Clinical Description
The published clinical descriptions of hereditary sensory and autonomic neuropathy type II (HSAN2) are inconsistent, possibly in part as a result of reports that lack molecular genetic confirmation of the diagnosis. Clinically, WNK1-related HSAN2 (HSAN2A), RETREG1 (FAM134B)-related HSAN2 (HSAN2B), and KIF1A-related HSAN2 (HSAN2C) appear to be very similar.
Autonomic dysfunction may be more pronounced in RETREG1-related neuropathy, and individuals with KIF1A-related HSAN2 also showed distal muscle weakness. SCN9A-related HSAN2 was reported in two families [Yuan et al 2013].
Table 2.
Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2): Gene-Phenotype Correlations
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Feature | Associated Gene (HSAN2 Subtype) |
---|
WNK1 (HSAN2A) | RETREG1 (HSAN2B) | KIF1A (HSAN2C) | SCN9A (HSAN2D) |
---|
Sensory deficit | +++ | +++ | +++ | +++ |
Autonomic dysfunction | ++ | +++ | ++ | + |
Distal motor involvement | + | + | ++ | - |
- +
++= most common; ++= less common; += rare; -= not observed
In molecularly confirmed HSAN2, onset is typically in the first two decades (often before puberty). It is characterized by progressive numbness of the hands and feet, together with reduced sensation to pain, temperature, and touch. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time, sensory function becomes severely reduced.
Neuropathic skin tends to produce excessive keratin and hyperkeratosis that may be forced down into the deeper layers of soft tissue and/or may crack, promoting ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common.
Secondary muscle atrophy and Charcot joints may occur. Painless fractures can complicate the disease.
Intellectual development is usually normal but can be impaired, especially in KIF1A-related HSAN2.
Sweating and tearing are usually normal but hyperhidrosis is present in some cases. Tonic pupils are observed. With progression of the disease urinary incontinence is reported.
Histopathology. Sural nerve biopsy shows signs of an axonal sensory neuropathy, pronounced absence of (small) myelinated fibers, and decreased unmyelinated fibers. Additionally, loss of large myelinated fibers may be seen in those with HSAN2D.
Nomenclature
HSAN2 has also been reported as the following:
Morvan's disease
Congenital sensory neuropathy
Neurogenic acroosteolysis
Hereditary sensory radicular neuropathy
Dyck originally proposed five different HSAN types on the basis of clinical manifestations and nerve biopsy specimens [Dyck 1993]. More recently, genetic and additional phenotypic heterogeneity has been described [Verhoeven et al 2006], suggesting a need for a detailed classification based on the underlying gene defects [Rotthier et al 2012, Schwartzlow & Kazamel 2019].
Prevalence
The worldwide prevalence of HSAN2 is unknown. Several hundred affected individuals have been reported.
For comparison, the overall prevalence of the closely related hereditary motor and sensory neuropathies (HMSN or Charcot-Marie-Tooth neuropathy) is about 30:100,000, and hereditary sensory and autonomic neuropathies (HSAN) occur with markedly lower frequency.
See Table 5 for WNK1 founder variants identified in eastern Canada [Roddier et al 2005] and Japan [Yuan et al 2017].