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Table 1 Genetic properties and complexities of ten conditions reported in humans with short or tall stature phenotypes (cases represent a cross-section of rare and extremely rare disorders)

From: Genetic architecture of body size in mammals

Syndrome Gene Stature effecta Inheritanceb Herterogeneity Notes References
Marfan syndrome (OMIM 154700) FBN1 (fibrillin 1) +2.2 SD Autosomal dominant; 25% de novo mutations; prevalence of 2 to 3 in 10,000 live births; most alleles exhibit haploinsufficiency (where the product from a single functional copy of the gene is insufficient for normal function) >500 mutations FBN1 is a very large (>600 kb) and highly fragmented (65 exons) gene; phenotypic heterogeneity and a spectrum of Marfan-like disorders suggest involvement of other genes; mutations in the functionally related transforming growth factor-β receptor, type II gene (TGFBR2) is also known to cause Marfan syndrome; symptoms include disproportionate overgrowth of limbs, and ocular and cardiovascular abnormalities [10, 3747]
Sotos syndrome (OMIM 17550) NSD1 (nuclear receptor binding SET domain protein 1) +2 SD Autosomal dominant; 95% de novo mutations; 1 in 14,000 live births >100 mutations NSD1 mutations in 80% to 90% of cases; symptoms include characteristic facial features, overgrowth and mild-to-severe learning disabilities with possible cardiac, dental and renal abnormalities; increased tumor risk [4850]
Beals syndrome (OMIM 121050) FBN2 (fibrillin 2) +2 SD Autosomal dominant; rare; mostly inherited 10 mutations Similar phenotype to Marfan syndrome but with fewer complications; FBN2 abnormalities in 27% to 70% of cases; probable involvement of other loci; reports of a lethal mutation and somatic/germline mosaicism [5154]
3 M syndrome (OMIM 273750) CUL7 (cullin 7) -5.6 SD Autosomal recessive; very rare, 40 to 50 cases reported >45 mutations Mutations in OBSL1 and CCDC8 can also cause 3 M syndrome; symptoms include severe prenatal and postnatal growth retardation, characteristic facial features and normal intelligence [5559]
Costello syndrome (OMIM 218040) HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) -5 SD Autosomal dominant; mostly de novo mutations; very rare, 250 cases worldwide >10 mutations Recurrent missense mutation in HRAS reported in up to 80% of cases; somatic/germline mosaicism confirmed in one case and suspected in others; symptoms include postnatal failure to thrive, intellectual disability, coarse facial features, cardiac abnormalities and an increased risk of malignant tumors [6063]
Achondroplasia (OMIM 100800) FGFR3 (fibroblast growth factor receptor 3) -5 SD Autosomal dominant; 80% de novo mutations; 0.5 to 1.5 in 10,000 live births >10 mutations Most common form of dwarfism; 97% of cases show one of two mutations that cause a missense glycine to arginine substitution at position 380 in FGFR3; missense mutation associated with gain-of-function and overactivation of negative growth control; evidence for increasing prevalence with increasing paternal age; other mutations in FGFR3 implicated in other diseases (including more severe skeletal dysplasias); symptoms include shortened limbs and facial features; unexplainably high prevalence and de novo mutations suggest other factors (such as positive selection of sperm) may influence the prevalence of the disease [11, 6472]
Cornelia de Lange syndrome
(OMIM 122470)
NIPBL (nipped-B homolog) (Drosophila) -2 SD Autosomal dominant; mostly de novo mutations; 1 in 10,000 to 1 in 30,000 live births >80 mutations NIPBL abnormalities reported in 60% of cases; mutations of SMC1A (X-linked) and SMC3 in <6% of cases; maybe involvement of other loci; germline mosaicism implicated; phenotypic heterogeneity, including characteristic facial features, postnatal growth retardation, hirsutism and possible oligodactyly (missing digits); symptoms may approach non-syndromic mental retardation [7377]
Growth hormone insensitivity syndrome (GHIS) (OMIM 262500) GHR (growth hormone receptor) -7 to -3.6 SD Mostly autosomal recessive; rare, 100 to 200 cases reported worldwide mostly in two large cohorts >50 mutations Biochemical and clinical heterogeneity; most severe form (Laron syndrome, effect -7 SD) to partial growth hormone insensitivity (-3.6 SD); one case of autosomal dominant inheritance; probable involvement of other loci as no abnormalities in GHR detected in some patients; symptoms may include severe postnatal growth failure, underdeveloped facial bones and slow motor development [7881]
Geleophysic dysplasia (OMIM 231050) ADAMTSL2 (ADAMTS-like 2) -4.5 SD Autosomal recessive; very rare, 31 reported cases >5 mutations Very similar to Weill-Marchesani syndrome and acromicric dysplasia; missense and nonsense mutations detected in 70% of individuals; possible involvement of other genes; high early childhood mortality (33%) resulting from cardiac and respiratory dysfunctions [82, 83]
Hypochrondroplasia (OMIM 146000) FGFR3 (fibroblast growth factor receptor 3) -3.2 SD Autosomal dominant; assumed mostly de novo mutations with prevalence similar to achondroplasia (that is, 1 in 15,000 to 1 in 40,000 births) >10 mutations Sever hypochondroplasia is similar to mild achondroplasia; most hypochondroplasia cases are associated with alanine-for-asparagine substitution in exon 10 of FGFR3; other mutations account for <2% of cases; suspected involvement of other loci for milder forms of the disorder [8486]
  1. aApproximate effect in standard deviation (SD) units; either the mid-point of the SD range or the mid-point of adult height converted to SD units (assuming mean height 174 cm and SD 7 cm, Australian Bureau of Statistics [61]); when there was no attempt to quantify 'short' or 'tall' stature effect size is assumed to be ± 2 SD; bfor cases reported as rare, the assumed frequency rate is 1/100,000 births. kb, kilobase; OMIM, Online Mendelian Inheritance in Man [87].