Most of the cartilaginous buds for the small bones in the hands and feet are present by the 7th week of gestation

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As mentioned in Chapter 5, four constitutive segments of the limb are recognized: a root or zono- skeleton; a proximal segment or stylopodium (hu- merus/femur); a medial segment or zeugopodium (radius/ulna, tibia/ﬁbula); and a distal part or auto- podium (hand and foot). Several complex processes are involved in the formation of these segments.

Their action is coordinated, but so far little is under- stood about it.

Just like the long bones, the short tubular bones in the hands develop by way of transformation of the primitive mesenchyme into an intermediate cartilaginous model, which subsequently undergoes ossification. Proliferation and ossification of the physeal cartilage and development of the secondary ossification centers are further steps in bone development.

These processes of chondrification and ossification both proceed during embryonic and fetal life, in a fixed and predictable order. Most of the cartilaginous buds for the small bones in the hands and feet are present by the 7th week of gestation. The primary ossification centers for the metacarpals appear at the 9th week of gestation, while those for the phalanges are evident between the 8th and 11th weeks of gestation. Considerable regularity also exists in the order in which the carpals and epiphyses (secondary ossification centers) begin to ossify after birth, and in the sequence in which the epiphyses eventually fuse with their shafts (Greulich and Pyle 1959). Although irreg- ularities in the order of beginning ossification seem to occur more frequently in the carpals than in the metacarpals and epiphyses, the sequence of ossification of all carpals except the scaphoid is still remark- ably constant in healthy children of both sexes. This sequence is: capitate (3 months of age), hamate, tri- quetral, lunate, trapezium, trapezoid, and pisiform.

The scaphoid ossifies before the trapezium in boys, and either closely precedes or follows ossification of the trapezoid in girls. The interval between appearance of the first (os capitate) and last (os pisiform) carpal ossification centers spans about 9 years in girls and 10 years in boys. The secondary ossification centers (a single center for each bone) make their ap-

pearance at about 1 year of age in girls and 1 year and 6 months in boys, starting in the heads of the 2nd, 3rd, and 4th metacarpals, in the base of the proximal phalanges of the same ﬁngers, and in the base of the distal phalanx of the thumb and extending to the remaining tubular bones in the next few months.

Ossiﬁcation of the individual bones in the hand con- tinues throughout childhood and adolescence until complete fusion of all epiphyses is accomplished at about 18 years in females and 19 years in males.

Any stage of this orderly sequential bone development can be altered, leading to the appearance of different anomalies in the hands.

The limb develops from an embryonic limb bud, in which rapid cell proliferation of the apical ectodermal ridge (AER) occurs within the so-called progress zone. Closely linked to this growth is the limb bud po- larization along the anteroposterior and dorsoventral axes. The processes of cell proliferation and regenera- tion are in constant equilibrium with the process of cell death (apoptosis), which in human embryos is also responsible for the separation of the digits around days 51–53. A major role in proximodistal axis pat- terning is that of the ﬁbroblast growth factor (FGF) pathway. For example, FGF10 triggers the synthesis of FGF8 in the ectoderm overlying the limb bud and the expression of Sonic Hedgehog (SHH) in the meso- derm. In mice FGF2, FGF4 and FGF8 are produced in the apical ectodermal ridge, and some of the FGF genes maintain the expression of SHH in the zone of polarizing activity, controlling the anteroposterior axis. Mutations of FGF receptor (FGFR) genes-1, -2, and -3 and of the TWIST gene, which encodes for a helix–loop–helix transcription factor and acts up- stream of the FGF genes, have been associated with distinct craniostenoses with limb anomalies. They in- clude FGFR1 in Pfeiffer syndrome or acrocephalosyn- dactyly (ACS) type V; FGFR2 in Apert syndrome (ACS type I), Saethre Chotzen syndrome (ACS type III), Pfeiffer syndrome (ACS type V), Jackson-Weiss syndrome, Beare-Stevenson syndrome, and Antley-Bixler syndrome; and FGFR3 in Saethre-Chotzen syndrome (ACS type III), Muenke syndrome, and SADDAN Alessandro Castriota-Scanderbeg, M.D.

Bruno Dallapiccola, M.D.

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dysplasia (Jabs 1998). The SHH genes encode pro- teins involved in intracellular signaling. In particular, SHH is an important morphogen with a key role in establishment of the anteroposterior polarity of the limbs. Although no SHH mutation has been demon- strated so far in human limb anomalies, some evidence supports this role. Notable examples include syndactyly of the 2nd and 3rd toes in Smith-Lemli- Opitz syndrome and shortening of the 4th metacarpal, pre- or postaxial polydactyly, or syndactyly of the 2nd and 3rd toes in Gorlin syndrome. In addition, the zinc-ﬁnger transcription factor GLI3, which is involved in SHH repression, is implicated in Greig syndrome. This disorder is associated with syndactyly of hands and feet, preaxial polydactyly of toes and, sometimes, postminimus of the hands. A deletion of the same gene is also implicated in postaxial polydactyly type A. Heterozygous mutations in the gene for cAMP-response element (CREB)-binding protein, which is a coactivator of different transcription factors, including the GLI family, cause Rubinstein- Taybi syndrome, in which limb anomalies consisting of broad deviated thumbs and great toes, sometimes with preaxial polydactyly of feet, are found. There- fore, while in mice absence of SHH signaling results in limb amputations, in humans anomalies of the SHH pathway cause syndactyly and polydactyly, which are preaxial in the case of up-regulation, and postaxial in the case of down-regulation. The dorsoventral axis of the limb bud is determined by several transcription factors, but most of them are unknown.

LMX1B (coding for a LIM homodomain protein) mutations are involved in the autosomal dominant nail-patella syndrome. The determination of limb identity and morphogenesis is deﬁned by multiple other genes, most of which are still unknown. At present, four major groups of genes have been implicated in limb malformations: those encoding for T-box transcription factors (TBX); bone morphogen- esis proteins (BMP); cartilage-derived morphogenet- ic proteins (CDMP); and homeobox (HOX) genes.

