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Incidence

The best epidemiological studies of incidence of congenital anomalies are total population studies; there are four total population studies of congenital anomalies of the upper extremity (CAUE) in the literature (Table 2.1). A 5-year birth registry study of Edinburgh, Scotland by Rogala et al. found the prevalence of babies born with any limb anomalies to be 30 out of 10,000 live births, and the incidence of upper limb anomalies to be 22.5 out of 10,000 live births [1]. Of those with upper limb anomalies, 35 % had another non-upper limb anomaly. They used an older classification, that of Temtamy and McKusick [2], so direct comparisons to more recent studies are difficult. One striking finding in this study is the complete lack of isolated simple syndactyly, which in other studies was found to be relatively common.

Table 2.1 Incidence and classification of congenital anomalies of the upper extremity (CAUE) in total population studies
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An 11-year total population study of Western Australia found the prevalence of babies born with upper limb anomalies to be 19.76 in 10,000 live births [3]. Forty-six percent of those affected had another non-hand congenital anomaly. Fifty-one percent had bilateral hand anomalies, and 17 % had multiple different hand anomalies. The most common anomalies were failures of differentiation (35 %), duplications (33 %), and failures of formation (15 %). Congenital upper limb anomalies were more common in boys; preterm, post-term, and multiple births; and older mothers. No significant differences in prevalence or frequency of anomalies were found between whites and nonwhites, left and right sides, and in babies that survived and those who died shortly after birth.

Similarly, an 11-year total population study of the Stockholm region of Sweden found a recorded incidence of congenital anomalies of the upper limb of 21.5 per 10,000 live births [4]. Fifty-four percent of the children with congenital anomalies of the upper limb were boys. The anomalies affected the right side only in 30 %, the left side only in 33 %, and both sides in 37 %. Non-hand anomalies were recorded in 23 % of the children with congenital anomalies of the upper limb, most commonly in the lower limbs. In 17 % of the affected children, there was a known occurrence among relatives. Failure of differentiation was the most common category (47 %) followed by duplication (26 %), failure of formation (18 %), undergrowth (3 %), generalized abnormalities and syndromes (2.4 %), overgrowth (1.7 %), and constriction ring syndrome (1.5 %).

There are more total population studies of limb deficiency anomalies, for example: a 9-year total population study of the national incidence of upper limb deficiencies in Finland found an incidence of congenital deficiency anomalies of the upper limb of 5.26 per 10,000 live births [5]. These studies approximate the “failure of formation” category of complete CAUE population studies (Table 2.2).

Table 2.2 Incidence of upper limb deficiency anomalies in total population studies
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Incidence figures derived by extrapolation from surveys of patients presenting for treatment show slightly lower incidence: an estimated 16–18 per 10,000 births [9–11]. It is thought that these population studies may underestimate incidence, as the milder deformities may never present for treatment. A comparison of a population-based study and clinic registry of Swedish children with CAUE showed an underestimation of incidence by 6 % in the clinic registry, and a low degree of correlation of classification of anomalies [12].

The IFSSH classification is a useful tool for classifying most CAUE and enables comparison between studies, but is based on theories of embryological failure and is subject to some differences of interpretation. Ambiguities in the categorization of anomalies may then lead to differences of incidence of certain classifications [13]. For instance, the IFSSH classification could classify polydactyly with complex syndactylies as duplication, but for clinical purposes it fits better into the category of failure of differentiation. Miura et al. [14] and Ogino [15, 16] suggested that a common teratological mechanism causes cleft hand, syndactyly, and polydactyly and that they should be put into a new category: failure of induction of digital rays. Classifying congenital absence of digits is also ambiguous; the distinctions between brachysyndactyly, symbrachydactyly (atypical cleft hand), and transverse arrest are not clearly defined.

In the Stockholm study thumb hypoplasia was categorized as failure of formation, longitudinal arrest, and radial ray deficiency, whereas in the study from Western Australia, thumb hypoplasia was categorized as undergrowth. The Stockholm study showed a much lower frequency of undergrowth as a result. There was also a surprisingly large disparity between the categories of transverse arrest and symbrachydactyly regarding associated non-hand anomalies. Other differences in relative frequencies are also likely caused by other differences of interpretation of classification strategies.

Epidemiologic studies are important for health care planning, detecting changes in incidence over time, and comparing differences among regions. These two total population studies of CAUE agree on total incidence figures. These population studies are slightly higher than the estimated 0.16–0.18 % incidence for CAUE of in surveys of patients presenting for treatment (Table 2.3) [9, 10, 17–19]. It is assumed that this is due to the fact that milder deformities may never present for treatment.

