The onset is usually as early as birth and initial symptoms include swallowing difficulties, self-mutilation, and delayed development [1]. Later on, the perception of pain and temperature may be either partially or completely absent, followed by depressed reflexes and autonomic dysfunction presenting with postural hypotension, excessive sweating and gastroesophageal reflux [1]. Frequent fractures, skin and corneal ulceration, intermittent fevers, irritability and behavioral issues (type IV), scoliosis and osteomyelitis after injury are also observed in a significant number of individuals [2] [4], whereas life-threatening recurrent aspirations are characteristic for type III [1].

• Weight Loss

  Constipation was a constant feature and there had been considerable weight loss over the past few months. He had anhidrosis with difficulties ih body temperature control. [jpma.org.pk]

  Visceral autonomic features are rare [Nicholson, unpublished data], with abdominal pain, diarrhea, and weight loss reported in some individuals in one family only [ Houlden et al 2006 ]. [ncbi.nlm.nih.gov]

  The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension in patients with autonomic failure. Br Med J (Clin Res Ed). 1986 Aug 9. 293(6543):353-4. [Medline]. Dalakas MC. [emedicine.com]

• Localized Pain

  pain followed by sensory disturbances and paralysis. [medical-dictionary.thefreedictionary.com]

• Acute Intermittent Porphyria

  Nerve pathology demonstrates loss of both small myelinated and unmyelinated fibers. [7] Acute intermittent porphyria and variegate porphyria Acute intermittent porphyria and variegate porphyria can both have forms of peripheral neuropathy. [emedicine.com]

• Lacrimation

  Clinical manifestations are present at birth and include diminished lacrimation, defective thermoregulation, orthostatic hypotension (HYPOTENSION, ORTHOSTATIC), fixed pupils, excessive SWEATING, loss of pain and temperature sensation, and absent reflexes [termsciences.fr]

  Subcutaneous administration of mecholyl or neostigmine in doses capable of producing lacrimation in normal children, failed to do so in these patients, despite their occasional spontaneous lacrimation. [jpma.org.pk]

  Japanese and Israeli-Bedouins. [8] HSAN type IV can be differentiated from other neuropathies by insensitivity to pain and fever, anhydrosis with dry skin, normal sense of touch, diminished or upset deep tendon reflexes, normal corneal reflex response, and lacrimation [saudija.org]

  View Article PubMed Google Scholar Riley CM, Day RL, Greely DMcL, Langford WS: Central autonomic dysfunction with defective lacrimation. Pediatrics. 1949, 3: 468-477. [doi.org]

• Neuropathic Arthropathy

  Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. [ncbi.nlm.nih.gov]

  Chronic skin ulcers, spontaneous fractures, and neuropathic arthropathy necessitating amputations are constitutive parts of the clinical presentation as well. [symptoma.com]

  Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), bone loss (osteonecrosis), spontaneous fractures, and inflammation and damage to the surrounding joints (neuropathic arthropathy). [rarediseases.org]

• Peripheral Neuropathy

  XPA mutations have been shown to cause peripheral neuropathy, and GAS1 is related to the PMP22 gene, which is critical in the pathogenesis of two other peripheral neuropathies. [ncbi.nlm.nih.gov]

  Types of Peripheral Neuropathy There are several different kinds of peripheral neuropathies that stem from a variety of causes. [webmd.com]

  See Hereditary Peripheral Neuropathy Testing Algorithm in Special Instructions. [mayomedicallaboratories.com]

• Numbness of the Hand

  The person may awaken at night with numbness in their hand or discover that when they perform activities like using a hair dryer, the numbness is more noticeable. In time, carpal tunnel injuries can weaken the muscles in the hand. [webmd.com]

  The first sign of the condition is usually numbness in the hands and feet. Soon after, affected individuals lose the ability to feel pain or sense hot and cold. [ghr.nlm.nih.gov]

  The sensory deficits begin with numbness in the hands and feet. There is some disagreement whether or not this disease is progressive. Regardless, these individuals have a severely reduced sense of pain, temperature, and touch. [medicalbag.com]

  The first sign of HSAN2 is usually numbness in the hands and feet. Soon after, affected individuals lose the ability to feel pain or sense hot and cold. People with HSAN2 often develop open sores (ulcers) on their hands and feet. [en.wikipedia.org]

  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. [ncbi.nlm.nih.gov]

• Limb Weakness

  In advanced stages, individuals may need powered mobility because of hand/upper limb weakness. Promote strengthening and use of proximal muscle in exercise and recreation. [now.aapmr.org]

• Aphasia

  急速に進行する若年性認知症の一例　2015年7月4日　第102回日本神経学会近畿地方会　大阪 白石智順、杉原芳子、出原亮、前田憲吾 : Logopenic progressive aphasiaを呈した大脳皮質基底核変性症の一例　2015年12月25日　第39回日本神経心理学会　札幌 前田憲吾、杉原芳子、出原亮、白石智順 ：神経軸索スフェロイドを伴う遺伝性びまん性白質脳症と診断された若年性認知症の一例　2015年12月25日　第39回日本神経心理学会　札幌 前田憲吾、出原亮 ：抗Ach-R抗体陽性 [higashiomi.hosp.go.jp]

A detailed patient history that reveals similar symptoms within the family or first-degree relatives may be one of the most important parts in the workup, together with a thorough physical examination that can confirm sensory and/or autonomic dysfunction [1]. The initial diagnosis should be made on clinical grounds, as genetic tests are available for only a few subtypes [1] [2]. Intradermal injection of histamine phosphate is a useful diagnostic method and in HSN patients [1]. Normally, a diffuse reaction around a central histamine-induced wheal should be observed, but if HSN is present, a reduced axonal flare manifesting as a narrow areola around the wheal will be seen in virtually all types [1].