TBX genes are probably relevant to the speciﬁcation of limb identity. Mutations of TBX-5, mapping to 12q24, have been related to Holt-Oram syndrome, an autosomal dominant disorder with malformations of the radial ray, including absent, hypoplastic, or tri- phalangeal thumb. TBX-3 is mutated in the Schinzel ulnar-mammary syndrome, presenting with a wide range of ulnar ray abnormalities, including agenesis or duplication of the 5th ﬁnger. BMPs are key regula- tors of the anteroposterior limb axis and HOX ex- pression, having a major role in initiation of chon- drogenesis and cartilage differentiation. However,

no mutation of BMP has been found to date in any of the human limb malformations. The Noggin (NOG) gene, which is an antagonist of the BMP signals, has been implicated in the autosomal dominant proximal symphalangism, a disorder characterized by ankylo- sis of the proximal interphalangeal joints and of the carpal and tarsal bones; and in the multiple synostosis syndrome, also characterized by multiple pro- gressive joint synostoses. Mutations in the transcrip- tion factor SALL1 (homologous to a Drosophila de- velopment regulator), which is functioning in the BMP pathway, have been found in patients with the Townes-Brocks syndrome, an autosomal dominant disorder with preaxial polydactyly and triphalangeal thumb associated with anal imperforation and ear and urogenital tract anomalies. CDMP (encoding for a member of the bone morphogenetic protein) or growth differential factor 5 is implicated in chondro- genesis and positioning of the joints. Homozygous mutations cause the autosomal recessive Hunter- Thompson acromesomelic dysplasia, in which anomalies are limited to the limbs. A similar, but more severe disease, the autosomal recessive Grebe dyspla- sia, is also caused by CDMP1 mutations. Patients show pronounced dysmorphism of the limbs with a proximodistal gradient of severity, consisting of carpal and tarsal fusions and agenesis of several car- potarsal bones and proximal and middle phalanges, sometimes with postaxial polydactyly. Heterozygous parents of Grebe dysplasia patients are affected by brachydactyly type C. (Heterozygous mutations in CDMP1 cause the autosomal dominant brachydacty- ly type C, whereas homozygous mutations in the same gene cause acromesomelic dysplasia, Hunter- Thompson type and Grebe chondrodysplasia.) The homodomain-containing HOX transcription factors, and in particular those of A and D complexes, are critical for limb development. For example, HOXD13 has been implicated in the formation of the au- topodium and its mutations cause synpolydactyly.

Heterozygotes have partial duplication and syndactyly of the 3rd and 4th hand rays, and 4th and 5th foot rays, sometimes with pre- and postaxial polydactyly or isolated postaxial polydactyly. Severe limb anomalies are found in HOXD13 homozygotes, in which complete disorganization of the bone structure, syndactyly of all ﬁngers, pre-, meso-, and postaxial polydactyly, abnormal carpus, tarsus, metacarpals and phalanges, and fusion of the metatarsals are found. Mutations of the HOXA13 gene have been associated with hand-foot-genital syndrome, an autosomal dominant disorder with short 1st metacarpal, distal phalanx of the thumb and middle

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phalanx of the 5th finger, and fusion or retarded mat- uration of the carpus. In conclusion, recent molecular discoveries are deciphering some of the molecular mechanisms underlying limb defects. While the current classification, which is based on clinical features, remains useful, it is likely that a new classification based on genetic defects will replace previous groupings in the near future. This, in turn, will facili- tate understanding of the mechanisms responsible for these defects (Winter and Tickle 1993; Manou- vrier-Hanu et al. 1999).

References

Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. Stanford University Press, Stanford, 1959 (2nd ed.), p. 24

Jabs EW. Toward understanding the pathogenesis of cran- iosynostosis through clinical and molecular correlates. Clin Genet 1998; 53: 79–86

Manouvrier-Hanu S, Holder-Espinasse M, Lyonnet S. Genetics of limb anomalies in humans. Trends Genet 1999; 15: 409–17 Winter RM, Tickle C. Syndactylies and polydactylies: embry- ological overview and suggested classiﬁcation. Eur J Hum Genet 1993; 1: 96–104

Reduction anomalies

Isolated – SHFM1 7q21.3-q22.1

mesoaxial SHFM2 Xq26

SHFM3 10q24-q25

Associated – Holt- 12q24.1 TBX5

preaxial Oram

Associated – Schinzel 12q24.1 TBX3 postaxial

Associated – EEC 7q11-q21; 19 mesoaxial

Hypoplasia of several segments

Hunter- 20q11.2 CDMP1

Thompson

Grebe 20q11.2 CDMP1

Brachydactylies

Isolated Type C ‘Haw’ 12q24

Type CDMP 20q11.2 CDMP1

Associated Hand-foot- 7p14.2-p15 genital

Trichorhino- 8q24.12 phalangeal

Syndactylies

Associated Pfeiffer 8p11 FGFR1

Apert 10q25.3-q26 FGFR2

Saethre- 10q25.3-q26 FGFR2 Chotzen

Pfeiffer 10q25.3-q26 FGFR2 Jackson- 10q25.3-q26 FGFR2 Weiss

Beare- 10q25.3-q26 FGFR2

Stevenson

Antley-Bixler 10q25.3-q26 FGFR2 Saethre- 4p16.3/7p21 FGFR3,

Chotzen TWIST

Muenke 4p16.3 FGFR3

SADDAN 4p16.3 FGFR3

Oculodento- 6q22-q24 digital

Goltz Xp22-p31

Polydactylies

Postaxial – Type A1 7p13 GLI3

isolated Type A2 13q21-q32

Postaxial – Smith-Lemli- 11q12-q13 Sterol

associated Opitz delta 7

Ellis-van Creveld 4p16

Bardet-Biedl 3, 11, 15, 16, etc

Meckel 17q21-q24

Kaufman- 20p12

McKusick

Oro-facio- Xp22.2-p22.3 digital 1

Simpson-Golabi Xq26 Glypican 3 Mesoaxial – Synpolydactyly 2q31-q32 HOXD13 isolated

Mesoaxial – Pallister-Hall 7p13 GLI3 associated

Preaxial – Greig 7p13 GLI3

associated Gorlin 9q22.3 PTC

Rubinstein-Taybi 16p13.3 CBP Townes-Brocks 16q12.1 SALL1

Pre-, Greig 7p13 GLI3

postaxial

Acrocallosal 12q11.2-q13.3 Other Preaxial 7q36 defects polydactyly

Triphalangeal 7q36 SHH

thumb+ sacral agenesis

Mirror polydactyly 7q36

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Shortening or Absence of Components of the Hands

‘Quantitative’ hand malformations include reduction (deficiency) and excess deformities. Excess malformation, notably macrodactyly, is discussed in a later section of this chapter. As already mentioned in Chapter 5, reduction deformities can be further clas- sified: according to their extent as complete (aplasia) or partial (hypoplasia) and according to their orien- tation as transverse or longitudinal, depending on whether they extend across the width of the hand or run parallel to its long axis (Frantz and O’Rahilly 1961; Maroteaux 1970; Kay 1974; Kay et al. 1975; Mi- tal 1976; Temtamy and McKusick 1978). In a study based on 271 nonchromosomal limb reduction defects, 35 % were terminal transverse, 35 % longitudinal (13 % preaxial, 12 % postaxial, 10 % intercalary), 26 % split limbs, and 4 % multiple types. An overall prevalence of 0.45 per 1,000 births (stable over 5 years) has been found for the limb reduction defects diagnosed during the first 2 years of life. The upper limbs were involved in 75 % of cases and the lower limbs, in 25 %. In cases with multiple limb involvement (28 %) two thirds had the same type of limb reduction defect in each limb (Lin et al. 1993).

