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Disproportionate short stature

MedGen UID:
168053
Concept ID:
C0878659
Finding
Synonym: Short stature, disproportionate
SNOMED CT: Disproportionate short stature (772086000); DSS - disproportionate short stature (772086000)
 
HPO: HP:0003498

Definition

A kind of short stature in which different regions of the body are shortened to differing extents. [from HPO]

Conditions with this feature

Metaphyseal chondrodysplasia, Spahr type
MedGen UID:
140928
Concept ID:
C0432225
Disease or Syndrome
A rare, genetic, primary bone dysplasia disease characterized by usually moderate, postnatal short stature, progressive genu vara deformity, a waddling gait, and radiological signs of metaphyseal dysplasia (i.e. irregular, sclerotic and widened metaphyses), in the absence of biochemical abnormalities suggestive of rickets disease. Intermittent knee pain, lordosis, and delayed motor development may also occasionally be associated.
Kyphomelic dysplasia
MedGen UID:
140930
Concept ID:
C0432239
Disease or Syndrome
A rare primary bone dysplasia characterized, radiologically, by short, stubby long bones, severely angulated femurs and lesser bowing of other long bones (mild, moderate or no bowing), short and wide iliac wings with horizontal acetabular roofs, platyspondyly and a narrow thorax, clinically manifesting with severe, disproportionate short stature. Regression of femora angulation is observed with advancing age.
Microcephalic osteodysplastic primordial dwarfism type II
MedGen UID:
96587
Concept ID:
C0432246
Disease or Syndrome
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities.
Dysosteosclerosis
MedGen UID:
98150
Concept ID:
C0432262
Disease or Syndrome
A rare genetic primary bone dysplasia disease characterized by progressive osteosclerosis and platyspondyly.
Acrocapitofemoral dysplasia
MedGen UID:
334681
Concept ID:
C1843096
Disease or Syndrome
Acrocapitofemoral dysplasia (ACFD) is an autosomal recessive skeletal dysplasia characterized by postnatal-onset disproportionate short stature, relatively large head, narrow thorax, lumbar lordosis, short limbs, and brachydactyly with small broad nails (Ozyavuz Cubuk and Duz, 2021).
Schinzel phocomelia syndrome
MedGen UID:
336388
Concept ID:
C1848651
Disease or Syndrome
The Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome (AARRS) is a rare autosomal recessive disorder characterized by severe malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. The disorder is believed to represent a defect of dorsoventral patterning and outgrowth of limbs (summary by Kantaputra et al., 2010).
Pelviscapular dysplasia
MedGen UID:
342400
Concept ID:
C1850040
Disease or Syndrome
Syndrome with characteristics of pelviscapular dysplasia with epiphyseal abnormalities, congenital dwarfism and facial dysmorphism. The facial dysmorphism has manifestations of frontal bossing, hypertelorism, narrow palpebral fissures, deep-set eyes, strabismus, low-set posteriorly rotated and malformed ears, dysplasia of conchae, a small chin, a short neck with redundant skin folds, and a low hairline. Intelligence may vary from normal to moderately impaired. Radiographic features comprise aplasia of the body of the scapula, hypoplasia of the iliac bone, humeroradial synostosis, dislocation of the femoral heads, and moderate brachydactyly. Mutations in the TBX15 gene have been identified as potentially causative. Pelviscapular dysplasia is phenotypically similar to pelvis-shoulder dysplasia.
Spondylometaphyseal dysplasia, Sedaghatian type
MedGen UID:
340816
Concept ID:
C1855229
Disease or Syndrome
Sedaghatian-type spondylometaphyseal dysplasia (SMDS) is a rare lethal disorder characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, delayed epiphyseal ossification, irregular iliac crests, and pulmonary hemorrhage. Affected infants present with severe hypotonia and cardiorespiratory problems; most die within days of birth due to respiratory failure. Cardiac abnormalities include conduction defects, complete heart block, and structural anomalies. Half of infants with SMDS are reported to have central nervous system malformations consistent with abnormal neuronal migration, including agenesis of the corpus callosum, pronounced frontotemporal pachygyria, simplified gyral pattern, partial lissencephaly, and severe cerebellar hypoplasia (summary by Smith et al., 2014).
