Novel Airway Challenges in DEGCAGS Syndrome: Managing Infant Laryngeal Hamartomas

Introduction

Hamartomas are rare benign lesions formed by mature, normal tissue arranged in an abnormal quantity and disordered pattern in the affected area. Hamartomas occurring in the laryngeal region as a congenital laryngeal malformation are even rarer. The occurrence of laryngeal hamartomas in children is particularly dangerous due to their relatively narrow airways, where even mildly growing tumors can severely impact respiration [1].

Developmental delay with gastrointestinal, cardiovascular, genitourinary, and skeletal abnormalities (DEGCAGS syndrome) is an autosomal recessive neurodevelopmental disorder caused by biallelic mutations in the ZNF699 gene [2]. It is typically characterized by developmental delays, coarse facial dysmorphism, and feeding difficulties. Additionally, the syndrome can involve severe structural anomalies, such as defects in the cardiovascular, genitourinary, gastrointestinal, and skeletal systems. However, research into syndromes caused by ZNF699 gene mutations is ongoing owing to the rarity of these mutations. This report describes the case of a 1-year-old infant with a confirmed diagnosis of DEGCAGS syndrome who presented with progressive stridor and respiratory distress.

Case Report

A 1-year-old girl presented with worsening stridor, hoarseness, respiratory distress, mouth breathing during sleep, and slight difficulty swallowing. She was born at term via spontaneous vaginal delivery, the fourth child in the third pregnancy, with a birth weight of 2700 g. The mother had a healthy pregnancy. Since birth, the child has experienced stridor, occasional choking during feeding, frequent coughing, and difficulty expectorating sputum. The local hospital suspected congenital laryngomalacia but did not provide specific treatment. Whole exome sequencing (Beijing ZhiYin DongFang Translational Medicine Research Center Co, Ltd) indicated a mutation in the ZNF699 gene, suggesting DEGCAGS syndrome. The family history was negative for similar conditions. The patient’s past medical history included leukopenia, recurrent pneumonia, immunodeficiency, patent ductus arteriosus, and patent foramen ovale. The child’s vital signs were normal, but her weight was 6 kg, and her growth and development were delayed compared with that of her peers. Physical examination revealed microcephaly (broad forehead and narrow occiput), coarse facial features, a wide mouth, a long tongue, no nasal flaring, tracheal tugging, and smooth new growths at the oropharyngeal base (Figure1).

Fiberoptic nasopharyngoscopy showed 2 smooth masses in the left nasopharynx, with potential congenital laryngomalacia and bilateral vocal cord dysfunction (Figure 2).

Computed tomography (CT) of the head, neck, and chest revealed a “tongue-shaped” soft-tissue mass at the nasopharyngeal apex extending into the nasopharyngeal cavity (Figure 3). Magnetic resonance imaging (MRI) of the head, neck, and chest (3.0T) suggested a mass in the left nasopharyngeal wall, suspected to be a polyp, with slight swelling and increased signal in the bilateral vocal cord muscles, possibly indicating edema (Figure 4). Echocardiography showed a patent foramen ovale with left-to-right shunt and normal overall systolic and diastolic function of the left ventricle.

The diagnosis included left nasopharyngeal mass, base of tongue mass, congenital laryngomalacia, bilateral vocal cord dysfunction, and DEGCAGS syndrome. Following preoperative evaluations, the patient underwent left nasopharyngeal mass excision, base of tongue mass excision, supraglottoplasty, and laryngeal reconstruction under general anesthesia in May 2024. During the procedure, endoscopic exploration revealed a 5×3-mm mass in the left nasopharynx, an 8×5-mm mass in the posterior nasal septum, and a 1-cm diameter smooth, round mass at the base of the tongue. During inhalation, the epiglottis slightly collapsed toward the glottis, with shortened aryepiglottic folds and redundant mucosa in the arytenoid area. The vocal cord structure appeared normal, but mobility was poor, despite preserved spontaneous breathing. The nasopharyngeal mass pedicle was vaporized with a plasma knife, the base of the tongue mass was cauterized with a laser, the base of the epiglottis was cauterized with a laser, the bilateral aryepiglottic folds were incised, and laryngeal function reconstruction was performed (Figure 5).

