Prenatal diagnosis is usually not indicated for isolated forms of brachydactyly, but may be appropriate in syndromic forms. Short phalanges may not be clearly evident by fetal ultrasonography early in development, and will only be visible later on, if expressed. Molecular studies of chorionic villus sampling 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.

If the brachydactyly follows an autosomal dominant pattern of inheritance, the chance of recurrence in offspring of affected individuals is 50% regardless of sex. Variability in severity and incomplete penetrance are common in several types of brachydactyly.

If the brachydactyly follows an autosomal recessive pattern of inheritance, the risk of recurrence in the sib of an affected case is 25%. Although variable symptoms may still be present in affected sibs, variability is usually smaller in autosomal recessive forms.

There is no general, 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.

(OMIM: 112500) (syn: FARABEE TYPE BRACHYDACTYLY)

(OMIM: 112600) (syn: MOHR-WRIEDT TYPE BRACHYDACTYLY)

(OMIM: 112700) (syn: BRACHYMESOPHALANGY V, BRACHYDACTYLY-CLINODACTYLY)

(OMIM: 112800) (syn: BRACHYMESOPHALANGY II AND V, TEMTAMY TYPE BRACHYDACTYLY)

(OMIM: 112900) (syn: ABSENT MIDDLE PHALANGES OF DIGITS 2–5 WITH NAIL DYSPLASIA)

Absence of the middle phalanges and nail dysplasia with duplicated terminal phalanx of the thumb was reported by Bass 27 and Cuevas-Sosa and Garcia-Segur 28. We think that this type can be included in type B brachydactyly.

There is absence or hypoplasia of the terminal parts of the index to little fingers with complete absence of fingernails. The thumbs are always intact but frequently show flattening, splitting or duplication of the distal phalanges. Digits are less severely affected on the radial side of the hand compared to those on the ulnar side. The feet are similarly but less severely affected. The deformity is symmetric. There is soft tissue syndactyly, symphalangism, carpal and/or tarsal fusions and shortening of metacarpals and/or metatarsals.

This is a rare hand malformation with only a few published pedigrees in the world literature 4.

Clinical examination of the thumb anomalies and distal phalangeal hypoplasia, and absence of nails sometimes with associated distal symphalangism. Radiological examination of the hands and pattern profile analysis.

MacKinder 29 described this hand deformity in six generations of a family. All studied cases in the literature demonstrated an autosomal dominant pattern of inheritance with variable severity. The range of variability of the trait is less extreme among various affected members of the same pedigree. Temtamy and McKusick 1 reported a pedigree with 11 affected individuals in 6 generations, also with autosomal dominant inheritance and variable expressivity.

In the majority of cases, BDB is caused by heterozygous truncating mutations in the receptor kinase-like orphan receptor 2 gene (ROR2) on 9q22. Patients affected with the distal mutations have a more severe phenotype than those with the proximal mutations 30. In a subset of ROR2-negative patients with BDB and additional occurrence of proximal symphalangism and carpal synostosis, Lehmann et al. 31 identified different mutations in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG). The authors argued for a functional connection between BMP and ROR2 signaling and support the findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface. Autosomal recessive Robinow syndrome is also caused by mutations in the ROR2 gene. The BDB phenotype, as well as the location and nature of the BDB mutations, suggest a specific mutational effect that can not be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome.

The hand deformity is characterized by brachymesophalangy of the index, middle and little fingers with hyperphalangy of the index and middle finger and shortening of the 1^st metacarpal. The ring finger is usually the longest digit. The proximal phalanx of the index finger has an anomalous configuration resulting in its ulnar deflection. Short metacarpals and symphalangism are occasionally present. The feet are either normal or show ordinary brachydactyly. Temtamy and McKusick 1 reported one family with 10 affected members from 3 generations representing autosomal dominant inheritance and variable expressivity. The proband and her identical twin were similarly affected, with mild variability. Considerable intra- and interfamilial variation has been observed in type C brachydactyly 32.

Radiographic findings suggest a disturbance in chondrification and ossification with maximal effect on the development of the epiphyses and shafts of certain bones of the digits. Schwabe et al. 33 found mild shortening in hand radiographs of heterozygous mutation carriers. Castriota-Scanderbeg et al. 34 described a woman and her daughter with BDC. The child had angle-shaped appearance of the proximal phalanges of index and middle fingers in one hand and more typical triangular epiphyses with elongation of their radial side at the opposite hand suggesting that this peculiar phalangeal configuration occurs as a transitory event in early or mid childhood in phalanges that are marked by severe ossification delay.

This type of brachydactyly is rare with only few reported pedigrees 4.

Clinical evaluation of hands. X-rays of hands and pattern profile analysis. The ring finger is always the longest, longer than the index (hyperphalangism detected on radiological examination).

