Dyschondrosteosis is an autosomal dominant form of mesomelic dysplasia, first described by Leri and Weill in 1929.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Dyschondrosteosis: autosomal dominant
b. Langer mesomelic dysplasia: autosomal recessive 2. Molecular basis
a. Caused by mutations and deletion of SHOX (short stature homeobox-containing) gene
i. The SHOX gene is mapped to Xp22.3, based on the observation of unbalanced translocation involving the pseudoautosomal region of the short arm of the X and Y chromosomes (PAR1) in dyschondrosteosis patients and of some degree of Madelung deformity in Turner syn- drome patients
ii. The Xp22.3 region encompasses the pseudoau- tosomal SHOX gene, which encodes isoforms of a homeo-domain transcription factor expressed in developing human limbs
iii. The gene in the Xp22.3 region escapes X-inacti- vation in females and participates in obligate recombination during male meiosis. Consequently, dyschondrosteosis segregates as an apparently
“autosomal” dominant disorder
b. Haploinsufficiency of the SHOX gene, implicated in the following disorders:
i. Turner syndrome: SHOX is haploinsufficient in females with 45,X Turner syndrome, accounting for approximately 2/3 of the characteristic growth deficit
ii. Idiopathic short stature: Observation that a point mutation that cosegregates with idiopathic short stature suggests that SHOX haploinsufficiency may also cause growth failure in the patients with normal karyotype. SHOX mutations have been found in 2–3% of patients with idiopathic short stature
iii. Leri-Weill dyschondrosteosis (including homozy- gous form of Langer mesomelic dysplasia) c. Identification of large-scale deletions or mutations in
the SHOX gene in the majority of the cases
d. SHOX mutations: causative for mesomelic growth retardation and Madelung deformity in Leri- Weill dyschondrosteosis and Langer mesomelic dysplasia
e. Leri-Weill syndrome as a part of contiguous gene syndrome with deletion of Xp22.3
3. Langer mesomelic dwarfism
a. A homozygous state of dyschondrosteosis gene b. Caused by deletion of both SHOX alleles (complete
SHOX deficiency)
CLINICAL FEATURES
1. Dyschondrosteosis
a. Mesomelic dwarfism (disproportionate short stature) b. Phenotypic inter- and intra-familial heterogeneity, a
frequent finding
c. Much more common and less severe than Langer mesomelic dysplasia
d. Females more commonly and more severely affected (more severe Madelung deformity) than males e. Intelligence: normal
f. Limbs
i. Mesomelia (disproportionate forelimb shorten- ing)
a) Shortened forearms b) Shortened forelegs
ii. A Madelung deformity of the forearms and wrists secondary to bowing of the radius and dorsal subluxations of the distal ulna
iii. Reduced radiocarpal motion
iv. Limited elbow and wrist pronation and superna- tion
v. Genu varum 2. Langer mesomelic dysplasia
a. The homozygous form of Leri-Weill syndrome b. Severe disproportionate short stature with marked
mesomelic and rhizomelic limb shortening
c. Parents of some children with Langer mesomelic dys- plasia have features of the more common dominantly inherited mesomelic skeletal dysplasia Leri-Weill dyschondrosteosis
d. Intelligence: normal e. Limb malformations
i. Aplasia or severe hypoplasia of the ulna and fibula ii. Thickened and curved radius and tibia
f. Hypoplasia of the mandible
g. A variable degree of Madelung deformity and mesomelic shortening in both parents
3. Prognosis
a. Minimal disability from the Madelung deformities of the wrists
b. Secondary arthrosis of the radiocarpal joint c. Osteoarthritis of the large joints
d. Langer mesomelic dysplasia: much more severe phe- notype than dyschondrosteosis
305
and Langer Mesomelic Dysplasia
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Mesomelic dysplasia
b. Madelung deformity of the wrists i. Short forearm
ii. Bowed radius iii. Bowed ulna
iv. Premature fusion of the ulnar half of the radial epiphysis
v. A V-shaped deformity of the wrist with slanting at the distal radial contour and dorsal dislocation of the ulna
vi. Wedging of the carpal bones between the deformed radius and protruding ulna, resulting in a triangular configuration with the lunate at the apex
