Hereditary Sensory and Autonomic Neuropathies (HSAN)

A family of Mendelian disorders of peripheral sensory and autonomic neurons, ranging from the adult-onset dominant forms (HSAN1) to the congenital recessive forms (HSAN2 to HSAN9), and including familial dysautonomia (HSAN III), congenital insensitivity to pain with anhidrosis (HSAN IV), and the channelopathy-related congenital insensitivities to pain.

Literature and regulatory information updated: 18 October 2026.

0. Reference Summary Table

The hereditary sensory and autonomic neuropathies (HSAN; also HSN, hereditary sensory neuropathies, when autonomic involvement is mild) form a clinical group (ORPHA:140471) of disorders dominated by loss of nociceptors, of thinly myelinated Aδ and unmyelinated C fibres and, to a variable degree, of sympathetic and parasympathetic neurons [1, 2]. Congenital insensitivity to pain (CIP) shares with the congenital HSAN the absence of nociception from birth and is covered in this article, because the genes NTRK1, NGF, SCN9A, SCN11A, and PRDM12 cause forms that are classified both as HSAN and as CIP [3]. The first table gathers the identifiers and the second the core clinical data; in them, AD denotes autosomal dominant inheritance, AR autosomal recessive, and XL X-linked; CNV denotes copy-number variation, GORD gastro-oesophageal reflux disease, CMT Charcot-Marie-Tooth disease, CANVAS cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, ADCA-DN autosomal dominant cerebellar ataxia, deafness, and narcolepsy, and SPG3A hereditary spastic paraplegia type 3A. The European Reference Network (ERN) responsible for all of these entities is EURO-NMD (European Reference Network for Rare Neuromuscular Diseases), through its peripheral nerve disease group [4].

Sources for the first table: GeneReviews and GeneGuidance for OMIM numbers and inheritance, NCBI Gene for cytobands, and Orphanet for ORPHA codes (HSAN VI maps to ORPHA:314381; ORPHA:412181 corresponds to epidermolysis bullosa simplex due to BP230 deficiency, also caused by DST) [2, 3, 5–29].

1. Introduction

1.1. From clinical descriptions to the Dyck classification

The term "hereditary sensory neuropathy" was first used by Hicks in 1922 for an English family in which ten members had perforating foot ulcers, lancinating pains resembling the lightning pains of tabes dorsalis, and progressive deafness, with onset between ages 15 and 36; the usual presentation was a callus on the great toe followed by a painless ulcer discharging bone fragments [5, 29]. Other families from southern England, studied by Ellison in Edinburgh and by Campbell and Hoffman in 1964, showed motor involvement, and the Australian families described by Jackson in 1949 and followed by Wallace share with the English families a common ancestor who, according to historical records, lived in southern England before 1800 [5, 29]. The congenital recessive forms received descriptive names that still appear in older records: Morvan disease, congenital sensory neuropathy, neurogenic acro-osteolysis (Giaccai, 1952), and hereditary sensory radicular neuropathy [2, 36]. The Newfoundland family described by Ogryzlo in 1946, with numbness of the hands and feet made worse by cold since childhood, would become the index family for HSAN2A [36].

In 1949, Riley and Day described five Jewish children with central autonomic dysfunction and deficient lacrimation, accompanied by episodic hypertension, hyperhidrosis, cyclic vomiting, and skin blotching; Smith and Dancis noted in 1963 the absence of an axon flare after intradermal histamine, and Smith and colleagues in 1965 the absence of fungiform papillae on the tongue [37, 38]. The review of 210 children from 172 families by Brunt and McKusick in 1970 established familial dysautonomia as an autosomal recessive disease almost exclusive to people of Ashkenazi Jewish ancestry [38]. Congenital insensitivity to pain with anhidrosis was described by Swanson and colleagues in 1963 in two brothers whose sweat glands looked normal on biopsy; one of them died after a 24-hour illness in which his temperature reached 109 °F, and autopsy showed almost complete absence of the first-order afferent system responsible for pain and temperature [39]. The first description of congenital analgesia is attributed to Dearborn in 1932, in a man who performed as a "human pincushion" [40].