Many studies support an autosomal dominant trait. Baraitser and Burn 35 described an affected brother and sister whose Iraqi first-cousin parents were unaffected, raising the possibility of autosomal recessive inheritance of this phenotype. Schwabe et al. 33 identified a mutation in the GDF5 gene in a consanguineous Turkish kindred with BDC. Homozygous offspring exhibited brachymesophalangy and hyperphalangy of the second, third, and fifth fingers with some phenotypic variability while all heterozygous mutation carriers showed mild shortening of metacarpals 4 and 5, suggesting a semidominant pattern of inheritance. Intra-familial variability and the observation of skipped generations in some families indicate that BDC may not be a true autosomal dominant condition due to mutation of a single gene 36.

Heterozygous mutations of cartilage derived morphogenetic protein 1 (CDMP1), also known as growth/differentiation factor-5 gene (GDF5), resulting in loss of function have been reported in BDC 37. Galjaard et al. 32 suggested that factors other than locus heterogeneity, such as genetic modifiers and/or environmental factors must play a role in phenotypic variability. Everman et al. 38 described heterozygous mutations in additional families with BDC and revealed non-penetrance in a mutation carrier. Schwabe et al. 33 described a novel missense mutation in the prodomain of CDMP1 indicating an important function of the prodomain for the folding, secretion and availability of biologically active CDMP1.

There is a considerable degree of phenotypic overlap between BDA2, BDB and BDC. Mutations in the BMPR1B gene cause BDA2, mutations in the ROR2 gene cause BDB and mutations in the GDF5 gene cause BDC. Sammar et al. 39demonstrated that all three components are involved in GDF5-induced regulation of chondrogenesis. They found that the functional interaction of ROR2 with GDF5 and BMPR1B is genetically confirmed by the presence of epistatic effects in crosses of ROR2, BMPR1B and GDF5 deficient mice. Lehmann et al. 40demonstrated that disturbances of the NOG-GDF5-BMPR1B signaling cascade can result in either a BDC/symphalangism like phenotype or BDA2 depending on the quantitative effect and mode of action of the specific mutations within the same functional pathway.

Characteristically, the distal phalanx of the thumb alone is shortened. There are various degrees of thumb shortening, either unilaterally or bilaterally. It has been noted that the base of the distal phalanx is broader than the surface of the proximal phalanx to which it articulates, and that the distal end of the bone often shows some hyperplasia. Other investigations confirmed that the short distal phalanx of the thumb results from early closure of its epiphyses.

This type of brachydactyly is common. The prevalence varies in different populations, ranging from 0.41% to 4.0%. Particularly high prevalence was reported among Israeli Arabs and in the Japanese population 1.

Clinical evaluation and radiographs show a broad and short distal phalanx of thumbs, unilateral or bilateral. The distal phalanges of other digits may also be broad and short. Great toes may be similarly affected.

Breitenbecher 41 described the trait as autosomal dominant. Various other studies supported an autosomal dominant pattern with reduced penetrance.

no gene or locus for BDD has yet been identified.

Variable shortening of the metacarpals with more or less normal length of phalanges (Fig. 3). Occasionally, the metatarsals are also short. This results from hypoplastic and partially fused metacarpal epiphyses, visible on radiographs. The terminal phalanges are often short. Hyperextensibility of the hand joints is frequently a striking feature. The axial triradius is often relatively high. Affected individuals are slightly short of stature. Temtamy and McKusick 1 reported a family with 17 affected members in three generations confirming autosomal dominant inheritance and variable expressivity.

Short metacarpals and metatarsals are frequent findings in other types of brachydactyly and are features of several genetic syndromes. Some individuals with BDE are moderately short of stature and have round facies but do not have ectopic calcification, mental retardation or cataract as in pseudopseudohypoparathyroidism (PPHP) which is otherwise a clinically similar entity. Poznanski et al. 42 concluded that 'brachydactyly E is indistinguishable radiologically from the PHP-PPHP syndrome'. Short stature, round facies, secundum type of atrial septal defect and BDE (in which shortening of the metacarpals was most pronounced but not limited to the 4th metacarpal), were described in a kindred by Czeizel and Göblyös 43.

Hertzog 44 suggested that there are at least three subtypes of BDE: E1, in which shortening is limited to the fourth metacarpals and/or metatarsals 45; E2, in which variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges 46 and E3, a dubious category which may have a variable combination of short metacarpals without phalangeal involvement.

