P3.N274: Teenager with Hennekam Syndrome

Introduction: Hennekam syndrome is an autosomal recessive disease resulting from malformations in the lymphatic system. It is characterized by primary lymphedema, intestinal lymphangiectasias, intellectual deficits, and facial anomalies. While the exact prevalence is unknown, fewer than one hundred cases have been reported in the literature. We report the case of a patient with Hennekam syndrome who had excellent response to subcutaneous immunoglobulin replacement therapy.

Case Description: A now sixteen-year-old female presented to our service at the age of nine due to recurrent (approximately ten) episodes of pneumonia over the previous seven years, including a hospitalization for right middle and left lower lobe pneumonia and bronchiectasis. She had known Hennekam syndrome that was diagnosed at age four months when she presented with chronic diarrhea, pedal edema, unusual facial characteristics, hypocalcemia, optic nerve anomalies, hearing loss, abnormal dentition, and failure to thrive. Immune workup revealed hypogammaglobulinemia (IgG 163, IgM 20, and IgA 14) and mild lymphopenia due to secondary immunodeficiency caused by protein losing enteropathy in the setting of intestinal lymphangiectasis, rather than a primary immunodeficiency defect. She started weekly subcutaneous immunoglobulin replacement therapy. Due to hypoalbuminemia secondary to her protein losing enteropathy, she was placed on sirolimus at fifteen years old. She was found to have nephropathy with proteinuria deemed sirolimus-induced. Sirolimus was thus discontinued with improvement in symptoms. Her lymphedema is treated with albumin infusions and furosemide as needed. She also receives intralipid infusions as needed for essential fatty acid deficiency and ADEK vitamin supplementation.

Discussion: Hennekam Syndrome is a rare disorder with multiorgan involvement characterized by intestinal and renal lymphangiectasias, lymphedema, dysmorphic facial features and intellectual disability. Physical characteristics can include but are not limited to flat facies, a broad and depressed nasal bridge as well as varying degree of lymphedema. Other symptoms include mild growth retardation, delayed puberty, teeth and oral cavity anomalies, seizures, and blood vessel anomalies. Lymphangiectasias are more common in the intestines but can also be present in the lungs, pericardium, thyroid, and kidneys. Protein-losing enteropathy in the setting of lymphangiectasias causes loss of immunoglobulins leading to recurrent infections. The inheritance pattern is autosomal recessive via pathogenic bi-allelic variants of the following genes: CCBE1 (18q21.32), FAT4 (4q28.1), ADAMTS3 (4q13.3).

Conclusion: Overall, treatment and management of patients with Hennekam syndrome can be challenging. Our teenage patient with Hennekam syndrome is doing well on weekly subcutaneous immunoglobulin without any episodes of pneumonia or significant infections since starting therapy. She had some delays in milestones in infancy, and, as she grew older, missed several days of school due to frequent hospitalizations. Family reports significant improvement in quality of life since initiating immunoglobulin replacement therapy. We thus suggest that immunoglobulin replacement therapy be considered in the treatment plan for patients with Hennekam Syndrome.