Postoperative pathological examination of all excised masses confirmed hamartomas, with immunohistochemical analysis showing positivity for cluster of differentiation 21 (CD21; follicular dendritic cells), CD3 (T lymphocytes), desmin (smooth muscle bundles), paired box gene 5 (PAX5; B lymphocytes), S-100 protein (scattered positive), and smooth muscle actin (SMA; smooth muscle bundles) (Figure 6).

Postoperatively, the patient was transferred to the Intensive Care Unit for monitoring. On postoperative day 1, after extubation, the patient’s breathing was smooth with supplemental oxygen at medium flow, and oxygen saturation was maintained above 97%. On postoperative day 2, due to agitation, stridor was observed with tracheal tugging; high-flow ventilation support was provided, along with ceftriaxone for infection, dexamethasone for laryngeal edema, and symptomatic treatment, including nebulization. By postoperative day 4, the patient occasionally had stridor while crying but maintained smooth breathing and oxygen saturation above 97% at rest. She was then transferred to a general ward where, with family reassurance, her breathing was smooth, and feeding was unimpeded and without choking. On postoperative day 5, fiberoptic nasopharyngoscopy showed no significant postoperative changes, and the patient was discharged (Figure 7). Follow-up in July 2024 showed smooth breathing, no abnormalities in respiration or swallowing, and no significant changes on fiberoptic nasopharyngoscopy (Figure 8).

Discussion

DEGCAGS syndrome is a systemic disorder associated with mutations in the ZNF699 gene and is characterized by developmental delays, immune deficiencies, cardiovascular anomalies, and other systemic abnormalities [2]. To date, approximately 30 cases of DEGCAGS syndrome have been reported worldwide [3]. The pediatric patient we describe, with a diagnosis of DEGCAGS syndrome, presented with several common clinical features, including congenital laryngomalacia, bilateral vocal cord immobility, past episodes of leukopenia, recurrent pneumonia, immune deficiencies, patent ductus arteriosus, and patent foramen ovale [4]. Notably, the occurrence of a concurrent pharyngeal mass has not been previously documented in the context of this syndrome.

The ZNF699 gene encodes a zinc finger protein that plays a critical role in cellular regulation. These proteins stabilize their structure through binding with zinc ions and are involved in essential processes such as transcriptional regulation, DNA repair, ubiquitin-mediated protein degradation, signal transduction, actin targeting, and cellular migration [5]. Numerous studies have identified mutations in various zinc finger proteins and their links to specific diseases. For example, the ZNF423 gene, which encodes a zinc finger protein, is implicated in DNA repair and cell proliferation and has been associated with breast and ovarian cancers [6]. Additionally, mutations in the ZNF384 gene can enhance the proliferation and survival of leukemia cells, correlating with acute lymphoblastic leukemia [7]. In hereditary conditions, ZNF302 has been associated with hypospadias, while dysregulation of ZNF763 has been linked to Down syndrome and primary hyperuricemia [8,9]. The connection between the ZNF699 gene and human genetic disorders was established only in 2021, highlighting its association with DEGCAGS syndrome; however, its relationship to other diseases remains uncertain [2].

Pharyngeal hamartomas are rare benign tumors typically lacking physiological function, generally not impairing normal organ operations. However, they can grow to compress vital structures or obstruct the airway, leading to symptoms such as nasal obstruction, hoarseness, and potentially severe respiratory distress [10,11]. The pathogenesis of pharyngeal hamartomas often relates to abnormal cellular proliferation, particularly in young children, in which genetic factors or immune deficiencies may play a role. Notably, many immune deficiency disorders are associated with the formation of hamartomas, potentially linked to increased susceptibility to infections. Severe combined immunodeficiency, a hereditary immune deficiency, increases the risk of various tumors, including hamartomas, due to significant immune system defects. DiGeorge syndrome, another congenital immune deficiency, frequently results from chromosomal abnormalities and has been associated with a heightened risk of tumors, including hamartomas [12]. In the case of DEGCAGS syndrome, the underlying immune deficiency can provoke chronic inflammatory responses, resulting in localized tissue hyperplasia and the subsequent development of pharyngeal hamartomas.