Dyck proposed a five-type classification based on clinical findings and nerve biopsy: HSAN I, dominant with adult onset; HSAN II, recessive with congenital or early onset; HSAN III (familial dysautonomia); HSAN IV (CIPA); and HSAN V, with selective loss of small myelinated fibres [2, 41]. In 1983, Dyck and colleagues argued that congenital "indifference" to pain, without histologic nerve abnormalities, was distinct from "insensitivity," with demonstrable nerve pathology, and that many older cases of indifference were probably HSAN [40]. The genetic heterogeneity uncovered from 2001 onward led to a gene-based classification that added types VI to IX and the channelopathy-associated CIPs [2, 42].

1.2. Milestones of molecular discovery

1.3. Nomenclature and reclassification

Several names have changed, and they need to be known in order to read the literature. The designation HSN1 was replaced by HSN1A in 2011, when other dominant genes were recognised [5]. GeneReviews notes that HSN and HSAN are not ideal terms for SPTLC1-related disease, which is a length-dependent axonal sensorimotor neuropathy, strictly a form of CMT2 with prominent loss of pain fibres; the name HSAN1A is retained despite the rarity of visceral autonomic signs [5]. HSAN1B (OMIM 608088), defined by chronic cough and gastro-oesophageal reflux, carries an OMIM note reclassifying the phenotype as CANVAS (OMIM 614575) [12, 29]. Spastic paraplegia SPG49 was reclassified as HSAN IX when the patient series showed that the core feature is sensory and autonomic neuropathy [8]. CIPA has been called "familial dysautonomia type II" and "congenital sensory neuropathy with anhidrosis" [7, 39]. Cox and colleagues proposed "channelopathy-associated insensitivity to pain" for the SCN9A form, because it is a nociceptor defect not detectable on routine histopathology [40]. The IKBKAP gene is now named ELP1, and FAM134B is now RETREG1 [2, 6].

1.4. Definitions of the entities in scope

HSAN1 is a group of slowly progressive autosomal dominant neuropathies of juvenile or adult onset, with predominantly distal sensory loss, ulcers, and mutilation, and variable motor and autonomic involvement; it includes the forms caused by SPTLC1 (1A), SPTLC2 (1C), ATL1 (1D), DNMT1 (1E), and ATL3 (1F) [5, 11]. HSAN2 is an autosomal recessive group with congenital onset or onset in the first two decades and profound loss of all sensory modalities, caused by WNK1 (2A), RETREG1 (2B), KIF1A (2C), and SCN9A (2D) [2, 13]. Familial dysautonomia (HSAN III) is an autosomal recessive disorder of the development and survival of sensory, sympathetic, and parasympathetic neurons, present from birth and with progressive degeneration, caused by ELP1 [6, 14]. CIPA (HSAN IV) is congenital insensitivity to all pain with anhidrosis and intellectual disability, due to biallelic loss of NTRK1 [7]. HSAN V, caused by NGF, is the selective or generalised loss of pain and thermal sensation, with normal intellect and sweating in the missense forms and a picture overlapping with CIPA in the null forms [16, 32]. HSAN VI (DST) combines infantile hypotonia, autonomic failure, and loss of pain sensation, with lethal neonatal forms and adult forms [17, 64]. HSAN VII (SCN11A) is an autosomal dominant CIP due to Nav1.9 gain of function, with intestinal dysmotility and hyperhidrosis [18, 65]. HSAN VIII (PRDM12) is an autosomal recessive CIP with corneal anaesthesia [19, 66]. HSAN IX (TECPR2) is a sensory and autonomic neuropathy with intellectual disability, central hypoventilation, and aspiration [8, 20]. SCN9A-related CIP is the complete congenital absence of nociception with anosmia and preservation of other modalities [3, 22]. CMT2B (RAB7A) and SPG3A (ATL1) are included only as allelic or differential disorders.

