IllnessCHARGE syndrome, differential diagnosis

NGS +

[Sanger]

Full-blown CHARGE syndrome includes coloboma, heart defects, atresia choanae, delayed growth, genital and ear abnormalities. The pattern of malformations varies among affected individuals, and the multiple health problems can be life-threatening in infancy. Most CHARGE patients present with colobomas, sometimes along with microphthalmia. Often one or both choanae are blocked, and cranial nerve function is impaired with dysphagia, facial paralysis, hyposmia/anosmia, mild to profound hearing loss also due to middle and inner ear abnormalities. The auricles may be abnormally shaped. Other features include heart defects, slow growth in late infancy, delayed development of motor skills, cleft lip and/or palate, hypogonadotropic hypogonadism, and tracheoesophageal fistulas. Most individuals with CHARGE syndrome also have prominent facial features including facial asymmetry. Affected individuals show a wide range of cognitive functioning, from normal intelligence to severe learning disabilities with absent speech as well as impaired communication. Less common features include kidney abnormalities, immune system problems, scoliosis/kyphosis and limb deformities. Inheritance is autosomal dominant, with many patients harboring spontaneous mutations. When the diagnostic criteria are strictly applied, 90% of affected individuals show pathogenic CHD7 mutations, although from a clinical point of view CHARGE syndrome is often merely to be ruled out, so that the molecular genetic yield is then more like 35%: 98% DNA sequence variations are matched by only 2% duplications/deletions. Atypical phenotypes additionally complicate definitive statements on molecular genetic diagnostic yield.

References: https://www.ncbi.nlm.nih.gov/books/NBK1117/

• DD syndromes: Kallmann s., Kabuki s., VACTERL, Renal coloboma s., Cat-eye s., Joubert s., BOR s.
• Sympt.: Coloboma, Heart anomaly, choanal Atresia, Retardation, Genital + Ear anomalies, CHARGE
• Alias: CHARGE association
• Alias: Hall-Hittner syndrome
• Allelic: Anterior segment anomalies with/-out cataract (EYA1)
• Allelic: Deafness, AD 23 (SIX1)
• Allelic: Encephalocraniocutaneous lipomatosis, somatic mosaic (FGFR1)
• Allelic: Glomerulosclerosis, focal segmental, 7 (PAX2)
• Allelic: Hajdu-Cheney syndrome (NO`TCH2)
• Allelic: Holoprosencephaly 9 (GLI2)
• Allelic: Leukodystrophy, hypomyelinating, 11 (POLR1C)
• Allelic: Microphthalmia, syndromic 5 (OTX2)
• Allelic: Osteoglophonic dysplasia (FGFR1)
• Allelic: Polydactyly, postaxial, types A1 + B (GLI3)
• Allelic: Polydactyly, preaxial, type IV (GLI3)
• Allelic:Trigonocephaly (FGFR1)
• Abruzzo-Erickson [CHARGE-like, XL] syndrome (TBX22)
• Alagille syndrome 1 (JAG1)
• Alagille syndrome 2 (NOTCH2)
• Branchiootic syndrome 1 (EYA1)
• Branchiootic syndrome 3 (SIX1)
• Branchiootorenal syndrome 1, with/-out cataracts (EYA1)
• Branchiootorenal syndrome 2 (SIX5)
• Cleft palate with ankyloglossia (TBX22)
• Culler-Jones syndrome [Hypopituitarism, growth hormone deficiency, +/- postaxial polydactyly] (GLI2)
• Deafness, congenital heart defects + posterior embryotoxon (JAG1)
• Feingold syndr. 1 [microceph., limb malform., esophagus + duodenal atresia, learn disab./MR] (MYCN)
• Greig cephalopolysyndactyly syndrome (GLI3)
• Hartsfield syndrome [holoprosencephaly, ectrodactyly, cleft/lip palate] (FGFR1)
• Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
• Hypogonadotropic hypogonadism 5 with/-out anosmia (CHD7)
• Jackson-Weiss syndrome (FGFR1)
• Kabuki syndrome 1 (KMT2D)
• Kabuki syndrome 2 (KDM6A)
• Leukoencephalopathy with dystonia + motor neuropathy (SEMA3E)
• Mandibulofacial dysostosis, Guion-Almeida type (EFTUD2)
• Microphthalmia, syndromic 3 (SOX2)
• Microphthalmia, syndromic 6 (BMP4)
• Mowat-Wilson syndrome [complex developmental disorder] (ZEB2)
• Optic nerve hypoplasia + abnormalities of the central nervous system (SOX2)
• Orofacial cleft 11 (BMP4)
• Otofaciocervical syndrome (EYA1)
• Pallister-Hall s. [Hypothal. hamart., pituit. dysfunct, cent. polydactyly, visc. malform.] (GLI3)
• Papillorenal syndrome (PAX2)
• Pfeiffer syndrome (FGFR1)
• Pituitary hormone deficiency, combined, 6 (OTX2)
• Retinal dystrophy, early-onset, with/-out pituitary dysfunction (OTX2)
• Tetralogy of Fallot (JAG1)
• Treacher Collins syndrome 1 (TCOF1)
• Treacher Collins syndrome 2 (POLR1D)
• Treacher Collins syndrome 3 (POLR1C)