Rhizomelic chondrodysplasia punctata type 2
MedGen UID:
341734
Concept ID:
C1857242
Disease or Syndrome
Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 (215100) is the most frequent form of RCDP (summary by Wanders and Waterham, 2005). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency (Waterham and Ebberink, 2012). For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.
Osteodysplastic primordial dwarfism, type 1
MedGen UID:
347149
Concept ID:
C1859452
Congenital Abnormality
Microcephalic osteodysplastic primordial dwarfism type I (MOPD1) is a severe autosomal recessive skeletal dysplasia characterized by dwarfism, microcephaly, and neurologic abnormalities, including mental retardation, brain malformations, and ocular/auditory sensory deficits. Patients often die in early childhood (summary by Pierce and Morse, 2012).
Spondylomegaepiphyseal dysplasia with upper limb mesomelia, punctate calcifications, and deafness
MedGen UID:
355893
Concept ID:
C1865022
Disease or Syndrome
Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
MedGen UID:
393098
Concept ID:
C2674173
Congenital Abnormality
SADDAN dysplasia (severe achondroplasia with developmental delay and acanthosis nigricans) is a very rare skeletal dysplasia characterized by the constellation of these features. Radiology reveals 'ram's horn' shaped clavicles and reverse bowing of lower limbs. Approximately half of patients die before the fourth week of life secondary to respiratory failure (summary by Zankl et al., 2008).
Immunoskeletal dysplasia with neurodevelopmental abnormalities
MedGen UID:
1381460
Concept ID:
C4479452
Disease or Syndrome
Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis
MedGen UID:
1676818
Concept ID:
C5193055
Disease or Syndrome
Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS)is characterized by disproportionate short stature, defective tooth enamel formation, and skeletal dysplasia with severe scoliosis in some patients. Variable features include facial dysmorphism, moderate hearing impairment, and mildly impaired intellectual development (Ashikov et al., 2018).
Acromesomelic dysplasia 4
MedGen UID:
1794238
Concept ID:
C5562028
Disease or Syndrome
Acromesomelic dysplasia-4 (AMD4) is characterized by disproportionate short stature due to mesomelic shortening of the limbs. Radiographic hallmarks include mild to moderate platyspondyly, moderate brachydactyly, iliac flaring, and metaphyseal alterations of the long bones that progressively increase with age (Diaz-Gonzalez et al., 2022). For a discussion of genetic heterogeneity of acromesomelic dysplasia, see AMD1 (602875).
Hemolytic uremic syndrome, atypical, 8, with rhizomelic short stature
MedGen UID:
1840221
Concept ID:
C5829585
Disease or Syndrome
Atypical hemolytic uremic syndrome-8 with rhizomelic short stature (AHUS8) is an X-linked disorder with variable manifestations. The age at onset of renal symptoms is variable, ranging from infancy to the early twenties. Features of atypical hemolytic uremic syndrome (aHUS) include acute renal dysfunction with proteinuria, thrombotic microangiopathy, anemia, thrombocytopenia, increased serum lactate dehydrogenase (LDH), and schistocytes on peripheral blood smear. Affected individuals also have short stature with short limbs. More variable features include immunodeficiency with recurrent infections, developmental delay, and dysmorphic features. Treatment with C5 inhibitors results in improvement of renal function. Female carriers may show an attenuated phenotype (Hadar et al., 2023; Erger et al., 2023). For a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400).

