IllnessIntellectual deficit + macrocephaly, differential diagnosis

NGS +

[Sanger]

Intellectual disability is due to neurological developmental deficits and is characterised by limitations in intellectual functioning and adaptive behaviour (lack of competence in social, conceptual and practical skills). The most common chromosomal cause of intellectual disability is Down syndrome, the most common genetic cause is Fragile X syndrome, and the most common known preventable or environmental cause is fetal alcohol syndrome. Many genetic disorders include macrocephaly as well as intellectual deficits. The latter is a broad term that includes megalencephaly and other causes of enlargement of the head without cerebral overgrowth, such as subdural fluid accumulation. Macrocephaly is common (2.5% of the population) and is often (partly) genetic (<200 OMIM entries). In a number of syndromes, mental retardation and macrocephaly occur in combination: Beckwith-Wiedemann, Cowden, IMAGE, Sotos, Marshall-Smith, Weaver and rarer syndromes; holoprosencephaly, hydrocephalus, leukodystrophies, etc. An inconspicuous genetic finding does not mean that the suspected clinical diagnosis is excluded.

References: https://www.ncbi.nlm.nih.gov/books/NBK560786/

https://www.ncbi.nlm.nih.gov/books/NBK148820/

https://www.ncbi.nlm.nih.gov/books/NBK542336/

https://www.ncbi.nlm.nih.gov/books/NBK1479/

https://www.ncbi.nlm.nih.gov/books/NBK1151/

https://www.ncbi.nlm.nih.gov/books/NBK1488/

• Alias: Intellectual disability, macrocephaly
• Alias: Psycho-motor retardation, macrocephaly
• Allelic: Basal cell carcinoma, somatic (PTCH1)
• Allelic: Basal cell nevus syndrome (PTCH1)
• Allelic: Basal cell nevus syndrome 1 (PTCH1)
• Allelic: Basal cell nevus syndrome 2 (SUFU)
• Allelic: Congenital myopathy with excess of muscle spindles (HRAS)
• Allelic: Cortical dysplasia, complex, with other brain malformations 10
• Allelic: Fragile X tremor/ataxia syndrome (FMR1)
• Allelic: Glioma susceptibility 2 (PTEN)
• Allelic: Goiter, multinodular 1,+/- Sertoli-Leydig cell tumors (DICER1)
• Allelic: Intellectual developmental disorder, AD 44, with microcephaly (TRIO)
• Allelic: Lujan-Fryns syndrome (MED12)
• Allelic: Lymphangioleiomyomatosis (TSC1)
• Allelic: Medulloblastoma (SUFU)
• Allelic: Meningioma (PTEN)
• Allelic: Meningioma, familial, susceptibility to (SUFU)
• Allelic: Ohdo syndrome, XL (MED12)
• Allelic: Pleuropulmonary blastoma (DICER1)
• Allelic: Premature ovarian failure 1 (FMR1)
• Allelic: Prostate cancer, somatic (PTEN)
• Allelic: Rhabdomyosarcoma, embryonal, 2 (DICER1)
• Allelic: Waisman syndrome (RAB39B)
• Bachmann-Bupp syndrome (ODC1)
• Beck-Fahrner syndrome (TET3)
• Beckwith-Wiedemann syndrome (CDKN1C)
• Brain malformations with/-out urinary tract defects (NFIA)
• Cohen-Gibson syndrome (EED)
• Costello syndrome (HRAS)
• Cowden syndrome 1 (PTEN)
• Cowden syndrome 5 (PIK3CA)
• Epileptic encephalopathy, early infantile, 69 (CACNA1E)
• Familial Wilms tumor [GeneReviews] (CTR9)
• Fragile X syndrome (FMR1)
• GAND syndrome (GATAD2B)
• GLOW syndrome, somatic mosaic: Global dev. delay, Lung cysts, Overgrowth, Wilms tumor (DICER1)
• Global develop delay, intellectual disability, macrocephal, alopecia, ectodermal dysplasia (ODC1)
• Glutaricaciduria, type I (GCDH)
• Holoprosencephaly 7 (PTCH1)
• Hypermethioninemia due to adenosine kinase deficiency (ADK)
• ID [MONDO:0001071], macrocephaly [HP:0000256] (CTR9)
• IMAGE syndrome (CDKN1C)
• Imagawa-Matsumoto syndrome (SUZ12)
• Intellectual developmental disorder with autism + macrocephaly (CHD8)
• Intellectual developmental disorder with macrocephaly, seizures + speech delay (PAK1)
• Intellectual developmental disorder, AD 48 (RAC1)
• Intellectual developmental disorder, AD 63, with macrocephaly (TRIO)
• Intellectual developmental disorder, AD 70 (SETD2)
• Intellectual developmental disorder, XL, syndromic, Wu type (GRIA3)
• Intellectual disability, macrocephaly [panelapp] (ATXN2L)
• Joubert syndrome 32 (SUFU)
• Kleefstra syndrome 1 (EHMT1)
• Lhermitte-Duclos syndrome (PTEN)
• Luscan-Lumish syndrome (SETD2)
• Macrocephaly, acquired, with impaired intellectual development (NFIB)
• Macrocephaly, dysmorphic facies, and psychomotor retardation (HERC1)
• Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, persistent fetal hemoglobin (ZBTB7A)
• Macrocephaly/autism syndrome (PTEN)
• Macrocephaly/megalencephaly syndrome, AR (TBC1D7)
• Marshall-Smith syndrome (NFIX)
• Megalencephalic leukoencephalopathy with subcortical cysts (MLC1)
• Megalencephalic leukoencephalopathy with subcortical cysts 2A (HEPACAM)
• Megalencephalic leukoencephalopathy, subcort. cysts 2B, remitting, +/- mental retardation (HEPACAM)
• 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, AR 41 (KPTN)
• Mental retardation, XL 72 (RAB39B)
• Mental retardation, XL 93 (BRWD3)
• Mental retardation, XL syndromic, Turner type (HUWE1)
• Mental retardation, XL, syndromic 14 (UPF3B)
• Mental retardation, XL, syndromic 15, Cabezas type (CUL4B)
• Mental retardation, XL, syndromic 34 (NONO)
• Neurodevelopmental disorder, language delay +/- structural brain abnormalities (PPP2CA)
• Opitz-Kaveggia syndrome (MED12)
• Phelan-McDermid syndrome (SHANK3)
• Polyhydramnios, megalencephaly + symptomatic epilepsy (STRADA syn. LYK5)
• Polyhydramnios, megalencephaly + symptomatic epilepsy (STRADA)
• Rabin-Pappas syndrome (SETD2)
• Rahman syndrome (HIST1H1E)
• Short stature, macrocephaly, intellectual disability + autism spectrum disorder [panelapp] (RHEB)
• Simpson-Golabi-Behmel syndrome, type 1 (GPC3)
• Smith-Kingsmore syndrome (MTOR)
• Snijders Blok-Campeau syndrome (CHD3)
• Sotos syndrome 1 (NSD1)
• Sotos syndrome 2 (NFIX)
• Sotos syndrome 3 (APC2)
• Spinocerebellar ataxia, AR 20 (SNX14)
• Tenorio syndrome (RNF125)
• Thauvin-Robinet-Faivre syndrome (FIBP)
• Tuberous sclerosis-1 (TSC1)
• Tuberous sclerosis-2 (TSC2)
• Weaver syndrome (EZH2)