Brachymetacarpalia

► [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 characterized by shortening of the metacarpals and meta-tarsals, 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 meta-carpal 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 infrequent, 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-pseudohypoparathy-roidism (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 (Poznanski et al. 1977; Steinbach and Young 1966). Shortening of the 3rd, 4th, and 5th metacarpals is another common pattern of brachydactyly E, while shortening of all the metacarpals is most typical of acro-dysostosis (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 relationship 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 (Poznanski et al. 1977), the absence of ectopic calcification, mental retardation, and cataract unambiguously identify brachydactyly E. When isolated, bra-chydactyly E follows an autosomal dominant inheritance. However, its occurrence in the context of disorders with either X-linked inheritance pattern (Albright hereditary osteodystrophy) or chromosomal aberration (Turner syndrome) points to the genetic heterogeneity of the defect (McKusick). In-

Albright Osteodystrophy Syndrome
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
Albright Hereditary Osteodystrophy
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)

Acrodysostosis

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)

Carpal Bones
Fig. 6.12. Mucopolysaccharidosis IV (Morquio syndrome) in a 9-year-old boy. The metacarpals are short, with wide metaphy-ses and preserved diaphyseal constriction. The bases of the 2nd through 5th metacarpals are conical. The carpals are small and irregular

stances of male-to-male transmission have been reported (McKusick and Milch 1964). Type E brachy-dactyly with multiple impacted teeth is regarded as a distinct entity, which has been designated 'crypto-dontic metacarpalia' (Gorlin and Sedano 1971). Unusually straight, short clavicles are also features. Brachydactyly type E has been found in association with a form of hypertension with a normally functioning renin-angiotensin-aldosterone system and sympathetic nervous system, thus resembling essential hypertension (Bilginturan syndrome, OMIM 112410) (Bilginturan et al. 1973). The defective gene, which is transmitted in an autosomal dominant fashion, has been mapped at chromosomal region 12p12.2-p11.2 (Schuster et al. 1996). Albright hereditary osteodystrophy (OMIM 103580) is the designation - used synonymously with PHP type 1A - for a condition characterized by short stature, brachy-dactyly type E, subcutaneous ossifications, mental retardation, parathyroid hormone-resistant hypocalcemia/hyperphosphatemia, elevated serum parathyroid hormone level, and parathyroid hyperplasia. Characteristically, hypocalcemia and hyperphosphatemia are unresponsive to exogenous parathyroid hormone. Albright hereditary osteodystrophy is differentiated from acrodysostosis on the basis of the absence of spinal stenosis and the type of brachy-

dactyly (short 4th and 5th metacarpals in Albright osteodystrophy, short 2nd to 5th metacarpals and phalanges in acrodysostosis) (Graham et al. 2001). Pseudo-pseudohypoparathyroidism (PPHP, OMIM 300800) is phenotypically indistinguishable from PHP type 1A but shows no evidence of endocrine abnormalities or resistance to the parathyroid hormone. In both disorders, a reduction in Gs-alpha activity/protein due to heterozygous inactivating mutations in the GNAS1 gene (located on chromosome 20) is found (Bianco et al. 2000; Ahrens et al. 2001). In contradistinction, PHP type IB (PHP1B, OMIM 603233), a condition involving renal resistance to parathyroid hormone without the developmental defects or endocrine abnormalities of Albright hereditary osteodystrophy, is most probably caused by mutations in regulatory regions of the maternal GNAS1 gene, resulting in a specific decrease in Gs-alpha activity in the renal proximal tubules (Zheng et al. 2001). In Ruvalcaba syndrome (OMIM 180870), features in the hand include marked shortening of the 3rd to 5th metacarpals, with broadening of the distal ends, and inconstant carpal fusion (triquetrum-lu-nate). Additional manifestations are mental retardation, short stature, microcephaly, peculiar facies with hooked nose and small mouth, narrow thorax, hy-poplastic genitalia, skin lesions, and Scheuermann-like changes in the spine (Ruvalcaba et al. 1971). Acrodysostosis (OMIM 101800) is a syndrome of nasal and maxillary hypoplasia, peripheral dysosto-sis, decreased interpedicular distance, advanced skeletal maturation, and mental retardation (Maro-teaux and Malamut 1968; Butler eta l. 1988). Increased paternal age supports the suspicion of autosomal dominant inheritance (Jones et al. 1975; Frey et l. 1982). The hands are short and stubby. Marked shortening of the metacarpals, together with cone-shaped epiphyses of Giedion type 35 in the phalanges and advanced carpal bone age are characteristic of the condition (Fig. 6.11). Metacarpal shortening with metaphyseal widening and typical tapering of their bases occurs in the mucopolysaccharidoses, notably in mucopolysaccharidosis type I-H (Hurler, OMIM 252800) and type IV (Morquio, OMIM 253000) (Fig. 6.12). Slanting of distal radial and ulnar growth plates toward each other is also characteristic of these disorders. The acromesomelic dysplasias are disorders with disproportionate short stature due to shortening of the middle segments (forearms and lower legs) and distal segments (hands and feet) of the appendicular skeleton. In the acromesomelic dys-plasia, Maroteaux type (OMIM 602875) (Maroteaux et al. 1971), an autosomal recessive disorder with the

