IllnessMicrocephaly, primary/secondary + growth retardation; differential diagnosis

NGS +

[Sanger]

While primary microcephaly is due to impaired prenatal brain development, secondary microcephaly develops postnatally. Both forms reduce the occipitofrontal head circumference significantly below the mean for age and sex, and they are sometimes associated with intrauterine growth retardation and/or short stature. The German guidelines "Classification and Diagnosis of Microcephaly" („Klassifikation und Diagnostik der Mikrozephalie“) explicitly prescribe a number of genes for testing in cases of additional small stature, which (including a typo correction of the ORC5 gene in the guidelines -> correctly ORC6) are included in the panel. In microcephaly with growth retardation, classic autosomal dominant and recessive inheritance patterns are observed, but multifactorial events appear prominent. The diagnostic rates also vary in this microcephaly category and depend primarily on the indication and the clinical results of the preliminary examination. An inconspicuous genetic finding does not mean exclusion of the clinical suspected diagnosis.

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

• Allelic: Mungan syndrome (RAD21)
• Allelic: Pancreatic carcinoma, somatic (RBBP8)
• Allelic: Roifman syndrome (RNU4ATAC)
• Allelic: UV-sensitive syndrome 2 (ERCC8)
• Allelicc: Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 6 (DNA2)
• Ataxia-telangiectasia (ATM)
• Cockayne syndrome, type A (ERCC8)
• Cohen syndrome (VPS13B)
• Cornelia de Lange syndrome 1 (NIPBL)
• Cornelia de Lange syndrome 2 (SMC1A)
• Cornelia de Lange syndrome 3 (SMC3)
• Cornelia de Lange syndrome 4 (RAD21)
• Cortical dysplasia, complex, with other brain malformations 7 (TUBB2B)
• Developmental + epileptic encephalopathy 85, with/-out midline brain defects (SMC1A)
• Holoprosencephaly 2 (SIX3)
• Holoprosencephaly 3 (SHH)
• Jawad syndrome (RBBP8)
• LIG4 syndrome (LIG4)
• Lissencephaly 3 (TUBA1A)
• Lowry-Wood syndrome (RNU4ATAC)
• 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)
• Menke-Hennekam syndrome 1 (BREBBP)
• Menke-Hennekam syndrome 2 (EP300)
• Microcephalic osteodysplastic primordial dwarfism, type I (RNU4ATAC)
• Microcephalic osteodysplastic primordial dwarfism, type II (PCNT)
• Microcephaly 1, primary, AR (MCPH1)
• Microcephaly 2, primary, AR, with/-out cortical malformations (WDR62)
• Microcephaly 5, primary, AR (ASPM)
• Microcephaly 6, primary, AR (CENPJ)
• Microcephaly 7, primary, AR (STIL)
• Microcephaly 9, primary, AR (CEP152)
• Nijmegen breakage syndrome (NBN)
• Nijmegen breakage syndrome-like disorder (RAD50)
• Rubinstein-Taybi syndrome 1 (CREBBP)
• Rubinstein-Taybi syndrome 2 (EP300)
• Schizencephaly (SIX3)
• Seckel syndrome 1 (ATR)
• Seckel syndrome 10 (NSMCE2)
• Seckel syndrome 2 (RBBP8)
• Seckel syndrome 4 (CENPJ)
• Seckel syndrome 5 (CEP152)
• Seckel syndrome 6 (CEP63)
• Seckel syndrome 7 (NIN)
• Seckel syndrome 8 (DNA2)
• Seckel syndrome 9 (TRAIP)
• Severe combined immunodef., microcephaly, growth retard., sensitivity to ionizing radiation (NHEJ1)
• Short stature, microcephaly + endocrine dysfunction (XRCC4)
• Smith-Lemli-Opitz syndrome (DHCR7)