IllnessPränataler Hydrozephalus, Differentialdiagnose

NGS +

[Sanger]

Prenatal hydrocephalus (HC) is usually inferred by the observed ventriculomegaly (VM) on prenatal ultrasound, e.g. due to increased intracranial pressure, usually caused by obstruction, eventually leading to progressive macrocephaly. The terms HC and VM are often used interchangeably. Sonographic signs encompass a heterogeneous spectrum of conditions, ranging from pathologic processes with serious consequences for neurologic development to normal changes. Causes of impaired CSF circulation and obstruction include aqueductal and monro-foraminal stenosis, neural tube defects, Dandy-Walker and primary brain malformations such as holoprosencephaly, cortical developmental and corpus callosum abnormalities. In addition to chromosomal defects (trisomies 21, 18, 13; complex aberrations etc.) and copy number variants, genetic HC syndromes are also caused by various single gene mutations. Disorders of neuronal adhesion, vesicle transport and Wnt signaling pathways are to be named in this context as well as dystroglycanopathies, ciliopathies, RASopathies, lysosomal storage diseases, impaired growth/transcription factor expression and many complex genetic syndromes. For example, the L1 syndrome covers a broad spectrum ranging from severe to mild and includes three clinical phenotypes: X-linked hydrocephalus with stenosis of the Sylvian aqueduct, MASA syndrome (Mental retardation, Aphasia, Spastic paraplegia, Adducted thumbs) including X-linked complicated hereditary spastic paraplegia type 1 and finally X-linked complicated corpus callosum agenesis. All phenotypes can be observed in affected individuals in the same family, reflecting the variability of the syndrome. In addition to environmental forms and multifactorial causes, all classical inheritance patterns are observed in monogenic HC. Despite of applying particularly extensive gene panels, the DNA diagnostic yield is limited, also largely depending on the clinical workup of the case and/or affected family. Thus, a negative molecular genetic result excludes the clinical diagnosis by no means.