Limb reduction defects often occur in combination with fusion and segmentation deformities (Castilla et al. 1977).

A spectrum of reduction defects can occur in the hands, varying from minimal shortening of the middle phalanx of the 5th finger to complete absence of the hand (acheiria). In the absence of a uniform con- sensus on the terminology for the hand defects, a de- tailed radiographic description is essential to char- acterize the defect both with reference to the anatomical location and in terms of deviation from its original shape, size, and structure. Appropriate X-ray examination of the hand includes single bone evaluation and analysis of the relationships among individual bones. Bone length measurement can also be required to assess size modifications that are not clinically obvious (Garn et al. 1972). A va- luable approach to objective appraisal of tubular bone shortening is the pattern profile analysis of Poznanski et al. (1997). This method consists in plot- ting the relative length of the tubular bones, ex- pressed in terms of standard deviations (z score) from the norms, against the specific location in the hand. Subtle bone shortening, which can be over- looked by direct observation, is detected by this technique. In addition, since the profiles are plotted against appropriate standards for age and sex, they

allow direct comparison between dissimilar individuals. Several patterns for speciﬁc disorders have been recognized, with good agreement of the proﬁle among different patients with the same disorder. An up-to-date bibliography covering the use of this method in bone dysplasias and malformation syndromes has been compiled by Poznanski and Garn (1997).

This section summarizes the situations characterized by shortening or absence of individual bones in the hand. The anatomical criterion is adopted throughout, and speciﬁc defects are discussed according to whether they affect the row or the ray, and to which portion of the row or ray is involved. Vari- able degrees of overlap are recognized among the various categories.

References

Castilla EE, Frias ML, Paz JE. Patterns of combined limb malformations. Teratology 1977; 16: 203–9

Frantz CH, O’Rahilly R. Congenital skeletal limb deﬁciencies.

J Bone Joint Surg Am 1961; 43: 1202–24

Garn SM, Hertzog KP, Poznanski AK, Nagy JM. Metacarpopha- langeal length in the evaluation of skeletal malformation.

Radiology 1972; 105: 375–81

Kay HW, Day HJ, Henkel HL, Kruger LM, Lamb DW, Marquardt E, Mitchell R, Swanson AB, Willert HG. The proposed international terminology for the classiﬁcation of congenital limb deﬁciencies. Dev Med Child Neurol 1975; 34:

1–12

Kay HW. A proposed international terminology for the classi- ﬁcation of congenital limb deﬁciencies. Orthot Prosth 1974;

28: 33–44

Lin S, Marshall EG, Davidson GK, Roth GB, Druschel CM. Eval- uation of congenital limb reduction defects in upstate New York. Teratology 1993; 47: 127–35

Maroteaux P. Nomenclature internationale des maladies os- seuses constitutionneles. Ann Radiol 1970; 13: 455–64 Mital MA. Limb deﬁciencies: classiﬁcation and treatment.

Orthop Clin North Am 1976; 7: 457–64

Poznanski AK, Garn S. A bibliography covering the use of metacarpophalangeal pattern proﬁle analysis in bone dysplasias, congenital malformation syndromes, and other disorders. Pediatr Radiol 1997; 27: 358–65

Poznanski AK, Garn SM, Nagy JM, Stern AM. Metacarpopha- langeal patterns proﬁles in the evaluation of skeletal malformation. Radiology 1972; 104: 1–11

Temtamy SA, McKusick VA. The genetics of hand malformation. Alan R. Liss, New York, 1978

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Brachytelephalangy

䉴 [Short distal phalanges]

The distal phalanges vary widely in size in the normal population, only the middle phalanx of the 5th digit in females varying more widely (Garn et al.

1972). Mild to moderate shortening of the distal phalanges can therefore be an isolated anomaly in other- wise normal individuals (Fig. 6.1). Short distal phalanges are also found in association with a number of syndromes and skeletal dysplasias, as well as in the context of acquired disorders. Acquired forms are usually characterized by asymmetrical and random distribution of the skeletal defect. Congenital forms are often associated with hypoplasia or absence of ﬁngernails. However, nail hypoplasia can occur in the absence of distal phalangeal hypoplasia. In addition to being short, the distal phalanges can be wide and broad, as they are in acrodysostosis, cleidocranial dysplasia, diastrophic dysplasia, and pseudoachondroplasia; or thin and small, as in Carpenter syndrome, Cofﬁn-Siris syndrome, and some chromoso- mal trisomy syndromes. The association between short distal phalanges and cone-shaped epiphyses is well established (Poznanski 1984). Shortening of the distal phalanx of the thumb is discussed in a sub- sequent section of this chapter.

Rudimentary or absent terminal phalanges are typically observed in brachydactyly type B (OMIM 113000), a heritable disorder caused by mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) gene mapping to 9q22. The ROR2 gene is also mutated in the autosomal recessive Robinow syndrome (OMIM 268310) (Gong et al. 1999; Oldridge et al. 2000). Affected individuals over multiple generations have been reported (Goeminne et al. 1970). Nail aplasia is a variable manifestation. Shortening of the middle phalanges can also occur (Fig. 6.2 a–c). This is the most severe form of brachydactyly. Both fingers and toes are affected. The thumb and big toe may be normal, but are usually variably deformed, with shortening, flattening, and bifidity. Symphalangism and mild syndactyly are possible additional manifestations, leading to the designation of ‘symbrachydacty- ly’ that is sometimes used for this entity. Features of type B brachydactyly (hypoplasia of the distal phalanges of the ulnar side) in combination with features of type E brachydactyly (metacarpal shortening) have been observed in 12 members of a family over four generations (brachydactyly, combined B and E types, OMIM 112440) (Pitt and Williams 1985). An association of anonychia-onychodystrophy, hypoplasia of

distal phalanges, metacarpals, and metatarsals, and absence of some metacarpals and phalanges has been described as a separate entity over five generations of a family (OMIM 106990) (Kumar and Levick 1986). Another unique combination of anomalies, observed in nine family members in four generations, includes brachydactyly type B (rudimentary or absent distal phalanges of fingers and toes, broad or bifid distal phalanx of the thumb and great toe, finger- and toenail aplasia/hypoplasia), bilateral pig- mented macular coloboma, unilateral renal aplasia, and bilateral sensorineural hearing loss (coloboma of macula with type B brachydactyly, OMIM 120400) (Sorsby 1935; Thompson and Baraitser 1988). Hy- poplasia of the distal phalanges is a cardinal mani- festation of chondrodysplasia punctata, brachytele- phalangic type (OMIM 302940), a recessive disorder with rhizomelic limb shortening, facial dysmorphism with a deeply set nose, atrophic and pigmen- tary skin lesions, mental retardation, and punctate epiphyseal calcifications that usually disappear within the first 2 years of life. Beyond this age, the radiographic diagnosis relies solely on the characteristic appearance of the distal phalanges: short and triangular, the apex of the triangle pointing proximally (Fig. 6.3). Short, angel-shaped middle phalanges and proximally deformed metacarpals are occasional manifestations of the disorder (Maroteaux 1989;

