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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 2  |  Issue : 2  |  Page : 110-112

Partial digeorge syndrome with hypertrophied arytenoids in a neonate: Expanding the clinical phenotype


1 Department of Neonatology, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, Tamil Nadu, India
2 Department of Pediatric Otorhinolaryngology, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, Tamil Nadu, India

Date of Submission16-Feb-2022
Date of Decision01-May-2022
Date of Acceptance02-May-2022
Date of Web Publication30-May-2022

Correspondence Address:
Dr. Siddharth Madabhushi
Department of Neonatology, Kanchi Kamakoti CHILDS Trust Hospital, 12-A, Nageswara Road, Nungambakkam, Chennai - 600 034, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipcares.ipcares_50_22

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  Abstract 

Background: DiGeorge Syndrome (DGS) is caused by the 22q11 deletion. There is wide variation in the phenotypic presentation due to incomplete penetrance. Since dysmorphism is subtle in neonates, a high index of suspicion should be kept. Clinical Description: A 2.8 kg term baby girl born of a cesarean section developed stridor and respiratory distress and was referred to our hospital at 14 days for the persistence of symptoms. The manifestations were severe, requiring respiratory support, and not explainable by clinical findings, radiological atelectasis, and normal echocardiography. The baby had hypocalcemia (that had been noted and treated earlier), hypoparathyroidism and Vitamin D deficiency, for which standard therapy was started. Airway endoscopy revealed hypertrophied arytenoids which have not been reported in DGS before. Management: The presence of abnormal laryngeal with hypocalcemia prompted us to consider DGS. The likelihood became stronger when a chest ultrasonogram detected athymia. The identification of 22q microdeletion by fluorescence in situ hybridization confirmed the diagnosis. It was decided to perform supraglottoplasty to avoid the postoperative complications associated with direct vocal cord repair. The postoperative period was uneventful. The immunological profile was normal, besides a low count of normal CD4+ naïve cells. The final diagnosis was partial DGS. Conclusion: Genetic testing for 22q11 deletion should be done in the presence of laryngeal pathology and any of the following: congenital cardiopathy, velopharyngeal insufficiency, thymic hypoplasia, and neonatal hypocalcemia.

Keywords: Di George syndrome, hypocalcemia, hypoparathyroidism, stridor, supraglottoplasty


How to cite this article:
Madabhushi S, Saravanamuthu T, Natarajan CK, Kumar VH. Partial digeorge syndrome with hypertrophied arytenoids in a neonate: Expanding the clinical phenotype. Indian Pediatr Case Rep 2022;2:110-2

How to cite this URL:
Madabhushi S, Saravanamuthu T, Natarajan CK, Kumar VH. Partial digeorge syndrome with hypertrophied arytenoids in a neonate: Expanding the clinical phenotype. Indian Pediatr Case Rep [serial online] 2022 [cited 2022 Jul 4];2:110-2. Available from: http://www.ipcares.org/text.asp?2022/2/2/110/346259

DiGeorge Syndrome (DGS) due to 22q11 deletion is the most common microdeletion syndrome with a global incidence of 1/4000–6000 live births, and affecting 0.1% fetuses.[1] The classical features of DGS popularized by the mnemonic CATCH 22, (cardiac abnormalities, abnormal facial features, thymic hypoplasia, cleft palate, and hypocalcemia), also include renal anomalies, parathyroid hypoplasia, velopharyngeal insufficiency, learning difficulties, behavioral abnormalities, and schizophrenia. In most cases, the underlying defect is a heterogeneous deletion of a 3 million base pair on the long arm at the 11.2 locus[2] that affects 30–50 genes. While an autosomal dominant inheritance is known in DGS, this is seen in only 10%. The majority of cases (90%) occur due to de novo mutations as the structure of the 22q11 region is prone to rearrangements.[3] Craniofacial and laryngeal malformations, in addition to anomalies of the heart, thymus, and parathyroid glands, are the result of dysregulation of the migration of neural crest cells, and differentiation of the branchial arches.[4] There is marked variability in clinical manifestations due to incomplete penetrance. The term complete DGS is used to describe those patients who are athymic and have no circulating T-cells (<1%), and partial DGS for those with thymic hypoplasia and the presence of circulating T-cells.[5] Milder variants are often missed since the facial dysmorphism is subtle in neonates and infants. Affected individuals are often only identified in the pediatric age group when they are evaluated for language delay or behavioral issues; and rarely later due to adult-onset diseases.