References: https://www.ncbi.nlm.nih.gov/books/NBK1484/

https://www.annualreviews.org/doi/pdf/10.1146/annurev-neuro-070815-014023

• Allelic: Chondrodysplasia punctata, XLD (EBP)
• Allelic: Osteolysis, familial expansile (TNFRSF11A)
• Allelic: Paget disease of bone 2, early-onset (TNFRSF11A)
• Acrocallosal syndrome (KIF7)
• Al-Gazali-Bakalinova syndrome (KIF7)
• Alexander disease (GFAP)
• Alkuraya-Kucinskas syndrome (KIAA1109)
• Angiopathy, hereditary, with nephropathy, aneurysms + muscle cramps (COL4A1)
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis (FGFR2)
• Apert syndrome (FGFR2)
• Band heterotopia (EML1)
• Bardet-Biedl syndrome 13 (MKS1)
• Basal cell nevus syndrome (PTCH2)
• Brain small vessel disease with/-out ocular anomalies (COL4A1)
• CLAPO syndrome, somatic (PIK3CA)
• CLOVE syndrome, somatic (PIK3CA)
• COACH syndrome (CC2D2A)
• COACH syndrome 1 (TMEM67)
• COACH syndrome 3 (RPGRIP1L)
• CRASH syndrome (L1CAM)
• Carey-Fineman-Ziter syndrome (MYMK)
• Caudal regression syndrome (VANGL1)
• Cerebellar ataxia, impaired intellectual development, dysquilibrium syndrome 2 (WDR81)
• Chitayat syndrome (ERF)
• Chondrodysplasia + platyspondyly, distinctive brachydactyly, hydrocephaly, microphthalmia (HDAC6)
• Chudley-McCullough syndrome (GPSM2)
• Ciliary dyskinesia, primary, 1, with or without situs inversus (DNAI1)
• Coffin-Lowry syndrome (RPS6KA3)
• Coffin-Siris syndrome 3 (SMARCB1)
• Cole-Carpenter syndrome 1 (P4HB)
• Cole-Carpenter syndrome 2 (SEC24D)
• Congenital hydrocephalus, aqueductal stenosis, septal agenesis [panelapp] (SMARCC1)
• Corpus callosum abnormalities [panelapp] (SMARCC1)
• Craniosynostosis 1 (TWIST1)
• Craniosynostosis 3 (TCF12)
• Craniosynostosis 4 (ERF)
• Craniosynostosis, nonspecific (FGFR2)
• Crouzon syndrome (FGFR2)
• Desmosterolosis (DHCR24)
• Developmental + epileptic encephalopathy 1
• Dysplasminogenemia (PLG)
• Ellis-van Creveld syndrome (EVC2)
• Endocrine-cerebroosteodysplasia (CILK1)
• Epileptic encephalopathy, early infantile, 49 (DENND5A)
• Erythrocytosis, familial, 2 (VHL) 3
• Fanconi anemia, complementation group B (FANCB)
• Focal segmental glomerulosclerosis 9 (CRB2)
• Greig cephalopolysyndactyly syndrome (GLI3)
• Hartsfield syndrome (FGFR1)
• Heterotaxy, visceral, 1, XL (ZIC3)
• Holoprosencephaly 3 (SHH)
• Holoprosencephaly 5 (ZIC2)
• Holoprosencephaly 7 (PTCH1)
• Hydranencephaly with abnormal genitalia (ARX)
• Hydrocephalus due to aqueductal stenosis (L1CAM)
• Hydrocephalus with Hirschsprung disease (L1CAM)
• Hydrocephalus with cong. idiopathic intestinal pseudoobstruction (L1CAM)
• Hydrocephalus, cong., 1 (CCDC88C)
• Hydrocephalus, congenital communicating, 1 (TRIM71)
• Hydrocephalus, congenital, 2, with/-out brain or eye anomalies (MPDZ)
• Hydrocephalus, congenital, 3, with brain anomalies (WDR81)
• Hydrolethalus syndrome (HYLS1)
• Hydrolethalus syndrome 2 (KIF7)
• Intellectual developmental disorder, XL 29 (ARX)
• Jackson-Weiss syndrome (FGFR1, FGFR2)
• Joubert syndrome 12 (KIF7)
• Joubert syndrome 14 (TMEM237)
• Joubert syndrome 16 (TMEM138)
• Joubert syndrome 17 (CPLANE1)
• Joubert syndrome 2 (TMEM216)
• Joubert syndrome 20 (TMEM231)
• Joubert syndrome 23 (KIAA0586)
• Joubert syndrome 24 (TCTN2)
• Joubert syndrome 27 (B9D1)
• Joubert syndrome 28 (MKS1)
• Joubert syndrome 32 (SUFU)
• Joubert syndrome 34 (B9D2)
• Joubert syndrome 5 (CEP290)
• Joubert syndrome 6 (TMEM67)
• Joubert syndrome 7 (RPGRIP1L)
• Joubert syndrome 9 (CC2D2A)
• LADD syndrome (FGFR2, FGFR3)
• Lhermitte-Duclos syndrome (PTEN)
• Lissencephaly 5 (LAMB1)
• Lissencephaly, XL 2 (ARX)
• Lymphangioleiomyomatosis (TSC1)
• MASA syndrome (L1CAM)
• MEND: Male Ebp disorder with Neurologic Defects syndrome (EBP)
• Macrocephaly/autism syndrome (PTEN)
• Mannosidosis, alpha-, types I + II MAN2B1)
• Meckel syndrome 1 (MKS1)
• Meckel syndrome 11 (TMEM231)
• Meckel syndrome 2 (TMEM216)
• Meckel syndrome 3 (TMEM67)
• Meckel syndrome 5 (RPGRIP1L)
• Meckel syndrome 6 (CC2D2A)