vii. Cubitus valgus c. Coxa valga
d. Lateral subluxation of the patella e. Short tibia
f. Exostosis of the proximal medial tibia g. Langer mesomelic dysplasia
i. Aplasia or severe hypoplasia of the ulna and fibula
ii. Thickened and curved radius and tibia 2. Molecular genetic analysis
a. SHOX deletions detected by FISH analysis using cosmid probe for SHOX
b. SHOX mutations by direct sequencing of genomic PCR products
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sibs
i. Not increased if neither parent is affected ii. 50% if one parent is affected
iii. 50% affected with dyschondrosteosis and 25%
affected with Langer mesomelic dysplasia if both parents are affected with dyschondrosteosis b. Patient’s offspring
i. 50% if the spouse is normal
ii. 50% affected with dyschondrosteosis and 25%
affected with Langer mesomelic dysplasia if the spouse is also affected with dyschondrosteosis 2. Prenatal diagnosis possible for at-risk families
a. Prenatal ultrasonography of skeletal features compat- ible with mesomelic dwarfism
b. Molecular analysis of previously identified disease- causing SHOX mutations in the proband or a parent from the fetal DNA obtained from amniocentesis or CVS
3. Management
a. Medical therapy of Madelung deformity
i. May be helpful in skeletally mature individuals with Madelung deformity who have mild-to- moderate short-term wrist pain
ii. Splints to relief joint pain
iii. Decrease manual activity levels to manage symptoms without surgery
b. Surgical therapy of Madelung deformity
i. Primary goals: pain relief and cosmetic improve- ment of Madelung deformity
a) Minimal improvement of range of motion, especially in pronation and supination b) Release of the Vickers ligament alone or in
combination with an osteotomy ii. Osteotomy of radius
iii. Radioulnar length adjustment iv. Ulnar resection
c. Tibial osteotomy and lengthening combined with epiphyseodesis of the distal fibular epiphysis for the tibio-fibular disproportion
d. Ongoing clinical trial with growth hormone therapy in patients with short stature due to SHOX mutations
REFERENCES
Anton JI, Reitz GB, Spiegel MB: Madelung’s deformity. Ann Surg 108:411–439, 1938.
Balci S, Zafer Y, Unsal M: Two female siblings from Turkey with Langer mesomelic dysplasia (homozygous Leri-Weill dyschondrosteosis syn- drome). Turk J Pediatr 41:531–539, 1999.
Beals RK, Lovrien EW: Dyschondrosteosis and Madelung’s deformity. Report of three kindreds and review of the literature. Clin Orthop 116: 24–28, 1976.
Belin V, Cusin V, Viot G, et al.: SHOX mutations in dyschondrosteosis (Leri- Weill syndrome). Nature Genet 19:67–69, 1998.
Blaschke RJ, Monaghan Adv Pediatr, Schiller S, et al.: SHOT, a SHOX-related homeobox gene is implicated in craniofacial, brain, heart, and limb devel- opment. Proc Natl Acad Sci USA 95:2406–2411, 1998.
Calabrese G, Fischetto R, Stuppia L, et al.: X/Y translocation in a family with Leri-Weill dyschondrosteosis. Hum Genet 105:367–368, 1999.
Carter AR, Currey HLF: Dyschondrosteosis (mesomelic dwarfism): a family study. Brit J Radiol 47:634–640, 1974.
Dawe C, Wynne-Davies R, Fulford GE: Clinical variation in dyschondrosteosis:
a report on 13 individuals in 8 families. J Bone Joint Surg 64B:377–381, 1982.
Espiritu C, Chen H, Woolley PV Jr: Mesomelic dwarfism as the homozygous expression of dyschondrosteosis. Am J Dis Child 129:375–377, 1975.
Espiritu CE, Chen H, Woolley PV Jr: Probable homozygosity for the dyschon- drosteosis genes. Birth Defects Orig Artic Ser 11:127–132, 1975.
Felman AH, Kirkpatrick JA Jr: Madelung’s deformity: observations in 17 patients. Radiology 93:1037–1042, 1969.
Felman AH, Kirkpatrick JA Jr: Dyschondrosteose: mesomelic dwarfism of Leri and Weill. Am J Dis Child 120:329–331, 1970.
Flanagan SF, Munns CFJ, Hayes M, et al.: Prevalence of mutations in the short stature homeobox containing gene (SHOX) in Madelung deformity of childhood. J Med Genet 39:758–763, 2002.
Fryns JP, Van den Berghe H: Langer type of mesomelic dwarfism as the possi- ble homozygous expression of dyschondrosteosis. Hum Genet 46:21–27, 1979.
Goepp CE, Jackson LG, Barr MA: Dyschondrosteosis: a family showing male- to-male transmission in 5 generations. (Abstract) Am J Hum Genet 30:52A only, 1978.
