Klinische FragestellungMikrozephalie, pränatal und postnatal; Differentialdiagnose

NGS +

[Sanger]

Primäre Mikrozephalie (MCPH) ist eine Störung der Gehirnentwicklung, die dazu führt, dass der okzipitofrontale Kopfumfang signifikant unter dem Mittelwert für (Schwangerschafts-) Alter und Geschlecht liegt. MCPH hat viele nicht-genetische Ursachen, während die genetisch-bedingten Mikrozephalien/Syndrome insgesamt relativ selten sind. Bei Mikrozephalie mutierte Gene kodieren für zentrosomale Proteine (Zentriolen-Biogenese) und viele verschiedene mechanistische Kategorien, insbesondere DNA-Replikation und -Reparatur. Der Schweregrad der Entwicklungsverzögerung/ intellektuellen Behinderung scheint mit dem Schweregrad der primären Mikrozephalie zu korrelieren. Dieses Mikrozephalie panel ist gemäß den Leitlinien (s.u.) zusammengestellt bzw. fasst die relevanten Gene mehrerer Kategorien zusammen. Alle klassischen Erbgänge werden bei Mikrozephalie beobachtet, multifaktorielle Geschehen stehen jedoch ganz im Vordergrund. Die Diagnoseraten schwanken zwischen den Mikrozephalie-Kategorien und sind vordringlich von den klinischen Voruntersuchungsergebnissen abhängig. Ein unauffälliger genetischer Befund bedeutet keinen Ausschluss der klinischen Verdachtsdiagnose.

Referenz: https://www.awmf.org/uploads/tx_szleitlinien/022-028l_S2k_Klassifikation_Diagnostik_Mikrozephalie_2019-11.pdf

