Severe laryngeal stenosis in newly born twins with 22q11.2 deletion syndrome: A case report

List of abbreviations

CHAOS

Congenital high airway obstruction syndrome

1 Introduction

22q11.2 deletion syndrome (DS) is the most common microdeletion syndrome with an estimated prevalence of 1/4,000 live births [1]. It is known to be associated with a wide range of clinical features including conotruncal cardiac malformations, velopharyngeal insufficiency, characteristic facies, parathyroid hypoplasia, immune deficiency, renal abnormalities, learning disabilities, and psychiatric disorders [2]. Due to the spectrum of disease, the phenotype of the deletion of 22q11.2 was historically referred to by a number of diagnostic terms including DiGeorge syndrome, velocardiofacial syndrome, Opitz G/BBB (autosomal dominant form) and conotruncal anomaly face or Takao syndrome. It is now understood that these are all the result of the same genetic abnormality, a 3 megabase interstitial deletion on band 11.2 of the long arm of chromosome 22, and are collectively referred to as the 22q11.2 deletion syndrome [1, 2]. Laryngeal abnormalities are increasingly recognized in the setting of deletion of 22q11.2, but often are mild to moderate and detected quite some time after birth [3–5].

2 Case report

Dichorionic diamniotic twin girls were born to a healthy 28-year-old mother. The pregnancy was complicated by unexplained polyhydramnios requiring two therapeutic amniocenteses. Antenatal ultrasounds showed normal fetal anatomy with no evidence of increased lung volume or echogenicity. The twins were born at 36 weeks gestational age by spontaneous vaginal delivery. Both girls were noted to have severe cyanosis and minimal respiratory effort at birth. They required prolonged cardiorespiratory resuscitation including chest compressions. Repeated trials of endotracheal intubation were unsuccessful, but the use of laryngeal mask airways produced some improvement. Both twins received emergency tracheostomy at 43 and 30 minutes of age. Although arterial cord gases were normal, the first arterial blood gases of Baby A showed severe mixed metabolic and respiratory acidosis. They were admitted to Neonatal Intensive Care Unit and received hypothermia treatment for 72 hours. Both twins showed remarkable clinical improvement and for each, subsequent neurological exam and brain MRI were reported as normal.

Review of the family history revealed that the father had a weak cry and developed recurrent croup as an infant. He was found to have a small anterior subglottic web at 12 months of age by direct laryngoscopy. He was also diagnosed to have Attention Defect Hyperactivity Disorder and a learning disability; however, as a child he did not have a genetics assessment or genetic testing for deletion 22q11.2.

During their stay in Neonatal Intensive Care Unit, each of the twins was noted to have long fingers, a prominent nasal root, bulbous nasal tip, and hypocalcemia secondary to hypoparathyroidism suggestive of 22q11.2 DS. Multiplex ligation-dependent probe amplification (MLPA) analysis of DNA from both infants and the father confirmed the diagnosis of 22q11.2 deletion in all three individuals. A detailed laryngoscopy at 3 months of age showed both girls to have fusion of the vocal cords with small pinhole connections to the trachea at the level of the arytenoids, consistent with severe type IV glottic webs (Figs. 1 and 2). Additional investigations following diagnosis showed no evidence of heart defects or immunologic disorders in the three individuals. The father, who was determined to have characteristic 22q11.2 DS facial features on examination by a geneticist, was subsequently diagnosed with hypocalcemia secondary to hypoparathyroidism.

3 Discussion

Laryngeal abnormalities have been reported in children with 22q11.2 DS, though are not recognized as a prominent clinical feature of the syndrome. Leopold et al. recently described 5 cases of laryngeal abnormalities of varying degrees in a series of 35 patients with 22q11.2 DS, giving it a frequency of 14% [3]. On the other hand, the frequency of 22q11.2 DS in children first presenting with glottic webs has been reported to be as high as 65% [6, 7]. This underlines the significance of investigating this genetic abnormality when a child presents with laryngeal abnormalities and vice versa.