Table 2.3 Comparison of classification of relative frequency of CAUE in population studies and large case series
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These studies do, however, reveal the difficulties in comparing studies owing to different classification strategies and weaknesses within the IFSSH classification. For example, two studies of CAUE in Edinburgh, UK [2, 10] and two studies from Japan [17, 18] show markedly different relative frequency of incidence of duplication; presumably such a finding in ethnically similar populations is due to differences in classification (see Table 2.3). We hope that the ongoing discussion of classification systems for CAUE (see Chap. 1) will inspire improvements in registration and population studies.

Associated Conditions

The genetics of hand formation have already been reviewed (Chap. 1). The genetic pathways were originally elucidated through chick and mouse studies. Genetic studies of human malformations and malformation syndromes have provided further insight. Congenital hand malformations can be categorized using a number of different criteria. A common classification scheme uses the broad designations of polydactyly, syndactyly, brachydactyly, and oligodactyly or reduction defects. Hand malformations can occur in isolation or as a part of a larger pattern of malformation. Although there are over a hundred recognized syndromes with hand anomalies as a part of their expression, this review will concentrate on only those syndromes for which the hand malformation is a cardinal or defining feature.

  1. 1.

    Syndromes with polydactyly

  2. 2.

    Syndromes with syndactyly

  3. 3.

    Syndromes with brachydactyly

  4. 4.

    Syndromes with oligodactyly

  5. 5.

    Syndromes with reduction defects

Syndromes with Polydactyly

Polydactyly was classified in 1978 by Temtamy and McKusick [20] into the following categories:

  • Postaxial type A—Postaxial extra digits that are well developed

  • Postaxial type B—Pedunculated postminimus

  • Preaxial type I—Duplication of thumbs/great toes

  • Preaxial type II—Triphalangeal thumbs/duplication of great toes

  • Preaxial type III—Absent thumbs, one or two extra preaxial digits

  • Preaxial type IV—Broad thumbs, preaxial polysyndactyly, postaxial postminimus

In 1998, Castilla reported on the congenital hand malformations using a study of Latin American Collaborative Study of Congenital Malformations [20]. He reviewed 5,927 consecutively born polydactyly cases. Castilla divided the polydactylies into postaxial, preaxial, and rare, a group in which he included mesoaxial and combinations of digits. These groups were then further subdivided into isolated or associated, depending upon whether there were other anomalies present. The associated category was then further subdivided into combined, if the other anomaly was a limb anomaly, syndromic, if the polydactyly occurred in a combination of anomalies representing a syndrome, and MCA, or multiple congenital anomalies, if the anomalies did not fit a recognizable pattern or syndrome.

From Castilla’s study, several patterns emerged. Postaxial is the most common type of polydactyly and the most likely to be isolated. The rare polydactylies, that is, not clearly only postaxial or only preaxial, are the most likely to be associated with an underlying syndrome. Trisomy 13, Meckel syndrome, and Down syndrome accounted for 75 % of the syndromic polydactyly cases in this study. In both Meckel and Trisomy 13 syndromes, postaxial polydactyly is a cardinal feature of the syndrome. For Down syndrome, although preaxial polydactyly can be seen in Down syndrome with a higher frequency than in the general population, it would not be considered a cardinal feature of Down syndrome. For the purposes of this chapter, only the syndromic category will be included, as the isolated forms are reviewed in other chapters.

Syndromes in which polydactyly is a cardinal feature can be subdivided using the classification of postaxial, preaxial, mesoaxial and combined, and further subdivided by the other common findings or by a common aspect of development.

Syndromes with Postaxial Polydactyly: Craniofacial Anomalies as a Primary Feature

Polydactyly is a cardinal feature for a group of syndromes in which the major or defining features are craniofacial abnormalities (Table 2.4). These include the various types of oral-facial-digital (OFD) syndrome. Various reviewers have described the different types of OFD syndromes on their various oral, facial, and digital abnormalities, and many are now known to be genetically distinct. The primary findings of the OFD syndromes are polydactyly and a combination of oral anomalies, most prominently, abnormalities of the tongue and frenula.

Table 2.4 Primarily craniofacial syndromes associated with postaxial polydactyly
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Postaxial Polydactyly as a Feature in Ciliopathies

Ciliopathies are a group of conditions in which the genes code for proteins that are important in the cilium-centrosome complex (CCC). The function of the CCC is to sense a wide variety of intracellular signals that affect polarity, proliferation, differentiation, and tissue maintenance. Many of the syndromes in which postaxial polydactyly is a cardinal feature belong to a group of conditions known as the single-gene ciliopathies [21] and are in Table 2.5.

