Hereditary Sensory and Autonomic Neuropathy Presenting With Mutilating Trophic Ulcers

Distal limb ulcers are commonly encountered in clinical practice. At times, ascertaining the cause of an ulcer can prove to be challenging and may not be diagnosed until later stages of underlying pathology. One such condition is a group of disorders known as hereditary sensory and autonomic neuropathy (HSAN). The authors present 2 case reports of offsprings of a second-degree consanguineous marriage that were diagnosed with this relatively rare condition in the hopes of familiarizing clinicians about its presentation and treatment.   

A 19-year-old woman born to apparently normal parents of second-degree consanguineous marriage presented to the Department of Dermatology, Sawai Man Singh Medical College Hospital (Jaipur, India) with complaints of recurrent, spontaneous ulcers of both the hands and feet. Symptoms began around 6 years of age and were progressive since that time. The ulcers developed mainly over the tips of the digits, palms, and soles bilaterally. Although not painful, the wounds took 3 to 4 months to heal. The lesions were recurrent and resulted in absorption and autoamputation of the finger digits of both hands during early adolescence. She had difficulty walking and carrying out routine activities due to deformities developed in the hands and feet. She also experienced occasional burning sensation of the body at night. 

An 18-year-old man (female patient’s brother) also presented to the hospital at the same time with similar complaints. The age of symptom onset and progression were the same in both, however, recurrences were less frequent and less severe for him compared with his sister. 

There was no history of any systemic illnesses, and none of the family members, including 6 other siblings, reported similar problems. Both patients had previously consulted multiple general practitioners and each time their ulcers were treated as traumatic wounds. This afforded temporary relief, but the symptoms inevitably recurred in 6 to 12 months’ duration.

At examination on both patients, physical development was appropriate for their respective age and sex, the skin of the palms and soles were hyperkeratotic, and the feet showed mutilation and distortion of toes. 

Both patients had nonhealing trophic ulcers of the soles as described below (Figures 1, 2). The woman had a single large ulcer on the mid-part of the plantar surface of the left foot measuring 7 cm x 8 cm. The brother had an ulcer on the plantar surface of the first metatarsal head of the left foot, measuring about 1 cm x 1 cm, and another measuring 1 cm x 0.5 cm over the dorsum of the right index finger. The ulcers had macerated margins and there was hypergranulation tissue formation and serous discharge of the wound floor. They were nontender on palpation and had no sign of acute inflammation. The distal phalanges of the woman’s fingers showed absorption, her ankle joints showed signs of Charcot arthropathy, and her nails showed hypertrophic and dystrophic changes. Peripheral pulses were felt normally in both patients. There were no skin patches of hypopigmentation, erythema, or infiltration. Bilateral posterior tibial nerves were thickened and nontender. On sensory examination, there was anesthesia in glove and stocking distribution. Perception to pain and temperature stimuli was absent, and tactile perception was subnormal. Vibration sense was preserved. Motor power was normal. Deep tendon reflexes in the lower limbs were sluggish. The woman had restricted range of movement at the ankle joints. Higher mental functions as well as examination of cranial nerves and gait were normal. No systemic abnormality was found on examination. The patients were investigated further for peripheral neuropathy. 

The investigative findings were similar in both patients. Routine hemogram, urine analysis, renal and liver function, thyroid profile, vitamin B12 assay, chest x-ray, electrocardiogram, and fasting blood sugar were normal. Human immunodeficiency virus (HIV) serology was nonreactive. Staphylococcus epidermidis was grown on microbial pus culture, which was sensitive to amoxicillin-clavulanate. Slit-skin smear for acid-fast bacilli was negative. X-ray of the feet showed acro-osteolysis and tarsal disintegration. Sweat test was normal. A nerve conduction study showed reduced sensory nerve action, potentially suggestive of sensory axonal and demyelinating neuropathy predominant in the lower limbs, and sural nerve biopsy for histopathology revealed small-sized nerve fascicles with severe loss of myelinated fiber. Changes predominantly involved the small fibers. Endoneurial fibrosis reflecting chronicity was observed. There was no axonal regeneration and features of Hansen’s neuritis. Wade-Fite stain for acid-fast bacilli and Congo red stain for amyloid were negative. The patients’ features were consistent with the diagnosis of HSAN; further, on the basis of autosomal recessive inheritance, childhood onset, predominant sensory loss, weak tendon reflexes, the presence of ulceromutilation, normal mental development, and the absence of severe autonomic dysfunction and anhidrosis, they were classified with type 2 of the disease (HSAN2).

Patients were managed symptomatically on a day-by-day basis. A prophylactic oral antibiotic (amoxicillin 500 mg with clavulanate 2x/day) was started as per culture sensitivity, and hydrocolloid dressings were applied every other day for 10 days. Plaster casts were applied to the leg with trophic ulcers for both patients to relieve weight-bearing on the sole skin. Admission and negative pressure wound therapy (NPWT) of the wound followed by reconstructive surgery to cover the residual defect was advised for the woman; however, she was not prepared for a longer hospital stay and wished to be admitted at a later date for NPWT and is due for follow-up. Daily neurotropic supplements containing alpha-lipoic acid, folic acid, methylcobalamin, pyridoxine hydrochloride (Nurobest OD, TTK Healthcare Ltd, Chennai, India), and vitamin D3 (5 mcg/day) were prescribed to both patients. Antipyretics and cold sponging of the body were recommended on an as-needed basis. Physiotherapy, protective hand gloves, and padded footwear were advised to protect them from trivial injuries. Counseling also was advised for self-care and genetic nature of the disease. Prenatal genetic diagnosis was recommended to prevent further transmission of the disease. The ulcers at the time of their leave had just begun to heal with sloping edges; patients are due for follow-up. 

