Hereditary Sensory and Autonomic Neuropathy Type II

Clinical characteristics.

Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.

Diagnosis/testing.

The diagnosis of HSAN2 is established in a proband with suggestive clinical and electrophysiologic findings and biallelic pathogenic variants in one of four genes: KIF1A, RETREG1 (FAM134B), SCN9A, or WNK1.

Management.

Treatment of manifestations: Treatment is symptomatic and often involves a team including neurologists, orthopedic surgeons, and physiotherapists. Training in the care of the sensory-impaired limb, often in a diabetic foot care clinic, is important and includes self-examination – especially of the feet – for any signs of trauma. To prevent osteomyelitis, and hence the need for amputation, wounds require cleaning and protection along with antiseptic treatment. To prevent callous formation, the skin of neuropathic limbs requires hydration and lipid-based unguents. Appropriate shoes and socks are recommended.

Surveillance: The feet should be inspected daily for injuries or sources of wear. Annual follow up in centers with comprehensive care of diabetics and/or persons with Charcot-Marie-Tooth neuropathy is recommended.

Agents/circumstances to avoid: Ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking.)

Genetic counseling.

HSAN2 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the HSAN2-causing pathogenic variants in the family are known, carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

Hereditary sensory and autonomic neuropathy type II (HSAN2) should be suspected in individuals with the following clinical and electrophysiologic findings and family history.

Clinical findings

• Congenital or early-onset (1st to 2nd decade) sensory deficit
• Sensory loss affecting all modalities
• Ulcerations of hands/feet often requiring amputation
• Acral mutilations
• Painless fractures and neuropathic arthropathy in some
• Varying degree of autonomic involvement: hyperhidrosis, urinary incontinence, and slow pupillary reaction to light

Electrophysiologic findings

• Reduced/absent sensory nerve action potentials
• Preserved or reduced motor nerve conduction velocities (NCV)
• Variably reduced compound muscle action potentials (CMAP)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of HSAN2 is established in a proband with suggestive clinical and electrophysiologic findings and biallelic pathogenic variants in one of four genes: KIF1A, RETREG1 (FAM134B), SCN9A, or WNK1. (See Table 1.)

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of a pure sensory neuropathy has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

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].

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.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known. Inter- and intrafamilial phenotypic variability is reported.

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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary sensory and autonomic neuropathy type II (HSAN2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Neurologic examination to determine extent of sensory loss and involvement of autonomic and motor nervous system
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of HSAN2 in order to facilitate medical and personal decision making

Treatment of Manifestations

Treatment is symptomatic and often involves a multidisciplinary team including neurologists, orthopedic surgeons, and physiotherapists.

Training in the care of the sensory-impaired limb is important and includes self-examination – especially of the feet – for any signs of trauma. A diabetic clinic is a good source of advice. Appropriate shoes and socks are recommended.

It is best to prevent callous formation in neuropathic skin; once present, calluses should be treated with hydration and lipid-based unguents to prevent cracking and may require medical consultation.

Cleaning and protection of wounds on neuropathic limbs in combination with antiseptic treatment to eradicate infections helps prevent osteomyelitis and the possible future need to amputate a limb.

Surveillance

The feet should be inspected daily for injuries and sources of wear.

Affected individuals should be followed annually by centers with comprehensive care, such as those for diabetic foot care and/or Charcot-Marie-Tooth neuropathy, also known as hereditary motor and sensory neuropathy.

Agents/Circumstances to Avoid

Avoid ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of at-risk sibs in order to identify those who will develop sensory loss and would benefit from measures to prevent injury to limbs and/or self-mutilation.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Hereditary sensory and autonomic neuropathy type II (HSAN2) is an autosomal recessive disorder caused by biallelic KIF1A (HSAN2C), RETREG1 (HSAN2B), SCN9A (HSAN2D), or WNK1 (HSAN2A) pathogenic variants.

Risk to Family Members

Parents of a proband

• In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a KIF1A, RETREG1 (FAM134B), SCN9A, or WNK1 pathogenic variant.
• In rare families, only one parent is heterozygous for a pathogenic variant and the child has HSAN2 as the result of uniparental isodisomy and consequent homozygosity for the HSAN2-causing pathogenic variant from the carrier parent. (Uniparental isodisomy has been reported in a child with RETREG1-related HSAN2 [Park et al 2019].)
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an HSAN2-causing pathogenic variant. If carrier testing detects the pathogenic variant in only one parent:
  • And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [Park et al 2019]);
  • And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one de novo pathogenic variant. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic except for the report of increased sensitivity to thermal stimuli in individuals who are heterozygous for an HSAN2-related WNK1 pathogenic variant [Loggia et al 2009].

Sibs of a proband

• If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
• Significant clinical variability between affected sibs can be observed.
• If the proband has HSAN2 as the result of uniparental isodisomy, if only one parent is heterozygous for an HSAN2-causing pathogenic variant, and if neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being a carrier and an approximately 50% chance of being unaffected and not a carrier. (The risk to sibs of a proband of being affected is unknown but is presumed to be <1%.)
• Heterozygotes (carriers) are typically asymptomatic (see exception in Parents of a proband).

Offspring of a proband. Unless an individual with HSAN2 has children with an affected individual or a carrier (see Prevalence), his/her offspring will be obligate heterozygotes (carriers) for an HSAN2-causing pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an HSAN2-causing pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the HSAN2-causing pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the HSAN2-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Mechanism of disease causation for all genes. Given the spectrum of pathogenic variant types in the HSAN2-related genes (nonsense variants, frameshift variants, and splice-site variants are part of the mutation spectrum), biallelic loss of function can be assumed.

Gene-specific laboratory technical considerations. Alternate splicing of WNK1 results in the inclusion of exon 10 ("HSN2" exon). HSN2 was first reported as a single-exon gene located in intron 8 of WNK1, with both genes transcribed from the same strand [Lafreniere et al 2004]. Subsequently, HSN2 was found to be an alternatively spliced exon present in a nervous system-specific isoform of WNK1 [Shekarabi et al 2008]. The majority of HSAN2-causing variants in WNK1 reported to date are frameshift or nonsense variants in exon 10. Because pathogenic variants in other exons of WNK1 may also contribute to the HSAN2A phenotype, sequence analysis of all known exons from genomic DNA may be necessary if only one pathogenic variant is found in exon 10. Note: Homozygous or compound heterozygous null alleles affecting all WNK1 isoforms are thought to be embryonically lethal.

Author Notes

Website: www.ukaachen.de/en/clinics-institutes/institute-of-human-genetics

The Institute of Human Genetics offers HSAN testing on a research basis via the ENISNIP consortium. For further information regarding massive parallel sequencing of HSAN-relevant genes, please contact ikurth@ukaachen.de.

Revision History

• 1 April 2021 (bp) Comprehensive update posted live
• 19 February 2015 (me) Comprehensive update posted live
• 3 November 2011 (ik) Revision: added HSAN2C, caused by KIF1A pathogenic variants
• 23 November 2010 (me) Review posted live
• 14 July 2010 (ik) Original submission

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