• Meckel syndrome 7 (NPHP3)
• Meckel syndrome 8 (TCTN2)
• Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic (PIK3CA)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (PIK3R2)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (AKT3)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (CCND2)
• Mental retardation, AD 35 (PPP2R5D)
• Mental retardation, XL 19 (RPS6KA3)
• Mental retardation, XL 99 (USP9X)
• Mental retardation, XL 99, syndromic, female-restricted (USP9X)
• Mental retardation, XL syndromic 5 (AP1S2)
• Microangiopathy + leukoencephalopathy, pontine, AD (COL4A1)
• Microphthalmia with coloboma 5 (SHH)
• Mosaic variegated aneuploidy syndrome 1 (BUB1B)
• Mucopolysaccharidosis II (IDS)
• Mucopolysaccharidosis VII (GUSB)
• Mucopolysaccharidosis type VI [Maroteaux-Lamy] (ARSB)
• Muenke syndrome (FGFR3)
• Multiple sulfatase deficiency (SUMF1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anom.), A13 [MONDO:0014120] (B3GNT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 1 (POMT)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 10 (RXYLT1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 11 (B3GALNT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 12 (POMK)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 13 (B4GAT1)
• 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)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 7 (CRPPA)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 8 (POMGNT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 9 (DAG1)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 1 (POMT)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 2 (POMT2)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 3 (POMGNT1)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy (cong. with/-out mental retardation), type B, 5 (FKRP)
• Muscular dystrophy-dystroglycanopathy (cong. without mental retardation), type B, 4 (FKTN)
• Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 (POMGNT2)
• Myotubular myopathy, XL ((MTM1)
• Nephronophthisis 11 (TMEM67)
• Nephronophthisis 18 (CEP83)
• Nephronophthisis 3 (NPHP3)
• Neural tube defects (VANGL2)
• Neural tube defects, susceptibility to (VANGL1)
• Neurofibromatosis, type 1 (NF1)
• Neurofibromatosis, type 2 (NF2)
• Orofaciodigital syndrome VI (CPLANE1)
• Orofaciodigital syndrome [MONDO:0015375] (TBC1D32)
• Osteopetrosis, AR (TCIRG1)
• Osteopetrosis, AR 5 (OSTM1)
• Osteopetrosis, AR 7 (TNFRSF11A)
• Osteopetrosis, AR 8 (SNX10)
• Otopalatodigital syndrome, type I + II (FLNA)
• Pallister-Hall syndrome (GLI3)
• Partington syndrome (ARX)
• Peters-plus syndrome (B3GLCT)
• Pfeiffer syndrome (FGFR1, FGFR2)
• Pheochromocytoma (VHL)
• Plasminogen deficiency, type I (PLG)
• Polyhydramnios, megalencephaly + symptomatic epilepsy (STRADA)
• Primrose syndrome (ZBTB20)
• Proliferative vasculopathy + hydranencephaly-hydrocephaly syndrome (FLVCR2)
• Proud syndrome (ARX)
• RHYNS syndrome (TMEM67)
• Raine syndrome (FAM20C)
• Renal-hepatic-pancreatic dysplasia 1 (NPHP3)
• Ritscher-Schinzel syndrome 1 (WASHC5)
• Robinow-Sorauf syndrome (TWIST1)
• SADDAN (FGFR3)
• Saethre-Chotzen syndrome (FGFR2)
• Saethre-Chotzen syndrome with/-out eyelid anomalies (TWIST1)
• Schizencephaly (SHH)
• Short-rib thoracic dysplasia 14 with polydactyly (KIAA0586)
• Shprintzen-Goldberg syndrome (SKI)
• Single median maxillary central incisor (SHH)
• Sotos syndrome 1 (NSD1)
• Spastic paraplegia, intellectual disability, nystagmus + obesity (KIDINS220)
• Spinocerebellar ataxia 26 (EEF2)
• Stromme syndrome (CENPF)
• Sweeney-Cox syndrome (TWIST1)
• Tenorio syndrome (RNF125)
• Tetra-amelia syndrome 1 (WNT3)
• Tuberous sclerosis-1 (TSC1)
• Tuberous sclerosis-2 (TSC2)
• VACTERL association (HOXD13)
• VACTERL association, XL (ZIC3)
• Ventriculomegaly and arthrogryposis (KIDINS220)
• Ventriculomegaly with cystic kidney disease (CRB2)
• Watson syndrome (NF1)
• Weyers acrofacial dysostosis (EVC2)
• von Hippel-Lindau syndrome (VHL)