CHARGE syndrome patient with novel CHD7 mutation presenting with severe laryngomalacia and feeding difficulty

Abstract

We report a case of CHARGE syndrome with atypical phenotype and a novel mutation in the CHD7 gene. Laryngomalacia and swallowing difficulties are prominent features in this case. These are commonly found in patients with CHARGE syndrome and are well described in previous studies. However, with the traditional diagnostic criteria, diagnosis is difficult without the presence of coloboma or choanal atresia. Early diagnosis is possible with the aid of clinical genetics. The current diagnostic criteria would need to be broadened with the inclusion of pathogenic CHD7 variant status as a major criterion. Further research on the function of CHD7 gene may also give us more insight on the pathogenic mechanism of various clinical features of CHARGE syndrome.

Background

CHARGE syndrome consists of a non-random association of coloboma, heart disease, atresia choanae, retarded growth and development, genital hypoplasia and ear anomalies. It is a clinical diagnosis. Major and minor diagnostic criteria were proposed by Blake et al¹ in 1998 and further modified by Verloes in 2005.² However, not all CHARGE patients have coloboma or choanal atresia. On the other hand, such patients may have defects more than those described in the original acronym, which complicates the diagnosis. We hereby report a case of CHARGE syndrome presenting primarily with severe laryngomalacia and feeding difficulty. A de novo heterozygous mutation in the CHD7 gene, which has never been reported in literature, is found in this patient.

Case presentation

This was a 9-month-old patient born at 36 weeks gestation due to preterm onset of labour, with a birth weight of 2.79 kg. Antenatal screening tests were normal and the perinatal course was otherwise uneventful. There was no family history of inherited disease and parents were non-consanguineous. He presented to our unit at 1 month of life with noisy breathing, feeding difficulty and poor weight gain, with a body weight of only 3.14 kg at that time.

Multiple anomalies were noted during physical examination. These included dysmorphic features with abnormal ear shapes (figure 1) and preauricular skin tag. The left palpebral fissure was smaller than right side but the ocular examination was otherwise normal. There were multiple lentigines on his body, mainly over his trunk and back (figure 2). He was in respiratory distress with inspiratory stridor and in-sucking of the chest wall. Heart sounds were normal but there was a soft systolic murmur at the left upper sternal border. The angle of mouth was deviated which was compatible with absent left depressor angular oris. There was generalised hypertonia with slightly brisk deep tendon reflexes. There was micropenis with a stretched penile length of 2.5 cm and width of 0.5 cm. Both testes were small in size.

Figure 1.

Abnormal ear shape.

Figure 2.

Multiple lentigines over the back.

Multiple disciplines were involved in the evaluation and management of his condition. Airway endoscopy was performed by ear, nose and throat surgeons. It showed features of laryngomalacia with prominent arytenoids and tubular, retroverted epiglottis. There was no evidence of choanal atresia or stenosis. Structures below vocal cords were normal. He required nocturnal continuous positive airway pressure and daytime oxygen supplementation for his breathing problem.

Assessment of his feeding difficulties found poor sucking–swallowing–breathing coordination and pharyngeal dysphagia. Moderate to severe gastro-oesophageal reflux also contributed to his feeding problem. No tracheo-oesophageal fistula was evident in contrast swallow study. There was no cleft lip or cleft palate. Laparoscopic gastrostomy and fundoplication were performed at 3 months of life with improvement in weight gain afterwards.

Other organ systems were also involved. He has patent ductus arteriosus and small atrial septal defect, with heart failure requiring diuretics until spontaneous closure of the cardiac lesions at 6 months of life. The generalised hypertonia was largely contributed by gastro-oesophageal reflux as extensive metabolic workup and ultrasound scan of the brain were normal, and the muscle tone improved after fundoplication was done. No tone-reduction medication was needed. Brainstem auditory evoked potential revealed bilateral profound hearing loss, which is a mixture of conductive and neurosensory in nature.

