Problemi speciali
Il deficit del gene SHOX come causa di bassa statura
SHOX GENE DEFICIENCY AS THE UNDERLYING CAUSE OF SHORT STATURE
Lorenzo Iughetti1, Sergio Bernasconi2, Emanuela Caruso-Nicoletti3, Francesco Chiarelli4, Alessandro Cicognani5
1 2 3 4 5Clinica Pediatrica, 1Università di Modena e Reggio Emilia, 2Parma, 3Catania, 4Chieti, 5Bologna
Giugno 2011 - pagg. 367 -373
Abstract
SHOX gene (Short Stature Homeobox-containing gene) seems to play an important role in
the growth process. Indeed, patients with mutations or deletions of this gene present with
variable degrees of stature deficiency that in the most serious cases is accompanied by mesomelic
skeletal dysplasia. This characteristic variability is due to the fact that SHOX gene
is localized on both sexual chromosomes in a particular area defined as pseudoautosomal
region or PAR1 and in normal condition both genes must be present and active. Clinical
conditions that fall within SHOX gene alterations include Langer mesomelic dwarfism,
Léri-Weill dyschondrosteosis and Turner syndrome. Studies on the SHOX gene alterations
have been recently carried out also in patients with idiopathic short stature and the
importance of analysing these subjects carefully in order to identify those who might benefit
from a growth hormone treatment has been underlined. Indeed, it seems that the GH
therapy improves the statures of patients with SHOX gene deficiency, with a significant increase
similar to the one obtained in the patients with Turner syndrome.
Parole chiave
Classificazione MeSH
Bibliografia
1. Reynaud R, Saveanu A, Barlier A, Enjalbert
A, Brue T. Pituitary hormone deficiencies due
to transcription factor gene alterations.
Growth hormone IGF-1 Res 2004;14:422-8
2. Ballabio A, Bardoni B, Carrozzo R, et al.
Contiguous gene syndromes due to deletions
in the distal short arm of the human X chromosome.
Proc Nat Acad Sci 1989;86:10001-5.
3. Ogata T, Matsuo N. Sex chromosome aberrations
and stature: deduction of the principal
factors involved in the determination of adult
height. Hum Genet 1993;91:551-62.
4. Ogata I, Goodfellow P, Petit C, Aya M, Matsuo
N. Short stature in a girl with a terminal
Xp deletion distal to DXYS15: localisation of a
growth gene(s) in the pseudoautosomal region.
J Med Genet 1992:29:455-9.
5. Ogata T, Yoshizawa A, Muroya K, et al.
Short stature in a girl with partial monosomy
of the pseudoautosomal region distal to
DXYS15: further evidence for the assignment
of the critical region for a pseudoautosomal
growth gene(s). J Med Genet 1995;32:831-4.
6. Rao E, Weiss B, Fukami M, et al. FISH-deletion
mapping defines a 270-kb short stature
critical interval in the pseudoautosomal region
PAR1 on human sex chromosomes. Hum
Genet 1997;100:236-9.
7. Rao E, Blaschke RJ, Marchini A, Niesler B,
Burnett M, Rappold GA. The L�ri-Weill and
Turner syndrome homeobox gene SHOX encodes
a cell-type specific transcriptional activator.
Hum Mol Genet 2001;10:3083-91.
8. Clement-Jones M, Schiller S, Rao E, et al.
The short stature homeobox gene SHOX is involved
in skeletal abnormalities in Turner syndrome.
Hum Mol Genet 2000;9:695-702.
9. 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.
Nature Genet 1997;16:54-63.
10. 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 children with short stature. J
Clin Endocrinol Metab 2002;87:1402-6.
11. Zinn AR, Wei F, Zhang L, et al. Complete
SHOX deficiency causes Langer mesomelic
dysplasia. Am J Med Genet 2002;110:158-63.
12. Batch J. Turner syndrome in childhood
and adolescence. Best Pract Res Clin Endocrinol
Metab 1002;16:465-82.
13. L�ri A, Weill J. Une affection congenitale et
sym�trique du developpement osseux: la dyschondrosteose.
Bull Mem Soc Med Hosp
(Paris) 1929;35:1491-4.
14. Madelung V. Die spontane Subluxation der
Hand nach vorne. Arch Klin Chir 1878;23:395-
412.
15. Schiller S, Spranger S, Schechinger B, et
al. Phenotypic variation and genetic heterogeneity
in L�ri-Weill syndrome. Eur J Hum Genet
2000;8:54-62.
16. Fisher E, Scambler P. Human haploinsufficiency-
one for sorrow, two for joy. Nat Genet
1994;7:5-7.
17. Ogata T. SHOX: pseudoautosomal homeobox
containing gene for short stature and dyschondrosteosis.
Growth Horm IGF Res 1999;
9(Suppl. B):53-8.