Pitt and Williams 47 described a 'new' type of brachydactyly in 12 members of four generations combining features of types B and E with hypoplasia of the distal phalanges of the ulnar side of the hand and shortening of one or more metacarpals. The subjects were, however, not short of stature as in type E. Male-to-male transmission was noted in several instances. The authors called this phenotype brachydactyly type Ballard after the name of the family. Jensen and Hoo 48 described a similar family but pointed out that the manifestations in both families strongly resembled type E brachydactyly and were likely to represent a variant form of this phenotype. In particular, they considered the condition in both families to be compatible with the E2 subtype, as suggested by Hertzog 44.

Rare as an isolated anomaly 1.

Clinical and radiological evaluation of hand bones. Short 4^th metacarpal can be diagnosed by a positive metacarpal sign. On clinical examination (using a pencil touching the heads of the 3^rd and 5^th metacarpals of the back of the closed fist), the 4^th metacarpal is receding. The same sign can be identified on X-rays by drawing a line to touch tips of the heads of the 3^rd and 5^th metacarpals (Fig. 3).

As an isolated anomaly, type E brachydactyly is inherited as an autosomal dominant trait with variable expressivity and variable involvement of the metacarpals and/or metatarsals, with frequent bilateral asymmetry. This phenotype is a useful example of genetic heterogeneity, because in addition to the autosomal dominant isolated type and Albright hereditary osteodystrophy, it also occurs with Turner syndrome.

Brachydactyly type E occurs with short stature and severe hypertension as an autosomal dominant syndrome (OMIM: 112410). Mollica et al. 49 reported a kindred in which six individuals had anetodermia (macular atrophy of the skin), eight had multiple exostoses, and two had type E brachydactyly seemingly unrelated to exostoses. In all, 10 members had one or more of these features. The authors suggested that this is an autosomal dominant syndrome.

Brachydactyly type E as an isolated abnormality has not been mapped with confidence. Its occurrence was one feature of what appeared to be a contiguous gene syndrome due to a cytogenetically visible de novo deletion of 2q37. Johnson et al. 50 described missense mutations in the homeodomain of HOXD13 in two cases with distinctive limb phenotypes exhibiting overlap with BDD and BDE.

Ray and Haldane 51 described short fourth metatarsi resulting in unilateral or bilateral short fourth toes in 206 persons in Northeastern India with no instance of short metacarpals, distinguishing this form from BDE. The authors concluded that the trait is autosomal dominant with approximately 27% penetrance.

Not known, probably not rare.

Clinical and radiological evaluation of feet will show short 4^th metatarsals.

Sugarman et al. 52 described a new form of brachydactyly of which a conspicuous feature was a non-articulating great toe which was set dorsal and proximal to the usual position. The great toes were amputated. The fingers were very short and had no motion at the proximal interphalangeal joints. The consanguinity in the family and the presence of seven other affected members among the patient's relatives made autosomal recessive inheritance likely.

Radiographs of the case described by Sugarman et al. 52 were provided by Fujimoto et al. 53. The hands had bilateral double first metacarpals. The fifth fingers had only two phalanges; the proximal and distal phalanges did not show bony fusion. The mother's hands were normal. Fujimoto et al. 53 described an infant girl, sister of Sugarman's proband (with the same mother but a different father) who showed brachydactyly with major shortening in the proximal phalanges. The first toes were proximally placed and medially curved. A paternal aunt of the mother had three children with the same anomaly. Consanguinity of the paternal aunt and her husband was claimed by Sugarman et al. 52, but could not be confirmed by Fujimoto et al. 53 who proposed autosomal dominant inheritance with reduced penetrance.

Extremely rare. Only one affected family reported twice by both Sugarman et al. 52 and by Fujimoto et al. 53.

By clinical and radiological changes.

This malformation of the little finger was first described by Kirner in 1972 54. It consists of radial bowing of the terminal phalanx. The tip of the little finger points towards the thenar eminence. This malformation is usually bilateral.

In an isolated Japanese village, Saito 55 found a frequency of 0.46% in males and 0.63% in females. David and Burwood 56 estimated an incidence of 1 in 410, with a higher prevalence in females than in males.

Clinical examination shows radial bowing of the terminal phalanx of the little finger, which is short. Radiologically, the following manifestations were listed by David and Burwood 56:

• A well-defined radiolucent nidus of between 1 and 2 mm in diameter present in the terminal tuft.

• The diaphysis of the distal phalanx is short relative to the middle phalanx in a ventroradial angulation.

• The diaphysis is sclerotic with sparing of both the epiphysis and the tuft.

• The dorsopalmar diaphysis is reduced.

• Apparent overgrowth of the epiphysis of the distal phalanx is demonstrated at the ventral margin. They noted an anterior spur, which in the AP projection may mimic a cone shaped epiphysis. They considered the deformity of the little finger as congenital with lack of the radiological signs before epiphyseal ossification at about the age of 2 years.

Autosomal dominant with incomplete penetrance.

no gene or locus for Kirner deformity has yet been identified.