2. Molecular Genetics and Pathophysiology

2.1. Common principles

All causes of CIP affect nociceptors, either because they are present but do not function or because their neurodevelopment fails [3]. This principle organises the group into three mechanisms. In the first, neurodevelopmental, lack of trophic signalling or of lineage specification prevents the formation of nociceptive and sympathetic neurons (NTRK1, NGF, PRDM12, and in part ELP1); the deficit is congenital and, in the NGF-TrkA forms, complete and nonprogressive [7, 67, 68]. In the second, channelopathic, nociceptors are present but do not fire: loss of function of Nav1.7 (SCN9A) or sustained depolarisation due to gain of function of Nav1.9 (SCN11A) [34, 69]. In the third, length-dependent axonal degeneration, metabolic toxicity (deoxysphingolipids) and disturbances of the endoplasmic reticulum (atlastins, RETREG1), axonal transport (KIF1A, DST), or autophagy (TECPR2) cause progressive fibre loss [2, 8, 70]. The clinical picture mirrors the mechanism: the developmental forms are present from birth and do not progress, whereas the degenerative forms begin later and worsen.

2.2. Dominant HSAN1

2.2.1. SPTLC1 and SPTLC2: neurotoxic deoxysphingolipids

The SPTLC1 gene (9q22.31; OMIM 605712) encodes subunit 1 of serine palmitoyltransferase (SPT), a 473-amino-acid protein; the longest transcript has 15 exons [5]. SPT catalyses the condensation of L-serine with palmitoyl-CoA, the rate-limiting step of de novo sphingolipid synthesis; SPTLC1 pairs with SPTLC2 or SPTLC3 in the catalytic core, the SPTSSA and SPTSSB subunits determine acyl-CoA preference, and the complex is inhibited by the ORMDL proteins [71]. Only certain specific missense variants cause HSAN1: they alter substrate specificity so that the enzyme uses L-alanine or glycine, forming 1-deoxysphinganine and 1-deoxymethylsphinganine and the corresponding 1-deoxyceramides, which, lacking the C1 hydroxyl group, can be neither converted into complex sphingolipids nor degraded [53, 70]. These bases are neurotoxic to sensory neurites in culture and are elevated in the plasma of patients with different variants, which defines a gain-of-function mechanism [53]. In cells, the mutant C133W protein retained 10% to 20% of total activity, with the same affinity for serine but a lower Vmax and preferential condensation with alanine [29]. Overexpression of the normal allele reversed the phenotype in a mouse model [5].

In SPTLC2 (14q24.3; OMIM 605713), screening of 78 HSAN patients found three heterozygous missense variants in four families with typical HSAN-I, with accumulation of 1-deoxysphinganine; no variant was found in SPTLC3 [54]. SPTLC2 causes two dominant disorders with opposite mechanisms: HSAN1C, with altered substrate specificity, and childhood-onset amyotrophic lateral sclerosis (ALS), in which recurrent de novo variants, chiefly NM_004863.4:c.778G>A p.(Glu260Lys), escape feedback inhibition and produce an excess of canonical sphingolipids, with elevated ceramides in plasma and fibroblasts [72, 73]. The same is true of SPTLC1: four dominant variants in seven families with childhood ALS deregulate ORMDL inhibition and increase canonical sphingolipids [74]. This opposition has therapeutic consequences, because the rationale for serine supplementation applies only to variants that produce deoxysphingolipids; in the ALS variants, serine has no rationale and may worsen the excess of canonical sphingolipids [72].

