IllnessDwarfism, infants; differential diagnosis

NGS +

[Sanger]

Human height is a distinctly polygenic trait with ~80% heritability. More than 700 common genetic variants explain some 20% of the height variation in the normal population. Short stature is defined as a height that is 2 standard deviations or more below the mean height for children of that sex and chronological age in a given population. This corresponds to a height that is below the 2.3rd percentile. Short stature becomes most noticeable in infancy, as this is when larger growth spurts normally occur. The spectrum of causes is extraordinarily heterogeneous. Endogenous triggers include genetic endocrine disorders, chromosomal abnormalities, metabolic disorders and syndromal short stature. Other causes of short stature include familial and constitutional delay of growth and puberty. Almost any severe systemic disease can result in reduced growth as a secondary effect. Monogenic short stature can follow any of the classical hereditary schemes. Furthermore, a variety of genetic syndromes and congenital malformations are associated with short stature. Systematic phenotyping and extensive genetic testing allow elucidation of the origin of short stature in >30% of cases. But an inconspicuous genetic finding does not mean a definite exclusion of genetic involvement.

References: https://www.ncbi.nlm.nih.gov/books/NBK1215/

https://pubmed.ncbi.nlm.nih.gov/28476223/

• Alias: Short stature, infantile
• Allelic: Beckwith-Wiedemann syndrome (CDKN1C)
• Allelic: Bladder cancer, somatic (FGFR3)
• Allelic: Breast cancer, susceptibility to (RAD51)
• Allelic: CATSHL syndrome (FGFR3)
• Allelic: Cervical cancer, somatic (FGFR3)
• Allelic: Colorectal cancer, somatic (FGFR3)
• Allelic: Crouzon syndrome with acanthosis nigricans (FGFR3)
• Allelic: Fibromatosis, gingival, 1 (SOS1)
• Allelic: Hydatidiform mole, recurrent, 1 (NLRP7)
• Allelic: Hypercholesterolemia, familial, modifier of (GHR)
• Allelic: Increased responsiveness to growth hormone (GHR)
• Allelic: LADD syndrome (FGFR3)
• Allelic: Leri-Weill dyschondrosteosis (SHOX)
• Allelic: Leukemia, juvenile myelomonocytic (NF1)
• Allelic: Leukemia, juvenile myelomonocytic, somatic (PTPN11)
• Allelic: Metachondromatosis (PTPN11)
• Allelic: Mirror movements 2 (RAD51)
• Allelic: Muenke syndrome (FGFR3)
• Allelic: Multi Locus Imprinting Disturbance (PADI6)
• Allelic: Neurofibromatosis, familial spinal (NF1)
• Allelic: Neurofibromatosis, type 1 (NF1)
• Allelic: Nevus, epidermal, somatic (FGFR3)
• Allelic: Oocyte/zygote/embryo maturation arrest 16 (PADI6)
• Allelic: Oocyte/zygote/embryo maturation arrest 18 (NLRP2)
• Allelic: Preimplantation embryonic lethality 2 [MONDO:0014978, panelapp] (PADI6)
• Allelic: SADDAN (FGFR3)
• Allelic: Spermatocytic seminoma, somatic (FGFR3)
• Allelic: Thanatophoric dysplasia, type I-II (FGFR3)
• Allelic: Watson syndrome (NF1)
• 3-M syndrome 1 (CUL7)
• 3-M syndrome 2 (OBSL1)
• 3-M syndrome 3 (CCDC8)
• Aarskog-Scott syndrome (FGD1)
• Achondroplasia (FGFR3)
• Acid-labile subunit, deficiency of (IGFALS)
• Acromesomelic dysplasia, Maroteaux type (NPR2)
