Table 4.

Disorders of Interest in the Differential Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2)

GeneHSAN ClassificationMOITypical Age at OnsetClinical (Distinguishing) FeaturesReference
ATL1 HSAN1ADAdulthoodPainless ulcers, fractures; involvement of upper motor neurons describedSee HSN1D or allelic Spastic Paraplegia 3A.
ATL3 HSAN1ADAdulthoodPainless ulcers, fractures; spasticity in some persons; severely delayed wound healing; multiple fractures of foot skeletonOMIM 615632
CLTCL1 Not classifiedARCongenitalCIP, inability to feel touch, IDOMIM 601273
DNMT1 HSAN1ADAdulthoodLoss of pain, ulcers; sensorineural hearing loss, progressive dementia, sensory ataxia DNMT1-Related Disorder
DST HSAN6ARCongenitalAutonomic involvement; alacrimia, feeding difficulties, contractures, hypomimia, severeDD/IDOMIM 614653
ELP1 HSAN3ARCongenitalPredominant autonomic neuropathy; alacrimia, gastrointestinal dysfunction, vomiting, cardiovascular instability, blood pressure fluctuations, autonomic crises, scoliosis Familial Dysautonomia
FAAHP1 (FAAH-OUT)CIPAD
AR		CongenitalPain insensitivity & impaired anxietyOMIM 618377
FLVCR1 ARCongenitalPainless injuries, psychomotor delay, anemia Chiabrando et al [2016]
NGF HSAN5ARCongenitalSee phenotype of HSAN4. Congenital Insensitivity to Pain Overview
NTRK1 HSAN4ARCongenitalCIP w/anhidrosis, self-mutilations (biting the tongue, biting of fingertips), fever episodes (lack of sweat gland innervation), painless fractures, variable degree of ID, corneal lesions NTRK1 Congenital Insensitivity to Pain with Anhidrosis
PRDM12 HSAN8ARCongenitalPain insensitivity, facial injuries, sweating usually preserved, ID less common Congenital Insensitivity to Pain Overview
RAB7A ADAdulthoodStrong motor involvement, also classified as CMT2B Charcot-Marie-Tooth Hereditary Neuropathy Overview
SCN11A CIP/HSAN7ADCongenitalPredilection for skin ulcers to cervical region, pruritus, intestinal dysmotility, delayed motor development, joint hypermobility Congenital Insensitivity to Pain Overview
SPTLC1 HSAN1ADAdulthoodLoss of pain (may be assoc w/lancinating pain); ulcerations, mutilations, mild motor involvement (may be pronounced in some persons) SPTLC1-Related Hereditary Sensory Neuropathy
SPTLC2 HSAN1ADAdulthoodSimilar to SPTLC1-HSNOMIM 613640
ZFHX2 CIPADChildhoodHyposensitivity to painful thermal & capsaicin stimulation & painless injuries Congenital Insensitivity to Pain Overview

Adapted from Cox et al [2020], Table 1.

AD = autosomal dominant; AR = autosomal recessive; CIP = congenital insensitivity to pain; CMT = Charcot-Marie-Tooth hereditary neuropathy; DD = developmental delay; HSAN = hereditary sensory and autonomic neuropathy; HSN = hereditary sensory neuropathy; ID = intellectual disability; MOI = mode of inheritance

From: Hereditary Sensory and Autonomic Neuropathy Type II

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