Congenital Insensitivity to Pain with Anhidrosis: A Rare Entity.

Sir,

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is an autosomal recessive disorder. It is characterized by the absence of sensitivity to pain (and temperature) since birth, anhidrosis, intellectual disability, unintentional self-injury (and delayed wound healing), and recurrent episodes of hyperpyrexia (because of anhidrosis). Repeated injuries may result in multiple fractures, joint dislocation, joint deformity (Charcot joint) and osteomyelitis. It occurs because of a mutation in neurotrophic tyrosine receptor kinase 1 gene (NTRK1) that encodes the protein TrKA, a receptor tyrosine kinase for a nerve growth factor (NGF). CIPA lacks all the NGF-dependent neurons, which is responsible for the absence of pain sensation and anhidrosis.[1] It is a rare disorder, with only a few reports from the Indian subcontinent.

A 4-year-old boy born to second-degree consanguineous parentage, presented with complaints of hyperpyrexia and recurrent ulcerations over fingertips because of biting and auto-amputation of the left little toe with an ulcer on the right little toe. He was born with an uneventful antenatal period by normal vaginal delivery, but the child did not cry after birth. The other two siblings were absolutely normal. The child was apparently normal until he started crawling, after which he started developing trauma-induced ulcers. There was a history of self-injury after the eruption of primary teeth, by biting fingertips, lips, and tongue. His parents noticed that he did not respond to painful and thermal stimuli (burn because of hot utensils, vaccination, and after fall). Delay in developmental milestones was also noted. The parents also noticed that the child did not sweat even on sun exposure and had recurrent episodes of elevated body temperature. There was no history of involuntary movements suggestive of tremor, chorea, athetosis, dystonia, and others. Family history was non-contributory.

On examination, the child appeared irritable and hyperactive. Cutaneous examination showed generalized xerosis; lichenified skin over hands, feet, and the joints of the lower limbs; and atrophic scars from previous injuries. Other notable findings were ulcers over the lower limbs and tips of fingers and auto-amputation of the left little toe [Figures 1-3]. The front-row teeth were missing [Figure 4]. Sensory examination revealed complete insensitivity to pain (pin prick) and temperature, but the sensations of vibration and fine touch were intact. Deep tendon reflexes were normal and superficial tendon reflexes were sluggish. Cold pressure test was negative. Complete hemogram and biochemical tests, including serum uric acid, were within normal parameters. X-ray of both hands showed broken phalanges [Figure 5]. Histopathology from the palmar skin showed unremarkable epidermis and dermal structures with the presence of normal-appearing sweat glands [Figure 6]. Nerve conduction velocity (NCV) study of both upper and lower extremities showed severe sensorimotor neuropathy. Based on clinical and histopathological findings, a diagnosis of CIPA was done. NTRK1 molecular genetic testing could not be done because of logistic reasons. The patient was treated with appropriate antibiotics and emollients. Parents were explained about the disorder and they were counseled regarding preventive measures to be taken.

Figure 1

Ichthyosis and lichenification of the skin of lower limbs. Note the autoamputation of the left little toe

Figure 3

Atrophic scars (from previous injuries) on the knee joint

Figure 4

Absence of primary teeth in the front row

Figure 5

X-ray of both hands showing broken phalanges

Figure 6

Photomicrograph showing unremarkable epidermis and dermal structures with the presence of normal-appearing sweat glands (H and E, 100×)

Ulcerations on the tips of the fingers. Note the ulcers and scarring on the forearms

Half of the reported cases of CIPA/HSAN IV were seen in consanguineous parentage. Mutation in NTRK1 results in the failure of differentiation and migration of neural crest cells, which causes a complete absence of small myelinated and unmyelinated nerve fibers, resulting in loss of pain and temperature sensation. The normally formed sweat glands lack the nerve supply, leading to anhidrosis.[2]

The common findings in CIPA include recurrent episodes of fever, congenital insensitivity to pain and temperature, self-mutilation, intellectual disability, and anhidrosis, as seen in our patient. Uncommon features include joint deformity, multiple fractures, septic arthritis, neurotrophic keratitis, hyperkeratosis, and hypotonia, which were absent in the index case. Angular cheilitis (AC) and ulcers are present over the lips and on the ventral surface of the tongue, which are attributed to repeated biting. Anhidrosis leads to xerosis and lichenification. In addition, anhidrosis results in poor temperature control in summers, and early deaths (within 3 years of life) because of hyperpyrexia have been reported.[34] Various types of HSAN have been tabulated in Table 1. CIPA (HSAN IV) is unique among HSANs because it is associated with widespread anhidrosis.