• Allelic: Infantile liver failure syndrome 2 (NBAS)
• Allelic: Ovarian carcinoma (RRAS2)
• Bloom syndrome (BLM)
• Cardiofaciocutaneous syndrome (BRAF)
• Cardiofaciocutaneous syndrome 2 (KRAS)
• Cardiofaciocutaneous syndrome 3 (MAP3K1)
• Cardiofaciocutaneous syndrome 4 (MAP2K2)
• Cerebrooculofacioskeletal syndrome 1 (ERCC6)
• Cockayne syndrome (ERCC4)
• Cockayne syndrome, type A (ERCC8)
• Cockayne syndrome, type B (ERCC6)
• Coffin-Lowry syndrome (RPS6KA3)
• Cornelia de Lange syndrome 1 (NIPBL)
• Cornelia de Lange syndrome 2 (SMC1A)
• Cornelia de Lange syndrome 3 (SMC3)
• Cornelia de Lange syndrome 4 (RAD21)
• Cornelia de Lange syndrome 5 (HDAC8)
• Costello syndrome (HRAS)
• Crouzon syndrome with acanthosis nigricans (FGFR3)
• Culler-Jones syndrome (GLI2)
• De Sanctis-Cacchione syndrome (ERCC6)
• Diabetes mellitus, transient neonatal 1 (ZFP57)
• Diabetes mellitus, transient neonatal, 1; IUGR [MONDO:0011073] (ZFP57)
• Diets-Jongmans syndrome (KDM3B)
• Encephalopathy, progressive, with amyotrophy + optic atrophy (TBCE)
• Epiphyseal chondrodysplasia, Miura type (NPR2)
• Epiphyseal dysplasia, multiple, 6 (COL9A1)
• FINCA syndrome: FIbrosis, Neurodegeneration +Cerebral Angiomatosis (NHLRC2)
• Failure to thrive, developmental delay [panelapp] (CCDC186)
• Fanconi anemia, complementation group A-L (FANCA-L)
• Fanconi anemia, complementation group D1 (BRCA2)
• Fanconi anemia, complementation group J (BRIP1)
• Fanconi anemia, complementation group N (PALB2)
• Fanconi anemia, complementation group P (SLX4)
• Fanconi anemia, complementation group Q (ERCC4)
• Fanconi anemia, complementation group R (RAD51)
• Fanconi anemia, complementation group T (UBE2T)
• Floating-Harbor syndrome (SRCAP)
• Growth hormone deficiency with pituitary anomalies (HESX1)
• Growth hormone deficiency, isolated, type IA, IB, II (GH1)
• Growth hormone deficiency, isolated, type IV (GHRHR)
• Growth hormone insensitivity, partial (GHR)
• Growth retardation with deafness and mental retardation due to IGF1 deficiency (IGF1)
• Holoprosencephaly 9 (GLI2)
• Hypochondroplasia (FGFR3)
• Hypoparathyroidism-retardation-dysmorphism syndrome (TBCE)
• IMAGE syndrome (CDKN1C)
• IUGR phenotypes caused by maternal effect gene IUGR [panelapp] (NLRP2)
• Insulin-like growth factor I, resistance to (IGF1R)
• Intellectual developmental disorder, AD 23 (SETD5)
• Intellectual developmental disorder, XL 19 (RPS6KA3)
• Intellectual developmental disorder, XL, syndromic, 35 (RPL10)
• Intellectual developmental disorder, XL, with isolated growth hormone deficiency (SOX3)
• Isolated growth hormone deficiency due to defect in GHRF (GHRH) 1
• Isolated growth hormone deficiency, type III, with agammaglobulinemia (BTK)
• KBG syndrome (ANKRD11)
• Kabuki syndrome 1 (KMT2D)
• Kabuki syndrome 2 (KDM6A)
• Kenny-Caffey syndrome, type (TBCE)
• Kowarski syndrome (GH1)
• LEOPARD syndrome 1 (PTPN11)
• LEOPARD syndrome 2 (RAF1)
• LEOPARD syndrome 3 (BRAF)
• LIG4 syndrome (LIG4)
• Langer mesomelic dysplasia (SHOX)
• Laron dwarfism (GHR)
• Laurence-Moon syndrome (PNPLA6)
• Leprechaunism (INSR)
• Leri-Weill dyschondrosteosis (SHOX)