Herman et al. 2002). A similar pattern of brachytelephalangy, but with selective sparing of the 5th ﬁnger,

Fig. 6.1. Isolated brachytelephalangy in an adult male. All distal phalanges are abnormally short and wide. Capitate-hamate fusion is also present. Fingernail hypoplasia was a feature in this individual

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occurs in Keutel syndrome (OMIM 245150), an auto- somal recessive disease caused by mutations in the gene encoding the human matrix Gla protein and mapping to 12p13.1-p12.3 (Munroe et al. 1999). The syndrome is characterized by multiple peripheral pulmonary stenosis, mixed sensorineural and con- ductive hearing loss, and cartilaginous calciﬁcation of the auricular cartilages, larynx, trachea, and ribs (Keutel et al. 1972; Miller 2003). Further manifestations include midface hypoplasia, depressed nasal bridge, and saddle nose (Cormode et al. 1986). In infancy, the distal phalanges show punctate epiphyses and short, triangular phalanges with the apex located proximally. With increasing age, thickening of the epiphyses and further shortening of the phalanges is associated with physeal widening, giving the distal phalanges a radiographic appearance reminiscent of that seen in occupational acro-osteolyses (Fig. 6.4). Clubbing of affected ﬁngers, i.e., broaden- ing of the soft and/or bony tissues of the phalangeal tufts, is also typical of the disorder.

Fig. 6.2 a–c. Brachydactyly type B. a In a 13 1/2-year-old girl;

note absence of distal phalanges and hypoplasia of middle phalanges in ﬁngers 2 through 5. Fingernail hypoplasia was al- so present. b, c In an 8 1/2-year-old boy. There is aplasia of the distal phalanges 2 through 4, with marked hypoplasia of the 5th distal phalanx, and hypoplasia of the middle phalanges of ﬁngers 2 through 5 (b). The thumb is normal. Unexpectedly, in view of the severity of the defect, the nails were normal. Note absent distal phalanges and rudimentary middle phalanges of the toes (c); distal phalanges of the big toe is also rudimentary

a

b

c

Fig. 6.3. Chondrodysplasia punctata X-linked in a male new- born. Note the characteristic triangular appearance of the distal phalanges, with the apex of the triangle pointing proximally. Punctate calciﬁcations are recognized in the carpus. (From Herman et al. 2002)

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Radiographic Synopsis AP projection

1. Short distal phalanges (isolated brachytelepha- langy)

2. Rudimentary/absent distal phalanges of ﬁngers and toes; short, broad, and biﬁd thumb and big toe (brachydactyly type B)

3. Short, triangular distal phalanges; short, angel- shaped middle phalanges; hypoplastic, irregular metacarpals; punctate calciﬁcations (chondrodys- plasia punctata, X-linked)

Associations

• Aarskog syndrome

• Acrodysostosis

• Acro-osteolysis (familial, chemical, leprosy, etc.)

• Anonychia-onychodystrophy/brachydactyly type B/

ectrodactyly

• Asphyxiating thoracic dysplasia

• Brachydactyly type B

• Buerger’s disease

• Carpenter syndrome

• C syndrome (Opitz trigonocephaly syndrome)

• Chondrodysplasia punctata, X-linked

• Chondroectodermal dysplasia (Ellis-van Creveld)

• Chromosome trisomy syndromes (9p, 13, 18)

• Cleidocranial dysplasia

• Cofﬁn-Lowry syndrome

• Cofﬁn-Siris syndrome

• Diastrophic dysplasia

• Dilantin, maternal use

• DOOR syndrome

• Fanconi anemia

• Fetal alcohol syndrome

• Fibrodysplasia ossiﬁcans progressiva

• Frostbite

• Grebe chondrodysplasia

• Hand-foot-genital syndrome

• Holt-Oram syndrome

• Indifference-to-pain syndrome

• Keutel syndrome

• Larsen syndrome

• Liebenberg syndrome

• Mandibuloacral dysplasia

• Marshall-Smith syndrome

• Melnick-Needles syndrome

• Metaphyseal chondrodysplasia (Jansen)

• Mucolipidosis II

• Neurotrophic conditions (acrodystrophic neuropathy, amyloid neuropathy, Charcot-Marie-Tooth syndrome, diabetes, peripheral nerve injury, spinal cord trauma or disease, tabes dorsalis, familial dysautonomia)

• Onychonychia and absence and/or hypoplasia of distal phalanges

• Oto-palato-digital syndrome, types I and II

• Pachydermoperiostosis

• Porphyria

• Progeria

• Pseudoachondroplasia

• Pseudohypoparathyroidism

• Pseudo-pseudohypoparathyroidism

• Pseudoxanthoma elasticum

• Psoriasis

• Pyknodysostosis

• Raynaud’s disease

• Refsum syndrome

• Robinow syndrome

• Rothmund-Thomson syndrome

• Rüdiger syndrome

• Symphalangism

• Trauma

• Warfarin syndrome

Fig. 6.4. Keutel syndrome in a 3 1/2-year-old girl. Note marked shortening and clubbing of the distal phalanges of ﬁngers 1 through 4, with relative sparing of the 5th. The involved phalanges show thickened epiphyses and widened physes, which are somehow reminiscent of the ﬁndings in occupational acro- osteolysis. (From Miller SF 2003)

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References

Cormode EJ, Dawson M, Lowry RB. Keutel syndrome: clinical report and literature review. Am J Med Genet 1986; 24:

289–94

Garn SM, Hertzog KP, Poznanski AK, Nagy JM. Metacarpopha- langeal length in the evaluation of skeletal malformation.

