Hereditary sensory and autonomic neuropathy type iv L74.4

Very rare (OMIM: 256800) congenital autosomal recessive disease associated with reduced pain sensitivity and anhidrosis. To date, < 100 cases have been described. The disease belongs to the group of hereditary sensory autonomic neuropathies (HSAN), a clinically and genetically heterogeneous group of hereditary diseases of the peripheral nervous system.

Point mutations, deletions and splice site mutations of the NTRK1 gene (neurotrophic tyrosine receptor kinase 1). The NTRK1 gene codes for tropomyosin-related kinase A (TrkA). This tyrosine kinase receptor from the neurotrophin receptor family plays an important biological role as a "nerve growth factor", NGF. The NTRK1 gene is crucial for the development of the nociceptor nervous system. Since the eccrine sweat glands are innervated via the nociceptor nervous system, mutations of the NTRK1 gene lead to disorders of sweat gland function, thus to regulation disorders of body temperature and to disorders of pain perception.

Clinic: Anhidrosis with consecutive "inexplicable" fever attacks and reduced or completely absent pain perception. The disease is noticed when children do not react with pain to an obvious injury. Risk of burns and self-mutilation. Further poor wound healing and ulceration of the cornea.

Neuropathologically, the disease is characterized by the absence of non-myelinated axons, a reduced number of small myelinated axons and (histologically) normal but not innervated sweat glands. The motor and sensory nerve conduction velocity (large nerves) is usually normal. Intracutaneous histamine test and pilocarpine iontophoresis are usually negative.

1. Zhang Y et al (2014) Congenital insensitivity to pain and anhidrosis syndrome: two cases involving a brother and sister. Chin Med J 127:3999-4000
2. Pareyson D et al (2014) Charcot-Marie-Tooth Disease and Related Hereditary Neuropathies: From Gene Function to Associated Phenotypes. Curr Mol Med PubMed PMID: 25323870
3. Liu S et al (2014) Novel NTRK1 frameshift mutation in Congenital Insensitivity to Pain With Anhidrosis. J Child Neurol PubMed PMID: 25316729.
4. Auer-Grumbach M (2013) Hereditary sensory and autonomic neuropathies. Hand Clin Neurol 115:893-906