Catch 22 Digeorge

[Juvencio Parise]

NORDgratefully acknowledges John M. Graham, Jr., MD, ScD, Pediatric Consultant in Clinical Genetics and Dysmorphology, Department of Pediatrics, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, for assistance in the preparation of this report.

CHARGE syndrome affects multiple organ systems, resulting in multiple problems apparent at birth. Other characteristics of CHARGE syndrome may not become apparent until later in life. The diagnosis of CHARGE syndrome should be made by a medical geneticist based on the presence of at least one major criterion and several minor and/or occasional criteria of CHARGE syndrome (see below).

Coloboma

A coloboma is a cleft or failure of the eyeball to close during fetal development. This can result in a keyhole-shaped pupil (iris coloboma) and/or abnormalities in the retina, macula or optic nerve. Very small eyes (microphthalmia) or missing eyes (anophthalmia) can be severe forms of coloboma. Colobomas of the retina or optic nerve may result in significant vision loss, including blind spots, problems with depth perception or legal blindness. Colobomas occur most frequently in the retina and are present in at least 70-90% of patients with CHARGE syndrome. Examination of 38 eyes in 19 patients with CHARGE syndrome and confirmed CHD7 variants revealed colobomata affected the posterior segment of 35 eyes in 18 patients. Both retinochoroidal and optic disk colobomata were observed in both eyes (bilaterally) in 15 patients and unilaterally in 3 patients. The coloboma involved the macula totally or partially in 21 eyes of 13 patients. Bilateral large retinochoroidal colobomata are the typical eye feature of CHARGE syndrome in patients with confirmed CHD7 variants; however, even eyes with large colobomata can form maculas. Many children with colobomas (even just an iris coloboma) may be sensitive to bright light (photophobia).

Cranial nerve abnormalities

Sensorineural (nerve) hearing loss in CHARGE syndrome is due to abnormalities in cranial nerve VIII. Cranial CT scans often reveal hypoplastic cochlea (81%) with absent semicircular canals in most patients. Hearing loss and difficulty with balance are the most common features associated with cochlear hypoplasia and absent semicircular canals. CHARGE syndrome is associated with characteristic external ears that tend to protrude and lack lobes. Hearing loss can range from a mild hearing loss to profound deafness. Hearing loss can be very difficult to measure in young children. Most affected children also have balance problems (vestibular abnormalities) associated with absent semicircular canals, which is a key finding in making the diagnosis of CHARGE syndrome.

Most children with CHARGE syndrome have swallowing problems (cranial nerves IX/X). These swallowing problems include the inability to coordinate suck and swallow, leading to gagging and aspiration of food into the lungs, which can cause pneumonia. Many children require feeding via a gastrostomy tube (tube directly into the stomach through the abdominal wall) until they can swallow safely.

Many children with CHARGE syndrome have asymmetric facial palsy resulting in paralysis of one side of the face (cranial nerve VII). This results in a lack of facial expression, which is important when a child is working with teachers or therapists.

Most children with CHARGE syndrome have an absent or reduced sense of smell (cranial nerve I) which makes it harder to learn to eat. Most patients with CHARGE syndrome have absent or abnormal olfactory bulbs on MRI, leading to a diminished sense of smell. Smell-testing can predict the presence of a problem in the production of male hormones called hypogonadotropic hypogonadism. The combination of a diminished or absent sense of smell with hypogonadotropic hypogonadism (termed Kallman syndrome) results in small external genitalia. This is very common in CHARGE syndrome and warrants consultation with an endocrinologist.

Choanal atresia

Choanae are the passages from the back of the nose to the throat that make it possible to breathe through the nose. In about half of all children with CHARGE syndrome, these passages may be blocked (atresia) or narrowed (stenosis). Among 12 patients with bilateral choanal atresia, 10 had related malformations, 3 of which had CHARGE syndrome. Surgery can often correct these defects. Unilateral atresia can usually be corrected with one surgical procedure at a later age (median 6 years, range 6 months to 18 years), while patients with the bilateral form need a median of 2.85 interventions at an early age (median 25 days, range 6 days-6 years). If both sides are affected, immediate measures must be taken to allow the newborn to breathe properly and prevent respiratory failure.

Features less specific to CHARGE syndrome and/or not consistent enough to be considered major: heart defects, genital abnormalities, kidney abnormalities, cleft lip or palate, TE fistula or esophageal atresia, poor growth, hypotonia, typical CHARGE face and typical CHARGE hand.

