Table 1.
Overview of Genetics of Short Stature
| Genes | Function | Disorder | Key Clinical features | * GWA list |
|---|---|---|---|---|
| 1) Defects in intracellular pathways | ||||
| Intracellular signaling pathways | ||||
| FGD1 | Guanine nucleotide exchange factor | Aarskog-Scott (Faciogenital dysplasia) | IUGR, hypertelorism, ptosis, everted lower lip vermilion, joint hyper-extension, finger abnormalities, shawl scrotum [21–23] | No |
| PRKAR1A | Cyclic AMP (cAMP)-dependent regulatory subunit of protein kinase A | Acrodysostosis, type 1 | IUGR, skeletal dysplasia, severe brachydactyly, facial dysostosis, nasal hypoplasia, advanced bone age, obesity, hormone resistance [24] | No |
| PDE4D | Cyclic AMP-specific 3’, 5’-cyclic phospho-diesterase 4D | Acrodysostosis, type 2 | IUGR (variable), skeletal dysplasia, accelerated bone age progression, variable hormone resistance [25] | No |
| GNAS | G protein alpha subunit | Albright hereditary osteodystrophy | IUGR, obesity, round-shaped face, subcutaneous ossifications and brachymetacarpal bone (4th and 5th) [26–28] | Yes |
| RPS6KA3 | Serine/threonine kinase in RAS-MAPK pathway | Coffin-Lowry syndrome | No IUGR, microcephaly, facial dysmorphism, skeletal abnormalities, intellectual disability, hypotonia, X-linked disorder [9–10] | No |
| HRAS | Signal transduction with GTPase activity in RAS-MAPK pathway | Costello (faciocutaneoskeletal syndrome) | No IUGR, delayed development, intellectual disability, distinctive facial features, loose folds of extra skin (especially, hands and feet), flexible joints [11] | No |
| PTPN11, RAF1, BRAF | Protein-tyrosine phosphatase/RAS-MAP kinase regulation | Multiple lentigines syndrome (LEOPARD syndrome) | No IUGR, lentigines, hypertrophic myopathy, electro-cardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, sensorineural deafness [12–16] | Yes (RAF1) |
| NF1 | RAS signal transduction | Neurofibromatosis type 1 | No IUGR, cafe-au-lait spot, malignancy (pheochromocytoma and gastrointestinal stromal tumor), Lisch nodules, osteoporosis [17–18] | No |
| PTPN11, BRAF, SOS1, KRAS, RAF1, NRAS, RASA2, SHOC2, CBL, RIT1 (activating) | Protein-tyrosine phosphatase/RAS-MAP kinase regulation | Noonan Syndrome or Noonan-like syndrome | No IUGR, distinctive facial appearance, a broad or webbed neck, congenital heart defects, coagulopathy, skeletal malformations, developmental delay [11, 19–20] | Yes (RAF1) |
| ROR2, WNT5A, DVL1 | Cell surface receptor, secreted signaling protein | Robinow syndrome (acral dysostosis with facial and genital abnormalities) | IUGR (variable), short-limb dwarfism, costovertebral segmentation defects, abnormalities of head, face and external genitalia, chest deformities, rib fusions, scoliosis, brachydactyly, aplasia/hypoplasia of the phalanges and metacarpal/metatarsal bones [29–32] | Yes (WNT5A) |
| Transcriptional regulation | ||||
| LARP7 | Transcriptional regulator of polymerase II genes | Alazami syndrome | IUGR (variable), facial dysmorphism (triangular face), intellectual disability, tendon or skeletal abnormalities [48–49] | No |
| SOX9 | Chondrocyte differentiation factor | Campomelic dysplasia | IUGR, born with bowing of the long bones, short legs, dislocated hips, ambiguous genitalia, distinctive facial features [39–41] | Yes |
| BRF1 | RNA polymerase III transcription initiation factor | Cerebello-facio-dental syndrome | IUGR, facial dysmorphism, hypoplastic cerebellum, markedly delayed bone age [50] | No |
| SOX11 | Transcriptional regulation of GDF5 | Coffin-Siris syndrome | IUGR (variable), mental retardation, facial dysmorphism, hearing or vision impairment, severe scoliosis [51] | No |
| MLL2 (KMT2D), KDM6A | Histone methyltransferase/3 Histone demethylase | Kabuki syndrome | IUGR (variable), facial features that resemble the make-up worn by actors of kabuki (long eye openings slanting upwards, arched eyebrows, prominent ears, and corners of the mouth turning downwards), mild to moderate intellectual disability, problems involving heart, skeleton, teeth, and immune system [45–47] | No |
| ANKRD11 | Transcription regulator | KBG syndrome | IUGR (variable), facial dysmorphism, hearing loss, congenital heart defect, skeletal anomalies, global developmental delay, seizures, intellectual disability [52–53] | No |
