Hereditary sensory and autonomic neuropathy (HSAN) is
a rare syndrome characterized by congenital insensitivity to pain,
temperature changes and by autonomic nerve formation disorders. HSAN is
classified into five types: sensory radicular neuropathy (HSAN I),
congenital sensory neuropathy (HSAN II), familial dysautonomia or Riley
Day Syndrome (HSAN III), congenital insensitivity to pain with
anhidrosis (HSAN IV) and congenital indifference to pain (HSAN V)(1).
HSAN type IV inherited as an autosomal recessive
trait, is characterized by recurrent episodes of unexplained fever,
failure to thrive, absence or decreased perspiration (despite normal
sweat glands), insensitivity to pain, self mutilation and mental
retardation(2). Only few case reports of HSAN are available from
India(3-8). We report two patients with HSAN type IV. The purpose is to
introduce this rarely encountered disease, and to present information
related to diagnosis and management.
Case Report
A six-year-old female child, first product of a
non-consanguineous marriage, presented with painless ulceration of soles
of both feet since 2 years of age. The child was unable to tolerate the
high summer temperatures. On exposure to sun she would become extremely
hot. According to the mother, the child had no sweating and also never
seemed to feel pain. Her motor milestones were delayed though her mental
development was appropriate for age. There was no family history of
paraesthesias, leprosy or tuberculosis. Examination revealed pallor with
multiple ulcers on both feet. Her tongue was mutilated beyond
recognition. She was conscious, oriented with no cranial nerve deficit
and normal muscle bulk and power. There was generalized hypotonia with
absent deep tendon reflexes. The touch sensation was normal while pain
and temperature sensations were absent. There were no hypopigmented
patches or thickened, palpable nerves. The parents and an
eleven-month-old female sibling were normal.
Investigations revealed hemoglobin of 6.5 g/dL with
microcytosis and hypochromia on peripheral smear. Total and differential
leucocyte count, liver and renal function tests were within normal
limits. No sweat was formed on sweat induction though skin biopsy showed
presence of normal sweat glands. On subcutaneous injection of
pilocarpine the wheal and flare reaction was absent.
Electrophysiological studies were suggestive of a peripheral neuropathy,
which was pre-dominantly axonal, sensory, and showed involvement of
lower limbs more than upper limbs. X-rays of the limbs revealed
evidence of chronic osteomyelitis. Pus culture from the leg ulcers grew
Pseudomonas and was treated appropriately. Sural nerve biopsy was not
done in view of chronic osteomyelitis affecting the same region.
Case 2
The second case was a one-year-old boy brought to our
hospital for evaluation for cause of self-mutilation. There was history
of consanguinity with parents being first cousins. Parents noticed
multiple episodes of fever and absence of sweating since the child was 2
months old. None of these episodes of hyperpyrexia had any localization
for fever. The child started biting his tongue and fingers after his
teeth erupted at the age of six months. There was also history of
absence of crying after painful stimuli. His developmental milestones
were normal. The child had an elder male sibling with a similar illness
who died at 1½ years of age from a chest infection and a 7-year-old
sister, who is asymptomatic. On physical examination the child had mild
pallor with bites marks over the tongue and tips of the fingers. On
neurological examination, there was hypotonia with normal deep tendon
reflexes. The child responded to touch but there was no response to pain
and temperature.
Hereditary sensory autonomic neuropathy was suspected
and further investigations were conducted. Nerve conduction velocity
studies in sural and median nerves revealed normal SNAP latency,
conduction velocity and amplitude. There was no sweat production on
pilocarpine iontophoresis. Sural nerve biopsy showed feature suggestive
of focal segmental demyelination.
Discussion
The classification of various types of HSAN is based
on the inheritance pattern, clinical features, and systems of neurons
predominantly affected. HSAN I is autosomal dominantly inherited with
symptoms begin in the second decade or later. There is loss of pain and
temperature sensation but preservation of tactile sensation. Sural nerve
biopsy shows loss of unmyelinated fibres more than myelinated fibres.
HSAN II is an autosomal recessive disorder with onset in infancy. There
is generalized pansensory loss. Autonomic disturbances included bladder
dysfunction, impotence and distal anhidrosis. Motor function is
preserved but tendon reflexes are lost. There is loss of myelinated
fibres in the sural nerve biopsy. HSAN III is also autosomal recessively
inherited affecting mostly Ashkenazi Jews. The clinical manifestations
usually present at birth and are suggestive of defective autonomic
control. Nerve biopsy shows reduced number of unmyelinated fibres. HSAN
IV is an autosomal recessive disorder associated with bouts of pyrexia,
anhydrosis and mental retardation. Nerve biopsy reveals absent
unmyelinated fibres. HSAN V is an autosomal recessive disorder with
onset at birth and normal sweating. Motor functions and tendon reflexes
are normal. Sural nerve biopsy shows selective reduction in the number
of smaller myelinated fibres(1,8).
The clinical picture of our patients suggests the
diagnosis of HSAN type IV. Impaired sense of pain and temperature,
absence of sweating, signs of self-mutilation and presence of recurrent
fever with onset in infancy supports the diagnosis. Mental retardation
in HSAN IV is variable, from severe to mild, and some patients were
initially reported to be apparently normal, but later mild retardation
was showed by a formal assessment(9). Unfortunately, no formal
assessment was done in our cases to detect the presence of mild
retardation.
Though no disorder exactly mimics hereditary sensory
autonomic neuropathy, impairment of pain sensation and oral mutilation
have been reported in some syndromes such as Lesch-Nyhan syndrome,
Tourette syndrome and de Lange syndrome. Absence of nail and hair
abnormalities and presence of normal sweat glands on skin biopsy exclude
the anhidrotic ectodermal dysplasia.
As nerve conduction studies test only 1-2% of the
large myelinated fibres, they may not be sensitive enough to detect
abnormalities of small fibers as was evident in the second case. Focal
segmental demyelination seen on nerve biopsy in the second case has not
been reported so far. Presence of normal number of sweat glands on skin
biopsy is consistent with previous reports(10).
Acknowledgments
Prof. Veena Kalra (Professor & Head), Department of
Pediatrics, All India Institute of Medical Sciences, New Delhi who was
the overall in charge of the patient management and provided critical
comments on the manuscript.
Contributors: All authors were involved in
clinical management of the cases, and drafting the manuscript. TD will
act as guarantor for the paper.
Funding: None.
Competing interests: None stated.