The HSAN1A variants of SPTLC1, normalised to the MANE Select transcript, are NM_006415.4:c.399T>G p.(Cys133Trp), the most common, present in English and Canadian families and in US and Australian families of English origin; c.398G>A p.(Cys133Tyr), in two families of Austrian and German origin; c.431T>A p.(Val144Asp), in two Australian families of English and Scottish origin; and the codon 331 variants, c.992C>A p.(Ser331Tyr) and c.992C>T p.(Ser331Phe) [5, 73]. The c.1160G>C p.(Gly387Ala) variant (rs119482084), described in two Belgian sisters, has been observed in the general population and in the homozygous state in an unaffected woman, does not alter SPT activity, and is now considered likely benign [5, 29]. The functional analysis of 11 SPTLC1 missense variants by Bode and colleagues in 2016 found no loss of activity in any of them, and four, including V144D, did not increase deoxysphingolipids, which led the authors to question their pathogenicity; this discrepancy with the original description means that the classification of each missense variant must be interpreted in light of functional data [29].

2.2.2. ATL1 and ATL3: atlastins and the endoplasmic reticulum

Atlastin-1 (ATL1, 14q22.1) is a dynamin-family GTPase that fuses endoplasmic reticulum (ER) membranes and forms three-way junctions; the HSN1D variant NM_015915.5:c.1065C>A p.(Asn355Lys) reduces GTPase activity and disorganises the ER [73, 75]. Its discovery by sequencing a 14.3-Mb interval on 14q, with two additional dominant variants among 115 patients with HSN I, showed that HSN I and SPG3A are allelic [56]. Atlastin-3 (ATL3, 11q13.1) causes HSN1F; the recurrent variant NM_015459.5:c.575A>G p.(Tyr192Cys), found in two independent families with complete penetrance, has a dominant-negative effect on the tubular ER network [61, 73]. The mutants retain GTPase activity but fail to complete fusion, causing aberrant ER tethering and altered ER–mitochondria contacts [30]. An Alu-mediated 3-kb deletion of exons 11 and 12 has been described, and ClinVar lists 301 variants of uncertain significance (VUS) versus 8 pathogenic variants in ATL3, which calls for caution with novel missense variants and justifies CNV analysis when sequencing is negative [30].

2.2.3. DNMT1: targeting domain and methylation

DNMT1 (19p13.2) is the sole maintenance DNA methyltransferase. All pathogenic variants lie in the replication foci targeting sequence (TS) domain of the N-terminal regulatory region: those causing HSN1E in the N-terminal or middle portion of the domain, and those causing ADCA-DN in the C-terminal portion [9]. The mechanism combines global hypomethylation with local hypermethylation, with a possible toxic gain of function due to misfolding of the TS domain; penetrance is 100% in both sexes, with variable age at onset and progression [9, 57]. The founder variants of this entity were described as c.1484A>G p.(Tyr495Cys), in two American families and one Japanese family, and c.1470-1472TCC>ATA p.(Asp490Glu-Pro491Tyr), in a European family, in the notation of the original article [57].

2.3. Recessive HSAN2

2.3.1. WNK1 and the HSN2 exon: a matter of nomenclature

WNK1 (12p13.33) encodes a serine/threonine kinase with multiple isoforms. In 2004, Lafreniere and colleagues mapped HSAN2 in two large Newfoundland pedigrees (LOD 8.4) to a 1.06-Mb interval and described a single-exon "HSN2" gene within intron 8 of WNK1, with three truncating variants in five families from Newfoundland, rural Quebec, and Nova Scotia [48]. A variant in the same exon was also described in a consanguineous Lebanese family [76]. In 2008, Shekarabi and colleagues showed that "HSN2" is in fact an alternative, nervous system–specific exon of a WNK1 isoform expressed in sensory neurons, satellite cells, and Schwann cells [51]. Most HSAN2A variants are frameshift or nonsense variants in that exon; biallelic null variants affecting all isoforms are presumably embryonic lethal, and when only one variant is found in the HSN2 exon, all exons should be sequenced [2].

