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Leri Weill dyschondrosteosis(LWD)

MedGen UID:
75562
Concept ID:
C0265309
Congenital Abnormality
Synonyms: Dyschondrosteosis; LWD; Léri-Weill dyschondrosteosis; SHOX-Related Haploinsufficiency Disorders
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Leri-Weill syndrome (17818006); Leri-Weill dyschondrosteosis (17818006)
 
OMIM®: 127300
Orphanet: ORPHA240

Definition

The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX), ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to nonspecific short stature at the mild end of the spectrum. In adults with SHOX deficiency, the proportion of LWD versus short stature without features of LWD is not well defined. In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shorted in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. The phenotype of short stature caused by SHOX deficiency (in the absence of mesomelia and Madelung deformity) is highly variable, even within the same family. [from GTR]

Additional descriptions

From GeneReviews
The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX), ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to nonspecific short stature at the mild end of the spectrum. In adults with SHOX deficiency, the proportion of LWD versus short stature without features of LWD is not well defined. In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shorted in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. The phenotype of short stature caused by SHOX deficiency (in the absence of mesomelia and Madelung deformity) is highly variable, even within the same family.  https://www.ncbi.nlm.nih.gov/books/NBK1215
From OMIM
Leri-Weill dyschondrosteosis (LWD) is a dominantly inherited skeletal dysplasia characterized by short stature, mesomelia, and Madelung wrist deformity. Although the disorder occurs in both sexes, it is usually more severe in females, perhaps due to sex difference in estrogen levels. However, pubertal development and fertility are generally normal in both sexes with the disorder (summary by Ross et al., 2005). The Madelung wrist deformity includes deformity of the distal radius and ulna and proximal carpal bones (Langer, 1965). See also Langer mesomelic dysplasia (LMD; 249700), a more severe phenotype that results from homozygous defect in the SHOX or SHOXY genes.  http://www.omim.org/entry/127300
From GHR
Léri-Weill dyschondrosteosis is a disorder of bone growth. Affected individuals typically have shortening of the long bones in the arms and legs (mesomelia). As a result of the shortened leg bones, people with Leri-Weill dyschondrosteosis typically have short stature. Most people with the condition also have an abnormality of the wrist and forearm bones called Madelung deformity, which may cause pain and limit wrist movement. This abnormality usually appears in childhood or early adolescence. Other features of Léri-Weill dyschondrosteosis can include increased muscle mass (muscle hypertrophy); bowing of a bone in the lower leg called the tibia; a greater-than-normal angling of the elbow away from the body (increased carrying angle); and a high arched palate.Léri-Weill dyschondrosteosis occurs in both males and females, although its signs and symptoms tend to be more severe in females. Researchers believe that the more severe features may result from hormonal differences.  https://ghr.nlm.nih.gov/condition/leri-weill-dyschondrosteosis

