TREX-1 related Aicardi-Goutières syndrome improved by Janus kinase inhibitor.

Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy classically characterized by early onset of severe neurologic injury with basal ganglia calcifications, white matter abnormalities, and progressive cerebral atrophy, along with lymphocytosis and raised interferon alpha (INFα) in the cerebrospinal fluid (CSF). Here, we report a 31/2 year-old patient born with prenatal onset AGS, first manifesting as intra-uterine growth retardation. Cranial ultrasonography and cerebral MRI revealed ventriculomegaly and periventricular and basal ganglia calcifications, along with cerebral atrophy. Perinatal infections and known metabolic disorders were excluded. Both CSF lymphocytosis and raised INFα were present. Molecular analysis disclosed two already described compound heterozygous pathogenic variants in TREX1 (c. 309dup, p.(Thr104Hisfs*53) and c. 506G > A, p.(Arg169His)). The evolution was marked by severe global developmental delay with progressive microcephaly. Promptly, the patient developed irritability, quadri-paretic dyskinetic movements, and subsequently tonic seizures. Sensorineural hearing loss was detected as well as glaucoma. Initially, he was symptomatically treated with trihexyphenidyl followed by levetiracetam and topiramate. At age 22 months, baricitinib (0.4 mg/kg/day) was introduced, leading to normal serum INFα levels. Clinically, dyskinetic movements significantly decreased as well as irritability and sleep disturbance. We confirmed that baricitinib was a useful treatment with no major side effect.

ROHHAD(NET) Syndrome: Systematic Review of the Clinical Timeline and Recommendations for Diagnosis and Prognosis.

CONTEXT: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET]) is a rare and potentially fatal disease. No specific diagnostic biomarker is currently available, making prompt diagnosis challenging. Since its first definition in 2007, a complete clinical analysis leading to specific diagnosis and follow-up recommendations is still missing. OBJECTIVE: The purpose of this work is to describe the clinical timeline of symptoms of ROHHAD(NET) and propose recommendations for diagnosis and follow-up. DESIGN: We conducted a systematic review of all ROHHAD(NET) case studies and report a new ROHHAD patient with early diagnosis and multidisciplinary care. METHODS: All the articles that meet the definition of ROHHAD(NET) and provide chronological clinical data were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis individual patient data guidelines. The data were grouped into 7 categories: hypothalamic dysfunction, autonomic dysregulation, hypoventilation, NET, psychiatric symptoms, other clinical manifestations, and outcome. RESULTS: Forty-three individual patient data descriptions were analyzed. The timeline of the disease shows rapid-onset obesity followed shortly by hypothalamic dysfunction. Dysautonomia was reported at a median age of 4.95 years and hypoventilation at 5.33 years, or 2.2 years after the initial obesity. A NET was reported in 56% of the patients, and 70% of these tumors were diagnosed within 2 years after initial weight gain. CONCLUSION: Because early diagnosis improves the clinical management and the prognosis in ROHHAD(NET), this diagnosis should be considered for any child with rapid and early obesity. We propose guidance for systematic follow-up and advise multidisciplinary management with the aim of improving prognosis and life expectancy.

Weaning from long term continuous positive airway pressure or noninvasive ventilation in children.

OBJECTIVES: A significant number of children are able to discontinue long term continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) but the underlying disorders, weaning criteria, and outcome of these children have not been studied. STUDY DESIGN: Retrospective cohort follow up. SUBJECT SELECTION: Consecutive children who were weaned from long term CPAP/NIV between October 2013 and January 2016. METHODOLOGY: Underlying disorders, weaning criteria, and clinical outcome were analyzed. RESULTS: Fifty eight (27%) of the 213 patients on long term CPAP/NIV could be weaned from CPAP/NIV with 50 patients being weaned from CPAP and 8 from NIV. Most patients were young children with upper airway anomalies, Prader Willi syndrome or bronchopulmonary dysplasia. CPAP/NIV was discontinued following spontaneous improvement of sleep-disordered breathing in 33 (57%) patients, upper airway surgery (n = 14, 24%), maxillofacial surgery (n = 6, 11%), neurosurgery (n = 1, 2%), upper airway and neurosurgery (n = 2, 3%), or switch to oxygen therapy (n = 2, 3%). CPAP/NIV was discontinued due to normal nocturnal gas exchange during spontaneous breathing in all patients, with an obstructive apnea-hypopnea index ≤6 events/h on a combined poly(somno)graphy in 27 patients. A relapse of obstructive sleep apnea was observed after a median delay of 2 years in six patients who resumed CPAP and in one patient who underwent midface distraction. CONCLUSIONS: Weaning from CPAP/NIV is possible in children treated with long term CPAP/NIV but is highly dependent on the underlying disorder. Spontaneous improvement is possible but most children need specific surgery. Long term follow-up is necessary in children with underlying disorders.