syndrome. Similar changes were observed in his elder sister, who died when she was 2 months old. On the basis of this familial observation the nosology of Smith-Lemli-Opitz syndrome is discussed.     

Absence of limbs and gross body wall defects: an epidemiological study of related rare malformation conditions.

The study is based on almost 10 million births and reports on 215 infants with two unusual malformations: amelia and gross body wall defect. Amelia without body wall defect was present in 116 cases, 67 had body wall defects without amelia, and 32 had both. The total rate was 2.2 per 100,000 births. The infants were divided into five mutually exclusive groups. There were 40 infants (0.4 per 100,000) with agenesis of the body stalk, 18 with amelia and other types of gross body wall defects (0.2 per 100,000), 56 with amelia and malformations other than gross body wall defects (0.6 per 100,000), 41 with amelia (with or without other limb reduction defects) but no nonlimb malformations (0.4 per 100,000), and 60 infants with gross body wall defects of a type other than agenesis of body stalk and without amelia (0.6 per 100,000). A weak trend of decreasing prevalence of these malformations was found during the observation period. Infants with agenesis of the body stalk and infants with amelia combined with other types of gross body wall defects occurred at an increased rate in infants of young women. This maternal age effect is also found with gastroschisis, but not with omphalocele, and may indicate etiological or pathogenetic similarities between gastroschisis and the two former groups of defect. In infants with amelia, additional limb reduction defects could be of any type: transverse, longitudinal, or intercalary. Therefore, amelia may be the end result of different types of disturbances of limb morphogenesis. There was an increased rate of twinning. The relationship with amniotic band syndrome is discussed.     

Advances in the Molecular Genetics of Non-syndromic Syndactyly

Syndactyly, webbing of adjacent digits with or without bony fusion, is one of the most common hereditary limb malformations. It occurs either as an isolated abnormality or as a component of more than 300 syndromic anomalies. There are currently nine types of phenotypically diverse nonsyndromic syndactyly. Non-syndromic syndactyly is usually inherited as an autosomal dominant trait, although the more severe presenting types and subtypes may show autosomal recessive or X-linked pattern of inheritance. The phenotype appears to be not only caused by a main gene, but also dependant on genetic background and subsequent signaling pathways involved in limb formation. So far, the principal genes identified to be involved in congenital syndactyly are mainly involved in the zone of polarizing activity and sonic hedgehog pathway. This review summarizes the recent progress made in the molecular genetics, including known genes and loci responsible for non-syndromic syndactyly, and the signaling pathways those genetic factors involved in, as well as clinical features and animal models. We hope our review will contribute to the understanding of underlying pathogenesis of this complicated disorder and have implication on genetic counseling.     

A boy with Weyers-like ulnar ray/oligodactyly reduction limb defects and split hand malformation: case report

Weyers ulnar ray/oligodactyly syndrome is characterized by variable ulnar, radial, or fibular ray limb reductions, single central incisor, and renal, splenic or cardiac anomalies. Split hand/split foot malformation is a central reduction defect of the hands and feet, and may occur either as an isolated malformation or as a part of syndrome. We describe a patient with Weyers-like ulnar ray/oligodactyly reduction limb defects and split hand malformation.     

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

Brachydactyly ("short digits") is a general term that refers to disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis. The various types of isolated brachydactyly are rare, except for types A3 and D. Brachydactyly can occur either as an isolated malformation or as a part of a complex malformation syndrome. To date, many different forms of brachydactyly have been identified. Some forms also result in short stature. In isolated brachydactyly, subtle changes elsewhere may be present. Brachydactyly may also be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism. For the majority of isolated brachydactylies and some syndromic forms of brachydactyly, the causative gene defect has been identified. In isolated brachydactyly, the inheritance is mostly autosomal dominant with variable expressivity and penetrtance. Diagnosis is clinical, anthropometric and radiological. Prenatal diagnosis is usually not indicated for isolated forms of brachydactyly, but may be appropriate in syndromic forms. Molecular studies of chorionic villus samples at 11 weeks of gestation and by amniocentesis after the 14^th week of gestation can provide antenatal diagnosis if the causative mutation in the family is known. The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms. There is no specific management or treatment that is applicable to all forms of brachydactyly. Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed. Physical therapy and ergotherapy may ameliorate hand function. Prognosis for the brachydactylies is strongly dependent on the nature of the brachydactyly, and may vary from excellent to severely influencing hand function. If brachydactyly forms part of a syndromic entity, prognosis often depends on the nature of the associated anomalies.     

