Ashleigh Hansen, MSc, LCGC, CCGC, Robin D. Clark, MD

Case History:

A genetics consultation was requested for a 23-day-old term male infant with dysmorphic features and poor feeding after balloon valvulotomy for pulmonary artery stenosis.

This pregnancy was complicated by a suspected fetal cardiac anomaly on prenatal ultrasound. Maternal serum screening was normal. The mother did not gain weight during the pregnancy. At 39-week 0-day gestation, this AGA male was born by spontaneous vaginal delivery to an obese 23-year-old G1P0 mother. Apgar scores were 81 and 95. The birth weight, 3470 g, and the length was 52 cm were appropriate for gestational age.

The infant was admitted to the NICU. Asymmetric facial movement, low set, malformed pinnae of the ears, hallux varus, and micropenis were noted. An echocardiogram revealed pulmonary valve dysplasia and severe pulmonary stenosis, small muscular VSD, small PFO versus Secundum ASD, bilateral SVC without bridging vein, and a large PDA and moderate hypertrophy of the right ventricle. On day of life 3, a genetics consultant recommended a chromosome microarray which was normal. On day 9, “acute onset right-sided facial droop and ptosis” raised concern for an acute stroke given the presence of PFO. A brain MRI showed no evidence of a recent infarct. On day 10 of life, a comprehensive congenital heart disease gene panel was ordered, and results are pending. Poor feeding was attributed to the cardiac defect, but feeding remained a problem even after severe pulmonary stenosis was successfully treated on day 11 with balloon valvuloplasty resulting in mild stenosis.

ENT consulted on day 16 for pharyngeal dysphasia and a video swallow study that noted pooling/retention of residual thin barium in the hypopharynx. Laryngomalacia, erythematous arytenoids, prolapsing epiglottis over vocal folds, and a left vocal cord paresis were noted on flexible nasal laryngoscopy. On day 21, a brain MRI for the cranial nerve deficit and dysphagia showed abnormal dysplastic vestibule, semicircular canals, and possibly the right cochlea, as well as non-visualization of the seventh cranial nerves.

Family history:

Family history was significant for a maternal uncle with congenital heart disease but was otherwise non-contributory. Parents are both of Hispanic ancestry from Mexico. Consanguinity was denied. The patient is the only child of his parents, who are both age 23 years.

Genetics evaluation:

The genetic counselor obtained a detailed history of teratogen exposure from the mother, who reported consuming 3-4 alcoholic drinks 4-5 days/week and occasional marijuana use during the first 11 weeks of pregnancy. The mother denied other exposures, illnesses, or maternal diabetes.

On exam, he had a square forehead, right facial palsy, epicanthal folds, low-set ears with absent helical and antihelical folds and triangular concha, high nasal bridge, asymmetry of the mandible, R<L.

Figure 1: Both ears have a simple and flat appearance without a helical fold. There is no lobule on the right ear, which is characteristic of CHARGE syndrome. Both ears have a triangular concha, also a classic feature.

The clinical diagnosis of CHARGE syndrome was based on the characteristic ear anomaly, multiple cranial nerve palsies, micropenis, and a cardiac defect. There was no evidence of coloboma on a dilated eye exam, and choanae were patent. Although the diagnosis was clear, the mother expressed her doubts because it was her experience that a new doctor had a different explanation for what was wrong with her son every day. The mother eventually accepted the diagnosis after the geneticist explained all of the features that were compatible with the diagnosis and invoked the ancient parable from India about the six blind men who encountered an elephant for the first time: each blind man felt a different part of the elephant and thought he understood the whole based on the part he had examined. One explained that he was feeling the trunk of a tree (he examined the leg), another said it was a fan (he felt the ear), the next a rope (the tail), then a snake (the trunk), then a spear (the tusk) and finally a wall (the flank).