An early diagnosis of DGS, therefore, requires a high index of suspicion by the clinician. We report a baby referred to us for persistent stridor and the need for ventilatory support since birth, in whom a diagnosis of DGS was finally established. While multiple types of laryngeal abnormalities have been reported in literature, to our knowledge, this is the first case of DGS with hypertrophied arytenoids that required surgery.


  Clinical Description Top


A baby girl was born to a 26-year-old primigravida at term gestation. The antenatal course had been unremarkable, except for a maternal COVID infection in the 2nd trimester, which resolved without hospitalization. The baby was born via cesarean section in view of a transverse lie. The birth weight was 2.8 kg. Although the baby cried immediately at birth and did not require any resuscitation, she was noted to have a weak cry with stridor. In view of persistent stridor, recurrent apnea, and cyanosis during crying, the baby was referred to another center on day 2 of life. Her medical documents revealed that she was treated for hypocalcemia (level unknown), right-sided pneumonia (based on chest radiograph), and probable sepsis (details not available). During 12 days of hospitalization, she received antibiotics (nature unknown), calcium supplementation, oxygen administration by nasal prongs, and nasogastric feeds (as described by parents). The parents left against medical advice, and brought the baby to us on day 14 of life.

At admission, the baby had cold stress, a heart rate of 155/min (min), respiratory rate 58/min, respiratory distress with suprasternal and intercostal retractions (Downe score 3/10), and saturation of 90% on room air. The baby had still not regained her birth weight (11% weight loss on day 14 of life). There was no pallor, cyanosis, gross congenital deformity, or obvious facial dysmorphism. Chest auscultation revealed reduced air entry on left side with normal cardiovascular exam. The rest of the systemic examination was normal.

The baby was placed under a radiant warmer. Bedside investigations revealed euglycemia and compensated respiratory acidosis on arterial blood gas analysis (pH 7.37, PO2 34 mm Hg, PCO2 65 mm Hg, and HCO3 37 mmol/L). Respiratory support was provided by heated humidified high-flow nasal cannula with a flow of 5 l/min, and 35% FiO2. A provisional diagnosis of persistent pneumonia and laryngomalacia was kept.


  Management and Outcome Top


The chest radiograph, showed right-sided segmental atelectasis in the left lobe [Figure 2]. The thymic shadow was appreciated. Though the initial hemogram showed leukocytosis and neutrophilia (total leukocyte count 22,700/mm3 with 68% neutrophils and 30% lymphocytes, and platelet count 4.35 lakh/mm3), the sepsis workup (C-reactive protein <5 g/dL), and blood culture (sterile) excluded active infection. The nasopharyngeal swab for the respiratory syncytial virus was negative. Salient abnormalities included hypocalcemia (ionized Ca2+ 0.89 mmol/L, total 8.3 mg/dl), hyperphosphatemia (9.2 mg/dl), parathyroid hormone (PTH) levels of 25 pg/ml – that though within the normal range, was relatively low considering the level of hyperphosphatemia), and Vitamin D insufficiency (13 ng/ml). We suspected transient hypoparathyroidism and started the baby on calcitriol, a phosphate binder oral calcium acetate, and oral calcium supplementation after administering intravenous calcium gluconate (presuming the stridor to be symptomatic hypocalcemia).
Figure 1: Airway endoscopy revealing large hypertrophied arytenoids, very short aryepiglottic folds and bulky ventricular folds

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Figure 2: X-ray chest of the neonate at admission showing atelectasis of the left mid zone

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In view of persisting respiratory distress and stridor, two-dimensional echocardiography and airway endoscopy were planned. The former revealed a structurally normal heart. The airway endoscopy showed large bulky arytenoids, very short aryepiglottic (AE) folds, bulky ventricular folds, and mobile vocal cords [Figure 1]. There was inspiratory collapse of supraglottic structures, with redundant tissue around the AE folds. A clinical suspicion of DGS was kept in view of the recurrent hypocalcemia, hypoparathyroidism, and unusual laryngeal findings. Since the thymus had been reported on the radiograph, a chest ultrasonogram was done to confirm its presence. As it was not visualized, it was deemed as absent. Confirmatory genetic evaluation of DGS was done by Fluorescence in situ hybridization testing, which revealed a 22q microdeletion. Immunological workup comprising B- and T-cell markers (memory and naïve T-cells) revealed no abnormality, aside from a low count of normal CD4+ naïve cells. A final diagnosis of partial DGS was made, and the parents underwent genetic counseling. No other anomalies or organ dysfunction associated with DGS were found.

