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Case Reports

Indian Pediatrics 2002; 39:870-874  

Four Siblings with Type II Hereditary Sensory and Autonomic Neuropathy

 

Sriparna Basu
Dilip Kumar Paul
Somprakas Basu

Bengal Medical College and Hospitals, Sushrutnagar, Darjeeling, West Bengal, India.

Correspondence to: Dr. Sriparna Basu, 113, Ultadanga Main Road, Kolkata-700 067, West Bengal, India.

E-mail: [email protected]

Manuscript received: June 20, 2001;

Initial review completed: August 3, 2001;

Revision accepted: April 22, 2002.

expression in the parents. The rarity of the disease is highlighted and the intragroup variations are discussed.

 

The Hereditary Sensory and Autonomic Neuropathies (HSAN) are a group of rare disorders characterized by prominent sensory and autonomic neuropathy without motor involvement(1). They reflect failure of development or degeneration of sub-populations of peripheral sensory and autonomic neurons. Classification is done into five main groups based on inheritance, clinical features and the population of sensory neurons affected. Impaired pain appreciation results in mutilating acropathy with skin ulceration and fissuring, long bone fractures, Charcot’s joints and digit amputation. The precise symptoms and signs and the nerve conduction abnormalities of each type are determined by the subpopulation of sensory neurons predominantly affected(2). We report a family in which all four siblings were affected with HSAN Type II without any

Case Report

Four children (siblings), two males and two females presented with history of insensitivity to pain and temperature and multiple painless ulcerations over various parts of the body since infancy. They were born of consanguineous marriage in a Muslim family. All were of full term normal vaginal delivery at home with uneventful antenatal, intranatal and postnatal period. There was no history of recurrent episodes of fever, bladder and bowel habits were normal and the immunization history was complete. The course of the disease was slowly progressive, the eldest siblings being most affected. Both parents were phenotypically normal. There was no history of abortion or stillbirth and no family history of such illness in either of the parents’ side.

Examination revealed generalized loss of all modalities of sensation, more marked on the distal parts of the limbs and cornea. Multiple ulcerations were present on the hands, feet, lips and alae of the nose. All showed mutilating acropathy in the form of complete and/or partial loss of digits and foot deformities (Fig. 1). Other features included anhidrosis over distal parts of limbs, palmer and planter callosities, corneal opacities (cases 1 and 2), bowing of legs with radiological evidence of rickets (cases 2 and 3) (Table I). There was no sign of peripheral nerve thickening. Except total areflexia (superficial and deep), motor functions were well preserved. Fundus examination, rest of the central nervous system and other systemic examinations including blood pressure were normal. Anthropometric measurements as per Indian Council of Medical Research standard(3) and developmental milestones were within normal limits. Besides high serum alkaline phosphatase (> 1000 IU/L), routine hematological investigations were normal. Detailed biochemical assessment was done in all. Serum calcium, blood urea and creatinine were within normal limits while serum phosphorus was slightly below normal. Based on the above features a provisional clinical diagnosis of HSAN was made and electrophysiological studies and nerve biopsies were performed in all the siblings to confirm the diagnosis. Motor nerve conduction veloctiy (MNVC) studies were done on the median and ulnar nerves on both sides, with a stimulus of 3mV, 63mA, sweep of 2msec, duration of 0.1 sec and recording distance of 140 mm. Result was interpreted by computerized graphical representation. The mean latency difference was 2.84 milliseconds (range 2.40 - 3.68) and mean conduction velocity (CV) was 57.69 meters/sec (range 51.47 - 62.50). The sensory nerve conduction velocity (SNVC) studies were done by ring electrodes on the digital nerves of the upper extremity by the principle of orthodromic conduction. All showed non-recordable sensory conduction. NCV studies were not done on the parents as they were phenotypically normal and showed no evidence to indicate sensory neuropathy. Sural nerve biopsies showed complete absence of myelination and no evidence of Schwann cell proliferation.

 


Fig. 1. Siblings showing mutilating acropathy.

 

The cases were managed conservatively. Infected ulcers were treated with antibiotics and antiseptic dressings. Proper foot and skin care was ensured and adequate counselling was done to prevent trauma and improve personal hygiene to prevent infections. Rickets (overt and subclinical) was treated with a single intramuscular injection of 6,00,000 IU of vitamin D and oral calcium supplementation. After 3 weeks, biochemical parameters were reassessed. A definite decrease was seen in serum alkaline phosphatase levels indicating response to megadose vitamin D therapy. Serum phosphorus levels showed improvement and radiological signs of healing rickets were seen in all.

Discussion

According to the descriptive classification of Donaghy et al(4) HSAN type-I or hereditary sensory radicular neuropathy is dominantly inherited. Symptoms begin in second or later decades with sensory loss and subsequent tissue injury. Pain is more affected than touch. Sural nerve biopsy shows loss of unmyelinated fibres more than the myelinated ones. Type-II HSAN is recessively inherited and begins in infancy. There is generalized pansensory loss. Autonomic disturbances include bladder dysfunction, impotence and anhidrosis of hands and feet. Motor function is preserved but tendon reflexes are usually lost. Association of retinitis pigmentosa, motor weakness and neurotrophic keratitis with sensory neuropathy has been described(1,2). Sensory nerve action potentials are absent and there is loss of myelinated fibres in sural nerve biopsy(1). Types-III, IV and V are also autosomal recessive and type-III is associated with prominent autonomic involvement(1,5). Nerve biopsy shows reduced number of unmyelinated fibres. Type-IV is associated with bouts of pyrexia, failure to thrive, anhidrosis and mental retardation. Clinical manifestations of Type-V include mutilating acropathy and bilateral neurotrophic keratitis. Motor functions and tendon reflexes are normal. Sural nerve biopsy shows selective reduction of smaller myelinated nerve fibre population(2).