This history has a practical consequence for reading reports. The HSN2 exon (exon 10 of the isoform described in GeneReviews) does not exist in the WNK1 MANE Select transcript, NM_018979.4; a variant in that exon appears, when described on the MANE transcript, as deep intronic [73]. For example, NM_213655.5:c.2952del p.(Glu984AspfsTer10), on the neural isoform, corresponds to NM_018979.4:c.2140-2842del, and NM_213655.5:c.3301C>T p.(Gln1101Ter) corresponds to NM_018979.4:c.2140-2493C>T [73]. The report should therefore give the variant on the isoform containing the HSN2 exon (NM_213655.5) together with the MANE equivalent, so that a pathogenic variant is not filtered out as intronic. The older aliases derive from the numbering of the putative HSN2 gene, whose first codon lay 12 amino acids 3′ of the initially presumed methionine: 594delA corresponds to c.2952del p.(Glu984AspfsTer10); 918_919insA (918insA) to c.3276dup p.(Ser1093IlefsTer13); 943C>T (Q315X) to c.3301C>T p.(Gln1101Ter); and the Japanese founder variant is c.3492dup p.(Asp1165Ter) [2, 73]. GeneReviews groups the first three among the French Canadian variants; in southern Quebec, Roddier and colleagues identified two founder variants in 16 patients from 13 families, Q315X (56% of patients homozygous) and 918insA (6% homozygous), with the remaining 38% compound heterozygous for both [2, 36].

The same gene causes autosomal dominant pseudohypoaldosteronism type II (PHA2C, familial hyperkalemic hypertension) through gain of WNK1 activity in the distal nephron, with 41-kb and 21-kb deletions in intron 1 in the original families [77]. HSAN2 variants truncate only the neural isoform and are not associated with hypertension, because expression of the isoform lacking the HSN2 exon is unaffected; the management of the two diseases should not be confused [2, 36].

2.3.2. RETREG1, KIF1A, and SCN9A

Saudubray classifies these two entities among the disorders of cellular trafficking: KIF1A among the cytoskeletal disorders and RETREG1 (FAM134B) among the Golgipathies [78]. RETREG1 (FAM134B, 5p15.1) encodes reticulophagy regulator 1; in 2009 Kurth and colleagues described loss-of-function variants in this cis-Golgi protein in patients with HSAN II, and its knockdown induces apoptosis in dorsal root ganglion neurons [2, 52]. No other RETREG1 phenotypes are known [2].

KIF1A (2q37.3) encodes a plus-end–directed microtubule motor required for anterograde axonal transport of synaptic vesicle precursors and dense-core vesicles [79]. The protein interacts with the domain encoded by the WNK1 HSN2 exon, and HSAN2C variants, almost restricted to an alternatively spliced exon, were described in a consanguineous Afghan family and in three families among 112 patients with ulcero-mutilating neuropathies [55]. Within the spectrum of KIF1A-associated neurological disorders (KAND), HSAN accounts for about 3% of cases, with biallelic variants that include at least one frameshift in alternative exon 25b; HSAN and ALS variants cluster in the tail domain, whereas those causing neurodevelopmental disorder (KIF1A-NDD) and the pure form (SPG30, dystonia, neuropathy) lie in the motor domain [80].

SCN9A (2q24.3; OMIM 603415) encodes Nav1.7, a 1,977-amino-acid alpha subunit with four domains of six transmembrane segments each, which generates a rapidly inactivating, tetrodotoxin-sensitive sodium current and is expressed mainly in dorsal root ganglion and sympathetic neurons [69]. Nav1.7 mediates the depolarisation phase of the action potential and controls nociceptor excitability [81]. The allelic spectrum is a mirror image: heterozygous gain-of-function variants cause dominant neuropathic pain syndromes (primary erythromelalgia, paroxysmal extreme pain disorder, and small fibre neuropathy), whereas biallelic loss of function causes CIP and HSAN2D [69]. Cox and colleagues showed in 2006 that three homozygous truncating variants abolish the current, establishing Nav1.7 as an essential, non-redundant requirement for human nociception [50]. In the published designation (NM_002977 numbering), these are two nonsense variants, S459X and W897X, and a 1 bp deletion, c.2298delT (“I767X”), which creates an immediate stop codon; on the MANE transcript they correspond to NM_001365536.1:c.1376C>G p.(Ser459Ter), NM_001365536.1:c.2724G>A p.(Trp908Ter), and NM_001365536.1:c.2331del p.(Ala777_Ile778insTer) [82]. The association of SCN9A with monogenic epilepsies, including generalised epilepsy with febrile seizures plus (GEFS+), was not confirmed in a 2020 study and should not be presented as established [81].