• DNA repair disorders + dysmorphism + congenital abnormality syndromes
• Alias: Primary microcephaly - microcephalic dwarfism spectrum
• Allelic: Aplastic anemia (NBN)
• Allelic: Ataxia-oculomotor apraxia 4 (PNKP)
• Allelic: Basal cell nevus syndrome (SUFU)
• Allelic: Breast cancer, susceptibility to (ATM)
• Allelic: Cardiac valvular dysplasia, XL (FLNA)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 20 (DYNC1H1)
• Allelic: Charcot-Marie-Tooth disease, type 2B2 (PNKP)
• Allelic: Chilblain lupus (TREX1)
• Allelic: Chilblain lupus 2 (SAMHD1)
• Allelic: Colorectal cancer, somatic (EP300)
• Allelic: Congenital short bowel syndrome (FLNA)
• Allelic: Cutaneous telangiectasia + cancer syndrome, familial (ATR)
• Allelic: Deafness, AD 20/26 (ACTG1)
• Allelic: Developmental + epileptic encephalopathy 1 (ARX)
• Allelic: Dyschromatosis symmetrica hereditaria (ADAR)
• Allelic: Dystonia, juvenile-onset (ACTB)
• Allelic: Encephalocraniocutaneous lipomatosis, somatic mosaic (FGFR1)
• Allelic: Epilepsy, familial temporal lobe, 7 (RELN)
• Allelic: FG syndrome 2 (FLNA)
• Allelic: FG syndrome 4 (CASK)
• Allelic: Fibrosis of extraocular muscles, congenital, 3A (TUBB3)
• Allelic: Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
• Allelic: Intestinal pseudoobstruction, neuronal (FLNA)
• Allelic: Leukemia, acute lymphoblastic (NBN)
• Allelic: Lymphoma, B-cell non-Hodgkin, somatic (ATM)
• Allelic: Lymphoma, mantle cell, somatic (ATM)
• Allelic: Medulloblastoma, desmoplastic (SUFU)
• Allelic: Meningioma, familial, susceptibility to (SUFU)
• Allelic: Mental retardation, XL 29 + others (ARX)
• Allelic: Mental retardation, with/-out nystagmus (CASK)
• Allelic: Microphthalmia with coloboma 5 (SHH)
• Allelic: Multiple myeloma, resistance to (LIG4)
• Allelic: Otopalatodigital syndrome, type I (FLNA)
• Allelic: Otopalatodigital syndrome, type II (FLNA)
• Allelic: Single median maxillary central incisor (SHH)
• Allelic: Singleton-Merten syndrome 1 (IFIH1)
• Allelic: Spinal muscular atrophy, lower extremity-predominant 1, AD (DYNC1H1)
• Allelic: Symmetric circumferential skin creases, congenital, 1 (TUBB)
• Allelic: Systemic lupus erythematosus, susceptibility to (TREX1)
• Allelic: T-cell prolymphocytic leukemia, somatic (ATM)
• Allelic: Vasculopathy, retinal, with cerebral leukoencephalopathy + systemic manifestations (TREX1)
• Aicardi-Goutieres syndrome 1, AD + AR (TREX1)
• Aicardi-Goutieres syndrome 2 (RNASEH2B)
• Aicardi-Goutieres syndrome 3 (RNASEH2C)
• Aicardi-Goutieres syndrome 4 (RNASEH2A)
• Aicardi-Goutieres syndrome 5 (SAMHD1)
• Aicardi-Goutieres syndrome 6 (ADAR)
• Aicardi-Goutieres syndrome 7 (IFIH1)
• Angelman syndrome (UBE3A)
• Ataxia-telangiectasia (ATM)
• Baraitser-Winter syndrome 1 (ACTB)
• Baraitser-Winter syndrome 2 (ACTG1)
• Beaulieu-Boycott-Innes syndrome (THOC6)
• Cerebellar hypoplasia + mental retardation with/-out quadrupedal locomotion 1 (VLDLR)
• Cerebrooculofacioskeletal syndrome 1 (ERCC6)
• Cockayne syndrome, type A (ERCC8)
• Cockayne syndrome, type B (ERCC6)
• 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)
• Cortical dysplasia, complex, with other brain malformations 1 (TUBB3)
• Cortical dysplasia, complex, with other brain malformations 2 (KIF5C)
• Cortical dysplasia, complex, with other brain malformations 3 (KIF2A)
• Cortical dysplasia, complex, with other brain malformations 4 (TUBG1)
• Cortical dysplasia, complex, with other brain malformations 5 (TUBB2A)
• Cortical dysplasia, complex, with other brain malformations 6 (TUBB)
• Cortical dysplasia, complex, with other brain malformations 7 (TUBB2B)
• Culler-Jones syndrome (GLI2)
• De Sanctis-Cacchione syndrome (ERCC6)
• Developmental + epileptic encephalopathy 2 (CDKL5)
• Developmental + epileptic encephalopathy 85, with/-out midline brain defect (SMC1A)
• Feingold syndrome 1 (MYCN)
• Filippi syndrome (CKAP2L)
• Frontometaphyseal dysplasia 1 (FLNA)
• Growth hormone deficiency with pituitary anomalies (HESX1)
• Hartsfield syndrome (FGFR1)
• Heterotaxy, visceral, 5 (NODAL)
• Heterotopia, periventricular, 1 (FLNA)
• Holoprosencephaly 11 (CDON)
• Holoprosencephaly 2 (SIX3)
• Holoprosencephaly 3 (SHH)
• Holoprosencephaly 4 (TGIF1)
• Holoprosencephaly 5 (ZIC2)
• Holoprosencephaly 7 (PTCH1)
• Holoprosencephaly 9 (GLI2)
• Holoprosencephaly [MONDO:0016296] (DISP1)
• Hydranencephaly with abnormal genitalia (ARX)
• Hypogonadotropic hypogonadism 6 with/-out anosmia (FGF8)