Radiology 1972; 105: 375–81

Goeminne L, Agneessens A, Kunnen M. Perodactylie of apicale dystroﬁe: brachydactylie door hypofalangie II-V met biﬁde telefalangie I, in vijf generaties. Tijdschr Geneeskd 1970; 9:

469–72

Gong Y, Chitayat D, Kerr B, Chen T, Babul-Hirji R, Pal A, Reiss M, Warman ML. Brachydactyly type B: clinical description, genetic mapping to chromosome 9q, and evidence for a shared ancestral mutation. Am J Hum Genet 1999; 64:

570–7

Herman TE, Lee BC, McAlister WH. Brachytelephalangic chondrodysplasia punctata with marked cervical stenosis and cord compression: report of two cases. Pediatr Radiol 2002; 32: 452–6

Keutel J, Jorgensen G, Gabriel P. A new autosomal recessive syndrome: peripheral pulmonary stenoses, brachytelepha- langism, neural hearing loss and abnormal cartilage calciﬁ- cations-ossiﬁcation. Birth Defects Orig Art Ser 1972; 8:

60–8

Kumar D, Levick RK. Autosomal dominant onychodystrophy and anonychia with type B brachydactyly and ectrodactyly.

Clin Genet 1986; 30: 219–25

Maroteaux P. Brachytelephalangic chondrodysplasia punctata:

a possible X-linked recessive form. Hum Genet 1989; 82:

167–70

Miller SF. Brachytelephalangy with sparing of the ﬁfth distal phalanx: a feature highly suggestive of Keutel syndrome.

Pediatr Radiol 2003; 33: 186–9

Munroe PB, Olgunturk RO, Fryns J-P, van Maldergem L, Ziereisen F, Yuksel B, Gardiner RM, Chung E. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet 1999; 21: 142–4

Oldridge M, Fortuna AM, Maringa M, Propping P, Mansour S, Pollitt C, DeChiara TM, Kimble RB, Valenzuela DM, Yan- copoulos GD, Wilkie AOM. Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet 2000; 24: 375–8

Pitt P, Williams I. A new brachydactyly syndrome with similar- ities to Julia Bell types B and E. J Med Genet 1985; 22: 202–4 Poznanski AK. The hand in radiologic diagnosis. W.B. Saun-

ders Company, Philadelphia, 1984 (2nd ed.), pp. 155–6 Sorsby A. Congenital coloboma of the macula, together with

an account of the familial occurrence of bilateral macular coloboma in association with apical dystrophy of hands and feet. Br J Ophthalmol 1935; 19: 65–90

Thompson EM, Baraitser M. Sorsby syndrome: a report on further generations of the original family. J Med Genet 1988;

25: 313–21

Brachymesophalangy

䉴 [Short middle phalanges]

The skeletal phenotype seen as short middle phalanges has been called type A brachydactyly by Bell (1951). According to the distribution of the defect in the hand, several types have been recognized. These various types, however, are not always distinct entities, and large intrafamilial variability is seen.

Brachydactyly syndrome, type A1 (OMIM 112500) is characterized by rudimentary or absent middle phalanges of all digits in the hands and feet and by shortening of the proximal phalanx of the thumb and big toe. Usually, the 2nd and 5th ﬁngers are involved to a greater extent than the others. Synostosis between rudimentary middle phalanges and distal phalanges is common. The phenotype displays a certain degree of intra- and interfamilial variability. For example, shortening of the proximal phalanges also may occur, thus overlapping with the phenotype of brachydactyly type C (OMIM 113100, see next section). Fur- thermore, severe cases of type A1 brachydactyly can be associated with shortening of the metacarpals, notably the 4th and 5th. Accessory carpal bones in the distal row have also been reported (Hoefnagel and Gerald 1966). Stiff thumb, short stature, and mental retardation have been observed in subjects with this phenotype (Haws and McKusick 1963; Piussan et al.

1983). Brachydactyly type A1 has been shown to be caused by mutations in the Indian Hedgehog (IHH) gene, which is located on chromosome 2 (Yang et al.

2000; Gao et al. 2001). Linkage to chromosome 5 has also been found in a family with mild type A1 brachydactyly and short stature but no other clinical features (this type has been termed A1B) (Armour et al. 2002). Unilateral short middle phalanges in association with syndactyly are seen in the Poland syndrome. Type A1 brachydactyly also occurs in some syndromes, notably Carpenter syndrome (acro- cephalopolysyndactyly type II, OMIM 201000), atelosteogenesis type 2 (OMIM 256050), tricho-rhino-phalangeal syndrome type 2 (OMIM 150230), and Smith-Lemli-Opitz syndrome (OMIM 270400) (Fig. 6.5). In the rare brachydactyly syndrome type A2 (OMIM 112600), shortening is confined to the middle phalanx of the index finger and the 2nd toe, all other digits being more or less normal (Temtamy and McKusick 1978; Rasore-Quartino and Camera 1977). The hypoplastic phalanx can be rhomboid or triangular, resulting in radial deviation of the finger.

The epiphysis is often lacking, perhaps as a result of early fusion (Lawrence et al. 1989). The defect is in-

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herited as an autosomal dominant trait with high penetrance and variable expressivity. Type A2 brachydactyly has been observed in association with microcephaly (OMIM 211369) (Graham 1989) and seems to occur consistently with sclerosteosis (OMIM 269500). A phenotype reminiscent of type A2 brachydactyly is seen in the autosomal recessive du Pan syndrome (fibula aplasia and complex brachydactyly, OMIM 228900). In this condition a trapezoid middle phalanx of the index finger with radial deviation is associated with shortening of various metacarpals, small carpals, and bilateral absence of the fibula with tibiotarsal dislocation (du Pan 1924). Bell’s type A3 brachydactyly (brachymesophalangy V, OMIM 112700) consists in shortening of the middle phalanx of the 5th finger. This defect is very common, occurring in 0.5–24% of the general population (Poz- nanski 1984; Sugiura et al. 1962; Garn et al. 1967) and is usually inherited as a mendelian dominant trait with 50–60% penetrance (Temtamy 1966). As in the case of the index finger, the rhomboid or triangular shape of the rudimentary phalanx often results in radial deviation (clinodactyly) (Fig. 6.6). The finger can also be straight, however. Cone-shaped epiphyses at the 5th middle phalanx with early union are com-

mon associated ﬁndings. An association with short stature is also well documented (Garn et al. 1972).