Previous studies have described a wide range of laryngeal anomalies in 22q11.2 DS, such as vocal cord nodules, laryngomalacia, subglottic narrowing, and laryngeal webs [3, 9]. Prior to the identification of the 22q11.2 deletion region, Moerman et al. described a case of complete laryngeal atresia in an infant who died at a few minute of age following unsuccessful intubation. Autopsy showed thymus and parathyroid hypoplasia in keeping with the “DiGeorge developmental field defect” (10). The most severe laryngeal abnormality reported in association with confirmed 22q11.2 DS described a newborn infant presenting with stridor a few hours after birth and requiring tracheostomy at three days of life due to a failed attempt at repair of a type III glottic web (4). To the best of our knowledge, our report is the first to describe a severe life-threatening type IV glottic web presenting at birth in an infant with genetically confirmed 22q11.2 DS.

Deletion of 22q11.2 is usually a de novo mutation, but can be inherited in a dominant fashion in up to 28% of cases [2]. An affected parent, therefore, has a 50% chance of passing the mutation on to children. In our case, the father had an anterior subglottic web, Attention Defect Hyperactivity Disorder, and learning difficulties as a child and was not suspected to have 22q11.2 DS until his twins were born. The twins each had a much more severe laryngeal malformation, but shared with their father the characteristic facial features and parathyroid hypoplasia seen in 22q11.2 DS. There is only one prior report of a family history of laryngeal web in association with 22q11.2 DS. In 1992, Marble et al. described a case of subglottic web detected in a three-day-old male infant with 22q11.2 deletion. He also had an interrupted aortic arch and thymic aplasia, while his mother with 22q11.2 DS presented with a subglottic web at four years of age and had learning difficulties in school [11]. In this report as well as in our case, the laryngeal stenosis was more severe in the offspring. These cases highlight the variation in the phenotypic expression of this deletion, as well as the importance of suspecting 22q11.2 DS early in the setting of a family history of laryngeal anomalies.

Congenital high airway obstruction syndrome (CHAOS) is a term used to describe complete laryngeal atresia or near-complete high airway obstruction either with or without an esophageal fistula [12]. While rare, it is a highly lethal condition making prenatal diagnosis extremely important. A number of studies have described CHAOS findings on prenatal ultrasound to include hyperechogenic lungs, increased lung volumes, dilated trachea containing fluid, fetal hydrops, and polyhydramnios [13]. Recognition of these signs can lead to the correct prenatal diagnosis and facilitate preparing appropriate interventions. The ex utero intrapartum treatment (EXIT) procedure, whereby a tracheostomy is performed before clamping the umbilical cord has been successfully used in the setting of CHAOS [12, 14].

It is likely that in our case, the above signs were not all present on the prenatal ultrasound given that there was a small pinhole connection to the trachea. A review of the ultrasound images did not show hyperechogenic enlarged lungs or dilated trachea. However, unexplained polyhydramnios was observed and could have been attributed to the upper airway obstruction, pressure on the esophagus and decreased fetal swallowing [14]. The positive family history of a laryngeal abnormality, ADHD and learning difficulties in the father, combined with the ultrasound finding of unexplained polyhydramnios, in retrospect, could have raised the possibility of upper airway obstruction and 22q11.2DS. These babies would have benefitted from a prenatal diagnosis but did well because they happened to be delivered in a tertiary center with emergency access to neonatal and pediatric otolaryngologic services.

In the setting of unexplained polyhydramnios, assessment should include examination of fetal thoracic structures to look for possible CHAOS, as well as a review of family history. 22q11.2 DS should be on the differential as a significant underlying cause of upper airway obstruction. To optimize outcomes, if CHAOS is suspected, delivery plans should be adjusted to ensure a place of delivery with appropriate tertiary level services.

Disclosure statements

Financial Disclosure Statement: The authors indicate that they have no financial relationships and no potential, perceived, or real conflict of interest relevant to this article. This project was conducted with no specific financial support. No honorarium, grant, or other form of payment was given to anyone to produce this manuscript.

Human Research Statement: This case report was prepared in accordance with the guidelines outlined by the Research Ethics Board at the IWK Health Centre. Informed consent to publish the medical information and laryngoscopy images were obtained from the legal guardians of the patients described in this study. The family was provided with a copy of the completed manuscript.