Klinische FragestellungKleinwuchs, frühe Kindheit; Differentialdiagnose

NGS +

[Sanger]

Die Körpergröße des Menschen ist ein ausgesprochen polygenes Merkmal mit ~80%iger Erblichkeit. Mehr als 700 häufige genetische Varianten erklären 20% der Größenvariation in der Normalbevölkerung. Kleinwuchs ist definiert als Körpergröße, die 2 Standardabweichungen oder mehr unter der mittleren Körpergröße für Kinder dieses Geschlechts und chronologischen Alters in einer gegebenen Population liegt. Dies entspricht einer Körpergröße, die unter der 2,3-Perzentile liegt. Kleinwuchs wird vor allem im Kleinkindalter auffällig, da hier normalerweise größere Wachstumsschübe ablaufen. Das Ursachen-Spektrum ist außerordentlich heterogen. Zu den endogenen Auslösern zählen genetisch bedingte endokrine Störungen, Chromosomenanomalien, Stoffwechselerkrankungen sowie syndromaler Kleinwuchs. Weitere Ursachen für Kleinwuchs sind familiäre und konstitutionelle Verzögerung von Wachstum und Pubertät. Fast jede schwere Systemerkrankung kann zu reduziertem Wachstum als sekundärer Auswirkung führen. Monogen bedingter Kleinwuchs kann allen klassischen Erbschemata folgen. Weiterhin sind eine Vielzahl von genetischen Syndromen und angeborenen Fehlbildungen mit Kleinwuchs assoziiert. Systematische Phänotypisierung und umfangreiche genetische Tests ermöglichen in >30% der Fälle, die Entstehung des Kleinwuchses zu eruieren. Aber ein unauffälliger genetischer Befund bedeutet keinen sicheren Ausschluss der genetischen Beteiligung.

