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)
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 |