The lentigines over patient’s trunk gradually subsided by 4–6 months of age. Skin biopsy was not performed due to its invasive nature and the skin pigmentation was resolving. Endocrine workup was performed for the micropenis and small testes. The biochemical profile was compatible with hypogonadotrophic hypogonadism.

Investigations

In view of his dysmorphism and multiple clinical problems, the clinical geneticist was consulted for evaluation of the underlying condition. Trio whole-exome sequencing revealed de novo heterozygous NM_017780.3:c.1510C>T p.(Gln504Ter) mutation in exon 2 of the CHD7 gene. This was confirmed by Sanger sequencing. The diagnosis of CHARGE syndrome was obtained.

Further evaluation was done to screen for associated anomalies of CHARGE syndrome. Ophthalmic examination was normal without any coloboma. Ultrasound scan of kidneys was normal. Immunology tests including immunoglobulin pattern and lymphocyte subset were normal.

Outcome and follow-up

He was discharged at around 4.5 months of life with regular intensive training at an out-patient setting for his global developmental delay. Bedside flexible laryngoscopy at 10 months old showed improvement in laryngomalacia. MRI of brain and spine was performed at 17 months of life, showing small right olfactory bulb, small left internal auditory meatus and low-lying spinal cord which ended at L2–3 level. Cochlear implantation was performed at 20 months of life, and found the fusion of malleus and incus, absent stapes and absent mastoid cavity.

Discussion

Hall first described 17 patients with multiple congenital anomalies who shared choanal atresia as a common feature in 1979.³ In the same year, Hittner et al ⁴ reported 10 patients with coloboma and multiple congenital anomalies. Such association was grouped into the acronym CHARGE association by Pagon et al in 1981.⁵ With more understanding of this condition, it was later considered as a condition with single pathogenetic basis, qualifying it as CHARGE syndrome.⁶ In 2004, a mutation in the CHD7 gene was found to be accountable for the disease in most affected individuals.⁷ Since then, more mutations were found in the CHD7 gene in patients with CHARGE syndrome. We report a novel CHD7 mutation from this patient with CHARGE syndrome. The mutation found in this case is deleterious to the gene or gene product as supported by multiple lines of computational evidence. It is classified as pathogenic according to the American College of Medical Genetics and Genomics 2015 guidelines.⁸

Respiratory distress due to severe laryngomalacia and swallowing dysfunction is the major problem in this patient. Laryngomalacia occurs in more than 30% of patients and up to 80% of patients have abnormal swallowing.^9–11 External ear anomaly is one of the major diagnostic criteria for CHARGE syndrome, while hearing loss can occur in a variable degree.¹² Genital hypoplasia is well described in the original acronym. Heart defects are highly variable in patients with CHARGE syndrome.¹³ However, with all these features, one still cannot fulfil the clinical diagnostic criteria for CHARGE syndrome.

The original Blake criteria require four major or three major and three minor criteria to arrive at the diagnosis. The major criteria, include coloboma, choanal atresia/stenosis, characteristic ear anomalies and cranial nerve dysfunction.¹ In this patient, only two major criteria are met. Diagnosis is difficult where coloboma or choanal atresia is absent. The diagnosis of CHARGE syndrome is only made after genetic mutation in the CHD7 gene is found in this patient. This illustrates the need to consider CHARGE syndrome as a diagnosis even in the absence of coloboma or choanal atresia, especially in those with atypical phenotype. It also supports the view of broadening the current diagnostic criteria and include pathogenic CHD7 variant status as a major criterion.¹⁴

Finally, the nature and cause of the lentigines in this patient remain unanswered. Hyperpigmentation has never been reported as a feature in CHARGE syndrome. Ongoing research on the function of the CHD7 gene may give us more insight in this aspect.¹⁵

Learning points.

• Airway anomalies and swallowing problems are common presenting features in patients with CHARGE syndrome.

• The atypical phenotype of CHARGE syndrome needs to be considered in the differential diagnosis even in the absence of coloboma or choanal atresia.

• Early diagnosis of CHARGE syndrome is possible with the genetic evaluation of the CHD7 gene, even when the clinical diagnostic criteria are not fulfilled.