Polyneuropathy in a young Belgian patient: A novel heterozygous mutation in the WNK1/HSN2 gene

Hereditary sensory autonomic neuropathy (HSAN) is a rare condition, predominantly affecting the peripheral sensory nervous system, although variable motor and dysautonomic symptoms can be present. At least 7 clinical types of HSAN have been described, and different genetic mutations have been identified for each of these. HSAN IIA (OMIM #201300) is characterized by loss of pain and loss of temperature and touch sensation, with onset usually before the first decade. The mode of inheritance is autosomal recessive.¹ The causative gene, WNK1/HSN2, is located on locus 12p13.33 and is an isoform of the WNK1 (lysine deficient protein kinase 1) gene, which contains the HSN2 exon.^2,3 We describe 2 new heterozygous mutations in the WNK1/HSN2 gene in a Belgian patient with early-onset sensory polyneuropathy.

Case report.

The patient is an 18-year-old male with recurrent acral infections due to an inherited sensory neuropathy of unknown cause. No other family members are known to be affected. His parents are not consanguineous (figure, A). At age 3, the patient had frequent ecchymoses of the toes, according to his mother as if “he did not feel his shoes were too small.” At age 6, he sustained a nonpainful traumatic lower arm fracture. At age 10, difficulties with attention and concentration led to the diagnosis of attention deficit disorder with hyperactivity. During this workup, the assessing pediatric neurologist ordered further testing. Nerve conduction study showed absent sensory action potentials in both upper and lower limbs. Motor nerve conduction and electromyography results were within normal limits. Routine blood analysis results were normal. Sural nerve biopsy was not performed. Over the following years he developed recurrent digital osteomyelitis and tenosynovitis of digits III and IV of his left hand, followed by amputations of several distal and medial phalanges (figure, B). He currently complains of episodic postural hypotension, gastroesophageal reflux, and hyperhidrosis of the hands with diffuse purple discoloration when exposed to cold.

Figure. Clinical and genetic features of a Belgian patient with HSAN IIA.

(A) Three-generation pedigree of a family with HSAN IIA in the index patient (arrow). Black filled symbol = affected patient; half-filled symbol = heterozygote carrier; open symbol = unaffected individual. Asterisks indicate genetically analyzed individuals. (B) Plain radiography of both hands and feet, demonstrating amputations of distal and medial phalanges (digitus IV left hand and digitus III right foot, white arrows) and bone resorption in several phalanges.

Physical examination confirmed the absence of nociception, thermoception, and touch sensation, distally from both wrists and ankles (“glove and sock”) with decreased sensation from both elbows and knees downward. The vibration sense was intact. No muscle weakness was observed. The deep tendon reflexes were not present. His gait was normal. His distal extremities showed no signs of ulcerations or arthropathy. His blood pressure was 130/90 mm Hg.

Informed consent was obtained from the patient and his parents prior to blood sample analysis. DNA was extracted from peripheral blood lymphocytes using standard methods. Sanger sequencing of the HSN2 exon of the WNK1/HSN2 gene (NM_213655.2–HSN2) unveiled a heterozygous variant with a single base modification c.718A>T resulting in a predicted new stop codon p.(Lys240*), and a deletion of 5 nucleotides c.1192_1196del producing a predicted amino acid change from phenylalanine to leucine on position 398, leading to a frameshift and a read-through with a 9 amino acid longer open reading frame p.(Phe398Leufs*46). Both asymptomatic parents were found to be heterozygous carriers. The mother is a carrier of the c.718A>T mutation; the father is a carrier of the c.1192_1196del mutation.

Discussion.

We describe 2 new genetic mutations in the WNK1/HSN2 gene in a patient with early-onset sensory polyneuropathy. Prior to analysis, the phenotype of this patient was thoroughly investigated and compared with the known clinical features of the different HSAN types. An evaluation of HSAN IIA was preferred given the age at onset of symptoms in early childhood, an evocative sensory deficit with “glove and sock” distribution, unimpaired vibration sense, and absent deep tendon reflexes.^1,4 Dysfunction of the autonomic nervous system is possible in HSAN II^1,4 and could explain the postural hypotension, gastroesophageal reflux, and hyperhidrosis with reactivity to cold. Excessive hand sweating also occurred in a French patient with a heterozygous mutation in the WNK1/HSN2 gene and exon 6 of the WNK1 gene.³

Genetic analysis is essential for definitive diagnosis and counseling and should be guided by careful clinical evaluation. Testing of unaffected relatives and prenatal counseling (if appropriate) could be proposed if wished for, in order to prevent new cases, which has already been successful in HSAN III.⁵

Treatment is challenging. The sensory deficit causes neuropathic ulcerations, osteomyelitis, and arthropathy leading to progressive amputations. The consequences in this patient were relatively mild, although progressive mutilations are likely to be expected. Preventive care, early detection, and treatment of infection are crucial.^1,4