Stridor as an Initial Manifestation of Underlying PHACE Syndrome in an Infant: A Case Report and Comprehensive Review

Abstract

Stridor is a common presenting complaint in infancy. Its aetiology ranges from benign to severe, life-threatening conditions. We report here a 2-month-old child who presented with respiratory distress and stridor since 20 days of life, with intermittent worsening. On examination, there was a haemangioma on the right ear lobe. A similar lesion in the airway was suspected, and flexible bronchoscopy revealed an airway haemangioma in the larynx extending up to the carina. Further workup was performed given haemangioma in the facial region that led to a diagnosis of the Posterior fossa malformations, Arterial anomalies, and Coarctation of the aorta, along with other cardiac defects and Eye abnormalities (PHACE) syndrome. Following oral propranolol, there was a significant improvement in symptoms. This case highlights that airway haemangioma should be suspected in infants presenting with stridor and haemangioma, especially in the facial area. Once the diagnosis is confirmed, the child should be further evaluated for underlying PHACE syndrome.

Introduction

Stridor is a common clinical presentation in children. Its aetiology ranges from benign to severe, life-threatening conditions. Sometimes it may be a clue to underlying disorders. Airway haemangioma is a rare cause of stridor in infancy. It may be isolated or associated with underlying disorders. ¹ Haemangioma in the head and neck region is often associated with Posterior fossa malformations, Arterial anomalies, and Coarctation of the aorta, along with other cardiac defects and Eye abnormalities (PHACE) syndrome. It has a variable presentation, which may pose a diagnostic dilemma. ¹ Airway haemangioma is seen in 16% to 50% of cases of PHACE syndrome. ² Early identification is necessary to avoid potentially life-threatening complications. Here, we describe an infant who presented with stridor and, on evaluation, was diagnosed with PHACE syndrome.

Case History

A 2-month-old female infant developed recurrent episodes of respiratory distress and noisy breathing since the 20th day of life. These episodes required multiple hospital visits, and there was a transient response to nebulised bronchodilator and oral steroids. She was born to non-consanguineous parents without any significant family history and had a smooth perinatal period. On examination, the child had respiratory distress (respiratory rate of 64/min with suprasternal, subcostal, and intercostal retractions). There was a haemangioma of 1.5 × 1.5 cm on the right ear (Figure 1A and B). Respiratory examination showed biphasic stridor. Other systems were normal. Given the possibility of airway haemangioma, a flexible fibreoptic bronchoscopy was performed, revealing haemangioma on the left lateral tracheal wall extending from the subglottic region to the carina (Figure 1C and D).

Figure 1.

Haemangioma on the right ear lobe (A and B). Flexible bronchoscopy Image showing haemangioma in the subglottic region obstructing the airway lumen (black arrow in (C)), extending up to the carina (blue arrow in (D)).

A thorough evaluation was conducted to determine the presence of other associated anomalies, given the suspicion of PHACE syndrome. Ophthalmological examination revealed a morning glory disc appearance, and a Magnetic Resonance Imaging (MRI) of the brain showed vascular anomalies (agenesis of the right internal carotid artery, hypoplastic right vertebral artery, focal acute infarct in the left caudate nucleus), right choroid plexus haemorrage with multiple extracranial hemangiomatous lesions. Contrast-Enhanced Computed Tomography (CECT) thorax revealed haemangioma in the subglottic airway on the left lateral wall, along the lateral tracheal fence extending up to the superior mediastinum with agenesis of the right lobe of the thyroid and isthmus, and an aberrant right subclavian artery (Figure 2). Multiple hemangiomatous lesions were also found in the subglottic, base of the epiglottis, base of the tongue, right supraclavicular region, bilateral parotid glands and right lateral chest wall along the fourth to seventh ribs with scalloping of the underlying ribs, and spleen. The patient was diagnosed with PHACE syndrome based on the presence of right earlobe (facial) haemangioma with 3 significant criteria (agenesis of the right Internal Carotid Artery [ICA], aberrant right subclavian artery, and morning glory sign) and one minor criterion of thyroid agenesis. Thyroid functions were normal. The patient was managed with supportive care and started on oral propranolol at 1 mg/kg/day, with gradual increases to 1.5 mg/kg/day. Aspirin was started due to cerebrovascular involvement. The patient has shown improvement on follow-up, with a resolution of stridor and a significant reduction in earlobe haemangioma. Propranolol was stopped at 12 months of therapy. She remained asymptomatic till 15 months of follow-up and had normal developmental milestones. The parents had not reported any therapy-related adverse effects. A follow-up bronchoscopy was not performed, as the child remained asymptomatic and the parents declined the procedure in the absence of symptoms. Repeat bronchoscopy remains planned if clinical symptoms recur.

Figure 2.

