ESPE Abstracts

Background: Pathologic mutations in RAI1 gene (typically microdeletions) cause SMS. Patients have characteristic physical appearance, developmental delay, sleep disturbances, and obesity; without hypothalamic dysfunction. Thaker et al published a case of a child with clinical diagnosis of ROHHAD with a mutation in the RAI1 gene (c.3265C>T: p.R1089X) found by whole exome sequencing. He had a physical appearance consistent with SMS and sleep cycle disturbances. 83% of ROHHAD patients require mechanical ventilation for hypoventilation within 5 years of rapid weight gain.

Case Description: We describe a 7 year old girl with accelerated weight gain since 4.5 months of age, hypotonia, motor and speech delays. Notable dysmorphic features of deep set eyes, midface hypoplasia, flattened nasal bridge, and brachycephaly, features seen in SMS. At age 6 she presented with hypernatremia (Na 206 mMol/L) and respiratory failure due to pneumonia. She was ultimately diagnosed with diabetes insipidus based on urine studies and supported by absent pituitary bright spot on MRI and was started on DDAvP. Sleep study showed severe mixed sleep apnea (OAHI 28/hr, CAI of 158/hr, no hypoventilation). She was started on BiPAP with increased needs. One year later returned with severe hyperglycemia (1135mg/dL), new onset of Diabetes Mellitus, HbA1c 9.6%, and Islet cell autoimmune antibodies negative. Other hormonal evaluation showed growth hormone deficiency with low IGF-1 [44ng/mL (55-238)] and IGFBP3 [1.66 mg/L (2.02-5.52)]. She was started on GH therapy. A clinical diagnosis of ROHHAD was made based on rapid weight trend, sleep apnea, and worsening hypothalamic dysfunction such as hypopituitarism.

Results: A genetic obesity panel resulted with a heterozygous variant of currently classified as of uncertain significance (VUS) in the RAI1 gene (c.604C>T, p.Pro202Ser).

Conclusions: This is the second reported case of a patient with a missense mutation in the RAI1 gene with clinical features of both ROHAHD syndrome and SMS. The two cases shared similar clinical course. Both developed obesity prior to age 2 and have a missense mutation rather than microdeletions. The hypoventilation has progressed slowly. The original patient underwent tracheostomy at age 10; our proband has yet not developed hypoventilation. The ability to accurately diagnose ROHHAD syndrome is crucial as it will lead to appropriate surveillance and management. As comprehensive genetic testing becomes more readily available, we will continue to establish a genetic basis for rare syndromes such as ROHHAD and SMS.