A 9-year-old boy (45 kg,1.49 mts), full-term normal delivery, 2nd child in the family, born of the nonconsanguineous marriage, having good intelligence (std 5, rank holder in the class), completed all the immunization without any complication and was apparently healthy. He presented with recurrent episodes of abdominal pain, moderate grade fever(37.5-38  C), complete loss of appetite with nausea but no vomiting for last two years along with a feeling of soreness all over the body. This paroxysmal presentation was coming on once every 4-6 weeks without any apparent relation to food, weather or other environmental or extraneous factors. The paroxysm lasted for 3-4 days, without any skin rash, aphthous ulcers in the mouth, or a sore throat. There were no cold sores. He did not have any skin rash or skin ulcers. There were no sore throat or lymphadenopathy. He was clinically examined during 3 of his attacks when he was found to be withdrawn, apparently suffering continuous pain by his expression. His clinical examination showed a well-built child with hyper stretchable skin, fish mouth scars, and hypermobile joints. There was no iridodonesis, and his vision was normal (6/6 both eyes), there was no other suggestion of Marfan's syndrome on various measurements of the body. Mild diffuse tenderness was found all over the abdomen with normal bowel sounds. There was no organomegaly, and the pain was poorly localized. There were no cardiac murmur, respiratory abnormality, focal neurological abnormality, and the rest of the clinical examination was essentially normal. He recovered automatically after 3-4 days of the ordeal.
He had history neither of any serious illness nor of food or drug allergy.
Elder brother (14 years of age) and parents had no such illness, but the mother has lax joints and skin. There were no pets in the house and no family history of a similar disease in the extended family.
His complete blood count showed neutrophilic leukocytosis (TLC 14-15000/ul with 76 percent polymorphs and no eosinophils during the acute stage) with normal hemoglobin and platelet counts. There were no abnormalities in the morphology of any of the cells seen. His biochemical investigations which involved the liver, renal function tests, electrolytes also showed no abnormality. Blood and urine culture and routine urine examination were unremarkable. Urine for porphobilinogen showed a mild increase (Figure 1) however the quantitation of PBG (porphobilinogen) on 24-hour urine during acute stage was normal so also the blood lead levels (<10ugm/L). Serum amylase, lipase, and lipid profile were normal. CRP levels were raised during the acute stage (170mg/L) and was quickly normalized(3mg/L) within 72 hours of resolution of abdominal pain. Upper GI endoscopy and fundoscopy (eye) showed no abnormality. Serum immunoglobulins including IgD levels were normal. Ultrasound examination of abdomen and pelvis, CT scan with contrast and MRI scan of chest and abdomen was essentially normal.
Because of the paroxysmal nature of the attack, a provisional diagnosis of acute intermittent porphyria or one of the autoinflammatory syndromes was made.
Targeted sequencing of exome involving porphyrin metabolism, autoinflammatory conditions, and immunologically important 280 genes was executed following transposase digestion of isolated DNA from the peripheral blood mononuclear cells of the patient on Illumina 2500 Hi seq platform. Except for nine genes (CD55, CFHR1, CORO1A, ITCH1, MAGT1, TNFRS11A, TBX1, FCGR1A, NCF1, 85-98 % coverage), all genes were covered to the tune of 100 % of the exomes including intron-exon boundaries.
Except for common polymorphisms, none of the genes showed any harmful sequence changes or known mutations. However, there was a heterozygous mutation of NLRP12 gene in exon 3 (c 779C>T, p Thr 260> Meth) in the evolutionarily conserved nucleotide sequence on NACHT1 domain of the molecule. This sequence change has not been described previously and was found to be harmful by using Polyphen 2 Sift, Mutation tester-2 software.
This sequence change was confirmed using Sanger sequencing but was not found in any of the parents or his elder brothers DNA sequences. Hence it presented a de novo change. So a final diagnosis of NLRP12 associated autoinflammatory syndrome was made. The patient did not respond to colchicine, and by trial and error with various combinations of anti-inflammatory medicines, Naproxen gave a partial response with a combination of a short course of corticosteroids (Prednisolone, 15 mg/day, administered when paroxysms started once in the morning after breakfast and was continued for seven days.