| SHOX | Transcription factor | Leri-Weill dyschondrosteosis, mesomelic dysplasia (Langer type) | No IUGR, skeletal dysplasia, Madelung deformity [42–44] | No |
| CREBBP, EP300 | Transcriptional coactivator | Rubinstein-Taybi syndrome | IUGR (variable), facial dysmorphism, moderate to severe intellectual disability, broad thumbs and first toes [54–55] | Yes (CREBBP) |
| DNA repair | ||||
| BLM | DNA repair enzyme | Bloom syndrome | IUGR (as case report), increased risk of cancer, sun-sensitive skin changes on face, hands and/or arms, a high-pitched voice, distinctive facial features including a long, narrow face, small lower jaw, large nose and prominent ears [72–73] | No |
| ERCC6, ERCC8 | DNA repair | Cockayne syndrome | IUGR (variable), microcephaly, photosensitivity progeroid appearance, progressive pigmentary retinopathy, sensorineural deafness [74–75] | No |
| FANCA, FANCC, FANCG | DNA repair | Fanconi anemia | IUGR, absence of thumb, hyperpigmentation, early onset bone marrow failure, predisposition to cancers [56] | Yes (FANCA) |
| LIG4 | DNA repair | LIG 4 syndrome | No IUGR, distinctive facial features, microcephaly, pancytopenia, various skin abnormalities, immune deficiency [69] | No |
| NSMCE2 | DNA repair | Microcephalic primordial dwarfism-insulin resistance syndrome | No IUGR reported, microcephaly, insulin resistance [76] | No |
| NBN (NBS1) | DNA repair | Nijmegan breakage syndrome | No IUGR, microcephaly, distinctive facial features, immunodeficiency, and cancer predisposition [70–71] | No |
| SMARCAL1 | DNA repair | Schimke immunoosseous dysplasia | IUGR, kidney disease, immune deficiency, stroke, bone marrow failure, kidney failure [77] | No |
| ATR, ATRIP, CENPJ, CEP152, CEP63, DNA2, PCNT, PLK4, RBBP8, XRCC4 | DNA repair, centrosome maintenance, DNA stability | Seckel syndrome | IUGR, microcephaly, beak-like protrusion of nose, facial dysmorphism [56–66] | Yes (DNA2) |
| Other fundamental cellular processes | ||||
| CUL7, OBSL1, CCDC8 | Microtubule stabilization and genome stability | 3-M syndrome | IUGR, facial dysmorphism (triangular face), relatively large head circumference, prominent fleshy heels [78–80] | No |
| ALMS1 | Microtubule organization | Alström syndrome | No IUGR, vision and hearing abnormalities, childhood obesity, diabetes mellitus, heart disease and slowly progressive kidney dysfunction [96] | No |
| SMARCB1, SMARCE1, SMARCA4, ARID1A, ARID1B | Chromatin remodeling | Coffin-Siris syndrome | IUGR (variable), mental retardation, facial dysmorphism, hearing or vision impairment, severe scoliosis [89] | Yes (ARD1B) |
| NIPBL (50%), SMC1A, HDAC8, RAD21, SMC3, | Cohesin pathway (sister chromatid cohesion) | Cornelia de Lange syndrome | IUGR, dysmorphic facial features (facial hirsutism), microcephaly, limb reduction defects, cardiac defect, and intellectual disability [81] | Yes (NIPBL) |
| SRCAP | Chromatin remodeling | Floating-Harbor syndrome | IUGR (variable), facial dysmorphism, abnormal thumb, delayed bone age, early puberty, delay in expressive language [86–88] | No |
| LMNA | Nuclear stability | Hutchinson-Gilford Progeria | No IUGR, failure to thrive, distinctive facial features (aged-looking skin), alopecia, loss of subcutaneous fat, joint abnormalities [82–83] | No |
| RNU4ATAC | Minor intron splicing | MOPD I | IUGR, microcephaly, dysmorphic face, skin and skeletal abnormalities, developmental delay [90–91] | No |
| PCNT | Mitotic spindle/chromosome segregation | MOPD II | IUGR, facial dysmorphism, microcephaly, near normal intelligence, cancer susceptibility [67–68] | No |
| TRIM37 | Persoxisomal protein, possibly ubiquitin-dependent degradation | Mulibrey nanism | IUGR, dysmorphic craniofacial features, heart disease (constrictive pericardium), hepatomegaly, Wilms tumor [92–94] | No |
| CRIPT | Interaction with cytoskeleton | Primordial dwarfism | IUGR (not established), facial dysmorphism, microcephaly, ophthalmological abnormalities, intellectual disabilities, skeletal abnormalities, pigmentation abnormalities [95] | No |
| POC1A | Centriole assembly/ciliogenesis | SOFT syndrome | IUGR, disproportionate short stature, onychodysplasia, facial dysmorphism, and hypotrichosis [84–85] | No |