Table 2.5 Ciliopathy syndromes associated with postaxial polydactyly
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The single-gene ciliopathies with postaxial polydactyly include a group of skeletal dysplasias characterized by their narrow thoraces and short ribs: short rib polydactyly Types I, II, and IV, Ellis van–Creveld, and Jeune asphyxiating thoracic dysplasia, Type 1 and 2. The short rib polydactylies are characterized by early respiratory distress related to very small thoracic cages resulting in lung hypoplasia, and often, early infant death. Ellis–van Creveld, and Jeune Thoracic Dystrophy, also include short ribs as a defining feature, but have other distinctive features that separate them from the short rib polydactyly group. The configuration of the ribs is different in these last two conditions as well.

Ciliopathies also include Bardet–Biedl syndrome and Meckel–Gruber syndrome. Both of these syndromes can be caused by one of multiple genes, but all of the genes share the property that they encode proteins important in the CCC [21].

Bardet–Biedl is a multisystem disorder in which the primary features are retinal degeneration, cystic kidney disease or urinary tract malformation, intellectual disability, diabetes mellitus, obesity, infertility, and postaxial polydactyly. The delineation of the genetics of Bardet–Biedl syndrome helped establish ciliopathies as an important disease entity when it was shown that many of the proteins formed by genes responsible for BBS were expressed in the ciliated sensory neurons of the nematode C. elegans [22]. The polarization of cells required for the formation of the tubules in the kidney represent the action of these ciliary proteins that are affected by BBS gene mutations [21].

Both McKusick–Kaufman syndrome and Bardet–Biedl 6 (BBS6) are caused by mutations in the MKKS gene. McKusick–Kaufman is an autosomal recessive, multisystem condition with polydactyly, heart defects, and genital abnormalities, and is most common in the Old Order Amish community. MKKS codes for a protein important in centrosomal function, possibly acting as a chaperonin. Silencing of the transcript of that gene leads to multinucleate and multicentrosomal cells with cytokinesis defects [5].

Meckel–Gruber is a recessively inherited condition in which the cardinal features include central nervous system malformations, particularly occipital encephalocele, Arnold–Chiari malformation, absence of midline structures such as the corpus callosum and septum pellucidum, and cerebellar malformations. Other major findings include cystic changes in the kidneys and liver. The genes that cause Meckel–Gruber code for proteins that localize to the centrosome, pericentriolar region or to the cilium itself.

Oral-facial-digital syndrome, type 1 (OFD1) is an X-linked disorder in which the gene product has been shown to localize in the renal epithelial cells in the polarized region. Expression of OFD1 is necessary for primary cilia formation and left–right axis specification [21, 24], making OFD1 a ciliopathy syndrome as well. The hand findings in OFD1 are variable and primarily involve asymmetric shortening of the digits in the hands with variable syndactyly and preaxial polydactyly of the feet. However, postaxial and preaxial polydactyly of the hands has also been reported.

Other Syndromes with Polydactyly of Varying Types

Table 2.6 lists some of the many other syndromes associated with polydactyly. Grebe chondrodysplasia is a dwarfing condition in which all of the long bones are severely shortened, particularly the distal portions and is associated with postaxial polydactyly of the hands. Grebe chondrodysplasia is caused by mutations in the growth differentiation factor 5 (GDF5) gene, also known as the cartilage-derived morphogenetic protein 1 (CDMP1) gene. This gene has been found to be responsible for other types of chondrodysplasias including acromesomelic dysplasia, Hunter–Thompson type, Du Pan syndrome (fibular hypoplasia and complex brachydactyly), Multiple synostosis syndrome 2, as well as isolated heritable hand malformations including brachydactyly types A1, A2, and C and proximal symphalangism type 1B (OMIM gene 601146).

Table 2.6 Other selected syndromes associated with polydactyly
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Greig cephalopolysyndactyly is a multiple malformation syndrome that is usually ascertained through the limb abnormalities, but includes craniofacial findings such as macrocephaly with an unusual head shape. In Greig, the hand and foot abnormalities are quite variable and include a combination of polydactyly and syndactyly. The polydactyly can be postaxial, preaxial, mesoaxial, or a mixture of all three, and can vary from limb to limb in the same individual. Greig is caused by mutations in the Gli-Kruppel Family member 3 (GLI3) gene on 7p13. GLI3 is a gene in the zinc finger gene family and is also the gene responsible for Pallister–Hall syndrome, a syndrome in which the polydactyly can be postaxial or mesoaxial and other cardinal features include hypothalamic hamartoma, pituitary dysfunction, and visceral malformations. Mutations in GLI3 are also found in some of the isolated heritable forms of polydactyly, including postaxial polydactyly types A1 and B, and preaxial polydactyly type IV [25, 26].

