Klinische FragestellungMentale Retardierung bei Kleinwuchs, Differentialdiagnose

NGS +

[Sanger]

Die meisten Kinder mit Kleinwuchs haben mittlere Testwerte für Intelligenz und Verhalten. Doch von >1100 genetischen Syndromen mit Kleinwuchs sind zwei Drittel mit mentaler Retardierung verbunden. Genetische Ursachen können für ein erhöhtes Risiko für Kinder mit Kleinwuchs verantwortlich sein, intellektuelle Defizite aufzuweisen. Prominente Beispiele hierfür sind das Noonan-, das LEOPARD- (Noonan-Syndrom mit multiplen Lentigines) und das kraniofaziokutane Syndrom sowie zahlreiche noch viel seltenere Erkrankungen. Die meisten der definierten Syndrome mit den Symptomen des Kleinwuchses und intellektueller Defizite werden autosomal-dominant, seltener autosomal-rezessiv vererbt. Während die DNA-Diagnoseausbeute beim Noonan-Syndrom bei über 80% liegt, ist sie bei den anderen Syndromen mit der gleichen Kombination von Kardinalsymptomen geringer bzw. bei den meisten echten Orphan-Krankheiten praktisch unbekannt.

Referenzen: https://www.ncbi.nlm.nih.gov/books/NBK1124/

https://www.ncbi.nlm.nih.gov/books/NBK1383/

https://www.ncbi.nlm.nih.gov/books/NBK1186/

• Alias: Intellectual deficit + small stature
• Alias: Intellectual disability + short stature
• Alias: Psycho-motor retardation + short stature
• Allelic: Adenocarcinoma of lung, somatic (BRAF)
• Allelic: Arteriovenous malformation of the brain, somatic (KRAS)
• Allelic: Autism susceptibility, XL 3 (MECP2)
• Allelic: Bladder cancer, somatic (HRAS)
• Allelic: Bladder cancer, somatic (KRAS)
• Allelic: Breast cancer, somatic (KRAS)
• Allelic: Breast cancer, susceptibility to (RAD51)
• Allelic: Cardiomyopathy, dilated, 1NN (RAF1)
• Allelic: Colorectal cancer, somatic (BRAF)
• Allelic: Colorectal cancer, somatic (NRAS)
• Allelic: Congenital myopathy with excess of muscle spindles (HRAS)
• Allelic: Epidermal nevus, somatic (NRAS)
• Allelic: Fibromatosis, gingival, 1 (SOS1)
• Allelic: Gastric cancer, somatic (KRAS)
• Allelic: Hyperphenylalaninemia, non-PKU mild (PAH)
• Allelic: Infantile liver failure syndrome 2 (NBAS)
• Allelic: Intellectual developmental disorder, XL 19 (RPS6KA3)
• Allelic: Juvenile myelomonocytic leukemia (CBL)
• Allelic: Leukemia, acute myeloid, somatic (KRAS)
• Allelic: Leukemia, juvenile myelomonocytic (NF1)
• Allelic: Leukemia, juvenile myelomonocytic, somatic (PTPN11)
• Allelic: Lung cancer, somatic (KRAS)
• 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: Neurocutaneous melanosis, somatic (NRAS)
• Allelic: Neurofibromatosis, familial spinal (NF1)
• Allelic: Neurofibromatosis, type 1 (NF1)
• Allelic: Nevus sebaceous or woolly hair nevus, somatic (HRAS)
• Allelic: Nonsmall cell lung cancer, somatic (BRAF)
• Allelic: Pancreatic carcinoma, somatic (KRAS)
• Allelic: Pigmentary disorder, reticulate, with systemic manifestations, XL (POLA1)
• Allelic: RAS-associated autoimmune leukoproliferative disorder (KRAS)
• Allelic: RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic (NRAS)
• Allelic: Schwannomatosis-2, susceptibility to (LZTR1)
• Allelic: Spitz nevus or nevus spilus, somatic (HRAS)
• Allelic: Thyroid carcinoma, follicular, somatic (HRAS, NRAS)
• Alzahrani-Kuwahara syndrome (SMG8)
• Bloom syndrome (BLM)
• Cardiofaciocutaneous syndrome (BRAF)
• Cardiofaciocutaneous syndrome 2 (KRAS)
• Cardiofaciocutaneous syndrome 3 (MAP2K1)
• Cardiofaciocutaneous syndrome 4 (MAP2K2)
• Coffin-Lowry syndrome (RPS6KA3)
• Congenital disorder of glycosylation, type IIj (COG4)
• Costello syndrome (HRAS)
• Developmental delay, short stature, dysmorphic facial features + sparse hair (DPH1)
• Diamond-Blackfan anemia 21 (HEATR3)
• Diets-Jongmans syndrome (KDM3B)
• Encephalopathy, neonatal severe (MECP2)
• Failure to thrive and developmental delay (CCDC186)