Professional guidelines

PubMed

Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A
Nat Rev Nephrol 2019 Jul;15(7):435-455. doi: 10.1038/s41581-019-0152-5. PMID: 31068690Free PMC Article
Sewell MD, Chahal A, Al-Hadithy N, Blunn GW, Molloy S, Hashemi-Nejad A
J Back Musculoskelet Rehabil 2015;28(3):575-90. doi: 10.3233/BMR-140558. PMID: 25391330
Wright MJ, Irving MD
Arch Dis Child 2012 Feb;97(2):129-34. Epub 2011 Apr 3 doi: 10.1136/adc.2010.189092. PMID: 21460402

Recent clinical studies

Etiology

Hoover-Fong JE, Schulze KJ, Alade AY, Bober MB, Gough E, Hashmi SS, Hecht JT, Legare JM, Little ME, Modaff P, Pauli RM, Rodriguez-Buritica DF, Serna ME, Smid C, Liu C, McGready J
Orphanet J Rare Dis 2021 Dec 23;16(1):522. doi: 10.1186/s13023-021-02141-4. PMID: 34949201Free PMC Article
Ain NU, Fatima Z, Naz S, Makitie O
BMC Musculoskelet Disord 2021 Jul 20;22(1):630. doi: 10.1186/s12891-021-04503-2. PMID: 34284742Free PMC Article
Wright MJ, Irving MD
Arch Dis Child 2012 Feb;97(2):129-34. Epub 2011 Apr 3 doi: 10.1136/adc.2010.189092. PMID: 21460402
Cormier-Daire V
Best Pract Res Clin Rheumatol 2008 Mar;22(1):33-44. doi: 10.1016/j.berh.2007.12.009. PMID: 18328979
Savarirayan R, Rimoin DL
Best Pract Res Clin Endocrinol Metab 2002 Sep;16(3):547-60. doi: 10.1053/beem.2002.0210. PMID: 12464233

Diagnosis

Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A
Nat Rev Nephrol 2019 Jul;15(7):435-455. doi: 10.1038/s41581-019-0152-5. PMID: 31068690Free PMC Article
Mehlman CT, Ain MC
Orthop Clin North Am 2015 Oct;46(4):523-31. Epub 2015 Aug 6 doi: 10.1016/j.ocl.2015.06.006. PMID: 26410640
Cormier-Daire V
Best Pract Res Clin Rheumatol 2008 Mar;22(1):33-44. doi: 10.1016/j.berh.2007.12.009. PMID: 18328979
Baujat G, Legeai-Mallet L, Finidori G, Cormier-Daire V, Le Merrer M
Best Pract Res Clin Rheumatol 2008 Mar;22(1):3-18. doi: 10.1016/j.berh.2007.12.008. PMID: 18328977
Savarirayan R, Rimoin DL
Best Pract Res Clin Endocrinol Metab 2002 Sep;16(3):547-60. doi: 10.1053/beem.2002.0210. PMID: 12464233

Therapy

Ertl DA, Le Lorier J, Gleiss A, Trabado S, Bensignor C, Audrain C, Zhukouskaya V, Coutant R, Berkenou J, Rothenbuhler A, Haeusler G, Linglart A
Orphanet J Rare Dis 2022 Nov 12;17(1):412. doi: 10.1186/s13023-022-02562-9. PMID: 36371259Free PMC Article
Savarirayan R, Irving M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, Le Quan Sang KH, Dickson P, Harmatz P, Phillips J, Owen N, Cherukuri A, Jayaram K, Jeha GS, Larimore K, Chan ML, Huntsman Labed A, Day J, Hoover-Fong J
N Engl J Med 2019 Jul 4;381(1):25-35. Epub 2019 Jun 18 doi: 10.1056/NEJMoa1813446. PMID: 31269546
Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A
Nat Rev Nephrol 2019 Jul;15(7):435-455. doi: 10.1038/s41581-019-0152-5. PMID: 31068690Free PMC Article
Bouali H, Latrech H
Pediatr Endocrinol Rev 2015 Jun;12(4):388-95. PMID: 26182483
Delvecchio M, Cavallo L
J Endocrinol Invest 2010 Jan;33(1):61-8. doi: 10.1007/BF03346551. PMID: 20203539