Imaging findings of PHACE syndrome. (A and B) Axial contrast-enhanced CT images show haemangiomas in bilateral parotid glands (red arrows in (A)), and subglottic haemangioma (black arrows in (B)) causes luminal narrowing. (C) Coronal time-of-flight (TOF) MR angiography, maximum intensity projection image showing agenesis of the right internal carotid artery (ICA) with the formation of the right middle cerebral artery (yellow arrow) from the basilar artery (red arrow). The right vertebral artery is also hypoplastic. The left ICA is normal (black arrow).

Discussion

Infantile haemangiomas (IHs) commonly affect the head and neck region and can involve the subglottic airway, although subglottic involvement remains relatively rare and potentially life-threatening. IHs located in the ‘beard distribution’ (chin, lower lip, mandibular area, and anterior neck) have a significantly higher risk of airway involvement, which heralds a poor prognosis. ³ Conversely, the majority of infants diagnosed with airway haemangiomas are found to have cutaneous haemangiomas within the beard area, reinforcing this anatomical correlation. ⁴ PHACE syndrome accounts for 2% to 3% of all IH cases, with prevalence increasing to 20% to 31% among infants with large segmental haemangiomas of the face. It is 9 times more common in females. ¹ IH typically follows a characteristic course, which involves a proliferative phase during the first 3 to 5 months of life and an involution phase over the years. ¹

Airway haemangioma can cause symptoms such as noisy breathing, hoarse crying, biphasic stridor and wheezing. PHACE syndrome can also cause developmental delays, seizures, macrocephaly, vision and hearing issues, failure to thrive due to pituitary or thyroid gland involvement, feeding difficulties, cyanosis, etc. It can present acutely as a stroke, leading to hemiplegia or headache. Airway haemangioma can mimic croup clinically with transient improvement with inhalational or systemic steroids, as shown in the present case. Therefore, recurrence or worsening of respiratory symptoms despite routine treatment may be a sign of IH. ²

While many cases of PHACE syndrome, including ours, present acutely with respiratory distress or neurological symptoms, others may follow a more indolent course. For instance, Imrani et al reported 2 children, one a 12-year-old girl with stroke and another a 6-month-old infant with acute respiratory distress, similar to our patient. ⁵ In contrast, some cases present non-acutely. A 15-year-old girl was reported with a gradually progressive facial haemangioma since infancy, which became cosmetically concerning only by adolescence, without any neurological deficits. ⁶ Similarly, an 8-month-old female infant was referred for dermatological evaluation due to a progressively enlarging facial haemangioma since birth, without other systemic symptoms. ⁷ Another report described a 3-year-old girl presenting with visual difficulty, eyelid haemangioma, developmental delay and a history of seizures requiring phenytoin therapy. ⁸ These cases highlight the broad clinical spectrum of PHACE syndrome, ranging from acute life-threatening presentations to more subtle, slowly progressive forms that may go unrecognised for years.

Diagnosis for PHACE syndrome requires a haemangioma larger than 5 cm in diameter of the head, including the scalp, along with one major criterion or 2 minor criteria (Table 1). ³ However, characteristic haemangiomas are present only in 31% of the cases. In our case, the child had a smaller facial haemangioma. This may be explained by early diagnosis during the proliferative phase, when the haemangioma is still growing, or by a partial response to systemic steroids administered before presentation. In this context, PHACE syndrome was diagnosed without a large segmental cutaneous lesion but with 3 major criteria. This aligns with the updated diagnostic recommendations, which acknowledge that PHACE syndrome can be diagnosed even in the absence of large segmental cutaneous haemangiomas, particularly when extracutaneous anomalies fulfilling major criteria are present.³ These recent guidelines emphasise that infants without characteristic cutaneous haemangiomas should still be evaluated for PHACE syndrome if they exhibit other defining anomalies, thus broadening the diagnostic spectrum and improving early recognition. ³

Table 1.

Revised Diagnostic Criteria for PHACE Syndrome (Reproduced from Garzon MC et al The Journal of Pediatrics. 2016;178:24-33). ³

Organ systems	Major criteria	Minor criteria
Arterial anomalies	• Anomaly of major cerebral or cervical arteries • Dysplasia of large cerebral arteries • Arterial stenosis or occlusion with or without moyamoya collaterals • Absence or moderate-severe hypoplasia of large cerebral and cervical arteries • Aberrant origin or course of large cerebral or cervical arteries, except common arch variants • Persistent carotid-vertebrobasilar anastomosis	- Aneurysm of any cerebral artery
Structural brain	• Posterior fossa brain anomalies • Dandy-Walker complex • Other hypoplasia/ dysplasia of the mid and/or hind brain	• Midline brain anomalies • Malformation of cortical development
Cardiovascular	• Aortic arch anomalies • Coarctation of the aorta • Dysplasia • Aneurysm • Aberrant origin of subclavian artery with or without vascular ring	• Right aortic arch/double aortic arch • Ventricular septal defect • Systemic venous anomalies
Ocular	• Posterior segment abnormalities  - Persistent hyperplastic primary vitreous   ○ Persistent foetal vasculature   ○ Retinal vascular anomalies   ○ Morning glory disc anomaly  - Optic nerve hypoplasia  - Peripapillary staphyloma	• Anterior segment abnormalities  - Microphthalmia  - Sclerocornea  - Coloboma  - Cataracts
Ventral/midline	- Anomaly of the midline chest and abdomen - Sternal defect - Sternal pit - Sternal cleft - Supraumbilical raphe	- Ectopic thyroid hypopituitarism - Midline sternal papule/hamartoma
Definite PHACE
Haemangioma > 5 cm in diameter of the head, including the scalp, PLUS 1 major criterion or 2 minor criteria OR Haemangioma of the neck, upper trunk, or trunk, and proximal upper extremity, PLUS 2 major criteria.
Possible PHACE
Haemangioma > 5 cm in diameter of the head, including scalp, PLUS 1 minor criteria OR Haemangioma of the neck, upper trunk, or trunk and proximal upper extremity PLUS 1 major or 2 minor OR No haemangioma PLUS 2 major criteria

