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Revista chilena de pediatría

versión impresa ISSN 0370-4106

Rev. chil. pediatr. vol.90 no.5 Santiago oct. 2019 


Phenotypic spectrum of neonatal CHARGE syndrome

N. Sánchez1 

M. Hernández1 

JP. Cruz2 

C. Mellado1 

1 Pediatric Neurology and Genetic Section, Pediatrics Division, Medicine School, Pontifical Catholic University of Chile, Chile.

2 Neuroradiology Unit, Radiology Department, Medicine School, Pontifical Catholic University of Chile, Chile.



CHARGE syndrome is a genetic disorder of wide phenotypic variability, of autosomal dominant in heritance, caused by pathogenic variants in the CHD7 gene.


To describe the broad pheno typic spectrum of neonatal CHARGE syndrome, heterozygous for the CHD7 gene, and the usefulness of genome sequencing in diagnostic confirmation, considering differential diagnoses.

Clinical Case:

34-week preterm newborn, with severe prenatal history of polyhydramnios, increased nuchal trans- lucency, and hyperechogenic cardiac focus, with a TORCH study that ruled out congenital infection. Peripheral facial paralysis, choanal atresia, multiple dysmorphisms, congenital heart disease, and bilateral retinochoroidal coloboma were observed at birth. The neuroimaging study showed hypo plasia of the cochlea and bilateral semicircular canals, and pontocerebellar hypoplasia. The auditory evoked potentials showed deep right-sided sensorineural hearing loss and left anacusis. The patient developed hypocalcemia and immunological alterations, confirming hypoparathyroidism and thy mus hypoplasia. The karyogram was normal and 22q11.2 microdeletion was excluded through mul tiplex ligation-dependent probe amplification (MPLA). A pathogenic variant in the CHD7 gene was detected that confirmed the clinical suspicion of CHARGE syndrome.


The overlap of clinical characteristics of CHARGE syndrome requires molecular genetic confirmation, considering differences in evolution, therapies, and recurrence risks with other genetic syndromes.

Keywords: CHARGE syndrome; facial palsy; newborn; CHD7 gen; hipoacusia


CHARGE Syndrome is a complex syndrome of au tosomal dominant inheritance, and most of the cases are isolated. It has a wide phenotypic spectrum and may compromise almost all body organs and systems. Its prevalence is 1/8,500-15,000 live births with a high and variable comorbidity, and also the presence of lethal cases underdiagnosed in the neonatal period1.

In 1981, Pagon2 created the term ‘CHARGE asso ciation’ as an acronym to describe the presence of Co loboma of the eye, Heart defects, Atresia of the nasal choanae, Retardation of growth and/or development, Genitourinary anomalies, and Ear anomalies and dea fness. Other anomalies have been added over the years such as brain and cranial nerves alterations, cochlear dysplasia, scoliosis, hemivertebrae, kidney abnormalities, omphalocele/umbilical hernia, cleft lip and palate, thymus/parathyroid abnormalities, and autism spec trum disorder with a phenotype constantly expanding. Some anomalies have been incorporated to the major and/or minor clinical criteria (Table 1) described by Blake, Verloes and Hale in 1998, 2005 and 20153-5.

Table 1 Clinical criteria for CHARGE síndrome. 

In 2004, when Vissers et al6 described alterations in the CHD7 gene, this ‘CHARGE association’, defined as the non-random occurrence of a several anomalies combination observed in more than one individual without identified etiology, it became a syndrome7.

The CHD7 gene (chromodomain helicase DNA- binding) located on region q12 of the chromosome 8 is crucial for the mitigation of neural crest cells that are divided into five subpopulations (cranial, cardiac, vagal, sacral, and trunk), affecting a wide variety of tis sues including thymus/parathyroid structures8. 90% of typical cases that met diagnostic criteria and bet ween 65 to 70% of those typical and with suspicion of CHARGE syndrome occur due to CHD7 gene altera tions9. Most of the cases are de novo, so if neither pa rent is a carrier, the recurrence risk is lower than 3%.

Considering the described prevalence (in Chile, we should have 20 cases per year), we believe that there is a high rate of underdiagnosis due to the overlap of symptoms with other syndromes and the high morbi dity and mortality in the neonatal period. Among the differential diagnosis are the 22q11.2 microdeletion syndrome, Kallmann syndrome, Kabuki syndrome, Treacher Collins syndrome, Mowat Wilson syndrome, and the 3M syndrome10,11.