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

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

• Alias: Short stature, early infantile
• Allelic: Adenocarcinoma of lung, somatic (BRAF)
• Allelic: Adenomas, salivary gland pleomorphic, somatic (PLAG1)
• Allelic: Agammaglobulinemia 7, AR (PIK3R1)
• Allelic: Agammaglobulinemia, XL 1 (BTK)
• Allelic: Aplastic anemia (NBN)
• Allelic: Arteriovenous malformation of the brain, somatic (KRAS)
• Allelic: Beckwith-Wiedemann syndrome (CDKN1C)
• Allelic: Bladder cancer, somatic (FGFR3)
• Allelic: Bladder cancer, somatic (HRAS)
• Allelic: Bladder cancer, somatic (KRAS)
• Allelic: Breast cancer, early-onset, susceptibility to (BRIP1)
• Allelic: Breast cancer, male, susceptibility to (BRCA2)
• Allelic: Breast cancer, somatic (KRAS)
• Allelic: Breast cancer, susceptibility to (PALB2)
• Allelic: Breast cancer, susceptibility to (RAD51)
• Allelic: Breast-ovarian cancer, familial, 2 (BRCA2)
• Allelic: CATSHL syndrome (FGFR3)
• Allelic: Cardiofaciocutaneous syndrome (BRAF)
• Allelic: Cardiofaciocutaneous syndrome 2 (KRAS)
• Allelic: Cardiomyopathy, dilated, 1NN (RAF1)
• Allelic: Cervical cancer, somatic (FGFR3)
• Allelic: Colorectal cancer, somatic (BRAF)
• Allelic: Colorectal cancer, somatic (FGFR3)
• Allelic: Colorectal cancer, somatic (NRAS)
• Allelic: Congenital myopathy with excess of muscle spindles (HRAS)
• Allelic: Crouzon syndrome with acanthosis nigricans (FGFR3)
• Allelic: Epidermal nevus, somatic (NRAS)
• Allelic: Fibromatosis, gingival, 1 (SOS1)
• Allelic: Gastric cancer, somatic (KRAS)
• Allelic: Glioblastoma 3 (BRCA2)
• Allelic: Hypercholesterolemia, familial, modifier of (GHR)
• Allelic: Immunodeficiency 36 (PIK3R1)
• Allelic: Increased responsiveness to growth hormone (GHR)
• Allelic: Juvenile myelomonocytic leukemia (CBL)
• Allelic: LADD syndrome (FGFR3)
• Allelic: Leukemia, acute lymphoblastic (NBN)
• Allelic: Leukemia, acute myeloid, somatic (KRAS)
• Allelic: Leukemia, juvenile myelomonocytic (NF1)
• Allelic: Leukemia, juvenile myelomonocytic, somatic (PTPN11)
• Allelic: Lung cancer, somatic (KRAS)
• Allelic: Medulloblastoma (BRCA2)
• Allelic: Melanocytic nevus syndrome, congenital, somatic (NRAS)
• Allelic: Melanoma, malignant, somatic (BRAF)
• Allelic: Melorheostosis, isolated, somatic mosaic (MAP2K1)
• Allelic: Metachondromatosis (PTPN11)
• Allelic: Mirror movements 2 (RAD51)
• Allelic: Muenke syndrome (FGFR3)
• Allelic: Neurocutaneous melanosis, somatic (NRAS)
• Allelic: Nevus sebaceous or woolly hair nevus, somatic (HRAS)
• Allelic: Nevus, epidermal, somatic (FGFR3)
• Allelic: Nonsmall cell lung cancer, somatic (BRAF)
• Allelic: Oculoectodermal syndrome, somatic (KRAS)
• Allelic: Ovarian carcinoma (RRAS2)
• Allelic: Pancreatic cancer 2 (BRCA2)
• Allelic: Pancreatic cancer, susceptibility to, 3 (PALB2)
• Allelic: Pancreatic carcinoma, somatic (KRAS)
• Allelic: Progressive external ophthalmoplegia with mitoch. DNA deletions, AR 5 (TOP3A)
• Allelic: Prostate cancer (BRCA2)
• Allelic: RAS-associated autoimmune leukoproliferative disorder (KRAS)
• Allelic: RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic (NRAS)
• Allelic: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic (HRAS)
• Allelic: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic (KRAS)
• Allelic: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic (NRAS)
• Allelic: Schwannomatosis-2, susceptibility to (LZTR1)
• Allelic: Spermatocytic seminoma, somatic (FGFR3)
• Allelic: Spitz nevus or nevus spilus, somatic (HRAS)
• Allelic: Thyroid carcinoma, follicular, somatic (HRAS)
• Allelic: Thyroid carcinoma, follicular, somatic (NRAS)
• Allelic: Watson syndrome (NF1)
• Allelic: Wilms tumor (BRCA2)
• Allelic: Xeroderma pigmentosum, group F (ERCC4)
• Allelic: Xeroderma pigmentosum, type F/Cockayne syndrome (ERCC4)
• 3-M syndrome 1 (CUL7)
• 3-M syndrome 2 (OBSL1)