The ear, nose and throat (ENT) surgical team performed a supraglottoplasty, in which the AE fold was released, and coblator ablation of the redundant tissues was performed. The respiratory distress resolved, and she became oxygen independent by the 14th and 17th postoperative days, respectively. The baby was discharged on the 21st postoperative day, on prophylactic antibiotics and management of hypoparathyroidism, as per standard protocol. Currently, the infant is being followed up by a multidisciplinary team (pediatrics, endocrinology, ENT, genetics and hematology departments). Further immunological workup is planned at 3 months, to decide whether injectable human recombinant PTH will be required or not.


  Discussion Top


DGS is usually suspected in a newborn with cardiac defects, refractory hypocalcemic convulsions associated with low levels of PTH, or rarely due to clinical manifestations of severe immunodeficiency.[2] Laryngeal abnormalities are observed in 14% to 18%.[6],[7] The spectrum includes subglottic stenosis, glottic webs, vocal cord paralysis, laryngomalacia, vocal nodules, and bronchial malposition. This neonate had laryngomalacia with bulky arytenoids. Hypertrophied arytenoids have been documented in Richieri-Costa Pereira Syndrome.[8] To the best of our knowledge, this is the only case of DGS in which the hypertrophied arytenoids compromised the laryngeal inlet to such an extent that surgical intervention was required. The surgical team decided to take the cautious approach of supraglottoplasty, rather than direct arytenoid intervention. Iatrogenic laryngeal complications such as paralysis of the left vocal fold, posterior vocal fold erosion, and dislocated arytenoid, although rare (<5%), have been observed after multiple surgeries and airway evaluations. A recent study observed swallowing difficulties and nasal regurgitation in nearly 50%, even in the absence of palatal defects.[9] While partial DGS may not have absent T-cells (as in our case), patients are still predisposed to infections, with over 60% of them experiencing recurrent infections such as sinusitis and otitis media.[10]

It has been recommended to test for the 22q11 deletion in children with any laryngeal pathology associated with at least one of the following anomalies: congenital cardiopathy, velopharyngeal insufficiency, thymic hypoplasia, and neonatal hypocalcemia.[6] Our observation of hypertrophied arytenoids, a new laryngeal pathology not previously described, further reaffirms the above recommendation.



Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Grati FR, Molina Gomes D, Ferreira JC, et al. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat Diagn 2015;35:801-9.  Back to cited text no. 1
    
2.
McDonald-McGinn DM, Sullivan KE, Marino B, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers 2015;1:15071.  Back to cited text no. 2
    
3.
Shprintzen RJ. Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev 2008;14:3-10.  Back to cited text no. 3
    
4.
Maynard TM, Meechan DW, Dudevoir ML, et al. Mitochondrial localization and function of a subset of 22q11 deletion syndrome candidate genes. Mol Cell Neurosci 2008;39:439-51.  Back to cited text no. 4
    
5.
Müller W, Peter HH, Kallfelz HC, et al. The DiGeorge sequence. II. Immunologic findings in partial and complete forms of the disorder. Eur J Pediatr 1989;149:96-103.  Back to cited text no. 5
    
6.
Leopold C, De Barros A, Cellier C, et al. Laryngeal abnormalities are frequent in the 22q11 deletion syndrome. Int J Pediatr Otorhinolaryngol 2012;76:36-40.  Back to cited text no. 6
    
7.
Ebert B, Sidman J, Morrell N, et al. Congenital and iatrogenic laryngeal and vocal abnormalities in patients with 22q11.2 deletion. Int J Pediatr Otorhinolaryngol 2018;109:17-20.  Back to cited text no. 7
    
8.
Miguel HC, Carneiro CG, Tabith A Jr, et al. Laryngeal malformation in Richieri-Costa Pereira syndrome: New findings. Am J Med Genet A 2012;158A: 1967-70.  Back to cited text no. 8
    
9.
Giardino G, Radwan N, Koletsi P, et al. Clinical and immunological features in a cohort of patients with partial DiGeorge syndrome followed at a single center. Blood 2019;133:2586-96.  Back to cited text no. 9
    
10.
Davies EG. Immunodeficiency in DiGeorge Syndrome and options for treating cases with complete athymia. Front Immunol 2013;4:322.  Back to cited text no. 10
    


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