Year : 2006 | Volume
: 9 | Issue : 1 | Page : 39--41
Painless injuries in a child: Hereditary sensory and autonomic neuropathy
Anu Jacob1, C Sarada2, Sanjeev V Thomas2,
1 Department of Neurology, University of Liverpool and the Walton centre for Neurology and Neurosurgery, Liverpool, United Kingdom
2 Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Kerala, India
Department of Neurology, Walton Centre For Neurology and Neurosurgery, Liverpool - L97LJ
Hereditary sensory autonomic neuropathies (HSAN) are rare genetically determined neuropathies. They often manifest as painless injuries in children and there is a potential for misdiagnosis with other sensory neuropathies especially leprosy. We report two siblings who clinically, electrophysiologically and pathologically have HSAN. We also summarise the current classification and recent genetic advances.
|How to cite this article:|
Jacob A, Sarada C, Thomas SV. Painless injuries in a child: Hereditary sensory and autonomic neuropathy.Ann Indian Acad Neurol 2006;9:39-41
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Jacob A, Sarada C, Thomas SV. Painless injuries in a child: Hereditary sensory and autonomic neuropathy. Ann Indian Acad Neurol [serial online] 2006 [cited 2022 Aug 15 ];9:39-41
Available from: https://www.annalsofian.org/text.asp?2006/9/1/39/22821
A seven year old south Indian boy was referred for evaluation of recurrent painless non-healing ulcers, from leprosy centre in southern India, as an unusual case with multiple negative leprosy skin tests.
His parents were first cousins. He had a normal birth, and normal cognitive development. Physical examination showed normal blood pressure with out any postural drop. Cranial nerve examination including pupillary responses and tongue was normal- in particular fungiform papillae were absent. Muscle power was normal but all deep tendon reflexes were absent. Pain and temperature sensations were lost in all limbs in a glove and stocking distribution. Joint position sense and vibration sensation seemed relatively preserved. No bladder bowel disturbances were present. He had multiple ulcers on his feet and hands [Figure 1]. Some of his digits were resorbed. He had neuropathic ankle and knee joints. His left ankle had an indurated painless swelling which later turned out to be a foreign body granuloma due to an impacted fish bone. Examination of his younger sister showed very similar findings. Clinical examination of parents was normal. In view of an identical problem in his sibling, parental consanguinity and early age of onset, hereditary sensory and autonomic (HSAN) neuropathy was clinically suspected.
Routine blood tests were normal. Skin tests for leprosy were negative. Nerve conduction studies showed absence of sensory nerve action potentials in all 4 limbs. Motor conduction was essentially normal. Needle EMG did not show any denervation. Similar electrophysiological abnormalities were found in the sister. No histamine challenge was undertaken. Detailed autonomic function tests could not be done. Nerve conduction tests in the mother showed bilateral deep peroneal neuropathy. As she was clinically normal and there was no other nerve involvement these were attributed to local compression. Nerve biopsy from right sural nerve showed markedly reduced myelination. Genetic tests could not be performed.
The index child and his sister presented with severe mutilation of hands and feet on a background of symmetric distal sensory loss and minimal motor deficits. The common differential diagnoses of distal ulcero-mutilation with sensory loss in children include leprosy and hereditary neuropathies.
Paucibacillary tuberculoid type of leprosy presents with mononeuritis multiplex type of nerve involvement associated with nerve thickening. However multibacillary lepromatous type leprosy can have diffuse symmetric involvement with predominant pain and temperature (small fibre) involvement. Skin smears are invariably positive in them. In highly endemic areas, more than one member in the family can be affected by leprosy, although it is not a hereditary disease. Skin and nerve biopsy should be able to readily distinguish where diagnostic difficulties arise.
Hereditary Motor Sensory Neuropathy (HMSN) typically presents with predominant motor neuropathy of slow progression (type I and II) or rapid progression (type III) that can be distinguished from each other by the typical findings in nerve conduction velocities (marked slowing of motor nerve conduction velocity uniformly in all peripheral nerves in type I, near normal velocities in type II and profound slowing in the order of 5-10 m/s in type III HMSN). Nerves can be thickened in type I and III HMSN.