The objective of this article is to describe the wide phenotypic spectrum of the CHARGE syndrome in a female newborn, and the usefulness of the sequencing in diagnostic confirmation and warning about the suspicion of this condition and its differential diagnoses.

This article was approved by the Institutional Ethics Committee and the parents signed informed consent.

Clinical case

Second child of young non-consanguineous pa rents, without relevant family history. During preg nancy, the mother presents severe symptomatic po lyhydramnios managed with amnioreduction since the 31 weeks (negative cytochemical and bacterial culture). Prenatal ultrasounds showed a large-for-gestational- age fetus, nasal fold, nuchal edema, and a cardiac hy- perechogenic focus. The amniocentesis test was nega tive for connatal infection. The child born by cesarean section at 34 weeks of gestational age after lung matu ration with corticosteroids due to imminent preterm birth. The birth weight was 2,660 g (p75), height 45 cm (p50), and head circumference 31 cm (p10) (Alarcón- Pittaluga curves). APGAR score of the child was 2-7 (1’ and 5’) requiring intubation for mechanical venti lation where choanal atresia was observed.

The neurogenetic evaluation showed craniofacial dysmorphisms such as square face, facial asymmetry, low and narrow forehead, dysmorphic, low-set and posteriorly rotated ears, short neck, widely spaced nipples, short sternum, and brachydactyly (Figure 1). In the neurological examination was possible to obser ve cranial nerves dysfunctions (peripheral facial palsy, bulbar dysfunctions with swallowing disorders), and central hypotonia. A CHARGE syndrome diagnosis was suggested based on these findings. The neuro-ophthalmological examination showed bilateral cho rioretinal coloboma with no posterior embryotoxon or iris coloboma. The echocardiography showed se vere coarctation of the aorta with right-to-left shunt, ventricular septal defects, and patent ductus arterio sus (PDA) which required prostaglandins and subse quently surgery.

Figure 1 Square Face, right peripherial facial pa ralysis. 

CT scan and, subsequently, brain MRI confirmed right choanal atresia and showed cochlear and bilateral semicircular canal dysplasia and hypoplasia, and pon tocerebellar hypoplasia (Figure 2). The brainstem au ditory evoked potentials showed profound right-sided sensorineural hearing loss and total left-sided hearing loss.

Figure 2 A) Axial parinasal cavities computed tomography (CT) image, deviation of left convex nasal septum (White Arrow), with thickening of the vomer and right choanal atresia (black arrow head). B) Axial ears CT image, bilateral cochlear dysplasia, more pro minent at right with decreased size of apical and midle spire (white arrows). At left ear, a decrease in caliber of cochlear nerve canal (short arrow) which indicates hipoplasia/absence of the cochlear branch of VIII nerve. 

The patient required calcium treatment due to persistent hypocalcemia since the second day of life, with ionized calcium levels lower than 2.9 (adjus ted to pH 7, normal level 4.4-6 mg/dL), and hypo parathyroidism was subsequently confirmed. Sub sequent studies due to severe recurrent infections diagnosed immunodeficiency with lymphocyte sub populations, total T lymphocyte, low T helper and T suppressor cells, and hypogammaglobulinemia. She was treated with gamma globulin and immunization schedule modifications. Chest CT scan showed thy mic hypoplasia.

With the karyogram and the multiplex ligation- dependent probe amplification (MLPA), it was pos sible to rule out 22q11.2 microdeletion, CHD7 gene molecular study detected the pathogenic variant c.1926_1927delGA (p.lys644Glufs*31) confirming CHARGE syndrome.

Also during the course of the condition, the patient presented multiple episodes of apnea and periodic breathing, and the fiberoptic bronchoscopy showed se vere laryngomalacia with omega-shaped epiglottis and collapsible arytenoid cartilage that required tracheos tomy, and a Nissen fundoplication and gastrostomy were performed due to severe swallowing dysfunction. She was discharged on the fifth month of life with out patient follow-up.


The CHARGE syndrome presents high variability in its clinical expression with a combination of mul tiple inconstant and nonspecific associated abnorma lities. Nonetheless, the suspected diagnosis is clinical and the scores of the different diagnostic criteria of Blake, Verloes, and Hale4,5,12 have demonstrated their strength when contrasted with patients with pathoge nic variants in CHD7 (see Table 1).