The diagnosis of airway haemangioma requires a high index of suspicion in infants presenting with biphasic stridor, respiratory distress or poor response to conventional therapy. Flexible fibreoptic bronchoscopy remains the gold standard for diagnosis, as it allows direct visualisation of the lesion, assessment of the extent of involvement and evaluation of airway dynamics. ² Haemangiomas typically appear as compressible, reddish, submucosal masses, most commonly located in the subglottic region, though they may extend variably. Dynamic contrast-enhanced CT is a valuable non-invasive tool for evaluating airway haemangiomas. ⁹ It provides detailed anatomical information and can help identify characteristic features of haemangiomas. In cases where bronchoscopy findings are inconclusive or not feasible, CT may aid in confirming the diagnosis. However, its use should be balanced against the risks of radiation exposure, especially in infants, and should ideally be reserved for situations where bronchoscopy is either contraindicated or unavailable.

For the treatment of IH, propranolol therapy has a better safety profile and a lower rate of requirement for surgical interventions. In contrast, corticosteroids have various adverse effects, including Cushingoid features, gastroesophageal reflux, hypertension, hirsutism, and risk of life-threatening arterial bleeding secondary to ulceration. Therefore, propranolol should be considered as the first-line treatment option for IHs.

While there is no universal consensus on the optimal or maximum recommended dose of propranolol for infantile haemangioma, most guidelines recommend initiating treatment at a lower dose and gradually increasing it as tolerated, rather than starting at a higher dose. In our case, due to the presence of cerebral arteriopathy, propranolol was initiated cautiously at 1 mg/kg/day and increased by 0.5 mg/kg/day to a total dose of 1.5 mg/kg/day. This regimen was well tolerated and resulted in significant clinical improvement. Although many international guidelines recommend a target dose of 2 to 3 mg/kg/day, there is variation in this recommendation across different regions. A comparative analysis of published guidelines reveals that while American and Spanish recommendations permit dosing up to 3 mg/kg/day, the Australasian guidelines recommend a maximum dose of 1 to 2 mg/kg/day. ¹⁰ In light of these variations and the favourable response observed in our patient, a lower dose was considered both appropriate and effective.

Although propranolol helps circumvent the adverse effects associated with corticosteroids, it carries its own set of potential side effects, including hypotension, bradycardia, hypoglycaemia and the risk of worsening reactive airway conditions. ¹¹ In the context of PHACE syndrome, particular caution is warranted. Some experts have advised close monitoring in patients with cervical or cerebral arteriopathy, as systemic hypotension may theoretically reduce cerebral perfusion through narrowed or occluded arteries. ¹² Current recommendations advocate for a comprehensive evaluation for PHACE syndrome including cerebrovascular imaging prior to initiating propranolol in infants with large facial haemangiomas. ¹³ While PHACE syndrome is not an absolute contraindication to beta-blocker use, the benefits must be carefully weighed against potential risks. Propranolol should be continued for at least 6 months, often up to 12 months or longer. ¹⁰ Daily aspirin therapy is recommended for patients at high risk for acute ischaemic strokes with cerebrovascular anomalies, as seen in our index child. ¹⁴

The natural progression of IHs follows a predictable pattern, and endoscopy procedures are generally unnecessary during treatment. Bronchoscopy should be performed 1 month after propranolol discontinuation to assess for residual lesions or risk of recurrence. Flexible fibreoptic bronchoscopy is preferred over rigid bronchoscopy for follow-up evaluation, as it can often be performed safely under conscious sedation in stable patients, thereby avoiding the need for general anaesthesia.

Conclusion

Haemangioma in the head and neck region is a strong predictor of airway haemangioma, as shown in the index case. It could be associated with a complex underlying disorder such as PHACE syndrome. Therefore, in any child with stridor with facial haemangioma and not responding to a first-line of management, flexible bronchoscopy should be performed. Propranolol is an effective treatment for the management of airway haemangioma.

Highlight

• Stridor with haemangioma on the head and neck gives a clue to underlying airway haemangioma and PHACE syndrome.

• Propranolol is safe and effective in treating haemangioma, including airway haemangioma in PHACE syndrome.