The condition shows a characteristic sex and racial distribution, being more common in females, Mon- goloids and American Indians than in males, Whites and Blacks (Hertzog 1967). Several syndromes are associated with shortened 5th middle phalanx, including Down syndrome (OMIM 190685), oto- palato-digital syndrome, type I (OMIM 311300), Treacher-Collins syndrome (OMIM 154500), de Lange syndrome (OMIM 122470), Goltz-Gorlin syndrome

Fig. 6.5. Brachymesophalangy type A1 in a 3-year-old boy with Smith-Lemli-Opitz syndrome. Note hypoplasia of the middle phalanges, most prominent in the 2nd and 5th fingers, with clinodactyly of these two fingers. There is a pseudoepiphysis at the base of the 2nd metacarpal. Carpal ossification is retarded

Fig. 6.6. Brachymesophalangy of the 5th finger in a 13-year- old boy. The middle phalanx of the 5th finger is short and trapezoid, resulting in 5th finger clinodactyly

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(OMIM 305600), and Holt-Oram syndrome (OMIM 142900), among others. The uncommon type A4 bra- chydactyly (brachymesophalangy II, OMIM 112800) features brachymesophalangy affecting mainly the 2nd and 5th digits (Fig. 6.7). In a pedigree studied by Temtamy and McKusick (1978) occasional involvement of the 4th digit was associated with radial deviation of the distal phalanx owing to the abnormal shape of the short middle phalanx. Furthermore, absence of the middle phalanges in the lateral four toes was found. As in brachydactyly types A1 and A3 an association with short stature has been described (Ohzeki et al. 1993). In brachydactyly type A5 (OMIM 112900) absence of the middle phalanges occurs in association with nail dysplasia (Bass 1968; Cuevas- Sosa and Garcia-Segur 1971). The terminal phalanx of the thumb is duplicated. Male-to-male transmis- sion has been observed. Brachydactyly type A6 (Ose- bold-Remondini syndrome, OMIM 112910) is an association of hypoplastic or absent middle phalanges in the hands and feet, mesomelic limb shortening, mildly short stature, and normal intelligence. Addi- tional features include radial deviation of the terminal phalanges of the index ﬁngers, capitate-hamate fusion, and delayed coalescence of bipartite calcanei in infancy.As in brachydactyly type A5, male-to-male transmission has been described (Osebold et al. 1985;

Opitz and Gilbert 1985).

1. Rudimentary/absent middle phalanges of ﬁngers and toes; short proximal phalanx of thumb and big toe (brachydactyly A1)

2. Short, often rhomboid middle phalanx of 2nd ﬁn- ger and 2nd toe; radial deviation of 2nd ﬁnger (brachydactyly A2)

3. Short, often rhomboid middle phalanx of 5th ﬁn- ger, with radial deviation (brachydactyly A3) 4. Short middle phalanx of 2nd and 5th ﬁngers, with

or without 5th ﬁnger clinodactyly (brachydactyly A4)

5. Hypoplastic/absent middle phalanges of ﬁngers;

duplicated terminal phalanx of the thumb (bra- chydactyly A5)

6. Hypoplastic/absent middle phalanges of ﬁngers and toes; radial deviation of distal phalanges of 2nd ﬁngers; capitate-hamate fusion; bipartite cal- canei; mesomelic limb shortening (brachydactyly A6)

Associations

• Aarskog syndrome

• Aminopterin/methotrexate embryopathy

• Ankyloglossia superior

• Apert syndrome

• Arthritides

• Bloom syndrome

• Brachydactyly syndrome, types A1, A2, A3, A4, A5, A6

• Brachydactyly syndrome, type B

• Brachydactyly syndrome, type C

• Campomelic dysplasia

• Carpenter syndrome

• Chromosome trisomy syndromes (8, 9p, 13, 18, 21)

• Chromosome 4p– syndrome (Wolf syndrome)

• Chromosome XXXXX syndrome

• Chromosome XXXXY syndrome

• Cloverleaf skull

• Cofﬁn-Siris syndrome

• Cohen syndrome

• Cornelia de Lange syndrome

• Cri-du-chat syndrome

• EEC syndrome

• Ehlers-Danlos syndrome

• Fanconi anemia

• Focal dermal hypoplasia (Goltz-Gorlin syndrome)

• Holt-Oram syndrome

• Infection

• Klinefelter syndrome

Fig. 6.7. Brachydactyly type A4 in the same woman patient as depicted in Fig. 6.32. Note marked shortening of the middle phalanges of the 2nd and 5th ﬁngers, with 5th ﬁnger clinodactyly. The defects were bilateral. Short stature was also a feature in this patient

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• Laurence-Moon-Biedl syndrome

• Levy-Hollister syndrome

• Marfan syndrome

• Mental retardation/skeletal dysplasia/

abducens palsy

• Mesomelic dwarﬁsm (Nievergelt)

• Mitral valve insufﬁciency-deafness-skeletal malformation

• Multiple pterygium syndrome (Escobar syndrome)

• Nail-patella syndrome

• Neoplasm

• Noonan syndrome

• Normal variant

• Oculo-dento-osseous dysplasia

• Oro-facio-digital syndrome types I and II

• Oto-palato-digital syndrome, types I and II

• Poland syndrome

• Popliteal pterygium syndrome

• Prader-Willi syndrome

• Pseudohypoparathyroidism

• Pseudo-pseudohypoparathyroidism

• Pseudothalidomide syndrome

• Rieger syndrome

• Roberts syndrome

• Robinow syndrome

• Saethre-Chotzen syndrome

• Saldino-Mainzer syndrome

• Sclerosteosis

• Seckel syndrome

• Shwachman syndrome

• Sickle cell anemia

• Silver-Russel syndrome

• Symphalangism syndromes

• Thiemann disease

• Thrombocytopenia-absent radius (TAR) syndrome

• Trauma

• Treacher-Collins syndrome

• Tricho-rhino-phalangeal syndrome, types 1 and 2

• Williams syndrome

• Zellweger syndrome

References

Armour CM, McCready ME, Baig A, Hunter AGW, Bulman DE.

A novel locus for brachydactyly type A1 on chromosome 5p13.3-p13.2. J Med Genet 2002; 39: 186–9

Bass HN. Familial absence of middle phalanges with nail dysplasia: a new syndrome. Pediatrics 1968; 42: 318–23 Bell J. On brachydactyly and symphalangism. In: Penrose LS

(ed.) The treasury of human inheritance, vol 5. Cambridge University Press, London, 1951, pp. 1–31

Cuevas-Sosa A, Garcia-Segur F. Brachydactyly with absence of middle phalanges and hypoplastic nails: a new hereditary syndrome. J Bone Joint Surg Br 1971; 53: 101–5

Du Pan CM. Absence congenitale du perone sans deformation du tibia: curieuses deformations congenitales des mains.