2.4. Familial dysautonomia: ELP1 and tissue-specific splicing

ELP1 (9q31.3; OMIM 603722) encodes one of the six subunits of the Elongator complex, which facilitates transcriptional elongation and is required for efficient translation [6]. Because of Elongator's role in transfer RNA modification, Saudubray classifies familial dysautonomia among the disorders of transfer RNA metabolism and processing, with gastrointestinal dysfunction, orthostatic hypotension, hypertensive crises, alacrima, and absent fungiform papillae [83]. During embryogenesis it is expressed first in the central and peripheral nervous system and the gut, then in secretory tissues and cartilage, and finally in muscle; expression is most prominent in the nervous system and retina, and complete absence of ELP1 is embryonic lethal owing to failure of vasculogenesis and neurulation [6]. The founder variant NM_003640.5:c.2204+6T>C (IVS20+6T>C) alters the exon 20 donor site; skipping of exon 20 causes a frameshift and a premature stop codon in exon 21, but the aberrant splicing is tissue-specific: normal mRNA predominates in lymphoblasts, whereas only the deleted message is found in the brain [6, 46]. This splicing mosaicism explains the neurological predominance of the disease and the response to splicing modulators in models [38].

Mapping in 1993 (LOD 21.1 at 9q31-q33) and haplotype analysis in 1999 showed a major haplotype shared by 435 of 441 FD chromosomes, evidence of a strong founder effect [38]. The minor haplotype corresponds to the exon 19 missense variant NM_003640.5:c.2087G>C p.(Arg696Pro), which alters a protein phosphorylation site; it is extremely rare among Ashkenazi Jews and has never been detected in the homozygous state, so the homozygous phenotype is unknown [6, 46, 47, 73]. The founder variant accounts for more than 99.5% of pathogenic variants among Ashkenazi Jews; GeneReviews gives >99% in the methods table and >99.5% in the variants table, a difference due to the denominator used [6]. In 2003, Leyne and colleagues identified three rare variants in non-Jewish patients, one of whom had a mother of Irish-German and Sicilian ancestry, which removed Ashkenazi ancestry from the status of a diagnostic criterion [6, 38]. No genotype–phenotype correlations have been established [6].

Pathology shows that the disease begins before birth: the dorsal root ganglia show marked neuronal depletion in young patients, which continues with age, reaching 10% of the neuronal count of controls in the C8 ganglion; in adults, the volume of the superior cervical ganglion is reduced to 34% of normal and the preganglionic neurons of the first three thoracic segments to about half [38]. Sural nerve biopsy shows a reduction in myelinated fibres, especially small ones, and very few unmyelinated fibres, with no catecholaminergic endings on the accompanying arteries [38]. Failure of the afferent limb of the baroreflex prevents restraint of sympathetic outflow: during sympathetic activation, dopamine spills over into the circulation and acts on the chemoreceptor trigger zone of the area postrema, outside the blood–brain barrier, which provides the rationale for carbidopa [84].