Table 1

Types of Hereditary sensory and autonomic neuropathy

Type of HSAN	Clinical Features
Type I	Mild manifestation
	Present in 2nd to 4th decade of life
	Mainly affects the lower limb
Type II (Morvan’s syndrome)	Hyporeflexia and hypotonia
	Acral anhidrosis and episodic hyperhidrosis
	Hearing impairment
	Temperature and control of blood pressure are normal
Type III (Familial dysautonomia or Riley-Day syndrome)	Multisystemic involvement
	Hyporeflexia, hypotonia, and ataxia
	Kyphoscoliosis
	Less impaired pain and temperature sensation with acral anhidrosis
	Abnormal gastro-esophageal mobility resulting in feeding difficulty and aspiration pneumonia
Type IV (Congenital insensitivity to pain and anhidrosis), consistent with our case	Episodes of hyperthermia
	Anhidrosis
	Insensitivity to pain
	Palmar skin is thickened
	Charcot joints are commonly present
Type V	It is similar to HSAN IV with relatively milder intellectual disability and anhidrosis
	Selectively affects nociception
Type VI	Similar to HSAN III
Type VII	Diarrhea, constipation, hyperhidrosis, pruritus, and muscular weakness

HSAN=Hereditary sensory and autonomic neuropathy

The differential diagnoses for CIPA include other HSANs (discussed in Table 1); hypohidrotic ectodermal dysplasia (no evidence of generalized loss of pain sensation); Lesch–Nyhan syndrome (hyperuricemia, self-induced trauma, mental retardation, chorea, and athetosis); and Hansen's disease (presence of hypopigmented hypoesthetic patches and enlargement of nerves). The battered baby syndrome should be considered in clinical differentials and needs to be ruled out. The diagnosis of CIPA is made by characteristic clinical features and pharmacological and histopathological findings. However, the confirmation is done by identification of biallelic pathogenic variants in NTRK1. The histamine test shows wheal but not flare in CIPA patients. Sweating in response to pilocarpine test is minimal or absent. Skin biopsy shows normal adnexal structures, including sweat glands, but dermal nerves and innervations to sweat glands are absent (confirmed by special stains for nerves). Sural nerve biopsy shows a reduction in the small unmyelinated and myelinated nerve fibers. However, the large fibers are normal.[5]

Although there is no specific treatment modality for CIPA, it requires a multidisciplinary approach according to its manifestations.[6] The skin lesions and traumatic ulcers should be treated with antibiotics and emollients. Parents need to be educated about the condition and preventive measures that can be taken like avoiding excessive wrapping; frequent sponging to reduce hyperpyrexia and prevention of dehydration. Parents should also be asked to keep close attention of their kids to prevent injuries, burns, and self-mutilation. The treating pediatrician should be aware of diagnosis while giving treatment for hyperpyrexia to avoid unnecessary use of drugs. Due to frequent fractures, operative interventions are required in these children, and postoperative hypertension and tachycardia should raise the suspicion of inadequate analgesia. This occurs because of the unconscious physiologic response to pain though the patient is unaware of pain because of the decreased number of peripheral pain fibers.

As it is an autosomal recessive disorder, the importance of genetic counseling cannot be overemphasized. Parents should be explained about its genetic inheritance and consanguineous marriage should be discouraged. The identification of NTRK1 mutation is the only tool for its prenatal diagnosis and it becomes necessary when there is a positive family history of CIPA. The limitation of our documentation is that we could not perform molecular genetic testing and sural nerve biopsy because of logistic difficulties.

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Conflicts of interest

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