Grebe Syndrome

Fig. 6.13 a-c. Grebe chondrodysplasia in an 11-year-old male. a The fingers in both hands are severely hypoplastic, with constrictions at their base. The first two fingers are fused bilaterally. Partial webbing is evident between the 3rd and 4th fingers on both sides. b Radiograph of the forearm, showing a short ulna and a twisted radius with subluxation of the radial head. c Several metacarpals and phalanges are missing, and those remaining are severely hypoplastic and dysmorphic. (From Rao and Joseph 2002)

Fig. 6.13 a-c. Grebe chondrodysplasia in an 11-year-old male. a The fingers in both hands are severely hypoplastic, with constrictions at their base. The first two fingers are fused bilaterally. Partial webbing is evident between the 3rd and 4th fingers on both sides. b Radiograph of the forearm, showing a short ulna and a twisted radius with subluxation of the radial head. c Several metacarpals and phalanges are missing, and those remaining are severely hypoplastic and dysmorphic. (From Rao and Joseph 2002)

disease gene mapping to 9p13-q12 (Kant et al. 1998), the tubular bones in the hands and feet are very short and stubby, but they are all present (Langer and Garrett 1980). Involvement of the axial skeleton also occurs, with dorsal wedging of the vertebral bodies. Curved clavicles, metaphyseal flaring of long tubular bones, and hypoplasia of the basilar portions of the ilia are additional features. There is considerable variability in the clinical expression of the disease, which is explained in terms of genetic heterogeneity (Faivre et al. 2000). In acromesomelic dysplasia, Hunter-Thompson type (OMIM 201250) (Hunter and Thompson 1976), also of autosomal recessive inheritance, manifestations are different from and more severe than the Maroteaux type, resembling those of Grebe chondrodysplasia. The axial skeleton is not involved, changes being confined to the limbs. The tubular bones in the hands and feet are severely shortened, and some skeletal elements are absent or fused. Dislocations of several joints, including the elbows, ankles, hips, and knees, occur. Thus, the clinical manifestations of the Hunter-Thompson type of acromesomelic dysplasia are distinct from those of the Maroteaux type. In addition, the genetic background is different, the Hunter-Thompson type being caused by mutations in the cartilage-derived morphogenetic protein-1 at chromosomal locus 20q11.2. Grebe chondrodysplasia (OMIM 200700), another severe autosomal recessive form of acrome-somelic dysplasia, is also caused by mutations in the cartilage-derived morphogenetic protein-1 gene and is therefore allelic to the Hunter-Thompson type (Thomas et al. 1997; Langer et al. 1989). Radiographic manifestations include markedly shortened and deformed middle segments of the appendicular skeleton and severe changes in the hands and feet with absence of several metacarpals/metatarsals and phalanges (Fig. 6.13 a-c). Several joints are missing from the hands and feet, and the fingers and toes appear as small, bud-like protrusions. Carpotarsal fusion and postaxial polydactyly are further features. The head and trunk, including the vertebral column, are normal (Grebe 1952; Costa et al. 1992). A variety of mild skeletal abnormalities, including polydactyly, brachydactyly, hallux valgus, and metatarsus adduc-tus, may be manifestations in heterozygotes.

A short 5th metacarpal may be seen as an isolated finding in the absence of significant shortening of the 4th metacarpal. The designation 'brachydactyly E' does not seem to be appropriate for these cases (Poznanski 1984). This defect also occurs in chromosome 5p- syndrome (cri-du-chat, OMIM 123450) and in Silver-Russel syndrome (OMIM 180860).

Shortening of the 1st metacarpal can be part of the spectrum of brachydactyly type C or occur in association with disorders characterized by radial ray deficiency, as discussed in the sections "Radial Ray Deficiency" and "Thumb Hypoplasia/Aplasia" below.

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  • PETER
    Is there a cure for morquio syndrome?
    8 years ago

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