Minor anomalies: Diagnostic clues to aberrant human morphogenesis

Assessment of the degree of fluctuating asymmetry has been used in a variety of organisms as a measure of genetic and/or environmental stresses encountered during embryonic development. However, fluctuating asymmetry has not been widely used in humans in the diagnosis of congenital anomalies. Rather, assessment of patterns of minor anomalies has been utilized to infer the degree of embryonic developmental instability accompanying either genetic or teratogenic insults. A minor anomaly is a structural feature seen in less than 4% of the general population, which is of no cosmetic or functional significance to the affected individual. Minor anomalies may or may not have functional or diagnostic significance when taken in the context of the entire child. In dysmorphology, minor anomalies have been useful in three distinct ways. First, some minor anomalies have been external markers of specific occult major anomalies. In addition, the vast majority of malformation syndromes in clinical genetics are recognizable as patterns of minor anomalies. Finally, although 15% of normal newborns have one or more minor anomalies, the finding of three or more minor anomalies is distinctly unusual. The risk of having a major occult abnormality increases proportionately with the number of minor defects present, with three or more minor anomalies signalling a 20% risk of a major occult structural defect. In summary, just as fluctuating asymmetry may be a marker of abnormal environmental or genetic stress in the developing embryo, the presence of minor anomalies can be utilized to assess developmental instability.     

Hind limb malformations in free-living northern leopard frogs (Rana pipiens) from Maine, Minnesota, and Vermont suggest multiple etiologies

BACKGROUND: Reports of malformed frogs have increased throughout the North American continent in recent years. Most of the observed malformations have involved the hind limbs. The goal of this study was to accurately characterize the hind limb malformations in wild frogs as an important step toward understanding the possible etiologies. METHODS: During 1997 and 1998, 182 recently metamorphosed northern leopard frogs (Rana pipiens) were collected from Minnesota, Vermont, and Maine. Malformed hind limbs were present in 157 (86%) of these frogs, which underwent necropsy and radiographic evaluation at the National Wildlife Health Center. These malformations are described in detail and classified into four major categories: (1) no limb (amelia); (2) multiple limbs or limb elements (polymelia, polydactyly, polyphalangy); (3) reduced limb segments or elements (phocomelia, ectromelia, ectrodactyly, and brachydactyly; and (4) distally complete but malformed limb (bone rotations, bridging, skin webbing, and micromelia). RESULTS: Amelia and reduced segments and/or elements were the most common finding. Frogs with bilateral hind limb malformations were not common, and in only eight of these 22 frogs were the malformations symmetrical. Malformations of a given type tended to occur in frogs collected from the same site, but the types of malformations varied widely among all three states, and between study sites within Minnesota. CONCLUSIONS: Clustering of malformation type suggests that developmental events may produce a variety of phenotypes depending on the timing, sequence, and severity of the environmental insult. Hind limb malformations in free-living frogs transcend current mechanistic explanations of tetrapod limb development.     

Inhibitory effect of caffeine on 5-azacytidine-induced digital malformations in the rat

The effect of caffeine on 5-azacytidine (5-AC)-induced digital malformations in rat fetuses was investigated. Caffeine suppressed all types of digital defects in the fore- and hindlimbs except for syndactyly induced by 1.0 mg/kg of 5-AC; it was still effective when administered 24 hours after 5-AC treatment. However, fetal mortality increased as the frequency of malformations decreased. While the malformation results support the view that caffeine inhibits the processes leading to malformation expression, the relation between its suppressive effect on malformations and its enhancing effect on fetal mortality is unclear.