Familial autoinflammatory Behçet-like syndrome: A rare cause of failure to thrive in children

Case report

An 8-month old male infant was brought as an emergency to our tertiary care centre with recurrent vomiting and inability to gain weight for the last seven months. The vomiting was persistent and mostly associated with feeding. The child had a history of multiple hospital admissions since birth, with complaints of fast breathing and recurrent vomiting, including neonatal intensive care for about three weeks for feed intolerance and respiratory distress. The child was developmentally normal and completely immunised for his age.

At the time of admission, he weighed only 4.9 kg (below the third centile for his age). He was thinly built with a pale appearance and had aphthous ulcers over his lips and oral cavity. Respiratory examination was suggestive of pneumonia, with tachypnoea, subcostal retractions, and crepitations. The remaining systemic examination was normal.

A full blood count reflected anaemia with a microcytic hypochromic picture. Liver and renal function tests were within normal limits. Stool examination did not show any reducing substances or fat globules, and coeliac serology was negative. Hence, malabsorption syndromes were ruled out. The thyroid profile was normal. Cystic fibrosis was ruled out by a negative sweat chloride test and the absence of a cystic fibrosis trans-membrane conductance regulator gene mutation. Ophthalmological examination did not show any signs of uveitis. All radiological investigations, including abdominal ultrasound, contrast oesophagography, computed tomography chest scan, and magnetic resonance imaging brain scan, were normal.

An upper gastrointestinal endoscopy was done, which revealed numerous circumferential ulcers (5 mm in size) extending between mucosal folds involving >75% of the circumference of the oesophageal mucosa, not seen on oesohagography. However, no ulcers were seen in the stomach and proximal duodenum.

Based on these features, a probable diagnosis of Behçet syndrome was made. Whole exome sequencing identified a heterozygous missense mutation in exon 7 of the TNFAIP3 gene (c.1088G>A), resulting in an amino acid substitution of glutamic acid for glycine at codon 363 (p.Gly363Glu) and unlocking a new rare entity of familial Behçet-like autoinflammatory syndrome-1. Genetic testing of his parents could not be pursued owing to financial constraints. Although the TNFAIP3 gene mutations are known to be inherited in an autosomal dominant manner, the absence of any clinical signs and symptoms in parents and siblings might raise the possibility of other modes of inheritance for this particular variant.

The child was managed with prednisolone syrup at a dose of 2 mg/kg per day and continued for two weeks, following which it was gradually tapered off over the next three weeks, and azathioprine was added (at a dose of 3 mg/kg per day) to continue for 1–2 years depending upon response. He is currently on this and has shown a good response in the form of weight gain and resolution of the ulcers.

Discussion

Our case presented with Behçet disease-like symptoms in infancy, and upon genetic analysis, a novel missense mutation involving the TNFAIP3 gene was identified. Although few studies have reported an association between loss-of-function mutations in the TNFAIP3 gene and various autoinflammatory disorders,^1,2 limited research is available specifically addressing the clinical spectrum of this disease. Studies from Southeast Asian countries have identified such mutations in infants presenting with recurrent infections, mucosal ulcers and failure to thrive.^3,4 Hence, such children should be evaluated diligently, including genetic analysis, to identify the cause of failure to thrive and introduce targeted therapies for a better clinical outcome.