Physicians & Genetic Counselors
CHARGE syndrome is an extremely complex and variable syndrome most often caused by mutations in the CHD7 gene on chromosome 8. Diagnosis relies on key clinical features as well as DNA information. The range of intellectual ability in CHARGE covers the entire spectrum, with potential routinely underestimated.
The combination of complex (often life-threatening) medical issues and sensory deficits (especially impaired hearing, vision, and balance) significantly alters and delays both motor development and language acquisition. Appropriate management requires accurate diagnosis, management of medical issues, and accurate assessment and management of sensory issues. Here we provide a diagnostic testing algorithm, information on sensory deficits (deafblindness), medical management guidelines, and resources you can give to families and educators.
CHARGE Syndrome Diagnostic Testing
Diagnosis of CHARGE can be challenging because:
- Features overlap with many other syndromes (see differential diagnosis, below)
- Every feature of CHARGE can vary from severe to absent
- Each affected individual has a unique set of features
- 10-20% of individuals with CHARGE do not have an identifiable pathogenic CHD7 variant
CHARGE is primarily a clinical diagnosis, with overlapping criteria proposed by Blake (1998), Verloes (2005) (CHARGE Factsheet 3 Clinical Diagnosis and features), and Hale (2016).
CHARGE syndrome should be considered in anyone with multiple anomalies which include at least one of:
- Choanal atresia
- Typical CHARGE external ears
- CHARGE vestibular phenotype
Guidelines for CHD7 Analysis in patients suspected to have CHARGE syndrome (click to enlarge)
CGH comparative genomic hybridization (aka CMA); MLPA, multiplex ligation dependent probe amplification (del/dup). Figure from CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. Bergman JE, Janssen N, Hoefsloot LH, Jongmans MC, Hofstra RM, van Ravenswaaij-Arts CM. J Med Genet. 2011 May;48(5):334-42.
Letter of Medical Necessity (LMN)
Many insurance companies require a letter of medical necessity before considering coverage of genetic testing. For information relevant to CHD7 testing specifics and utility, see: Clinical utility gene card for: CHARGE syndrome – update 2015. van Ravenswaaij-Arts CM, Blake K, Hoefsloot L, Verloes A. Eur J Hum Genet. 2015 Nov;23(11).
Differential Diagnosis: What else looks like CHARGE?
CHARGE is a complex, multiple anomaly syndrome. Diagnosis is complicated by the overlap with other syndromes and the fact that not all individuals with CHARGE have identifiable pathogenic CHD7 variants. Below are the conditions with the most overlap with CHARGE syndrome.
- 22q deletion syndrome (aka VCFS, DiGeorge): can have many of the same medical features (see figure below).
– Dysmorphology (face, hands and ears) is usually different.
– Testing: Microarray (aka array CGH, CMA, aCGH) or FISH for del22q11.2; TBX1 gene testing
- Kabuki syndrome: can have many of the same medical and behavioral features.
– Dysmorphology is different (eyes, ears, fingertips) and puberty is early rather than late in Kabuki syndrome.
– Testing: Two Kabuki genes have been identified: KMT2D (aka MLL2) and KDM6A
- VATER/VACTERL association (Vertebral, Anal atresia, Cardiac, Tracheo-Esophageal fistula, Renal, and Limb) can result in similar birth defects. No particular dysmorphology, no specific genetic etiology.
- Chromosome abnormalities. Many chromosome abnormalities can have features that overlap with CHARGE syndrome.
– Testing: Microarray and karyotype
- Retinoic embryopathy: exposure to Accutane during pregnancy can produce similar ears and heart defects. Other features are different
- Changes in the PAX2 gene can cause colobomas, hearing loss and rare kidney problems
- Many other single gene conditions have overlapping features
Figure: Frequency of the most common clinical features seen in patients with a 22q11.2 deletion and patients with a CHD7 mutation (click to enlarge)
CHARGE syndrome is the most frequent genetic cause of combined hearing and vision loss. Deafblind is an educational term referring to individuals with combined hearing and vision loss. The majority of children who are deafblind also have additional physical, medical and/or cognitive problems. Most children with CHARGE will be considered deafblind even though most of them retain some usable hearing and/or vision. Children are considered to be deafblind (and eligible for deafblind services) when their combined hearing and vision loss causes such severe communication and other developmental and educational needs that they require significant and unique adaptations in their educational programs. Every state has a Deaf-Blind Project to provide services from birth to 21.
- National Center on Deaf-Blindness (NCDB): Overview on Deaf-Blindness – NCDB
The Management Manual for Parents contains many sections pertaining to sensory deficits in children with CHARGE.
See here for specific links: Sensory Deficits
Resources for Medical Management
Possible BREATHING and ANESTHESIA issues to note if CHARGE is a possibility:
- Incoordination of suck and swallow are common: there is risk of aspiration when anything is given by mouth
- Weak tracheal cartilage is common: trachea may collapse easily
- Many individuals have complications with anesthesia, especially difficulty with breathing when coming out of anesthesia. See: Postoperative airway events of individuals with CHARGE syndrome. Blake K, et al. Int J Pediatr Otorhinolaryngol. 2009 Feb;73(2):219-26. PMID: 19058860
Management of individuals with CHARGE includes both medical and developmental/educational management. Here are some resources to help with management of patients with CHARGE syndrome.
- The GeneReview for CHARGE (http://www.ncbi.nlm.nih.gov/books/NBK1117/) includes comprehensive information on the medical and behavioral issues that may be encountered in children with CHARGE and a list of potential medical specialists to consult.
- Diagnostic testing and management guidelines are clearly spelled out in CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. Bergman JE, Janssen N, Hoefsloot LH, Jongmans MC, Hofstra RM, van Ravenswaaij-Arts CM. J Med Genet. 2011 May;48(5):334-42.
- UK Sense Fact sheet on Collaborative working working lists services in all areas families will encounter
- CHARGE Across the Lifespan from Head to Toe lists the areas to be addressed at various ages
- Sections of the Management Manual for Parents contain useful information for both specialists and families
- CHARGE Syndrome Book: Published in 2010, and edited by Timothy Hartshorne, Ph.D, Margaret Hefner, MS, Sandra Davenport, MD, CM, and James Thelin, Ph.D, this book describes the sensory, physical, and behavioral findings in CHARGE, indicates what kinds of studies need to be done to confirm the findings, and describes how these findings affect the function and development of the individual with CHARGE. All royalties from this book benefit the CHARGE Syndrome Foundation. To order a copy, please visit http://www.pluralpublishing.com/publication_cs2.htm
Resources To Give To Families
New families may want a little information or a lot. If you provide them with a packet of information, they can look at it when they are ready. We recommend that every new family be given the following information.
The CHARGE Syndrome Foundation brochure provides a quick explanation of CHARGE syndrome and information about what the Foundation offers. Many families find this helpful in explaining CHARGE to family members or professionals who are unfamiliar with CHARGE.
The New Parent Packet is designed for families who have a newly-diagnosed son or daughter with CHARGE and includes information about the Foundation, facts about CHARGE syndrome and some family stories.
The Foundation has a dedicated Director of Outreach who works directly with families. Sheri can answer your questions and direct you to available resources in your area.
Since nearly all individuals with CHARGE have some degree of both hearing and vision loss, all families should be referred to specialists in deafblindness to assist with developmental and educational issues. In the US, each state has a federally funded Deafblind Project to assist families with children from birth through age 21. Other countries have parallel organizations.
There is a very active CHARGE Syndrome Foundation Facebook group – families can join by visiting https://www.facebook.com/groups/chargesyndrome/