ESPE Abstracts

Background: ROHHAD syndrome (rapid-onset obesity with hypothalamic dysfunction, central hypoventilation, autonomic dysregulation) – also defined as ROHHADNET when associated with neural tumors - is a rare condition with a high mortality rate. The aim of this study is to describe the phenotypes of a multicentric cohort of ROHHAD patients.

Patients and Methods: We retrospectively analyzed clinical data from 22 patients(10M,12F) with ROHHAD syndrome, followed at four centers in Glasgow, London(UK), Turin and Genova(Italy). ROHHAD diagnosis was based on at least three criteria: early, rapid-onset obesity, central hypoventilation, neural tumor, hypothalamic/pituitary disorders, and autonomic dysfunction, after excluding other forms of syndromic obesity. Median follow-up was7.4 years.

Results: Rapid-onset weight gain leading to early obesity was the first symptom in 20 patients (94.7%) at a median age of 3.0 years (1^st-3^rd quartile:2.1-3.7yrs); one patient was overweight but has not developed overt obesity as yet; in 4 patients, cardiovascular symptoms, water-electrolyte imbalance or autonomic dysfunction were present at diagnosis. Six patients (27.3%) were diagnosed with neural tumors at median age of 5.3 years(4.4-8.9yrs), with no gender difference in NET prevalence. Twenty patients(90.9%) had hyperprolactinemia –generally asymptomatic,16(72.7%) GHD, 15(68.2%) central hypothyroidism, and 11(50.0%) central adrenal insufficiency. Median GH peak after stimulation test was 0.49ng/ml (0.27-1.32). Early puberty was observed in females only(5/22, 22.7%, P=0.04), delayed puberty in 5/7subjects(2M,3F,71.4%). 20 patients(90.9%) developed sleep-related breathing disorders (either OSAS or central hypoventilation) during follow up. Excessive sweating was present in 9patients(40.9%), temperature dysregulation in 8(36.4%), and strabismus in 8(36.4%). 4 patients(18.2%, 1M, 3F) died from respiratory complications at a median age of 13.0 years. BMI SDS – both maximum and at latest visit – were lower in ROHHAD patients with GHD vs those without(3.7 vs 4.3 SDS, P=0.039 and 4.2 vs 6.2 SDS, P=0.007, respectively). Insulin insensitivity was more frequent in females(P=0.027). Given the unknown aetiology of ROHHAD/ROHHADNET syndrome, we performed molecular analysis using either Whole exome-(WES) or Whole Genome-(WGS)Sequencing in 9 individuals with identification of some potential candidate genes which are currently under further investigation.

Conclusion: These data highlight that early and rapid onset of obesity and hypothalamic dysfunction, including hyperprolactinaemia, are suggestive signs and symptoms of this condition. Due to its rarity, an effort on combining ROHHAD cohorts with careful phenotypic characterization is essential to improve our understanding and to strengthen our ability to manage this life-threatening disease.