P3D196: A Tough Pill to Swallow: Congenital Glottic Stenosis as a Clinical Manifestation of FREM1 Associated Disorders

Introduction: Respiratory distress occurs in 7 percent of term newborns, and is one of the most common reasons for neonatal intensive care unit (NICU) admission. The differential for respiratory distress following delivery is vast, and can include infectious, metabolic, cardiovascular, neuromuscular, pulmonary, or congenital pathologies. Further evaluation and intervention for respiratory distress should be guided by identifying the most common and life-threatening causes of respiratory distress in a newborn, perinatal risk factors and history, and the patient’s physical exam.

Case Description: A term female infant born via vaginal delivery developed respiratory distress soon after birth, necessitating NICU admission for non-invasive respiratory support. Prenatal history was complicated by right fetal unilateral dysplastic kidney and urgent induction of labor for decreased fetal movement and severe pre-eclampsia. The respiratory distress resolved, but aphonia was noted prompting direct laryngoscopy and bronchoscopy, which demonstrated Cohen Grade IV anterior glottic web and Grade 1 subglottic stenosis. Subsequent surgical lysis of the glottic web and balloon dilation was complicated by post-operative upper airway stenosis from readhesion, and two failed extubations, requiring tracheostomy and Keel placement. Genetic testing revealed compound heterozygous pathogenic variants in FREM1, establishing a diagnosis of FREM1-related autosomal recessive disorder.

Discussion: FREM1 autosomal recessive disorders include: Manitoba oculotrichoanal (MOTA syndrome), bifid nose with or without anorectal and renal anomalies (BNAR syndrome), and isolated congenital anomalies of kidney and urinary tract (CAKUT).

MOTA syndrome often presents with widely spaced eyes, ocular and eyebrow abnormalities, nasal dysmorphologies, anal stenosis and/or an anteriorly placed anus, and omphalocele or umbilical hernia.

BNAR syndrome can present with nasal dysmorphologies. It may also present with anorectal and renal abnormalities including anal stenosis, an anteriorly placed anus, renal agenesis, and renal dysplasia. There are typically no ocular manifestations as seen in MOTA syndrome. Our patient was noted to develop a median nose notch and wide nasal tip that became more prominent with age, consistent with BNAR syndrome (as shown in Figure 1).

Conclusion: The differential for respiratory distress in a term neonate is vast. A thorough physical exam can identify less common causes of respiratory distress in the term neonate, including congenital anomalies.

While congenital subglottic stenosis has been associated with various genetic syndromes (including 22q11.2 deletion syndrome, Down syndrome, and CHARGE syndrome), it has not yet been described in the FREM1 spectrum of disorders to our knowledge.