Furthermore, certain genetic mutations or chromosomal anomalies can facilitate the formation of pharyngeal hamartomas. The TP53 gene, which encodes the p53 protein – an essential tumor suppressor – plays a significant role in cell cycle regulation and DNA damage repair. Mutations or inactivation of TP53 can disrupt cell cycle control, leading to the abnormal cellular proliferation associated with hamartomas [13]. Thus, it is plausible that mutations in the ZNF699 gene may represent one mechanism underlying the development of pharyngeal hamartomas.

In managing pharyngeal hamartomas associated with DEGCAGS syndrome, early diagnosis is critical. Neonates and young children often exhibit severe respiratory distress and feeding difficulties shortly after birth, which can prompt parental concern. The ZNF699 gene may serve as a potential diagnostic biomarker for early identification and prevention of hamartoma formation.

In terms of treatment, the primary approach for our patient was complete surgical excision, without the need for chemotherapy or radiotherapy. The postoperative prognosis was favorable, with regular follow-ups. The child did experience respiratory distress following extubation, which was attributed to concurrent bilateral vocal cord immobility. Conservative management with antibiotics, corticosteroids, and nebulized anti-inflammatory treatments led to resolution of respiratory distress, allowing the child to resume normal breathing at rest. The need for further surgical intervention for vocal cord immobility remains to be assessed based on its long-term impact on the child’s quality of life. Given the child’s young age, ongoing monitoring for developmental delays and other systemic manifestations of DEGCAGS syndrome, as well as follow-up for the hamartoma, is warranted.

While the incidence of pharyngeal hamartomas is not dependent on age, affecting adults and infants, cases of DEGCAGS syndrome in children complicated by pharyngeal hamartomas are exceedingly rare. Mutations in the ZNF699 gene are linked not only to congenital laryngomalacia, bilateral vocal cord immobility, and immune deficiencies but also to the development of pharyngeal hamartomas. Therefore, in pediatric patients with DEGCAGS syndrome, it is essential to consider the potential presence of pharyngeal hamartomas, which can lead to significant respiratory distress and feeding challenges. This case emphasizes the importance of precise diagnostic strategies for DEGCAGS syndrome associated with pharyngeal hamartomas. The ZNF699 gene may serve as a valuable diagnostic marker, aiding in the early detection and prevention of related conditions [14].

Although laryngomalacia has not been previously documented in DEGCAGS syndrome, its manifestation in our patient suggests a potential expansion of the phenotypic spectrum associated with this disorder. Whole-exome sequencing (conducted by Zhiyun Oriental Laboratory) revealed variants that may implicate laryngeal involvement in DEGCAGS syndrome, including laryngomalacia, vocal cord paralysis, and distinctive crying patterns. However, given the lack of prior reports, this finding could also represent an incidental association rather than a definitive feature of the syndrome. Further studies involving additional patients with DEGCAGS syndrome are warranted to clarify whether laryngomalacia constitutes a novel clinical manifestation or an unrelated coincidental anomaly.

Conclusions

Although the occurrence of pharyngeal hamartomas is not age-related, with adults and infants at risk, cases of pediatric patients with DEGCAGS syndrome and pharyngeal hamartomas are rare. Mutations in the ZNF699 gene are associated not only with congenital laryngomalacia, bilateral vocal cord dysfunction, and immune deficiency but also with the development of pharyngeal hamartomas. Therefore, in children with DEGCAGS syndrome, the possibility of pharyngeal hamartomas, which can cause severe respiratory distress and feeding difficulties, should be considered. This case highlights the importance of precise diagnostic strategies for DEGCAGS syndrome with concurrent pharyngeal hamartomas. In clinical practice, ZNF699 gene mutations should be considered as potential diagnostic markers, which could aid in the early detection and prevention of related diseases.