Prognosis

Liau ZQG, Wang Y, Lin HY, Cheong CK, Gupta S, Hui JHP
Curr Opin Pediatr 2022 Feb 1;34(1):82-91. doi: 10.1097/MOP.0000000000001081. PMID: 34840250
Constantinides C, Landis SH, Jarrett J, Quinn J, Ireland PJ
Disabil Rehabil 2022 Oct;44(21):6166-6178. Epub 2021 Aug 17 doi: 10.1080/09638288.2021.1963853. PMID: 34403286
Ain NU, Fatima Z, Naz S, Makitie O
BMC Musculoskelet Disord 2021 Jul 20;22(1):630. doi: 10.1186/s12891-021-04503-2. PMID: 34284742Free PMC Article
Sewell MD, Chahal A, Al-Hadithy N, Blunn GW, Molloy S, Hashemi-Nejad A
J Back Musculoskelet Rehabil 2015;28(3):575-90. doi: 10.3233/BMR-140558. PMID: 25391330
Cormier-Daire V
Best Pract Res Clin Rheumatol 2008 Mar;22(1):33-44. doi: 10.1016/j.berh.2007.12.009. PMID: 18328979

Clinical prediction guides

Liang H, Hou Y, Pang Q, Jiang Y, Wang O, Li M, Xing X, Zhu H, Xia W
Calcif Tissue Int 2022 Mar;110(3):313-323. Epub 2021 Oct 28 doi: 10.1007/s00223-021-00920-6. PMID: 34709441
Constantinides C, Landis SH, Jarrett J, Quinn J, Ireland PJ
Disabil Rehabil 2022 Oct;44(21):6166-6178. Epub 2021 Aug 17 doi: 10.1080/09638288.2021.1963853. PMID: 34403286
Pellegrin MC, Tornese G, Barbi E
Arch Dis Child Educ Pract Ed 2021 Jun;106(3):149-151. Epub 2019 Aug 29 doi: 10.1136/archdischild-2019-317564. PMID: 31467065
Savarirayan R, Irving M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, Le Quan Sang KH, Dickson P, Harmatz P, Phillips J, Owen N, Cherukuri A, Jayaram K, Jeha GS, Larimore K, Chan ML, Huntsman Labed A, Day J, Hoover-Fong J
N Engl J Med 2019 Jul 4;381(1):25-35. Epub 2019 Jun 18 doi: 10.1056/NEJMoa1813446. PMID: 31269546
Jorge AA, Funari MF, Nishi MY, Mendonca BB
Pediatr Endocrinol Rev 2010 Dec;8(2):79-85. PMID: 21150837

Recent systematic reviews

Fano V, Kim CA, Rosselli P, Dib RE, Shediac R, Magalhães T, Mesojedovas D, Llerena J Jr
Orphanet J Rare Dis 2022 Jan 4;17(1):4. doi: 10.1186/s13023-021-02142-3. PMID: 34983594Free PMC Article
Sabir AH, Sheikh J, Singh A, Morley E, Cocca A, Cheung MS, Irving M
Am J Med Genet A 2021 Jan;185(1):73-82. Epub 2020 Oct 14 doi: 10.1002/ajmg.a.61912. PMID: 33051983
Foreman PK, van Kessel F, van Hoorn R, van den Bosch J, Shediac R, Landis S
Am J Med Genet A 2020 Oct;182(10):2297-2316. Epub 2020 Aug 17 doi: 10.1002/ajmg.a.61787. PMID: 32803853Free PMC Article
Schiedel F, Rödl R
Disabil Rehabil 2012;34(12):982-7. Epub 2011 Nov 23 doi: 10.3109/09638288.2011.631677. PMID: 22112021

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