• Jackson-Weiss syndrome (FGFR1)
• Joubert syndrome 32 (SUFU)
• LIG4 syndrome (LIG4)
• Lissencephaly 1 (PAFAH1B1)
• Lissencephaly 2 [Norman-Roberts type] (RELN)
• Lissencephaly 3 (TUBA1A)
• Lissencephaly 4 [with microcephaly] (NDE1)
• Lissencephaly 6, with microcephaly (KATNB1)
• Lissencephaly 7 with cerebellar hypoplasia (CDK5)
• Lissencephaly, XL (DCX)
• Lissencephaly, XL 2 (ARX)
• Lowry-Wood syndrome (RNU4ATAC)
• Mandibulofacial dysostosis, Guion-Almeida type (EFTUD2)
• Martsolf syndrome 1 (RAB3GAP2)
• Martsolf syndrome 2 (RAB3GAP1)
• 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)
• Melnick-Needles syndrome (FLNA)
• Menke-Hennekam syndrome 1 (CREBBP)
• Menke-Hennekam syndrome 2 (EP300)
• Mental retardation + microcephaly with pontine + cerebellar hypoplasia (CASK)
• Mental retardation, AD 13 (DYNC1H1)
• Mental retardation, XL syndromic, Christianson type (SLC9A6)
• Microcephalic osteodysplastic primordial dwarfism, type I (RNU4ATAC)
• Microcephalic osteodysplastic primordial dwarfism, type II (PCNT)
• Microcephaly + chorioretinopathy, AR, 1 (TUBGCP6)
• Microcephaly + chorioretinopathy, AR, 2 (PLK4)
• Microcephaly 1, primary, AR (MCPH1)
• Microcephaly 2, primary, AR, with/-out cortical malformations (WDR62)
• Microcephaly 3, primary, AR (CDK5RAP2)
• Microcephaly 4, primary, AR (KNL1)
• Microcephaly 5, primary, AR (ASPM)
• Microcephaly 6, primary, AR (CENPJ)
• Microcephaly 7, primary, AR (STIL)
• Microcephaly 9, primary, AR (CEP152)
• Microcephaly with/-out chorioretinopathy, lymphedema or mental retardation (KIF11)
• Microcephaly, epilepsy + diabetes syndrome (IER3IP1)
• Microcephaly, seizures + developmental delay (PNKP)
• Microcephaly, short stature + polymicrogyria with seizures (RTTN)
• Microcephaly-capillary malformation syndrome (STAMBP)
• Microhydranencephaly (NDE1)
• Mowat-Wilson syndrome (ZEB2)
• Mungan syndrome (RAD21)
• Muscular dystrophy-dystroglycanopathy, cong. with brain + eye anomalies, type A, 1 (POMT1)
• Muscular dystrophy-dystroglycanopathy, cong. with brain + eye anomalies, type A, 2 (POMT2)
• Muscular dystrophy-dystroglycanopathy, cong. with brain + eye anomalies, type A, 3 (POMGNT1)
• Muscular dystrophy-dystroglycanopathy, cong. with brain + eye anomalies, type A, 4 (FKTN)
• Muscular dystrophy-dystroglycanopathy, cong. with brain + eye anomalies, type A, 5 (FKRP)
• Neurodevelopmental disorder with progressive microcephaly, spasticity + brain abnormalities (MFSD2A)
• Nijmegen breakage syndrome (NBN)
• Nijmegen breakage syndrome-like disorder (RAD50)
• Osteoglophonic dysplasia (FGFR1)
• Partington syndrome (ARX)
• Periventricular heterotopia with microcephaly (ARFGEF2)
• Periventricular nodular heterotopia 6 (ERMARD)
• Periventricular nodular heterotopia 7 (NEDD4L)
• Pfeiffer syndrome (FGFR1)
• Pituitary hormone deficiency, combined, 5 (HESX1)
• Polymicrogyria, bilateral frontoparietal (ADGRG1)
• Polymicrogyria, bilateral perisylvian (ADGRG1)
• Pontocerebellar hypoplasia type 1A (VRK1)
• Pontocerebellar hypoplasia type 1B (EXOSC3)
• Pontocerebellar hypoplasia type 2A (TSEN54)
• Pontocerebellar hypoplasia type 2B (TSEN2)
• Pontocerebellar hypoplasia type 2C (TSEN34)
• Pontocerebellar hypoplasia type 3 (PCLO)
• Pontocerebellar hypoplasia type 4 (TSEN54)
• Pontocerebellar hypoplasia type 5 (TSEN54)
• Pontocerebellar hypoplasia type 6 (RARS2)
• Proliferative vasculopathy + hydranencephaly-hydrocephaly syndrome (FLVCR2)
• Proud syndrome (ARX)
• Pseudo-TORCH syndrome 1 (OCLN)
• Renpenning syndrome (PQBP1)
• Rett syndrome (MECP2)
• Rett syndrome, atypical (MECP2)
• Rett syndrome, congenital variant (FOXG1)
• Rett syndrome, preserved speech variant (MECP2)
• Roifman syndrome (RNU4ATAC)
• Rubinstein-Taybi syndrome 1 (CREBBP)
• Rubinstein-Taybi syndrome 2 (EP300)
• Schizencephaly (SHH)
• Schizencephaly (SIX3)
• Seckel syndrome 1 (ATR)
• Seckel syndrome 2 (RBBP8)
• Seckel syndrome 4 (CENPJ)
• Seckel syndrome 5 (CEP152)
• Seckel syndrome 6 (CEP63)
• Septooptic dysplasia (HESX1)
• Severe comb. immunodef., microceph., growth retard., sensitivity to ionizing radiat. (NHEJ1)
• Short stature, microcephaly + endocrine dysfunction (XRCC4)
• Smith-Lemli-Opitz syndrome (DKCR7)
• Subcortical laminal heterotopia, XL (DCX)
• Subcortical laminar heterotopia (PAFAH1B1)
• Terminal osseous dysplasia (FLNA)
• Trigonocephaly 1 (FGFR1)
• Warburg micro syndrome 1 (RAB3GAP1)
• Warburg micro syndrome 2 (RAB3GAP2)
• Warburg micro syndrome 3 (RAB18)