| DHCR7 | Steroid biosynthesis | Smith-Lemli-Opitz syndrome | IUGR, distinctive facial features, microcephaly, intellectual disability or learning problems, behavioral problems, malformations of heart, lungs, kidneys, gastrointestinal tract, and genitalia [97] | No |
| 2) Defects in cartilage extracellular matrix | ||||
| COL2A1 | Extracellular matrix, collagen | Achondrogenesis (Type II), hypochondrogenesis, Kniest dysplasia, Spondylo-epiphyseal dysplasia congenita, Stickler syndrome type 1 | IUGR, skeletal abnormalities and problems with vision and hearing [101–102] | No |
| FBN1 | Extracellular matrix, fibrillin 1 | Acromicric dysplasia, Geleophysic dysplasia 2 | No IUGR, short hands and feet, thickened skin and joint contractures, limited range of motion in fingers, toes, wrists, and elbows, cardiac issue [109] | Yes |
| COL11A1 | Extracellular matrix, collagen 11 | Fibrochondrogenesis | IUGR (variable), skeletal dysplasia, broad long bone metaphyses, pear-shaped vertebral bodies, flat midface with a small nose and anteverted nares, significant shortening of all limb segments [103] | Yes |
| COL10A1 | Extracellular matrix, collagen 10 | Metaphyseal dysplasia, Schmid type | No IUGR, coxa vara, relatively short limbs, bow legs, waddling gait [104] | No |
| MATN3, COL9A1, COL9A2, COL9A3 | Extracellular matrix, cartilage oligomeric matrix protein, collagen, matrillin-3 | Multiple epiphyseal dysplasia | No IUGR, skeletal dysplasia, Joint pain, joint deformity, waddling gait [105–108, 112] | Yes (COL9A2) |
| COMP | Extracellular matrix, cartilage oligomeric matrix protein | Multiple epiphyseal dysplasia, Pseudoachondroplasia | No IUGR, short arms and legs, a waddling walk, early-onset joint pain (osteoarthritis), limited range of motion at elbows and hips [110–111] | No |
| HSPG2 | Extracellular matrix, perlecan | Schwartz-Jampel syndrome | IUGR (not established), permanent myotonia (prolonged failure of muscle relaxation), skeletal dysplasia, kyphoscoliosis, bowing of diaphyses and irregular epiphyses [115] | No |
| ACAN | Extracellular matrix, aggrecan | Sponyloepimetaphyseal dysplasia, aggrecan/Kimberly type | IUGR, macrocephaly, severe midface hypoplasia, short neck, barrel chest, brachydactyly, advanced bone age [113–114] | Yes |
| 3) Defects in paracrine signaling | ||||
| FGFR3 (activating) | Fibroblast growth factor receptor | Achondroplasia, hypochondroplasia | IUGR, short upper arms and thighs, limited range of motion at elbows, relative macrocephaly with a prominent forehead, trident hand [119–121] | No |
| IHH | Secreted signaling molecule, Indian hedgehog | Acrocapitofemoral dysplasia, Brachydactyly, type A1 | No IUGR, brachydactyly [129] | No |
| NPR2 (inactivating) | CNP receptor | Acromesomelic dysplasia, Maroteaux type | IUGR (variable), short limbs and hand/foot malformations [126] | Yes |
| BMPR1B, GDF5 | BMP receptor/interacting protein (ligand) | Brachydactyly, type A1 and A2 | No IUGR, brachydactyly [135–136] | Yes (GDF5) |
| PTHLH | Secreted signaling molecules (PTH-related protein) | Brachydactyly, type E2 | No IUGR, shortening of fingers mainly in metacarpals and metatarsals [130–131] | No |
| IGF2 | Secreted signaling molecule (insulin-like growth factor-II) | IGF2 deficiency | IUGR, Silver-Russel like facies [137] | No |
| PTH1R | PTH and PTHrP receptor | Metaphyseal chondrodysplasia (Jansen type), Eikan Dysplasia, Chondrodysplasia (Blomstrand type) | No IUGR, skeletal dysplasia, micrognathia, failure of tooth eruption, low-set/posteriorly rotated ears, proptosis [132–133] | No |
| 4) Defects in endocrine ligands, receptors, and signaling pathways | ||||
| IGFALS | Acid labile subunit | ALS deficiency | IUGR (variable), low IGF-1 and IGF-BP3 [148–149] | No |
| GH1, GHRHR, SOX3, BTK | Growth hormone production | GH deficiency | No IUGR, GH deficiency [138] | No |
| IGF1 | IGF-1 | IGF1 deficiency | IUGR, microcephaly, mental retardation, low IGF-1 level [143–144] | No |
| IGF1R | Insulin-like growth factor receptor | IGF-1 insensitivity | IUGR, normal to high IGF-1 level [145–147] | Yes |
| STAT5B | Growth hormone signaling | Immune deficiency and GH resistance | No IUGR, elevated random GH but low IGF-1 or IGFBP-3, immunodeficiency [142] | No |
| GHR | Growth hormone receptor | Laron syndrome | IUGR, elevated growth hormone and low IGF-1[139–141] | No |
*
670 height–associated SNPs according to GWA study by Wood et al [5]