Guichet A, Briault S. Le Merrer M, et al.: Are t(X;Y)(p22;q11) translocations in females frequently associated with Madelung deformity? Clin Dysmorphol 6:341–345, 1997.
Herdman RC, Langer LO Jr, Good RA: Dyschondrosteosis, the most common cause of Madelung’s deformity. J Pediatr 68:432–441, 1966.
Huber C, Cusin V, Le Merrer M, et al.: SHOX point mutations in dyschondros- teosis. J Med Genet 38:281–284, 2001.
Kunze J, Klemm T: Mesomelic dysplasia, type Langer—a homozygous state for dyschondrosteosis. Europ J Pediatr 134:269–272, 1980.
Lamberti PM, Light TR: Madelung deformity. Emedicine, 2002.
http://www.emedicine.com
Langer LO Jr: Dyschondrosteosis, a heritable bone dysplasia with characteris- tic roentgenographic features. Am J Roentgen 95:178–188, 1965.
Langer LO Jr: Mesomelic dwarfism of the hypoplastic ulna, fibula, mandible type. Radiology 89:654–880, 1967.
Léri A, Weill J: Une affection congénitale et symétrique du développement osseux: la dyschondostéose. Bull Mém Soc Med Hosp 35:1491–1494, 1929.
Lichtenstein JR, Sundaram M, Burdge R: Sex-influenced expression of Madelung’s deformity in a family with dyschondrosteosis. J Med Genet 17:41–43, 1980.
Palka G, Stuppia L, Guanciali Franchi P, et al.: Short arm rearrangements of sex chromosomes with haploinsufficiency of the SHOX gene are associated with Leri-Weill dyschondrosteosis. Clin Genet 57:449–453, 2000.
Rao E, Weiss B, Fukami M, et al.: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16:54–62, 1997.
Rao E, Blaschke RJ, Marchini A, et al.: The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activa- tor. Hum Mol Genet 10:3083–3091, 2001.
Rappold GA, Fukami M, Niesler B, et al.: Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in chil- dren with short stature. J Clin Endocrinol Metab 87:1402–1406, 2002.
Robertson SP, Shears DJ, Oei P, et al.: Homozygous deletion of SHOX in a mentally retarded male with Langer mesomelic dysplasia. J Med Genet 37:959–964, 2000.
Ross JL, Scott C Jr, Marttila P, et al.: Phenotypes associated with SHOX defi- ciency. J Clin Endocrinol Metab 86(12): December, 2001.
Schiller S, Spranger S, Scheshinger B, et al.: Phenotypic variation and genetic heterogeneity in Leri-Weill syndrome. Eur J Hum Genet 8:54–62, 2000.
Shears DJ, Vassal HJ, Goodman FR, et al.: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis.
Nature Genet 19:70–73, 1998.
Shears DJ, Guillen-Navarro E, Sempere-Miralles M, et al.: Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation. Am J Med Genet 110:153–157, 2002.
Spranger S, Schiller S, Jauch A, et al.: Léri-Weill syndrome as part of a con- tiguous gene syndrome at Xp22.3. Am J Med Genet 83:367–371, 1999.
Stuppia L, Calabrese G, Borrelli P, et al.: Loss of the SHOX gene associated with Leri-Weill dyschondrosteosis in a 45,X male. J Med Genet 36:711–713, 1999.
Zinn AR, Wei F, Zhang L, et al.: Complete SHOX deficiency causes Langer mesomelic dysplasia. Am J Med Genet 110:158–163, 2002.
Zumkeller W, Wieacker P: Short stature homeobox-containing gene (SHOX):
genotype and phenotype. J Endocr Genet 2:141–150, 2001.
Fig. 1. A young lady with Leri-Weill syndrome showing disproportion- ate short stature, short forearms and legs, and Madelung deformity of the wrists. Radiographs illustrate typical Madelung deformity (curved radius and ulna with triangular configuration) corrected by surgery
Fig. 2. A young lady with Leri-Weill syndrome with short forearms and Madelung deformity demonstrated by radiographs
Fig. 3. A young lady with Leri-Weill syndrome showing dispropor- tionate short stature, short forearms and legs, and Mesomelic defor- mity illustrated by radiographs
Fig. 4. 2 sibs with Langer mesomelic dysplasia showing severe mesomelic dwarfism, Madelung deformities, and radiographic features of bowed and foreshortened radius and ulna, hypoplastic/aplastic fibula, and short and thick tibia. Both parents have dyschondrosteosis.
Fig. 5. Radiograph of the mother of above two children showing typ- ical Madelung deformity