• Slow Nerve Conduction Velocity

  Group 1 was characterized by slow nerve conduction velocities and evidence of hypertrophic demyelinating neuropathy. Group 2 was characterized by relatively normal nerve conduction velocities and axonal degeneration. [emedicine.medscape.com]

Supportive care is the mainstay of therapy, as there is no cure for HSN, regardless of the type. Topical lubricants are used to prevent corneal scarring, GABA agonists, anticholinergics and alpha-adrenergic agonists are used to cope with varying degrees of gastrointestinal dysfunction, hydration and exercise are recommended for long-term preservation of the cardiovascular system and various orthopedic measures in the form of splints and braces are used to reduce the burden of fractures [1] [4].

The quality of life is severely impaired in patients suffering from HSN, especially in the setting of pain and temperature sensation loss. Significant advances were made in the field of supportive care, however, and more patients are able to reach adulthood with current therapeutic options [1].

At this moment, seven types of HSN are recognized [1] [3]:

• Type I, acquired by autosomal dominant patterns of inheritance, is known as hereditary sensory radicular neuropathy. It is caused by progressive degeneration of dorsal root ganglia as a result of mutations in the subunit-1 of serine palmitoyltransferase gene (SPTLC1) on chromosome 9.
• Type II, congenital sensory neuropathy (CSN) is autosomal recessive and presumably involves mutations of unspecified genes on chromosome 12.
• Type III, familial dysautonomia (FD), is autosomal recessive as well and stems from mutations in IκB kinase complex-associated protein (IKAP) on chromosome 9.
• Type IV, congenital insensitivity to pain with anhidrosis (CIPA), is distinguished by mutations in neurotrophic tyrosine kinase receptor type 1 (NTRK1) mutations on chromosome 1, with an autosomal recessive pattern of inheritance.
• Type V, congenital insensitivity to pain with partial anhidrosis, has a similar pathogenesis as type IV, but the mode of inheritance is still not known.

Congenital autonomic dysfunction with universal pain loss (CAD) and progressive panneuropathy have also been proposed as subtypes of HSN [1].

Type III is estimated to occur in 1 per 3,600 live births and is exclusively seen in the Eastern European Jewish population, whereas types II and III are very rarely encountered in clinical practice [1]. Family history is considered as the most important risk factor for virtually all types.

Across all types, genetic mutations have shown to impair lipid metabolism, regulation of intracellular vesicular transport, the activity of nerve growth factors and regulators of transcription, eventually leading to neuronal atrophy and degeneration of sensory and autonomic fibers [1] [2].

Genetic counseling can be recommended to parents with known family members suffering from HSN.

Hereditary sensory neuropathy (HSN) is a term encompassing several disorders inherited through either autosomal dominant or recessive patterns [1]. At this moment, seven types have been recognized and classified as HSN subtypes, all distinguished with some form of sensory (disrupted sensation of pain and temperature, hyporeflexia) and/or autonomic (postural hypotension, excessive sweating, gastroesophageal reflux) dysfunction [1], which is why the term hereditary sensory and autonomic neuropathy (HSAN) is often used [1]. Chronic skin ulcers, spontaneous fractures, and neuropathic arthropathy necessitating amputations are constitutive parts of the clinical presentation as well [2]. The diagnosis is primarily made by obtaining a thorough patient history and a detailed physical examination, but a unique feature of almost all types is an abnormally reduced axonal flare after intradermal injection of histamine phosphate [1]. Genetic tests are not readily available and treatment is mainly supportive.

Hereditary sensory neuropathy (HSN) is a disorder characterized by degeneration of neurons that regulate sensory input, such as temperature and pain, and autonomic functions, including blood pressure regulation and activity of the gastrointestinal system. So far, seven types have been described in the literature, with five caused by genetic mutations that are inherited by children from their parents. The clinical presentation starts from birth, with main signs being swallowing difficulties, a reduced sense of pain and temperature perception leading to severe unintentional injuries and fractures, blood pressure changes, skin and corneal ulcerations, but also behavioral changes in the form of irritability and rage. The diagnosis is primarily made based on clinical signs and symptoms, whereas treatment mainly consists of supportive care, as there is no cure for any of the recognized subtypes. Genetic counseling is recommended for parents with a positive family history for HSN, as the condition profoundly impacts the quality of life of patients and their families.

1. Axelrod FB, Gold-von Simson G. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet J Rare Dis. 2007;2:39.
2. Auer-Grumbach M, Mauko B, Auer-Grumbach P, Pieber TR. Molecular genetics of hereditary sensory neuropathies. Neuromolecular Med. 2006;8(1-2):147-158.
3. Lee MJ, Stephenson DA, Groves MJ, Sweeney MG, Davis MB, An SF, et al. Hereditary sensory neuropathy is caused by a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4) gene. Hum Mol Genet. 2003;12(15):1917-1925.
4. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.