• Lowry-Wood syndrome (RNU4ATAC)
• MIRAGE syndrome (SAMD9)
• Mandibuloacral dysplasia progeroid syndrome (MTX2)
• Meier-Gorlin syndrome 1 (ORC1)
• Meier-Gorlin syndrome 2 (ORC4)
• Meier-Gorlin syndrome 3 (ORC6)
• Meier-Gorlin syndrome 4 (CDT1)
• Meier-Gorlin syndrome 5 (CDC6)
• Mental retardation, XL syndromic 16 (FGD1)
• Metachondromatosis (PTPN11)
• Microcephalic osteodysplastic dysplasia, Saul-Wilson type [MONDO:0019407, panelapp] (ANAPC1)
• Microcephalic osteodysplastic primordial dwarfism, type I (RNU4ATAC)
• Microcephalic osteodysplastic primordial dwarfism, type II (PCNT)
• Microcephaly and chorioretinopathy, AR, 2 (PLK4)
• Microcephaly, growth restriction + increased sister chromatid exchange 2 (TOP3A)
• Microphthalmia, syndromic 3 (SOX2)
• Mulibrey nanism (TRIM37)
• Muscular dystrophy, congenital hearing loss, ovarian insufficiency syndrome (GGPS1)
• Myopathy, mitochondrial + ataxia (MSTO1)
• Neurodevelopmental disorder with microcephaly, seizures, neonatal cholestasis (VPS50)
• Neurodevelopmental disorder, cataracts, poor growth, dysmorphic facies (INTS1)
• Neurodevelopmental disorder, multiple congenital abnormalities (FOXP4)
• Neurodevelopmental disorder, poor growth, large ears, dysmorphic face (ZNF668)
• Neurofibromatosis-Noonan syndrome (NF1)
• Nijmegen breakage syndrome (NBN)
• Noonan syndrome 1 (PTPN11)
• Noonan syndrome 10 (LZTR1)
• Noonan syndrome 11 (MRAS)
• Noonan syndrome 12 (RRAS2)
• Noonan syndrome 13 (MAPK1)
• Noonan syndrome 14 (SPRED2)
• Noonan syndrome 2 (LZTR1)
• Noonan syndrome 3 (KRAS)
• Noonan syndrome 4 (SOS1)
• Noonan syndrome 5 (RAF1)
• Noonan syndrome 6 (NRAS)
• Noonan syndrome 7 (BRAF)
• Noonan syndrome 8 (RIT1)
• Noonan syndrome 9 (SOS2)
• Noonan syndrome [panelapp] (RASA2)
• Noonan syndrome-like disorder +/- juvenile myelomonocytic leukemia (CBL)
• Noonan syndrome-like disorder with loose anagen hair 2 (PPP1CB)
• Noonan syndrome-like with loose anagen hair 1 (SHOC2)
• Pituitary hormone deficiency, combined or isolated, 7 (RNPC3)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 5 (TOP3A)
• Rabson-Mendenhall syndrome (INSR)
• Robinow syndrome, AD 1 (WNT5A)
• Rothmund-Thomson syndrome, type 1 (ANAPC1)
• SADDAN (FGFR3)
• SHORT syndrome (PIK3R1)
• Short stature with microcephaly and distinctive facies (CRIPT)
• Short stature with nonspecific skeletal abnormalities (NPR2)
• Short stature, IUGR [panelapp] (PADI6)
• Short stature, IUGR, failure to thrive, body asymmetry [panelapp] (NLRP5)
• Short stature, IUGR, fetal wastage [panelapp] (NLRP7)
• Short stature, advanced bone age, early-onset osteoarthritis and/or osteochondritis dissecans (ACAN)
• Short stature, idiopathic familial (SHOX)
• Short stature, optic nerve atrophy +Pelger-Huet anomaly (NBAS)
• Silver-Russell syndrome 3 (IGF2)
• Silver-Russell syndrome 4 (PLAG1)
• Silver-Russell syndrome 5 (HMGA2)
• Spondyloepimetaphyseal dysplasia, aggrecan type (ACAN)
• Spondyloepiphyseal dysplasia, Kimberley type (ACAN)
• Stickler syndrome, type IV (COL9A1)
• Syndromic ID, short stature [panelapp] (RAP1B)
• Thanatophoric dysplasia, type I + II (FGFR3)
• XFE progeroid syndrome (ERCC4)