Syndromes with Syndactyly

Syndactyly is harder to accurately study as mild cutaneous syndactyly is often not reported as a congenital anomaly. Significant cutaneous syndactyly and bony syndactyly is associated with a number of underlying syndromes. Complete syndactyly of the third and fourth digits of the hands, also called zygodactyly can be seen in fetuses with triploidy (karyotype with three copies of every chromosome) but can also occur as an isolated finding.

Syndactyly can be found as a defining feature in a group of syndromes with craniosynostosis as a major feature, often called acrocephalosyndactylies (Table 2.7). Syndactyly of all the fingers into a mitten like extremity occurs in Apert syndrome, an MCA syndrome in which there is significant craniosynostosis involving multiple sutures.

Table 2.7 Craniosynostosis syndromes associated with syndactyly
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Syndactyly is also seen in a number of other syndromes. It is a defining characteristic in only some of these, which are listed in Table 2.8.

Table 2.8 Other syndromes associated with syndactyly as a defining or significant feature
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Syndromes with Brachydactyly

Isolated Brachydactyly

Brachydactyly of the hands or shortened digits can be due to absent, underdeveloped, or abnormally shaped phalanges (brachyphalangy), or metacarpals (brachymetacarpia), or a combination of these. Brachydactyly can involve all of the digits or only some of the digits. Bell classified isolated brachydactyly in 1951 [2, 27] into Types A through E with subtypes.

Type A: Brachymesophalangy

  • Type A-1: Brachymesophalangy II–V; brachyphalangy I

  • Type A-2: Brachymesophalangy II

  • Type A-3: Brachymesophalangy V

Type B

  • Aplasia terminal phalanges, II–V

  • Hypoplasia middle phalanges, II–V

  • Broad distal phalanges, I

Type C

  • Brachymesophalangy II, III, V

  • Hypersegmentation, proximal phalanges, II, III

Type D

  • Short, broad thumb distal phalanx

Type E

  • Brachymetacarpia

  • Brachymetatarsia

Brachydactyly of one or all the digits can also be found as a feature of multiple syndromes (Table 2.9).

Table 2.9 Genetics of isolated brachydactyly
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Brachydactyly is a common finding in more than 50 different skeletal dysplasias, but rarely is the defining characteristic. Chapter 26 reviews many of these, and Table 2.10 lists many of these skeletal dysplasias as well.

Table 2.10 Skeletal dysplasias with brachydactylya
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There are single reports of families in which brachydactyly occurs as a dominant trait with one or two other features, but the genetics of these conditions is not well defined. These single-family reports will not be included in this review. Numerous multiple malformation syndromes have brachydactyly as a prominent or cardinal feature. Some of the more common of these are listed in Table 2.11.

Table 2.11 Syndromes with brachydactyly as a major feature
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Cornelia de Lange, or Brachman de Lange, syndrome is a multiple malformation syndrome that was first described in severely affected cases in which there was moderate to severe intellectual disability and severely affected upper limbs with oligodactyly and ulnar deficiency. Short stature and microcephaly were often severe. The facial appearance was also striking, with high arched eyebrows and synophrys, a small upturned nose, and a long philtrum with thin lips and a crescent-shaped mouth with downturned edges. Most cases were sporadic. When the first gene was identified, NIPBL, the phenotype was found to be much more variable in affected individuals. In particular the upper limb defects ranged from the classical findings of ulnar ray deficiency, to individuals with small hands, and individuals with brachydactyly. Following that, several more genes were identified that caused the same phenotype, confirming the inheritance as both autosomal dominant and X-linked.

Syndromes with Oligodactyly/Reduction Defects

The final category of syndromes with hand defects involves a group of syndromes in which the hands have reduction defects, resulting in either oligodactyly or adactyly (Table 2.12). Reduction defects are usually divided into those with radial ray defects and those with ulnar ray defects, and then a third category for conditions in which either or both rays might be involved. The reduction defects may just involve the digits, leading to oligodactyly, or may involve whole parts of the hand and/or upper extremity. They can be classified by the part of the hand structure that is involved.

Table 2.12 Syndromes with oligodactyly or adactyly
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Hand malformations are an important feature of many multiple malformation syndromes, and the genes involved give clues to the morphogenesis of the limbs as well as many other areas of development.