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Título

MUTILATING HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY ASSOCIATED WITH WNK1 GENE

Apresentação do caso

A 17-year-old girl presented recurrent skin injuries on both feet with onset at 2 years-old. She had labile skin temperature with unexplained hyperthermia episodes. Parents were consanguineous and had two healthy younger brothers. Past medical history included chronic osteomyelitis of the right foot after recurrent skin cellulitis.
On examination, there are acral mutilations on both hands and feet and dry skin; reduced bilateral and symmetrical length-dependent pain, touch and vibratory sensation to knees and elbows, absent on hands and feet. Deep tendon reflexes are globally absent, except triceps and pronator teres. Orthostatic hypotension and urinary or fecal incontinence are absent. Nerve conduction studies revealed absent sensory nerve action potentials on four limbs, with normal compound muscle action potentials. Hereditary sensory and autonomic neuropathies were suspected and a genetic panel confirmed a homozygous pathogenic variant c.3226C>T (p.Arg1076*) in WNK1 gene associated with autosomal recessive hereditary autonomic and sensory neuropathy type 2A (HSAN2A), but also a single pathogenic variant in DST gene, c.4152del (p.Glu1384Aspfs*2), associated with HSAN6.

Discussão

HSAN2A is a childhood-onset disorder that typically presents numbness affecting the hands and feet, reduced sensitivity to pain, and loss of touch and temperature. Although autonomic functions are not classically affected, HSAN6 is similar but with dysautonomia – including impaired sweating and heat intolerance.
Our patient also presented several episodes of unexplained hyperthermia and dry skin. Besides, the phenotype is typical of HSAN2A and genetic analysis confirmed homozygous mutation of WNK1 gene. In the long term, reduced sensitivity of extremities causes acral mutilations and infectious complications due to ulcerations. Autonomic features seen in our patient are unexpected in HSAN2A. Oddly, she is a carrier of single copy mutated DST gene associated with HSAN6, an autosomal recessive condition, more associated with autonomic features than HSAN2A.

Comentários finais

Despite HSAN2A phenotype and confirmed mutation of WNK1 gene, our patient is also a carrier of a single copy of DST gene mutation associated with HSAN6 phenotype. Oddly, some autonomic features presented in our case are not expected on HSAN2A but in HSAN6. Therefore, a single copy mutation of DST gene is insufficient to cause autosomal recessive DST-related conditions such as HSAN6, besides the reproductive risk of a carrier.

Referências (se houver)

1. HSAN-VI A spectrum disorder based on dystonin isoform expression Anisha Lynch-Godrei, Rashmi Kothary Neurol Genet Feb 2020, 6 (1) e389.
2. Axelrod, F.B., Gold-von Simson, G. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet J Rare Dis 2, 39 (2007).
3. Shekarabi, Masoud, et al. "Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II." The Journal of clinical investigation 118.7 (2008): 2496-2505.

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Doenças neuromusculares