Information on the thymus and the results of the following immunological tests were used: lymphocyte subset phenotyping (if available, absolute numbers of T-, B- and NK-cells), quantitative immunoglobulin analysis, and T-cell function by response on mitogens (phytohaemagglutinin). Relevant articles were studied in detail and their reference lists were scanned for additional publications ( Supplementary 2). The titles and abstracts of English language articles were reviewed for relevance. For our review, we only selected patients from these papers who fulfilled the diagnostic criteria of Blake et al 7 and/or Verloes, 8 and in whom a deletion of 22q11.2 (the cause of DiGeorge syndrome) had been excluded or was unknown. Before CHD7 was discovered, some patients with CHARGE syndrome were described as having DiGeorge syndrome (#MIM 188400) or as having DiGeorge syndrome with CHARGE association. We also decided to include articles prior to the identification of CHD7 as the causative gene, in order to have a complete overview. All patients with a proven variant in CHD7, which affects the normal function of the protein, were included in our review. Do these syndromes share immunological phenotypes? Last but not least, we try to identify gaps in our knowledge that need further study.Ī systematic search via the online database PubMed of publications on immunological aspects of CHARGE syndrome was performed ( Supplementary 1). We also explore what can be learned from the clinical overlap between CHARGE syndrome and other multiple congenital anomaly (MCA) syndromes.
Here, we provide an overview of the current literature on immunological dysfunction in CHARGE syndrome. 8, 9, 13 Furthermore, deficits in the immune system have been described in CHARGE patients, which might lead to morbidity and even mortality. In addition to the above symptoms, other common clinical features of CHARGE syndrome are: absent or hypoplastic semicircular canals, cranial nerve dysfunction (including facial nerve palsy), cleft lip and/or palate, anosmia, feeding difficulties and skeletal abnormalities. Since the genetic cause of CHARGE syndrome was identified, its phenotype has been further explored.
There is no clear genotype–phenotype correlation, but variants leading to a premature stop codon are, in general, associated with a more severe phenotype than variants with a non-truncating effect, that is, missense variants. Haploinsufficiency of CHD7 affects multiple organ systems, including the heart, the inner ear and the eye. 6, 9, 10, 11 The CHD7 gene encodes a member of the chromodomain helicase DNA-binding protein family that regulates the transcription of genes during embryonic development. A variant in CHD7 can be found in over 90% of all children who fulfil the clinical diagnostic criteria. 8 Since 2004, when the major genetic cause of CHARGE syndrome was identified as a dominant variant in the CHD7 gene (MIM# 608892), which usually occurs de novo, CHARGE syndrome can also be diagnosed by molecular diagnostics. The incidence of CHARGE syndrome (MIM# 214800) is estimated at 1 in 15 000–17 000 newborns 6 and its clinical diagnosis is based on the criteria proposed by Blake et al 7 or by Verloes. Then in 1981, Pagon et al 5 proposed the acronym CHARGE, which stands for the following symptoms: Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital abnormalities, and Ear abnormalities (external, middle and inner ear including deafness). 1, 2 However, the association between coloboma, congenital heart defects and choanal atresia was first recognized by both Hall 3 and Hittner et al 4 in 1979. Patients with a combination of coloboma and other multiple congenital abnormalities were first described in 1961.
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