PICTURE: The parable of the six blind men and the elephant can apply to examining an infant with multiple congenital anomalies. (Source https://www.adventisthealthcare.com/living-well/the-blind-men-and-the-elephant/)

The cardiac gene panel testing revealed a heterozygous Variant of Uncertain Significance (VUS) in CDH7: c.3641 A>C (p.Gln1214Pro). This variant has not been previously reported in the literature; however, a different variant affecting the same amino acid has been reported as de novo in two individuals with CHARGE syndrome. The variant has been reported as “pathogenic” in ClinVar and “likely pathogenic” by Franklin Genoox. The variant has not been reported in a large population database indicating its rarity. Although the variant is highly suspected as pathogenic, the interpretation remains uncertain due to the lack of conclusive functional and genetic evidence. Parental studies are in process. If this is a de novo variant, the laboratory confirmed that it would upgrade the classification of this variant to pathogenic.

Discussion:

CHARGE syndrome (MIM# 214800) is estimated at 1 in 15 000–17 000 newborns, which is common enough to be recognizable to astute clinicians in the NICU. However, CHARGE syndrome can present in many ways (1), which may confuse even experienced providers (even our first genetics consultant). In this case, the infant presented with multiple congenital anomalies consistent with the diagnosis but without the key components of coloboma or choanal Atresia. Medical consultants initially focused on the child’s acute problems and not the clinical picture as a whole. At first, the child’s heart defect was the primary issue, until the focus of attention switched to the baby’s poor feeding because it did not improve as expected after the heart defect was repaired. The baby’s facial paralysis raised concern for a stroke, but when a stroke was ruled out, interest in this problem declined.

Similarly, the infant’s ear anomalies and micropenis, which never demanded therapeutic attention, were not given much weight in the diagnostic process. It was only when multiple cranial nerve deficits became apparent that all the individual components of the diagnosis came together and pointed to the diagnosis of CHARGE syndrome. Later, brainstem auditory evoked potential was abnormal due to the absence of waves I-V in both ears.

The effect of prenatal alcohol exposure in this child is a confounding factor likely to adversely affect feeding and other neurodevelopment processes that would otherwise be attributed to CHARGE syndrome. He might function at the lower end of the CHARGE syndrome phenotype because of his early alcohol exposure. Interestingly, the baby had no facial characteristics or growth retardation of fetal alcohol syndrome.

CHARGE is an acronym for 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). In addition to the above symptoms, other common clinical features of CHARGE syndrome are immunologic deficits (lymphopenia in 60-80% and humoral defects in 16% of patients), absent or hypoplastic semicircular canals (95%), cranial nerve dysfunction (including facial nerve palsy), cleft lip and/or palate, anosmia, feeding difficulties, and skeletal abnormalities. T-cell lymphopenia is common (80%) in patients with CHARGE syndrome. It is associated with a reduced T-cell function and hypogammaglobulinemia but normal B-cell and NK-cells numbers. Thymic aplasia or hypoplasia might be the underlying cause of T-cell lymphopenia.

In 2004, the major genetic cause of CHARGE syndrome was identified as a dominant variant in CHD7 (MIM# 608892) that usually occurs de novo. Although CHARGE syndrome is a clinical diagnosis, it can also be diagnosed by molecular diagnostics. A variant in CHD7 can be found in over 90% of all children who fulfill the clinical diagnostic criteria.

Clinical Criteria for CHARGE syndrome:

The diagnosis of CHARGE syndrome is based on a combination of major and minor clinical criteria proposed separately by Blake2 and Verloes (3).