• 3-M syndrome 3 (CCDC8)
• Achondroplasia (FGFR3)
• Acid-labile subunit, deficiency of (IGFALS)
• Acromesomelic dysplasia 1, Maroteaux type (NPR2)
• Beckwith-Wiedemann syndrome (CDKN1C)
• Bloom syndrome (BLM)
• Cardiofaciocutaneous syndrome 3 (MAP2K1)
• Cardiofaciocutaneous syndrome 4 (MAP2K2)
• Congenital disorder of glycosylation, type IIj (COG4)
• Costello syndrome (HRAS)
• DNA damage repair defect [panelapp] (ZNF668)
• Diabetes mellitus, transient neonatal 1 (ZFP57)
• Diets-Jongmans syndrome (KDM3B)
• Epiphyseal chondrodysplasia, Miura type (NPR2)
• FINCA [FIbrosis, Neurodegeneration + Cerebral Angiomatosis] syndrome (NHLRC2)
• Failure to thrive + developmental delay [panelapp] (CCDC186)
• Fanconi anemia, complementation group A (FANCA)
• Fanconi anemia, complementation group B (FANCB)
• Fanconi anemia, complementation group C (FANCC)
• Fanconi anemia, complementation group D1 (BRCA2)
• Fanconi anemia, complementation group D2 (FANCD2)
• Fanconi anemia, complementation group E (FANCE)
• Fanconi anemia, complementation group F (FANCF)
• Fanconi anemia, complementation group G (FANCG)
• Fanconi anemia, complementation group I (FANCI)
• Fanconi anemia, complementation group J (BRIP1)
• Fanconi anemia, complementation group L (FANCL)
• 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, isolated, types IA, IB, II (GH1)
• Growth hormone insensitivity with immune dysregulation 1, AR (STAT5B)
• Growth hormone insensitivity with immune dysregulation 2, AD (STAT5B)
• Growth hormone insensitivity, partial (GHR)
• Growth retardation with deafness + mental retardation due to IGF1 deficiency (IGF1)
• Hydatidiform mole, recurrent, 1 (NLRP7)
• Hypochondroplasia (FGFR3)
• IMAGE syndrome (CDKN1C)
• Infantile liver failure syndrome 2 (NBAS)
• Insulin-like growth factor I, resistance to (IGF1R)
• Intellectual developmental disorder, AD 23 (SETD5)
• Isolated growth hormone deficiency, type III, with agammaglobulinemia (BTK)
• KBG syndrome (ANKRD11)
• Kowarski syndrome (GH1))
• LEOPARD syndrome 1 (PTPN11)
• LEOPARD syndrome 2 (RAF1)
• LEOPARD syndrome 3 (BRAF)
• Langer mesomelic dysplasia (SHOX)
• Laron dwarfism (GHR)
• Leri-Weill dyschondrosteosis (SHOX)
• Mandibuloacral dysplasia progeroid syndrome (MTX2)
• Microcephaly + chorioretinopathy, AR, 2 (PLK4)
• Microcephaly, growth deficiency, development delay, brain malform., face dysmor. [panelapp] (ZNF668)
• Microcephaly, growth restriction, increased sister chromatid exchange 2 (TOP3A)
• Mosaic variegated aneuploidy syndrome 2 (CEP57)
• Mulibrey nanism (TRIM37)
• Multiple congenital abnormalities [panelapp] (FOXP4)
• Muscular dystrophy, congenital hearing loss + ovarian insufficiency syndrome (GGPS1)
• Myopathy, mitochondrial + ataxia (MSTO1)
• Neurodevelopmental disorder [panelapp] (FOXP4)
• Neurodevelopmental disorder with cataracts, poor growth + dysmorphic facies (INTS1)
• Neurodevelopmental disorder with microcephaly, seizures, neonatal cholestasis (VPS50)
• Neurofibromatosis, familial spinal (NF1)
• Neurofibromatosis, type 1 (NF1)
• 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 with loose anagen hair 2 (PPP1CB)
• Noonan syndrome-like disorder with/-out juvenile myelomonocytic leukemia (CBL)
• Noonan syndrome-like with loose anagen hair 1 (SHOC2)
• Pituitary hormone deficiency, combined or isolated, 7 (RNPC3)
• Preimplantation embryonic lethality 2 (PADI6)
• Rothmund-Thomson syndrome, type 1 (ANAPC1)
• SADDAN (FGFR3)
• SHORT syndrome (PIK3R1)
• Saul-Wilson syndrome (COG4)
• Short stature with nonspecific skeletal abnormalities (NPR2)
• Short stature, advanced bone age, with/-out early-onset osteoarthr. and/or osteochondr. diss. (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)
• Syndromic intellectual disability, short stature [panelapp] (RAP1B)
• Thanatophoric dysplasia, type I + II (FGFR3)
• XFE progeroid syndrome (ERCC4)