Rev Orthop 1924; 11: 227–34

Gao B, Guo J, She C, Shu A, Yang M, Tan Z, Yang X, Guo S, Feng G, He L. Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nat Genet 2001; 28: 386–8 Garn SM, Fels SL, Israel H. Brachymesophalangia of digit ﬁve

in ten populations. Am J Phys Anthropol 1967; 27: 205–9 Garn SM, Nagy JM, Poznanski AK, McCann MB. Size reduction

associated with brachymesophalangia-5: a possible selective advantage. Am J Phys Anthropol 1972; 37: 267–70 Graham JM Jr. New syndrome of type A2 brachydactyly, mi-

crocephaly, and diabetes in siblings born to consan- guineous parents. Am J Hum Genet 1989; 45 [Suppl]: A76 Haws DV, McKusick VA. Farabee’s brachydactylous kindred re-

visited. Bull Johns Hopkins Hosp 1963; 113: 20–30 Hertzog KP. Shortened ﬁfth medial phalanges. Am J Phys

Anthropol 1967; 27: 113–8

Hoefnagel D, Gerald PS. Hereditary brachydactyly. Ann Hum Genet 1966; 29: 377–82

Lawrence JJ, Schlesinger AE, Kozlowski K, Poznanski AK, Bacha L, Dreyer GL, Barylak A, Sillence DO, Rager K. Un- usual radiographic manifestations of chondrodysplasia punctata. Skeletal Radiol 1989; 18: 15–9

Ohzeki T, Hanaki K, Motozumi H, Ohtahara H, Shiraki K, Yoshioka K. Brachydactyly type A-4 (Temtamy type) with short stature in a Japanese girl and her mother. Am J Med Genet 1993; 46: 260–2

Opitz JM, Gilbert EF.Autopsy ﬁndings in a still-born female in- fant with the Osebold-Remondini syndrome. Am J Med Genet 1985; 22: 811–9

Osebold WR, Remondini DJ, Lester EL, Spranger JW, Opitz JM.

An autosomal dominant syndrome of short stature with mesomelic shortness of limbs, abnormal carpal and tarsal bones, hypoplastic middle phalanges, and bipartite calcanei. Am J Med Genet 1985; 22: 791–809

Piussan C, Lenaerts C, Mathieu M, Boudailliez B. Dominance regulière d’une ankylose des pouces avec retard mental se transmettant sur trois générations. J Genet Hum 1983; 31:

107–14

Poznanski AK. The hand in radiologic diagnosis. W.B. Saun- ders Company, Philadelphia, 1984 (2nd ed.), p. 160 Rasore-Quartino A, Camera G. Type A2 brachydactily: report

of a new family. Acta Genet Med Gemellol 1977; 26: 141–50 Sugiura Y, Tajima Y, Sugiura I, Muramoto K, Wu WD.

Roentgenologic study on the skeletal variant in the hand and foot observed among Shizuoka school children. Jpn J Hum Genet 1962; 7: 67–77

Temtamy SA. Genetic factors in hand malformations. Johns Hopkins University, Baltimore, 1966

Temtamy SA, McKusick VA. The genetics of hand malformations. Alan R. Liss, New York, 1978

Yang X, She C, Guo J, Yu ACH, Lu Y, Shi X, Feng G, He L. A locus for brachydactyly type A-1 maps to chromosome 2q35-q36.

Am J Hum Genet 2000; 66: 892–903

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Brachyproxiphalangy

䉴 [Short proximal phalanges]

Familial shortening of the proximal phalanges does not seem to occur in isolation, but only in association with shortening of other bones in the hand, par- ticularly in the context of brachydactyly type C (OMIM 113100) (Poznanski 1984). This complex type of brachydactyly encompasses a heterogeneous spectrum of digital anomalies, whose distinctive feature is shortening of the proximal and middle phalanges of the 2nd and 3rd fingers combined with relatively normal distal phalanges. Marked shortening of the proximal phalanx of the index finger is sometimes associated with hypersegmentation, pro- ducing an extra, wedge-shaped bone at the base of the phalanx and ulnar deviation of the finger (Fig. 6.8) (Rowe-Jones et al. 1992). With increasing age, the extra bone eventually fuses with the phalanx, resulting in a permanent deformity of the affected finger. In the 3rd finger, the middle phalanx is typically shortened to a significant extent, while the terminal phalanx is usually unaffected. The 4th finger is essentially normal and projects beyond the other digits. In the original report of Haws, additional findings of brachydactyly C included triangula- tion of the 5th middle phalanx with radial deviation, brachymetapody, hyperphalangy, and symphalangism (Haws 1963). Shortening of the 1st metacarpal is also part of the phenotype in many cases. The condition shows considerable intra- and interfamilial variability (Debeer et al. 2001), which was initially explained as locus heterogeneity. [Link- age was originally – and erroneously – assigned to DNA markers in the 12q24 region (Polymeropoulos et al. 1996), and subsequently correctly to 20q11.2, a region harboring the cartilage-derived morphogenetic protein-1 (GDF5) (Polinkovsky et al. 1997).]

Thus, clinical variability can probably be explained in terms of genetic modiﬁers and/or environmental factors (Galjaard et al. 2001). In addition to the digital anomalies described as part of the spectrum of brachydactyly C, several other skeletal and nonskele- tal defects have been reported in different kindreds, including bilateral Madelung deformity (Robin et al.

1997), short hallux with hypersegmentation and small cup-shaped ears (Rowe-Jones et al. 1992), and Legg-Calvè-Perthes disease of the hip (Robinson et al. 1968). Although cases of brachydactyly type C may be confused with brachydactyly type A, the following criteria have been proposed to differentiate between these two defects: (1) the 1st metacarpal is

involved in brachydactyly type C, but not in brachydactyly type A; (2) the relative length of the digits is preserved in brachydactyly type A, but not in brachydactyly type C, where digit 4 is the longest and least involved; and (3) ‘hypersegmentation’ is classic in brachydactyly type C, but not in brachydactyly type A (Robin et al. 1997). Another type of brachydactyly with major involvement of the proxi- mal phalanges is referred to as Sugarman brachy- dactyly (OMIM 272150) (Sugarman et al. 1974).

In addition to major shortening of the proximal phalanges (Fujimoto et al. 1982), cardinal features include a proximally set, nonarticulating great toe, double 1st metacarpal, and proximal interphalangeal joint symphalangism. The inheritance pattern is unknown (Sugarman brachydactyly must not be confused with Sugarman syndrome, an alter- nate designation for oro-facio-digital syndrome type III).