2.5. CIPA and HSAN V: the NGF-TrkA pathway

NTRK1 (1q23.1; OMIM 191315) encodes TrkA, the high-affinity receptor tyrosine kinase for nerve growth factor (NGF) [7]. Biallelic loss of function abolishes dimerisation, autophosphorylation, and recruitment of SHC1, FRS2, SH2B1, and PLCG1, switching off the Ras-MAPK, PI3K-AKT, and PLCG1/NF-κB cascades; in the absence of signalling, TrkA actively promotes cell death [67]. During developmental apoptosis, NGF-dependent neurons are lost: postganglionic sympathetic neurons and small-diameter primary afferents (Aδ and C fibres), as well as NGF-dependent neurons in the central nervous system involved in pain, itch, inflammation, interoception, and the stress response [7]. The absence of pain and temperature perception results from the lack of dorsal root ganglion afferents; anhidrosis from the lack of sympathetic innervation of the sweat glands, which are present; and intellectual disability and behavioural abnormalities probably from central neuronal loss [7, 67]. Touch, vibration, and position sense, carried by large myelinated fibres, are preserved, and the deficit is complete and nonprogressive [67]. Skin biopsy shows an epidermis devoid of nerve endings and absence of autonomic fibres around sweat glands and hair follicles, without degenerative changes, pointing to a defect of nerve growth rather than a degenerative neuropathy [39].

Notable NTRK1 variants, normalised to the MANE Select transcript NM_002529.4, are c.1860_1861insT p.(Pro621SerfsTer12), a founder variant among Israeli Bedouins, in whom it accounts for 89% of pathogenic variants; c.1660del p.(Arg554GlyfsTer104), c.2020G>T p.(Asp674Tyr), and c.851-33T>A, frequent in Japan; c.287+2dup, with exon 2 skipping, in Korean and Chinese families; and c.1633-1G>T, with exon 14 skipping, a founder variant in the Turkish population [7, 73]. GeneReviews writes "p.Pro621SerfsTer21" in the prevalence section and "Ter12" in the variants table; validation in VariantValidator confirms p.(Pro621SerfsTer12) [7, 73]. Two variants common in Asia, c.851-33T>A and the allele with two intronic changes in cis, NM_002529.4:c.[851-798C>T;851-794C>G], are deep intronic, fall outside the region usually analysed by exon sequencing, and require an explicit request [7, 73]. The GeneReviews notation for the latter allele uses an underscore where a hyphen should be [73]. Intragenic deletions have been described in several Chinese families, and a 1.3-kb intragenic deletion was found in the 2023 international cohort [7, 85]. GeneReviews is not aware of other germline NTRK1 phenotypes; somatic NTRK1 fusions in tumours and familial medullary thyroid carcinoma are distinct entities [7, 67]. The TRK inhibitors used in NTRK fusion–positive tumours act in the opposite direction to what would be needed and have no place in these diseases [67].

NGF (1p13.2) is the ligand of TrkA, and the severity of HSAN V tracks residual function [32]. The northern Swedish family is homozygous for NM_002506.3:c.661C>T, described as p.Arg211Trp in the original article, in OMIM, and in GeneReviews; in VariantValidator and ClinVar (VCV000014045, "likely pathogenic") the protein change is p.(Arg221Trp), which is the correct designation [41, 49, 73, 86]. These patients have impaired deep pain and thermal sensation, Charcot joints, and normal intellect and sweating; some adult heterozygotes have mild to moderate joint problems and are not considered affected [3]. In a Bedouin family from the United Arab Emirates with five affected siblings, a homozygous null allele, described as c.680C>A with c.681_682del and giving rise to a V232fs precursor that is not secreted as mature NGF-β, causes complete insensitivity to pain, anhidrosis, mild intellectual disability, and an aged appearance, overlapping with CIPA [32, 41]. The two changes, validated separately, correspond to NM_002506.3:c.680C>A p.(Thr227Lys) and c.681_682del p.(Ala228LeufsTer43); the sources consulted describe a single allele, but the combined HGVS representation depends on the original article, which was not read [73]. At the mildest end, NM_002506.3:c.361C>T p.(Arg121Trp) affects the last residue of the proNGF furin cleavage motif and reduces production of mature NGF-β [32, 73]. NGF and NTRK1 thus form a single signalling spectrum, and clinically NGF-related and NTRK1-related CIPA cannot be reliably distinguished [7].