• Fanconi anemia, complementation group P (SLX4)
• Fanconi anemia, complementation group R (RAD51)
• Floating-Harbor syndrome (SCAP)
• Growth retardation with deafness and mental retardation due to IGF1 deficiency (IGF1)
• Hypogonadotropic hypogonadism 14 with/-out anosmia (WDR11)
• ID, autistism, seizures, microcephaly, short stature, abnormal skeletal system [panelapp] (UBAP2L)
• Immunodeficiency 23: ID, skeletal dysplasia, short stature, brachydactyly, facial features... (PGM3)
• Insulin-like growth factor I, resistance to (IGF1R)
• Intellectual developmental disorder, AD 23 (SETD5)
• Intellectual developmental disorder, X-linked syndromic, Lubs type (MECP2)
• Intellectual developmental disorder, XL, isolated growth hormone deficiency (SOX3)
• Intellectual developmental disorder, XL, syndromic 13 (MECP2)
• Intellectual developmental disorder, abnormal behavior, microcephaly + short stature (PUS7)
• Intellectual developmental disorder, short stature + behavioral abnormalities (IQSEC1)
• Intellectual developmental disorder, short stature, facial anomalies + speech defects (FBXL3)
• Intellectual developmental disorder, short stature, variable skeletal anomalies (WIPI2)
• KBG syndrome (ANKRD11)
• Koolen-De Vries syndrome (KANSL1)
• LEOPARD syndrome 1 (PTPN11)
• LEOPARD syndrome 2 (RAF1)
• LEOPARD syndrome 3 (BRAF)
• Leukodystrophy, hypomyelinating, 26, with chondrodysplasia (SLC35B)
• Menke-Hennekam syndrome 1 (CREBBP)
• Microcephaly and chorioretinopathy, AR, 2 (PLK4)
• Microcephaly, short stature + impaired glucose metabolism 1 (TRMT10A)
• Microcephaly, short stature + impaired glucose metabolism 2 (PPP1R15B)
• Microcephaly, short stature + limb abnormalities (DONSON)
• Microcephaly, short stature, polymicrogyria + seizures (RTTN)
• Microcephaly-micromelia syndrome (DONSON)
• Mosaic variegated aneuploidy syndrome 2 (CEP57)
• Neurodevelopmental disorder with cataracts, poor growth, dysmorphic facies (INTS1)
• Neurodevelopmental disorder with microcephaly, movement abnormalities, seizures (CHKA)
• Neurodevelopmental disorder with microcephaly, seizures, neonatal cholestasis (VPS50)
• Neurodevelopmental disorder with microcephaly, short stature, speech delay (TRAPPC10)
• Neurodevelopmental disorder with poor growth, large ears, dysmorphic facies (ZNF668)
• Neurodevelopmental disorder with severe motor impairment + absent language (DHX30)
• Neurodevelopmental disorder, dysmorphic facies, sleep disturbance + brain abnormalities (KAT5)
• Neurodevelopmental disorder, multiple congenital abnormalities [panelapp] (FOXP4)
• Neurofibromatosis-Noonan syndrome (NF1)
• Noonan syndrome 1 (PTPN11)
• Noonan syndrome 10 (LZTR1)
• Noonan syndrome 11 (MRAS)
• Noonan syndrome 12 (RRAS2)
• 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-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)
• Oculoectodermal syndrome, somatic (KRAS)
• Panhypopituitarism, XL (SOX3)
• Phenylketonuria (PAH)
• Rett syndrome (MECP2)
• Rett syndrome, atypical (MECP2)
• Rett syndrome, preserved speech variant (MECP2)
• Rubinstein-Taybi syndrome 1 (CREBBP)
• Saul-Wilson syndrome (COG4)
• Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic (HRAS, KRAS, NRAS)
• Short stature, brachydactyly, intellectual developmental disability + seizures (PRMT7)
• Short stature, developmental delay + congenital heart defects (TKT)
• Short stature, macrocephaly, ID + autism spectrum disorder [panelapp] (RHEB)
• Short stature, optic nerve atrophy + Pelger-Huet anomaly (NBAS)
• Short stature, rhizomelic, with microcephaly, micrognathia + developmental delay (ARCN1)
• Smith-Lemli-Opitz syndrome (DHCR7)
• Syndromic intellectual disability, short stature [panelapp] (RAP1B)
• Van Esch-O'Driscoll syndrome (POLA1)
• Watson syndrome (NF1)