1. Short proximal and middle phalanges of 2nd and 3rd fingers; hyperphalangy of the 2nd finger (in- constant); short, rhomboid 5th middle phalanx with radial deviation (not in all cases); short 1st metacarpal; normal 4th finger (brachydactyly C) 2. Short proximal phalanges of fingers and toes; du-

plication of 1st metacarpal; proximal sympha- langism; proximally set great toe (Sugarman bra- chydactyly)

Fig. 6.8. Brachydactyly type C in a woman patient. Note marked shortening of the proximal and middle phalanges of the 2nd and 3rd fingers, with relatively normal distal phalanges. There is bilateral hyperphalangy of the 2nd finger, resulting in ulnar deviation of both digits. The middle phalanx of the 5th finger is also markedly short, while the 4th digit is normal in length and has a clinodactylous distal phalanx pro- jecting beyond the other fingers. (From Castriota-Scanderbeg et al. 2005)

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Associations

• Apert syndrome

• Arthritides

• Brachydactyly syndrome, type A1

• Chromosome 18 trisomy syndrome

• Diastrophic dysplasia

• Infection

• Neoplasm

• Nevoid basal cell carcinoma (Gorlin syndrome)

• Sickle cell anemia

• Trauma

References

Castriota-Scanderbeg A, Garaci FG, Belufﬁ G. Angel-shaped phalanges in brachydactyly C: a case report, and specula- tion on pathogenesis. Pediatr Radiol 2005, 35: 535–8 Debeer P, de Smet L, Fryns JP. Intrafamilial clinical variability

in type C brachydactyly. Genet Couns 2001; 12: 353–8 Fujimoto A, Smolensky LS, Wilson MG. Brachydactyly with

major involvement of proximal phalanges. Clin Genet 1982;

21: 107–11

Galjaard RJH, van der Ham LI, Posch NAS, Dijkstra PF, Oostra BA, Hovius SER, Timmenga EJF, Sonneveld GJ, Hoogeboom AJM, Heutink P. Differences in complexity of isolated brachydactyly type C cannot be attributed to locus heterogeneity alone. Am J Med Genet 2001; 98: 256–62

Haws DV. Inherited brachydactyly and hypoplasia of the bones of the extremities. Ann Hum Genet 1963; 26: 201–12 Polinkovsky A, Robin NH, Thomas JT, Irons M, Lynn A, Good-

man FR, Reardon W, Kant SG, Brunner HG, van der Burgt I, Chitayat D, McGaughran J, Donnai D, Luyten FP, Warman ML. Mutations in CDMP1 cause autosomal dominant brachydactyly type C. Nat Genet 1997; 17: 18–9

Polymeropoulos MH, Ide SE, Magyari T, Francomano CA.

Brachydactyly type C gene maps to human chromosome 12q24. Genomics 1996; 38: 45–50

Poznanski AK. The hand in radiologic diagnosis. W.B. Saun- ders Company, Philadelphia, 1984 (2nd ed.), p. 166 Robin NH, Gunay-Aygun M, Polinkovsky A, Warman ML, Mor-

rison S. Clinical and locus heterogeneity in brachydactyly type C. Am J Med Genet 1997; 68: 369–77

Robinson GC, Wood BJ, Miller JR, Baillie J. Hereditary brachydactyly and hip disease. Unusual radiological and dermato- glyphic ﬁndings in a kindred. J Pediatr 1968; 72: 539–43 Rowe-Jones JM, Moss ALH, Patton MA. Brachydactyly type C

associated with shortening of the hallux. J Med Genet 1992;

29: 346–8

Sugarman GI, Hager D, Kulik WJ. A new syndrome of brachydactyly of the hands and feet with duplication of the 1st toes. Birth Defects Orig Art Ser 1974; 10: 1–8

Brachymetacarpalia

䉴 [Shortening of the metacarpals]

As in other forms of brachydactyly, metacarpal shortening can have congenital or acquired causes and can be conﬁned to one digit or extend to several digits in the hand and foot (brachymetatarsalia).

Moreover, metacarpal shortening can be an isolated ﬁnding, associated with other hand anomalies, or part of a more extensive malformation spectrum.

Brachydactyly type E (OMIM 113300) is character- ized by shortening of the metacarpals and metatarsals, with wide variability in the number of affected digits. The 4th digit is involved most typically (subtype E1) (Fig. 6.9), but other patterns are recognized, including a variable combination of metacarpal and phalangeal involvement (subtype E2) and a variable combination of metacarpal without phalangeal involvement (Hertzog 1968). Shortening of both the 4th and the 5th metacarpals is not infre- quent, and can be associated with varying degrees of shortening of the distal phalanges, especially in the thumb (75%), giving a pattern that is indistinguishable from those of pseudohypoparathyroidism (PHP) and pseudo-pseudohypoparathyroidism (PPHP) (Fig. 6.10). The combination of short 4th and 5th metacarpals/short distal phalanges is seen in the following conditions: PHP, PPHP, brachydactyly E, brachydactyly D, Turner syndrome, and acrodysostosis in declining order of frequency (Poz- nanski et al. 1977; Steinbach and Young 1966). Short- ening of the 3rd, 4th, and 5th metacarpals is another common pattern of brachydactyly E, while shortening of all the metacarpals is most typical of acrodysostosis (Fig. 6.11), occurring only occasionally in brachydactyly E and PHP-PPHP. In contrast to other forms of brachydactyly, which are evident at birth, metacarpal shortening is often not noticed until late childhood, suggesting a cause-and-effect relation- ship with early closure of the epiphysis (Poznanski 1984). Other ﬁndings in brachydactyly E may include short stature and round face. Stature can be normal or even tall, however. Although the hand anomalies are indistinguishable from those of PHP-PPHP (Poz- nanski et al. 1977), the absence of ectopic calciﬁca- tion, mental retardation, and cataract unambiguous- ly identify brachydactyly E. When isolated, brachydactyly E follows an autosomal dominant inheritance. However, its occurrence in the context of disorders with either X-linked inheritance pattern (Albright hereditary osteodystrophy) or chromoso- mal aberration (Turner syndrome) points to the genetic heterogeneity of the defect (McKusick). In-

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Fig. 6.9. Brachydactyly type E in a woman patient. Note marked shortening of the 4th metacarpal with no conspicuous anomalies in the other bones

Fig. 6.10. Pseudohypoparathyroidism in an adolescent girl. There is marked shortening of the metacarpals (especially the 4th and 5th) and most of the phalanges (especially the distal phalanx of the thumb). Fused cone-shaped epiphyses are seen in many of the phalanges

Fig. 6.11. Acrodysostosis in a 9-year-old boy. Note generalized brachydactyly, most severe in 2nd to 5th metacarpals. The phalanges are also strikingly short, with cone- shaped epiphyses. There is relative sparing of the thumb. Ossiﬁcation of the carpal bones is advanced. (From Graham et al.

2001)