18. Shears DJ, Vassal HJ, Goodman FR, et al.
Mutation and deletion of the pseudoautosomal
gene SHOX cause L�ri-Weill dyschondrosteosis.
Nat Genet 1998;19:70-3.
19. Belin V, Cusin V, Viot G, et al. SHOX mutations
in dyschondrosteosis (L�ri-Weill syndrome).
Nat Genet 1998;19:67-9.
20. Calabrese G, Fischetto R, Stuppia L, et al.
X/Y translocation in a family with L�ri-Weill
dyschondrosteosis. Hum Genet 1999;105:367-
8.
21. Stuppia L, Calabrese G, Borrelli P, et al.
Loss of the SHOX gene associated with L�ri-Weill dyschondrosteosis in a 45,X male. J Med
Genet 1999;36:711-3.
22. Grigelioniene G, Eklof O, Ivarsson SA, et
al. Mutations in short stature homeobox containing
gene (SHOX) in dyschondrosteosis
but not in hypochondroplasia. Hum Genet
2000;101:145-9.
23. Blaschke RJ, Rappold GA. SHOX in short
stature syndromes. Horm Res 2001;55(1):21-3.
24. Falcinelli C, Iughetti L, Percesepe A, et al.
SHOX point mutations and deletions in L�ri-
Weill dyschondrosteosis. J Med Genet 2002;
39:E33.
25. Brailsford JF. Dystrophies of the skeleton.
Brit J Radiol 1935;8:533-69.
26. Book JA. A clinical and genetical study of
disturbed skeletal growth (chondrohypoplasia).
Hereditas 1950;36:161-80.
27. Langer LO Jr. Mesomelic dwarfism of the
hypoplastic ulna, fibula, mandible type. Radiology
1967;89:654-60.
28. Blockey NJ, Lawrie JH. An unusual symmetrical
distal limb deformity in siblings. J Bone
Joint Surg Br 1963;45:745-7.
29. Carter AR, Currey HL. Dyschondrosteosis
(mesomelic dwarfism) - a family history.
Br J Radiol 1974;47:634-40.
30. Espiritu C, Chen H, Woolley PV Jr. Mesomelic
dwarfism as the homozygous expression
of dyschondrosteosis. Am J Dis Child
1975;129:375-7.
31. Lisker R, Gamboa I, Hernandez J. Dyschondrosteosis.
A Mexican family with two
affected males. Clin Genet 1972;3:154-7.
32. Fryns JP, Van Den Berghe H. Langer type
of mesomelic dwarfism as the possible homozygous
expression of dyschondrosteosis.
Hum Genet 1979;46:21-7.
33. Robertson SP, Shears DJ, Oei P, et al. Homozygous
deletion of SHOX in a mentally retarded
male with Langer mesomelic dysplasia.
J Med Genet 2000;37:959-64.
34. Turner HH. A syndrome of infantilism,
congenital webbed neck, and cubitus valgus.
Endocrinology 1938;23:566.
35. Rosenfeld R, Tesch L, Rodriguez-Rigau L.
Recommendation for diagnosis, treatment and
management of individuals with Turner syndrome.
Endocrinology 1996;4:351-8.
36. Kosko T, Muroya K, Nagai T, et al. Skeletal
features and growth patterns in 14 patients
with hyploinsufficiency of SHOX: implications
for the development of Turner syndrome. J
Clin Endocrinol Metab 1999;84:4613-21.
37. Ranke MB, Sanger P. Turner�s syndrome.
Lancet 2001;358:309-14.
38. Ogata T, Tyler-Smith C, Purvis-Smith, Turner
G. Chromosomal localization of a gene(s)
for Turner stigmata on Yp. J Med Genet 1993;
30:918-22.
39. Binder G, Schwarze CP, Ranke MB. Identification
of short stature caused by SHOX defects
and therapeutic effect of recombinant
human growth hormone. J CIin Endocrinol
Metab 2000:85:245-9.
40. Morizio E, Stuppia L, Gatta V, et al. Deletion
of the SHOX gene in patients with short
stature of unknown cause. Am J Med Genet A
2003;119:293-6.
41. Stuppia L, Calabrese G, Gatta V, et al.
SHOX mutations detected by FISH and direct
sequencing in patients with short stature. J
Med Genet 2003;40:E11.
42. Blum WF, Crowe BJ, Quigley CA, et al.
Growth hormone is effective in treatment of
short stature associated with short stature homeobox-
containing gene deficiency: two-year
results of a randomized, controlled, multicenter
trial. J Clin Endocrinol Metab 2007;92:219-28.
43. Blum WF, Cao D, Hesse V, et al. Height
gains in response to growth hormone treatment
to final height are similar in patients with
SHOX deficiency and Turner syndrome.
Horm Res 2009;71:167-72.
Corrispondenza: iughetti.lorenzo@unimore.it