Congenital Insensitivity to Pain with Anhidrosis (NTRK1 Mutation) and Early Onset Renal Disease: Clinical Report on Three Sibs with a 25-Year Follow-Up in One of Them

Abstract

Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve growth factor (NGF). We report the clinical course in three sibs with CIPA and proven NTRK1 gene mutations with a follow-up over a 25-year period in one of them. They had the characteristic clinical features of an abnormally high pain threshold, and mental retardation; in addition their clinical course was marked by the occurrence of early onset renal disease with recurrent microhematuria and proteinuria and frequent observations of increased serum creatinine and blood urea levels. Light microscopy study of a renal biopsy performed in one of them at age of 20 months showed focal glomerulosclerosis, interstitial fibrosis and tubular atrophy. This patient and his younger brother died because of renal failure at the age of 25 years and 14 years, respectively. The sister still alive showed renal impairment and deep venous thrombosis associated with lupus anticoagulant activity, decrease of circulating autoreactive CD5 (+) B lymphocytes and increased urinary levels of IgG and kappa and lambda light chains, suggesting a possible defect in regulation of B-lymphocyte function. In the light of the NGF-related molecular defect, the extraneurological tissue involvement in CIPA might in part reflect dysregulation of immune mechanisms which possibly brings about a chronic inflammatory response. This, in turn, could result in renal disease which should be mentioned among the life-threatening complications associated with this disorder.

NGF and Its Receptors in the Regulation of Inflammatory Response

“…CIPA patients are characterized by neurological alterations and the absence of pain and sensation, but they also show reduced wound healing and modified functions of immune cells. They have altered immune mechanisms that are responsible for recurrent infections and inflammatory complications [64,65] that lead to chronic inflammatory responses [66]. …”

Congenital insensitivity to pain and anhydrosis due to a rare mutation and that is complicated by inflammatory bowel disease and amyloidosis: a case report

“…Renal manifestations of CIPA are rare and have thus far included focal glomerulosclerosis, interstitial fibrosis, tubular atrophy 18, and renal amyloidosis 4. To our knowledge, renal amyloidosis was reported only once in association with CIPA 4.…”

Skoura – a genetic island for congenital insensitivity to pain and anhidrosis among Moroccan Jews, as determined by a novel mutation in the NTRK1 gene

“…NGF is also shown to play a pivotal role in the mediation of the inflammatory and immune response after tissue injury (30, 36–38), as evident in inflammation‐related hyperalgesia (19, 39, 40). Comparably, malfunction of the NGF–NTRK1 system may be the cause of the prolonged wound healing accompanying hypoalgesia in CIPA patients.…”

“…CIPA patients have been documented in diverse geographic regions and ethnicities, and consanguinity is frequent (3,6,(17)(18)(19)(20).…”

“…Enhanced TRPV1 (33) and increased hyperinnervation (34) have been associated with vulvodynia, a primary cause of dyspareunia, and a condition that affects as many as 16% of women during a period of their lives (35). NGF is also shown to play a pivotal role in the mediation of the inflammatory and immune response after tissue injury (30,(36)(37)(38), as evident in inflammation-related hyperalgesia (19,39,40). Comparably, malfunction of the NGF-NTRK1 system may be the cause of the prolonged wound healing accompanying hypoalgesia in CIPA patients.…”