Clinical features

Multiple congenital exostosis
MedGen UID:
4612
Concept ID:
C0015306
Congenital Abnormality
The disorder hereditary multiple osteochondromas (HMO), previously called hereditary multiple exostoses (HME), is characterized by growths of multiple osteochondromas (benign cartilage-capped bone tumors that grow outward from the metaphyses of long bones). Osteochondromas can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature, premature osteoarthrosis, and compression of peripheral nerves. The median age of diagnosis is three years; nearly all affected individuals are diagnosed by age 12 years. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk of malignant degeneration is low (~1%).
Madelung deformity
MedGen UID:
57537
Concept ID:
C0152441
Congenital Abnormality
An anomaly related to partial closure, or failure of development of the ulnar side of the distal radial growth plate, which results in an arrest of epiphyseal growth of the medial and volar portions of the distal radius. This leads to shortening of the radius and relative overgrowth of the ulna.
Coxa valga
MedGen UID:
116080
Concept ID:
C0239137
Finding
Coxa valga is a deformity of the hip in which the angle between the femoral shaft and the femoral neck is increased compared to age-adjusted values (about 150 degrees in newborns gradually reducing to 120-130 degrees in adults).
Mesomelia
MedGen UID:
107808
Concept ID:
C0549306
Congenital Abnormality
Shortening of the middle parts of the limbs (forearm and lower leg) in relation to the upper and terminal segments.
Hypoplasia of the radius
MedGen UID:
672334
Concept ID:
C0685381
Congenital Abnormality
A congenital deformity characterized by the presence of hypoplastic radius. It is usually associated with club hand deformity.
Fibular hypoplasia
MedGen UID:
316909
Concept ID:
C1832119
Finding
Underdevelopment of the fibula.
Short toe
MedGen UID:
322858
Concept ID:
C1836195
Finding
A toe that appears disproportionately short compared to the foot.
Tibial bowing
MedGen UID:
332360
Concept ID:
C1837081
Finding
A bending or abnormal curvature of the tibia.
Limited wrist movement
MedGen UID:
333479
Concept ID:
C1840088
Finding
An abnormal limitation of the mobility of the wrist.
Short 4th metacarpal
MedGen UID:
327074
Concept ID:
C1840309
Finding
Short fourth metacarpal bone.
Abnormality of the carpal bones
MedGen UID:
374491
Concept ID:
C1840535
Finding
An abnormality affecting the carpal bones of the wrist (scaphoid, lunate, triquetral, pisiform, trapezium, trapezoid, capitate, hamate).
Limited elbow movement
MedGen UID:
337930
Concept ID:
C1849955
Finding
Short tibia
MedGen UID:
338005
Concept ID:
C1850259
Finding
Underdevelopment (reduced size) of the tibia.
Dorsal subluxation of ulna
MedGen UID:
338835
Concept ID:
C1851988
Finding
Partial dislocation of the ulna in the dorsal direction.
Increased carrying angle
MedGen UID:
343361
Concept ID:
C1855478
Finding
An abnormal increase in the carrying angle, which is the angle he long axis of the extended forearm as it lies lateral to the long axis of the arm.
Radial bowing
MedGen UID:
347136
Concept ID:
C1859399
Finding
A bending or abnormal curvature of the radius.
Fryns Hofkens Fabry syndrome
MedGen UID:
395934
Concept ID:
C1860614
Finding
Underdevelopment of the ulna.
Abnormality of the humerus
MedGen UID:
867377
Concept ID:
C4021742
Anatomical Abnormality
An abnormality of the humerus (i.e., upper arm bone).
Abnormality of the metatarsal bones
MedGen UID:
446425
Concept ID:
CN001659
Finding
Abnormalities of the metatarsal bones (i.e. of five tubular bones located between the tarsal bones of the hind- and mid-foot and the phalanges of the toes).
Disproportionate short-limb short stature
MedGen UID:
342370
Concept ID:
C1849937
Finding
A type of disproportionate short stature characterized by a short limbs but an average-sized trunk.
Skeletal muscle hypertrophy
MedGen UID:
853739
Concept ID:
C2265792
Finding
Hypertrophy (increase in size) of muscle cells (as opposed to hyperplasia, which refers to an increase in the number of muscle cells).