A trophic ulcer is a pressure ulcer caused by external trauma to a part of the body that is in poor condition due to disease, vascular insufficiency (vasculopathic), or loss of afferent nerve fibers (neuropathic).¹ Neuropathic ulcers usually develop at sites exposed to repetitive high pressures during activities of daily living (eg, walking or working) like the soles of the feet or fingertips. Sensory neuropathy causes an insensate foot or hand with loss of protective pain, pressure, and temperature. In people with normal sensation, avoidance measures, such as changing gait or modifying activity level, would relieve the discomfort of the repetitive insults; however, in patients with peripheral sensory deficits, with the protective pain perception absent, they do not relieve pressures, thus the repetitive trauma leads to skin breakdown and ulceration. Neuropathy of the sympathetic autonomic system leads to vasodilatation as well as loss of or decreased sweating, leading to warm, dry hands and feet that are prone to cracks and fissures that may get infected and form ulcers.²

Differential diagnoses for peripheral neuropathy mostly include diabetes, infectious and inflammatory conditions (eg, leprosy, HIV-associated neuropathy, Guillain-Barré syndrome, chronic idiopathic demyelinating polyneuropathy, and paraproteinemia), hereditary neuropathies (such as Charcot-Marie-Tooth disease and familial amyloidosis), paraneoplastic conditions, chemical toxicity, and alcohol consumption.³

The HSAN encompasses a group of inherited disorders characterized by insensitivity to noxious stimuli and autonomic dysfunctions associated with pathological abnormalities of peripheral nerves. Four numerical types of HSAN were originally described by Dyck and Ohta⁴ according to the mode of inheritance, age of onset, clinical symptoms, and neuropathological findings. However, several other variants have been added to the list since then, and the features often overlap one another among the 4 types.^5-7

Hereditary sensory and autonomic neuropathies 2, also called Morvan’s disease, is a rare disorder with a prevalence of less than 1 in 1 million people.⁸ The inheritance is autosomal recessive and affects both sexes equally. Mutations have been identified on a number of genes (lysine deficient protein kinase 1 on chromosome 12p13.33, reticulophagy regulator 1 on chromosome 5p15.1, kinesin family member 1A on chromosome 2q37.3, and sodium channel protein type 9 subunit alpha on chromosome 2q24.3), on which HSAN2 is further divided into 4 subtypes (types A-D).⁹ The onset of sensory loss in HSAN2 usually occurs shortly after birth or during early childhood. The lower extremities and distal portions are more severely affected than the upper extremities. Patients experience a progressive numbness and tingling followed by reduced sensation to temperature, pain, and touch, which eventually leads to complete loss of sensation. Erosions, blisters, and trophic ulcers may develop and heal poorly. Complications such as osteomyelitis, acro-osteolysis, and spontaneous painless fractures may develop and result in deformities. Additional features include symptoms of autonomic dysfunction (eg, disturbances in sweating, gastroesophageal reflux, postural hypotension, slow pupillary reaction, and urinary incontinence); hyperkeratosis of the palms of the hands and soles of the feet, dysgeusia, dysphagia, scoliosis, and loss of fungiform papillae of the tongue also can be seen. Clinical features may mimic leprosy^10,11; however, diagnosis can be confirmed by histopathological study of sensory nerves, which shows selective loss of small myelinated fibers.

Conservative clinical management requires a multidisciplinary approach^12,13 aimed at protecting the sensory-impaired limbs from traumatic injuries and preventing the development of deformities. Adequate nutrition is required to enhance wound healing, and neurotropic drugs may prove beneficial to patient outcomes. Patients should be educated on wearing protective gloves, socks, and appropriately fitting padded footwear; keeping the acral parts of the body moisturized; periodically removing calluses; performing self-examinations of their body for signs of trauma; and seeking medical attention early. The ulcers are treated with antiseptics and dressings, surgical intervention is often required for large nonhealing ulcers and infective complications, and physiotherapy is helpful for improving joint mobility and gait correction.

Hereditary sensory and autonomic neuropathy is a rare cause of chronic limb ulcers with, unfortunately, no cure. Although the onset of symptoms is early, they often go undiagnosed as in the present patients due to the slow progressive nature and a lack of clinical suspicion. However, this report highlights the importance of sensory testing and/or nerve pathology in all cases of nonhealing ulcers, which can potentially detect such progressive disorders at the earliest stages and help patients adapt measures to prevent further damage and transmission.

Affiliations: Department of Dermatology, Sawai Man Singh Medical College Hospital, Jaipur, India; and Department of Pathology, Sawai Man Singh Medical College Hospital

Correspondence: Chaitra Prakash, MD, Department of Dermatology, Sawai Man Singh Medical College Hospital, JLN Marg, Jaipur 302004, India; drpchaitra@gmail.com 

Disclosure: The authors disclose no financial or other conflicts of interest.