Other unusual causes of ulceromutilation with or without neuropathy include Fabry's disease (X linked and usually manifests in males), Lesch Nyhan syndrome (associated with mental retardation)
and porphyria (predominant motor neuropathy). These are unlikely in our case due to lack of associated features.
HSANs (also called hereditary sensory neuropathy - HSN) are genetically determined neuropathies that have been genetically classified to large extent., They have been phenotypically classified into five types.
HSAN 1 is autosomal dominantly inherited condition with a genetic locus on chromosome 9q22.1-q22.3, in the SPTLC1 gene. Affected persons usually manifest symptoms in the second decade or later with mean age of onset being 25 years. Symptoms begin in the second to fourth decade of life with slowly progressive numbness, paresthesias and sensory defects, and plantar ulcers, with less obvious motor deficit. HSAN I secondary to SPTLC1 mutations, is quite similar phenotypically to Charcot-Marie-Tooth (CMT) 2B secondary to RAB7 gene mutation. Clinical differentiation is difficult though lancinating pains may be more common in SPTLC1 mutations and more motor involvement at presentation with RAB7 mutations. HSAN1B, recently reported in two Australian kindreds has a sensory neuropathy suggestive of HSAN I but with the additional features of a high incidence of cough and gastroesophageal reflux. It has been linked to chromosome 3p22-24.
HSAN type II is an autosomal recessive disease. The disease presents in infancy or early childhood with distal numbness in the upper and lower limbs and a glove and stocking sensory loss. As the disease progresses some patients develop complications of a sensory neuropathy including ulcers and spontaneous amputations, and some patients develop atrophy and hyporeflexia. There is an absence of myelinated axons, with fewer unmyelinated axons on nerve biopsy. Recently, the first causative gene for HSAN II, HSN2 on chromosome 12q13.33, has been reported in five Canadian families. HSN2 is a novel protein and consists of a single exon located within intron 8 of the PRKWNK1 gene. It is postulated that HSN2 may play a role in the development or maintenance of peripheral sensory neurons or their supporting Schwann cells.
HSAN III (familial dysautonomia or Riley- Day syndrome) is also autosomal recessive and occurs rather exclusively in Ashkenazi Jewish families. It is associated with mutations of the gene coding inhibitor of k light polypeptide gene enhancer in B cells kinase complex-associated protein (IKBKAP) on chromosome 9q31. It usually begins at birth and is characterised by a variety of symptoms, which include decreased sensitivity to pain and temperature, cardiovascular instability, recurrent pneumonias, vomiting crises and gastrointestinal dysfunction. Emotional stimuli produce episodic hypertension profuse sweating and marked skin blotching caused by defective autonomic control. There is a characteristic absence of fungiform papillae of the tongue and can later develop fingernail dystrophy.
HSAN IV has an autosomal recessive inheritance and is associated with several defects of the gene NTRK1 coding for the neurotrophic tyrosine kinase A nerve growth factor receptor on chromosome 1q21-q22. These children have congenital insensitivity to pain, recurrent febrile episodes, anhidrosis, self-mutilating behaviour, and mental retardation. Early death from hyperpyrexia occurs in up to 20% of patients, and septicaemia is frequent. The histamine tests show no axon flare response, and there is no tear formation and sweating with pilocarpine. Sympathetic skin responses are absent. Nerve conduction velocities are normal, but small fibre studies are abnormal. Absence of small sensory neurons in the dorsal root ganglia, the absence of innervation of eccrine and sweat glands, and reduced skin innervation has been reported.
HSAN V is phenotypically similar disorder to HSAN IV. The main difference between HSAN IV and HSAN V was thought to be the pattern of nerve fibre loss, and the greater severity of anhidrosis in the former and the lack of mental retardation in patients with the latter. A mutation in the coding region of nerve-growth factor beta on chromosome 1p11.2-p13.2 may be involved in its pathogenesis.
Though we were unable to carry out genetic tests we believe that the clinical profile, electrophysiological characteristics and pedigree analysis are most consistent with HSAN type 2.
Though no curative treatment is possible, advice regarding protective footwear, clothing, avoidance of injuries and prompt treatment of wounds and infections is crucial.
This case illustrates that careful history about onset, progression and involvement of family members is important to differentiate this condition from mimics like leprosy. This is particularly important in regions where prevalence of both consanguinity and leprosy are high.
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