Multiple congenital exostosis
MedGen UID:
4612
Concept ID:
C0015306
Congenital Abnormality
The disorder hereditary multiple osteochondromas (HMO), previously called hereditary multiple exostoses (HME), is characterized by growths of multiple osteochondromas (benign cartilage-capped bone tumors that grow outward from the metaphyses of long bones). Osteochondromas can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature, premature osteoarthrosis, and compression of peripheral nerves. The median age of diagnosis is three years; nearly all affected individuals are diagnosed by age 12 years. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk of malignant degeneration is low (~1%).
Scoliosis
MedGen UID:
21278
Concept ID:
C0037932
Finding
Deformities of the SPINE characterized by abnormal bending or flexure in the vertebral column. They may be bending forward (KYPHOSIS), backward (LORDOSIS), or sideway (SCOLIOSIS).
Madelung deformity
MedGen UID:
57537
Concept ID:
C0152441
Congenital Abnormality
An anomaly related to partial closure, or failure of development of the ulnar side of the distal radial growth plate, which results in an arrest of epiphyseal growth of the medial and volar portions of the distal radius. This leads to shortening of the radius and relative overgrowth of the ulna.
Coxa valga
MedGen UID:
116080
Concept ID:
C0239137
Finding
Coxa valga is a deformity of the hip in which the angle between the femoral shaft and the femoral neck is increased compared to age-adjusted values (about 150 degrees in newborns gradually reducing to 120-130 degrees in adults).
Mesomelia
MedGen UID:
107808
Concept ID:
C0549306
Congenital Abnormality
Shortening of the middle parts of the limbs (forearm and lower leg) in relation to the upper and terminal segments.
Hypoplasia of the radius
MedGen UID:
672334
Concept ID:
C0685381
Congenital Abnormality
A congenital deformity characterized by the presence of hypoplastic radius. It is usually associated with club hand deformity.
Fibular hypoplasia
MedGen UID:
316909
Concept ID:
C1832119
Finding
Underdevelopment of the fibula.
Short toe
MedGen UID:
322858
Concept ID:
C1836195
Finding
A toe that appears disproportionately short compared to the foot.
Tibial bowing
MedGen UID:
332360
Concept ID:
C1837081
Finding
A bending or abnormal curvature of the tibia.
Limited wrist movement
MedGen UID:
333479
Concept ID:
C1840088
Finding
An abnormal limitation of the mobility of the wrist.
Short 4th metacarpal
MedGen UID:
327074
Concept ID:
C1840309
Finding
Short fourth metacarpal bone.
Abnormality of the carpal bones
MedGen UID:
374491
Concept ID:
C1840535
Finding
An abnormality affecting the carpal bones of the wrist (scaphoid, lunate, triquetral, pisiform, trapezium, trapezoid, capitate, hamate).
Limited elbow movement
MedGen UID:
337930
Concept ID:
C1849955
Finding
Short tibia
MedGen UID:
338005
Concept ID:
C1850259
Finding
Underdevelopment (reduced size) of the tibia.
Dorsal subluxation of ulna
MedGen UID:
338835
Concept ID:
C1851988
Finding
Partial dislocation of the ulna in the dorsal direction.
Increased carrying angle
MedGen UID:
343361
Concept ID:
C1855478
Finding
An abnormal increase in the carrying angle, which is the angle he long axis of the extended forearm as it lies lateral to the long axis of the arm.
Radial bowing
MedGen UID:
347136
Concept ID:
C1859399
Finding
A bending or abnormal curvature of the radius.
Fryns Hofkens Fabry syndrome
MedGen UID:
395934
Concept ID:
C1860614
Finding
Underdevelopment of the ulna.
Abnormality of the humerus
MedGen UID:
867377
Concept ID:
C4021742
Anatomical Abnormality
An abnormality of the humerus (i.e., upper arm bone).
Abnormality of the metatarsal bones
MedGen UID:
446425
Concept ID:
CN001659
Finding
Abnormalities of the metatarsal bones (i.e. of five tubular bones located between the tarsal bones of the hind- and mid-foot and the phalanges of the toes).
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLeri Weill dyschondrosteosis
Follow this link to review classifications for Leri Weill dyschondrosteosis in Orphanet.

