An Infant With Primary Tooth Loss and Palmar Hyperkeratosis: A Novel Mutation in the NTRK1 Gene Causing Congenital Insensitivity to Pain With Anhidrosis

Abstract

ABSTRACT. Patients with congenital insensitivity to pain and anhidrosis (CIPA), caused by mutations in the NTRK1 gene, can be difficult to diagnose because of their variable presentation, the lack of simple diagnostic tests, and the paucity of cases reported in North America. We describe a 1-year-old infant who had tooth loss and palmar hyperkeratosis as the primary manifestations of CIPA. He was initially evaluated by a pediatric dentist and epidermal dysplasia syndromes were considered, but insensitivity to pain was suspected after a skeletal survey revealed an unrecognized skull fracture. Nerve conduction studies were normal, as was his response to subdermal histamine injection. Sequence analysis of his NTRK1 gene revealed 2 mutations: 1 mutation is novel, while the other has been described previously in a patient of northern European descent. An antibody directed against NTRK1 revealed persistent expression in keratinocytes, consistent with the mutations in this patient. Skin biopsy specimens revealed a lack of epidermal and sweat gland innervation. Immunohistochemistry of skin biopsy specimens, together with routine nerve conduction studies, can provide quick and reliable confirmation if CIPA is clinically suspected. Pediatrics 2003;112:e237-e241. URL: http://www.pediatrics.org/cgi/content/full/112/3/e237; CIPA, NTRK1, tooth loss, hyperkeratosis, insensitivity to pain.

Congenital Insensitivity to Pain and Anhydrosis: Diagnostic and Therapeutic Dilemmas Revisited

“…Primary tooth loss and palmar hyperkeratosis were seen in this child corresponding to the reported case by Bonkowsky et al 5 This observation of a premature loss of teeth along with soft tissue injuries may be of great value and dentists should bear in mind that these may be the clinical signs of a rare hereditary disorder. 20 …”

“…The molecular diagnosis of CIPA has been confirmed for about 80 patients reported in the medical literature (Bonkowsky et al). 5 A variety of genes are held responsible for the etiology of the condition according to various authors (Table 1). …”

NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone

“…For example, mutations in the TRKA gene cause congenital insensitivity to pain with anhidrosis (CIPA) (Indo et al, 1996), an autosomal recessive syndrome associated with skeletal disorders such as short stature, tooth loss, and delayed fracture healing (Bonkowsky et al, 2003; Toscano et al, 2000). Similarly, patients with familial dysautonomia (FD) have progressive sensory neuron loss and low bone mass (Jackson et al, 2014), as do children with perinatal brachial plexus palsy (PBPP), a flaccid paralysis of the arm caused by nerve damage at birth (Ibrahim et al, 2011).…”

Recent advances in hereditary sensory and autonomic neuropathies

“…On examination there is widespread anhidrosis, decreased temperature sensation, as well as other sensory abnormalities but muscle strength and deep tendon reflexes are usually preserved [54,55]. Nerve conduction velocity studies are normal [56] but sympathetic skin responses are absent. Histopathological findings may consist of complete absence or decrease in small myelinated and unmyelinated fibres [57,58].…”