 

Table - Comparison of Characteristics of the Patients
	
 
Case 1
Case 2
Case 3
Case 4
Age (years)
9
7
6
4
Sex
F
F
M
M
Age of onset
Infancy
Infancy
Infancy
Infancy
Skin ulceration
+
+
+
+
Mutilating acropathy
+
+
+
+
Motor function
Preserved
Preserved
Preserved
Preserved
Tendon reflexes
Distal anhidrosis
+
+
+
+
Bladder & bowel habits
N
N
N
N
Corneal opacity
+
+
Fundus examination
N
N
N
N
Clinical and radiological rickets
+
+
Serum alkaline phosphatase
­­
­­
­­
­­
Sensory nerve conduction velocity
No AP
No AP
No AP
No AP
Motor nerve conduction velocity
N
N
N
N
Sural nerve biopsy
Complete absence of myelinated nerve fibres and
no evidence of schwann cell proliferation 
	
AP = Action Potential

In view of the history of consanguinity, autosomal recessive transmission was likely in our patients. Clinical features, nerve conduction velocity studies and sural nerve biopsies of all the siblings correlate well with those of type-II variety of HSAN(1,2,6). A similar form of HSAN may be inherited as x-linked recessive trait(7). The usual autonomic disturbances in the form of bladder and bowel involvement and hypertension were absent in our cases, though distal anhidrosis was present uniformly in all. In this regard it is highlighted that anhidrosis is a prominent manifestation of type-IV variety. Motor functions were well preserved. Association of spastic paraplegia with HSAN type-II has been reported by Cavanagh et al(8) though such feature was absent in our cases.

Uniformity in the presence or absence of clinical features was seen in all except for corneal opacities and clinical and radiological evidence of rickets. Only 2 cases showed corneal opacities. Though serum alkaline phosphatase was raised in all of them, two had bowing of legs and classical radiological features of rickets (Table I). Since the biochemical profile indicated no abnormality of renal function the cause of rickets was most likely nutritional and probably coincidental as also supported by the response to megadose vitamin D therapy. However, in light of anthropometric measurements the nutrition of the children was good and no evidence of clinical nutritional deficiency was seen except overt rickets in only two of them. HSAN is a rare disorder. In India, Balachandran et al(6) has reported type-II variety in siblings. Initial delay in diagnosis can occur due to similarity of the mutilating acropathy with that of leprosy, a more common disease in India. Hence the latter should always be excluded prior to diagnosis of this rare disorder.

All the described features may not be found in a single case of HSAN. Intragroup variations are present and are still being reported(9,10). The spectrum of clinical features, nerve conduction studies, inheritance patterns and nerve biopsies form the mainstay of diagnosis and subtyping. Treatment is usually symptomatic. Prevention of trauma to the anesthetized parts and appropriate management of the sequele of autonomic neuropathy are the aims. Prognosis is guarded as adequate long term follow up series are lacking(1,4).

Contributors: SB and SPB did the clinical work up and drafted the paper. DKP coordinated the case management and supervised the drafting. SB will act as the guarantor for the paper.

Funding: None.

Competing interests: None stated.

Key Messages

• Diagnosis of HSAN type-II was based on pansensory loss, mutilating acropathy, corneal anesthesia and total areflexia with normal motor function. Though bladder and bowel functions and blood pressure were normal, distal anhidrosis was seen. Sensory nerve conduction was absent and sural nerve biopsy showed loss of myelination.

 

 

 References

1. Bosch EP, Mitsumoto H. Disorders of Peripheral Nerves. In: Neurology in Clinical Practice; The Neurological Disorders. Eds. Bradley WG, Daroff RB, Fenichel GM, Marsden CD. Vol-II, Second Edition, Newton, USA. Butterworth Heinemann Publication, 1996; pp 1881-1952.

2. Donaghy M. Disorders of peripheral nerves. In: Brain’s Diseases of the Nervous System. Ed. Walton J. Tenth Edition. New York, Oxford Medical Publications, 1993; pp 555-624.

3. ICMR: Growth and physical development of Indian infants and children. Technical Report Series, 18, 1972.

4. Donaghy M, Hakin RN, Bamford JM. Hereditary sensory neuropathy with neurotrophic keratitis. Description of an autosomal recessive disorder with a selective reduction of small unmyelinated nerve fibres and a discussion of the classification of the hereditary sensory neuropathies. Brain 1987; 110: 563-583.

5. Axelrod FB, Abularrage JJ. Familial dysautonomia: A propsective study of survival. J Pediatr 1982; 101: 234-236.

6. Balachandran C, Sabitha L, Kantharaj GR. Hereditary sensory autonomic neuropathy - type-II in siblings. Indian J Lepr 1996; 373-374.

7. Jestico JV, Urray PA, Efphimiou J. A hereditary sensory and autonomic neuropathy transmitted as an X-linked recessive trait. J Neurol Neurosurg. Psychiat 1985; 48: 1259-1264.

8. Cavanagh NP, Eames RA, Galvin RJ, Brett EM, Kelly RE. Hereditary sensory neuropathy with spastic paraplegia. Brain 1979; 102: 79-94.

9. Polo A, Aldegheri R, Bongiovanni LG, Cavallaro T, Rizzuto N. Painless fractures and thermoregulation disturbances in sensory-autonomic neuropathy; electrophysiological abnormalities and sural nerve biopsy. Neuropediatrics 2000; 31: 148-150.

10. Shah U, Arshad M, Mozaffar T. Dysphagia in hereditary sensory autonomic neuropathy type IV. J Pak Med Assoc 1999; 49: 121-123.

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