Recent clinical studies

Etiology

Shima H, Tanaka T, Kamimaki T, Dateki S, Muroya K, Horikawa R, Kanno J, Adachi M, Naiki Y, Tanaka H, Mabe H, Yagasaki H, Kure S, Matsubara Y, Tajima T, Kashimada K, Ishii T, Asakura Y, Fujiwara I, Soneda S, Nagasaki K, Hamajima T, Kanzaki S, Jinno T, Ogata T, Fukami M; Japanese SHOX study group.
J Hum Genet 2016 Jul;61(7):585-91. Epub 2016 Mar 17 doi: 10.1038/jhg.2016.18. PMID: 26984564
Bunyan DJ, Baffico M, Capone L, Vannelli S, Iughetti L, Schmitt S, Taylor EJ, Herridge AA, Shears D, Forabosco A, Coviello DA
Am J Med Genet A 2016 Apr;170A(4):949-57. Epub 2015 Dec 24 doi: 10.1002/ajmg.a.37524. PMID: 26698168
Hisado-Oliva A, Garre-Vázquez AI, Santaolalla-Caballero F, Belinchón A, Barreda-Bonis AC, Vasques GA, Ramirez J, Luzuriaga C, Carlone G, González-Casado I, Benito-Sanz S, Jorge AA, Campos-Barros A, Heath KE
J Clin Endocrinol Metab 2015 Aug;100(8):E1133-42. Epub 2015 Jun 15 doi: 10.1210/jc.2015-1612. PMID: 26075495
Benito-Sanz S, Royo JL, Barroso E, Paumard-Hernández B, Barreda-Bonis AC, Liu P, Gracía R, Lupski JR, Campos-Barros Á, Gómez-Skarmeta JL, Heath KE
J Med Genet 2012 Jul;49(7):442-50. doi: 10.1136/jmedgenet-2011-100678. PMID: 22791839
Hirschfeldova K, Solc R, Baxova A, Zapletalova J, Kebrdlova V, Gaillyova R, Prasilova S, Soukalova J, Mihalova R, Lnenicka P, Florianova M, Stekrova J
Gene 2012 Jan 10;491(2):123-7. Epub 2011 Oct 14 doi: 10.1016/j.gene.2011.10.011. PMID: 22020182

Diagnosis

Shima H, Tanaka T, Kamimaki T, Dateki S, Muroya K, Horikawa R, Kanno J, Adachi M, Naiki Y, Tanaka H, Mabe H, Yagasaki H, Kure S, Matsubara Y, Tajima T, Kashimada K, Ishii T, Asakura Y, Fujiwara I, Soneda S, Nagasaki K, Hamajima T, Kanzaki S, Jinno T, Ogata T, Fukami M; Japanese SHOX study group.
J Hum Genet 2016 Jul;61(7):585-91. Epub 2016 Mar 17 doi: 10.1038/jhg.2016.18. PMID: 26984564
Abasq-Thomas C, Schmitt S, Brenaut E, Metz C, Chiesa J, Misery L
Acta Derm Venereol 2016 Aug 23;96(6):814-5. doi: 10.2340/00015555-2356. PMID: 26832328
Bunyan DJ, Baffico M, Capone L, Vannelli S, Iughetti L, Schmitt S, Taylor EJ, Herridge AA, Shears D, Forabosco A, Coviello DA
Am J Med Genet A 2016 Apr;170A(4):949-57. Epub 2015 Dec 24 doi: 10.1002/ajmg.a.37524. PMID: 26698168
Rodríguez FA, Unanue N, Hernandez MI, Basaure J, Heath KE, Cassorla F
J Pediatr Endocrinol Metab 2013;26(7-8):729-34. doi: 10.1515/jpem-2013-0023. PMID: 23729538
Hirschfeldova K, Solc R, Baxova A, Zapletalova J, Kebrdlova V, Gaillyova R, Prasilova S, Soukalova J, Mihalova R, Lnenicka P, Florianova M, Stekrova J
Gene 2012 Jan 10;491(2):123-7. Epub 2011 Oct 14 doi: 10.1016/j.gene.2011.10.011. PMID: 22020182