Heart defects

About 75-80% of children with CHARGE syndrome have congenital heart defects. Although all types of heart defects have been seen in children with CHARGE syndrome, the most common are tetralogy of Fallot (33%), VSD (ventricular septal defect), AV (atrioventricular) canal defect and aortic arch anomalies. The heart defects can range from an innocent murmur to life-threatening heart defects involving the outflow tracts of the heart. Most require medication and/or surgery. Severe heart defects are a major cause of death in children with CHARGE. The heart defects in CHARGE are similar to those seen in a chromosome abnormality called 22q11.2 deletion syndrome.

Genital abnormalities

Most males with CHARGE syndrome have a small penis, often with undescended testes (cryptorchidism). The urethral opening may not be at the end of the penis (hypospadias). Females may have small labia. Among 46 males with hypogonadotropic hypogonadism, 14 (30.4%) had Kallmann syndrome, 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had hypogonadotropic hypogonadism without an abnormal sense of smell. Most children with CHARGE syndrome require hormone therapy to achieve puberty due to hypogonadotropic hypogonadism, and a pediatric endocrinologist should evaluate pituitary gonadal axis.

Kidney abnormalities

About 40% of children with CHARGE syndrome have kidney abnormalities. These can include hydronephrosis (extra fluid in the kidneys) or reflux (backflow into the kidneys); horseshoe kidney; small or absent kidney; or multicystic dysplastic kidneys. All children with CHARGE syndrome should have a kidney ultrasound.

Cleft lip and/or cleft palate

About 25% of children with CHARGE syndrome have a cleft lip or cleft palate. The cleft lip can be one-sided or two-sided and may or not include the palate. Some have cleft palate without cleft lip. The submucous cleft palate (just the muscle, not the bone in the posterior roof of the mouth) may be hard to diagnose. A family history of an individual with an apparently isolated unilateral major CHARGE syndrome anomaly, or someone with a few of the minor features, should be offered genetic testing for the affected child and both parents for CHD7 variants.

Tracheoesophageal fistula/esophageal atresia

About 15-20% of children with CHARGE syndrome are born with an esophageal atresia (EA), where the food pipe is not connected to the stomach or with tracheoesophageal fistula (TEF), where there is a connection between the windpipe (trachea) and the food pipe (esophagus). Both conditions require surgery. In addition, the trachea may be weak or floppy due to weak cartilage. This can complicate surgery to treat these conditions.

Poor growth

Although birth weight is usually normal, many children with CHARGE syndrome are small after birth. Sometimes this is due to nutritional problems, heart problems or multiple illnesses. Some children with CHARGE syndrome have growth hormone insufficiency, which can be evaluated with a growth hormone stimulation test.

Hypotonia of the trunk

Most children with CHARGE syndrome have upper body weakness (hypotonia). They are weak, especially in the trunk, and may have sloping shoulders. This weakness, especially combined with balance problems and/or vision problems, will delay walking. The average age of walking is about 3 or 4 years in children with CHARGE syndrome, and this results from the combination of hypotonia and diminished balance due to their underdeveloped semicircular canals.

Typical CHARGE face

Children with CHARGE syndrome often look like one another. The typical child has a square face, with broad prominent forehead, arched eyebrows, large eyes, occasional droopy eyelids, a prominent nasal bridge with square root, small nostrils, prominent nasal columella, flat midface, small mouth, occasional small chin, which improves with age. The face is often very asymmetric.

Other features

These features may be important for management, but not very helpful in making the diagnosis. Brain abnormalities, including small head (microcephaly), enlarged cerebral ventricles or other abnormalities identified by brain imaging such as MRI or CT scan are occasionally seen. Apnea and seizures are rarely seen in children with CHARGE syndrome. Weak cartilage (as seen in the ears) can also affect the trachea (windpipe) making it weak. Sometimes the baby has a very weak cry due to laryngomalacia (weak vocal cords). A few children with CHARGE syndrome have missing or extra nipples. Some have a relatively wide neck, with occasional cervical vertebral abnormalities. Rarely, children with CHARGE syndrome have an umbilical hernia, omphalocele or limb abnormalities, such as abnormal thumbs or extra fingers.

A few children with CHARGE syndrome have DiGeorge sequence, consisting of a complex heart defect, immune deficiency and abnormalities of the thyroid and parathyroid glands. Because these features are also seen in chromosome 22q11.2 deletion syndrome, children with possible CHARGE syndrome and no variants in CHD7 should have chromosomal microarray testing done. Some children with CHARGE syndrome appear to have a poor immune response, and in the presence of hypocalcemia should prompt an immunologic evaluation. Most children with CHARGE syndrome and immunodeficiency have T-cell deficiency.

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