Idiopathic Short Stature: What to Expect from Genomic Investigations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Eligibility Criteria
3. Historic Aspects of Idiopathic Short Stature
4. Genetic Basis of Idiopathic Short Stature
5. Genes Related to “Idiopathic Short Stature”: Monogenic Conditions
5.1. Genes Related to the GH-IGF1 Axis
5.1.1. GH1
5.1.2. GHR
5.1.3. GHSR
5.1.4. STAT5B
5.1.5. IGF1 and IGF1R
5.1.6. Ternary Complex Defects (IGFALS and PAPP-A2)
5.2. Genes That Regulate Growth Plate Physiology
5.2.1. SHOX
5.2.2. NPR2 and NPPC
5.2.3. ACAN
5.2.4. IHH
5.2.5. FGFR3
5.2.6. COL2A1 and Other Collagen Genes
5.3. Genes Related to RAS-MAPK Pathway
5.3.1. PTPN11
5.3.2. NF1
6. Conclusions and What to Expect from Genomic Investigations
Reference | Total Cohort | ISS Cohort | Methodology | Diagnostic Yield (Total Cohort) | Diagnostic Yield (ISS Cohort) | Discussion |
---|---|---|---|---|---|---|
Wang et al. (2013) [6] | 192 | 14 | Target gene panel with 1077 genes | 4/192 (2%) | 3/14 (21.4%) | Included syndromic children |
Guo et al. (2014) [7] | 14 | 3 | Exome | 5/14 (35.7%) | 0 | Only genes related to syndromic short stature |
Hattori et al. (2017) [8] | 86 | 86 | Target gene panel with 10 genes | 18 (20.9%) | 18 (20.9%) | Excluded SGA and syndromic children |
Hauer et al. (2018) [9] | 200 | 13 | Exome | 38/200 (19%) | 11/13 (84.6%) | 134 children initially classified as having ISS but included children born SGA and with syndromic features |
Freire et al. (2019) [10] | 179 | 55 | Target gene panel/exome | 8/55 (14.5%) | 8/55 (14.5%) | Included only children with isolated short stature born SGA |
Perchard et al. (2020) [11] | 263 | 18 | Target gene panel | 27/263 (10%) | 5/18 (27.8%) | Included children with GH deficiency and dysmorphic features |
Fan et al. (2021) [13] | 561 | 257 | Exome | 135/561 (24%) | 11.3% (29/257) | Included genes associated with hypopituitarism, skeletal dysplasia, and chronic and metabolic disorders with the positive results in the ISS group. |
Sentchordi-Montané et al. (2021) [12] | 108 | 108 | Target gene panel | 21/108 (19.4%) | 12/108 (11.1%) | Skeletal dysplasia NGS panel and SHOX-related genes were excluded. Included children born SGA. |
Andrade et al. (2022) [121] | 102 | 102 | Target gene panel | 17/102 (16.7%) | 17/102 (16.7%) | Only children classified as having ISS |
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Year of Description in ISS | Prevalence in ISS | Evidence | Observation | Ref |
---|---|---|---|---|---|
GHR | 1995 | 5% | Limited | Laboratory findings suggestive of partial GH insensitivity | [33,48] |
SHOX | 1997 | 2.4% | Definitive | Short stature with mild body disproportion | [49] |
GH1 | 2003 | No data | Limited | Severe postnatal short stature, normal to elevated GH peaks in stimulation tests, and low levels of IGF-1 and IGFBP-3 | [35] |
IGF1R | 2003 | No data | Moderated | The majority were born small for their gestational age and had high levels of IGF-1 | [36,50,51] |
IGFALS | 2004 | No data | Limited | Severe deficiency of IGF1 and IGFBP-3, disproportional to the severity of short stature | [52] |
GHSR | 2006 | Only case report | Limited | Associated with GHD and short stature in the same family | [38,53] |
NPR2 | 2013 | 2 to 13.6% | Strong | Proportional or disproportional short stature and unspecified skeletal findings at time of X-ray of bone age | [39] |
PTPN11 | 2013 | Only case report | Limited | Short stature with or without mild phenotype of Noonan syndrome | [6] |
IGF1 | 2013 | No data | Limited | Variable degree of pre- and postnatal growth retardation with serum IGF-1 at the lower end of normal | [40] |
ACAN | 2014 | No data | Moderated | Short stature with or without advanced bone age | [41] |
FGFR3 | 2015 | Only one case report | Limited | Only one family described with proportional short stature | [42] |
PAPP-A2 | 2016 | Only case report | Limited | High levels of IGF-1 and IGFPB-3 | [43] |
NPPC | 2018 | No data | Limited | Brachydactyly | [44] |
IHH | 2018 | 3.3% | Moderated | Proportional or disproportional short stature, with or without unspecific skeletal findings as shortening of middle phalanges of the 2nd and 5th digits | [45] |
STAT5B | 2018 | Only case report | Limited | Eczema and laboratory results suggestive of partial GH insensitivity | [46] |
NF1 | 2019 | No data | Limited | Short stature without clinical features of neurofibromatosis | [54] |
COL2A1 | 2021 | 5.7% | Limited | Unspecific skeletal findings and disproportionate short stature | [47] |
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Andrade, N.L.M.; Cellin, L.P.; Rezende, R.C.; Vasques, G.A.; Jorge, A.A.L. Idiopathic Short Stature: What to Expect from Genomic Investigations. Endocrines 2023, 4, 1-17. https://doi.org/10.3390/endocrines4010001
Andrade NLM, Cellin LP, Rezende RC, Vasques GA, Jorge AAL. Idiopathic Short Stature: What to Expect from Genomic Investigations. Endocrines. 2023; 4(1):1-17. https://doi.org/10.3390/endocrines4010001
Chicago/Turabian StyleAndrade, Nathalia Liberatoscioli Menezes, Laurana Polli Cellin, Raissa Carneiro Rezende, Gabriela Andrade Vasques, and Alexander Augusto Lima Jorge. 2023. "Idiopathic Short Stature: What to Expect from Genomic Investigations" Endocrines 4, no. 1: 1-17. https://doi.org/10.3390/endocrines4010001