Therapy

Salmon-Musial AS, Rosilio M, David M, Huber C, Pichot E, Cormier-Daire V, Nicolino M
Horm Res Paediatr 2011;76(3):178-85. Epub 2011 Sep 10 doi: 10.1159/000329359. PMID: 21912078
Binder G, Renz A, Martinez A, Keselman A, Hesse V, Riedl SW, Häusler G, Fricke-Otto S, Frisch H, Heinrich JJ, Ranke MB
J Clin Endocrinol Metab 2004 Sep;89(9):4403-8. doi: 10.1210/jc.2004-0591. PMID: 15356038
Tauber M, Lounis N, Coulet J, Baunin C, Cahuzac JP, Rochiccioli P
Eur J Pediatr 2004 Aug;163(8):475-81. Epub 2004 Jun 9 doi: 10.1007/s00431-004-1471-4. PMID: 15197587
Binder G, Fritsch H, Schweizer R, Ranke MB
Horm Res 2001;55(2):71-6. doi: 10.1159/000049973. PMID: 11509862
Wei F, Cheng S, Badie N, Elder F, Scott C Jr, Nicholson L, Ross JL, Zinn AR
Am J Med Genet 2001 Sep 1;102(4):353-8. PMID: 11503163

Prognosis

Kozin SH, Zlotolow DA
J Hand Surg Am 2015 Oct;40(10):2090-8. Epub 2015 Sep 1 doi: 10.1016/j.jhsa.2015.03.033. PMID: 26341718
Huguet S, Leheup B, Aslan M, Muller F, Dautel G, Journeau P; French Society of Pediatric Orthopaedics (SOFOP).
Orthop Traumatol Surg Res 2014 Oct;100(6 Suppl):S349-52. Epub 2014 Sep 10 doi: 10.1016/j.otsr.2014.06.007. PMID: 25217032
Bunyan DJ, Baker KR, Harvey JF, Thomas NS
Am J Med Genet A 2013 Jun;161A(6):1329-38. Epub 2013 May 1 doi: 10.1002/ajmg.a.35919. PMID: 23636926
Albuisson J, Schmitt S, Baron S, Bézieau S, Benito-Sanz S, Heath KE
Eur J Hum Genet 2012 Aug;20(8) Epub 2012 Apr 18 doi: 10.1038/ejhg.2012.64. PMID: 22510850Free PMC Article
Munns CF, Glass IA, LaBrom R, Hayes M, Flanagan S, Berry M, Hyland VJ, Batch JA, Philips GE, Vickers D
Hand Surg 2001 Jul;6(1):13-23. PMID: 11677662

Clinical prediction guides

Benito-Sanz S, Royo JL, Barroso E, Paumard-Hernández B, Barreda-Bonis AC, Liu P, Gracía R, Lupski JR, Campos-Barros Á, Gómez-Skarmeta JL, Heath KE
J Med Genet 2012 Jul;49(7):442-50. doi: 10.1136/jmedgenet-2011-100678. PMID: 22791839
Salmon-Musial AS, Rosilio M, David M, Huber C, Pichot E, Cormier-Daire V, Nicolino M
Horm Res Paediatr 2011;76(3):178-85. Epub 2011 Sep 10 doi: 10.1159/000329359. PMID: 21912078
Barca-Tierno V, Aza-Carmona M, Barroso E, Heine-Suner D, Azmanov D, Rosell J, Ezquieta B, Montané LS, Vendrell T, Cruz J, Santos F, Rodríguez JI, Pozo J, Argente J, Kalaydjieva L, Gracía R, Campos-Barros A, Benito-Sanz S, Heath KE
Eur J Hum Genet 2011 Dec;19(12):1218-25. Epub 2011 Jun 29 doi: 10.1038/ejhg.2011.128. PMID: 21712857Free PMC Article
Jorge AA, Souza SC, Nishi MY, Billerbeck AE, Libório DC, Kim CA, Arnhold IJ, Mendonca BB
Clin Endocrinol (Oxf) 2007 Jan;66(1):130-5. doi: 10.1111/j.1365-2265.2006.02698.x. PMID: 17201812
Benito-Sanz S, del Blanco DG, Aza-Carmona M, Magano LF, Lapunzina P, Argente J, Campos-Barros A, Heath KE
Hum Mutat 2006 Oct;27(10):1062. doi: 10.1002/humu.9456. PMID: 16941489

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