The prenatal diagnosis is infrequent y probably these cases represent the most severe form of the cli nical spectrum. Among the prenatal findings, 25% of cases present polyhydramnios, therefore, Legendre13 in these cases suggests looking for major criteria signs of CHARGE syndrome, both in directed ultrasound and in fetal MRI. In our case, we believe that the clinical spectrum of our patient was serious. Due to the nuchal edema, polyhydramnios, and hyperechogenic heart tissues, a prenatal chromosome study was suggested but not performed.

The association of cardiac, craniofacial, and airway abnormalities and cranial nerves alterations has high morbidity and mortality in the neonatal period. Our patient required prostaglandins for stabilization and later correction of her congenital heart disease and a tracheostomy/gastrostomy to prevent reflux and aspi ration and optimize nutrition.

The most frequent cranial nerve abnormalities are in the facial nerve (peripheral facial palsy), cochlear nerve (deafness), olfactory tracts, and bulbar dys functions (IX-XII) which are rarely diagnosed. These findings during clinical examination should be com plemented with swallowing studies, laryngoscopy, esophageal pH tests and polysomnography.

Our patient met major criteria for the CHARGE syndrome diagnosis, described by the three authors mentioned above but along with these criteria a neo natal phenotype of the 22q11.2 deletion (Di George) was overlapped with congenital heart disease, hy pocalcemia, and immunodeficiency which is infre quently described in CHARGE syndrome and is not part of major or minor criteria (Table 1). The con genital heart disease of our patient corresponded to coarctation of the aorta which is described in 22q11.2 deletion but is infrequent in the CHARGE syndrome. Cardiac malformations in this syndrome represent 75-85% of cases but they are not a major criterion, and the Tetralogy of Fallot is the most frequently des cribed.

The prevalence of immunological abnormalities in patients with CHARGE syndrome is little described in the literature, and of these, most have no molecular confirmation14,15. This alteration was considered as a risk factor for serious and recurrent infections in our patient. Due to the severity of this associated anomaly, early immunological evaluation is suggested in patients with CHARGE syndrome to optimize therapeutic and preventive management.

The clinical characteristics overlapping between the 22q11.2 deletion and the CHARGE syndrome could be explained by the interaction between the TBX1 gene (one of the candidate genes for anomalies associated with 22q11.2 deletion) and the CHD7 gene, and that they are required in the pharyngeal ectoderm for the pharyngeal arches, thymus, and semicircular canals development16.

Another differential diagnoses of CHARGE syn drome are the Kabuki syndrome, renal-coloboma syn drome, Cat-eye syndrome, Joubert syndrome, Bran- chiootorenal (BOR) syndrome, retinoic acid embryo pathy, and VACTERL association10,11,17,18.

Given the multiple systems potentially affected in the CHARGE syndrome and not described in the cli nical diagnostic criteria of Verloes, Blake, and Hale, it is necessary to specifically search for them to prevent serious complications. Consider the support of multi ple specialists because major criteria such as coloboma, usually retrochoroidal, middle and inner ear disorders, and choanal atresia require ophthalmologists and ra diologists for detection. Multidisciplinary teams are also required that bring together geneticists, otolaryn gologists, maxillofacial surgeons, neurologists, neuro rehabilitation (developmental delay, anomalies of I, II, VII, VIII, IX and X cranial nerves), cardiologists (conotruncal septal anomalies), endocrinologists (growth retardation, hypocalcemia, hypoparathyroidism), im munologists, and urologists19-22.


Despite the complexity of the diagnosis and pathogenesis of CHARGE syndrome since the CHD7 gene alterations affect a large number of development pathways, a clinical diagnosis is possible conside ring the criteria of Blake, Verloes, or Hales. Howe ver, when there is a wide phenotypic spectrum and it shares several symptoms with other syndromes as our case, confirmation with molecular diagnosis is necessary. With the accurate diagnosis, it is possible to know the natural history of the disease, to follow-up according to international recommendations, and perform genetic counseling to the patient and his/her family.

Ethical Responsibilities

Human Beings and animals protection: Disclosure the authors state that the procedures were followed ac cording to the Declaration of Helsinki and the World Medical Association regarding human experimenta tion developed for the medical community.

Data confidentiality: The authors state that they have followed the protocols of their Center and Local regu lations on the publication of patient data.

Rights to privacy and informed consent: The authors have obtained the informed consent of the parents (tu tors) of the patients and/or subjects referred to in the article. This document is in the possession of the correspondence author.

Conflicts of Interest: Authors declare no conflict of interest regarding the present study.

Financial Disclosure: Authors state that no economic support has been asso ciated with the present study.


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Received: February 04, 2019; Accepted: May 02, 2019

Correspondence: Mellado C. E-mail:

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