• The presence of all 4 Major criteria establishes the diagnosis of CHARGE syndrome.
• These Classic 4C’s are Choanal Atresia, Coloboma, Characteristic ears, and Cranial nerve anomalies (Blake et al. 2006). Any of these four major criteria should suggest CHARGE syndrome as a diagnostic possibility.
  • Coloboma: in CHARGE, colobomas mainly affect the retina. Order an ophthalmology consult.
  • Choanal Atresia: this may be membranous or bony; bilateral or unilateral. Pass a #6 French feeding tube in both nares
    • Many individuals with CHARGE syndrome, such as our patient, do not have choanal Atresia or coloboma.
  • Cranial nerves: multiple cranial nerve dysfunctions is common. Facial palsy is the most common cranial nerve deficit after hearing loss.
  • Characteristic ear anomalies: Hypoplastic semicircular canals and Mondini malformation on CT of the petrous bones or MRI. Unusually shaped ears: the lack of a lobule and the triangular concha are classic; Hearing loss: conductive and/or nerve deafness ranges from mild to severe deafness. Order a hearing test early – do not wait for discharge.
• Minor criteria
  • Mediastinal organs (cardiac, esophagus): major and minor congenital heart defects (most common tetralogy of Fallot) in 75-80% of patients.
  • Hypothalamo-hypophyseal dysfunction (including GH and gonadotrophin deficiencies): Underdeveloped male external genitalia is common, less apparent in females.
    • As a rule of thumb, you can assume that microphallus in a baby with facial palsy is due to CHARGE syndrome until proven otherwise
  • Intellectual disability: IQ ranges from normal to profound intellectual disability
  • Feeding adaptation: requires early aggressive feeding therapy.
  • Characteristic face: look for a square forehead

This patient has two major (multiple cranial nerve involvement, typical ear anomalies) and four minor criteria (cardiac, genital, poor feeding, face), which is sufficient to consider the diagnosis of CHARGE according to Blake (2) and which meets the criteria proposed by Verloes (3) for atypical CHARGE syndrome. Interestingly, the four major criteria listed above do not demand intensive intervention in the NICU and, for that reason, may be overlooked as the attention focuses on anomalies that present more life-threatening concerns. The message here is that the signs that establish the diagnosis of CHARGE syndrome may not be the ones that demand therapeutic attention – a holistic approach to the baby may reward the careful practitioner with a timely diagnosis.

This patient has two major (multiple cranial nerve involvement, typical ear anomalies) and four minor criteria (cardiac, genital, poor feeding, face), which is sufficient to consider the diagnosis of CHARGE according to Blake (2) and which meets the criteria proposed by Verloes (3) for atypical CHARGE syndrome. Interestingly, the four major criteria listed above do not demand intensive intervention in the NICU and, for that reason, may be overlooked as the attention focuses on anomalies that present more life-threatening concerns. The message here is that the signs that establish the diagnosis of CHARGE syndrome may not be the ones that demand therapeutic attention – a holistic approach to the baby may reward the careful practitioner with a timely diagnosis.

Practical applications:

1. In the infant with multiple congenital anomalies, pay as much attention to anomalies that do not demand therapeutic attention as the ones that do; these are often the key to the diagnosis.
2. Recognize the importance of the major and minor criteria in the diagnosis of CHARGE syndrome – especially the 4 Cs: Coloboma, Choanal atresia, Cranial nerve dysfunction, and Characteristic ear anomalies and semicircular canal dysplasia.
   • Understand that coloboma and choanal Atresia are not always present.
3. Recognize the important association of micropenis and facial palsy as a clue to the diagnosis of CHARGE syndrome.
4. Consider the whole patient and make a diagnosis based on all the features: Do not be one of the six blind practitioners who examined the elephant!

References:

1. van Ravenswaaij-Arts CM, Hefner M, Blake K, Martin DM. CHD7 Disorder. 2006 Oct 2 [updated 2020 Sep 17]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301296
2. Blake KD, Prasad C. CHARGE syndrome. Orphanet J Rare Dis. 2006 Sep 7;1:34. doi: 10.1186/1750-1172-1-34. PMID: 16959034; PMCID: PMC1586184. https://doi.org/10.1186/1750-1172-1-34
3. Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A. 2005 Mar 15;133A(3):306-8. doi: 10.1002/ajmg.a.30559. PMID: 15666308.

Disclosures: The authors have no disclosures