2.6. HSAN VI, VII, VIII, and IX

Dystonin (DST, 6p12.1) is a cytoskeletal linker protein with neuronal, muscle, and epithelial isoforms. Nonsense variants in the plakin domain, which affect all isoforms, cause HSAN VI, whereas those affecting only the coiled-coil domain of the epithelial isoform BPAG1-e cause epidermolysis bullosa simplex due to BP230 deficiency [33]. The neuronal isoforms maintain the microtubule network and dynein/dynactin retrograde axonal transport [33]. The original description was of four infants with a lethal familial dysautonomia–like sensory-autonomic neuropathy with contractures [58]. Italian families with onset in childhood or adulthood had compound heterozygous variants affecting only the neuronal isoform a2 (Manganelli 2017) or an isoform-specific N-terminal region (Fortugno 2019); the authors of the latter study propose that biallelic truncating variants of all isoforms cause the severe congenital disease, now also listed in OMIM as congenital myopathy 29 with contractures [64].

The Nav1.9 channel (SCN11A, 3p22.2) is a "threshold" channel expressed almost exclusively in dorsal root ganglion and trigeminal nociceptors, which contributes to the resting potential and amplifies subthreshold stimuli [34]. In HSAN VII, the de novo variant NM_001349253.2:c.2432T>C p.(Leu811Pro) makes the channel overactive at the resting potential: sustained depolarisation inactivates sodium channels and prevents action potentials, and the knock-in mouse reproduces the hypoalgesia and self-inflicted injuries [60, 73]. Other recurrent de novo variants are c.3904C>T p.(Leu1302Phe) and c.1187T>C p.(Leu396Pro), and recurrent variants may also be inherited [3, 73]. A milder gain of function, with hyperexcitability, causes familial episodic pain syndrome 3 (FEPS3), in two Chinese families [34]. Expression of SCN11A in nonpeptidergic unmyelinated neurons and the scratching behaviour of the carrier mouse explain the pruritus in these patients [65].

PRDM12 (9q34.12) is an epigenetic transcriptional regulator that specifies the nociceptive lineage from neural crest progenitors, activates NEUROD1, BRN3A, and ISL1, and represses non-nociceptive fates; it remains necessary in adulthood for nociceptor excitability [68]. Chen and colleagues found ten different homozygous variants in individuals with CIP from 11 families, including missense variants and expansions of the C-terminal polyalanine tract, which abolish histone-modifying potential [62, 66].

TECPR2 (14q32.31) encodes a large protein with an N-terminal WD domain, an unstructured central region, and a C-terminal TECPR domain with six repeats and an LC3-interacting region (LIR) motif, which interacts with ATG8 proteins and positively regulates autophagy [8, 10]. Patient fibroblasts have reduced SQSTM1 (p62) and LC3, especially LC3-II; the knockout mouse accumulates autophagosomes and has neuroaxonal dystrophy with spheroids in sensory pathways, and Spanish water dogs homozygous for p.Arg1337Trp have similar findings [8, 87]. The mechanism is loss of function; missense variants, almost half of those associated with the disease and clustered in the N- and C-terminal β-propeller repeat regions, are difficult to classify under ACMG/AMP criteria [8, 35]. The founder variants are NM_014844.5:c.3416del p.(Leu1139ArgfsTer75), among Bukharan Jews, and c.1319del p.(Leu440ArgfsTer19), among Ashkenazi Jews [8, 73]. GeneGuidance gives the cytoband as 14q32.33, but NCBI Gene and GeneReviews give 14q32.31, which is the correct location [10, 87].

2.7. Other congenital insensitivity to pain genes

CLTCL1 (22q11.21) causes a recessive CIP with severe intellectual disability, described in a single family [3, 88]. ZFHX2 causes autosomal dominant Marsili-type CIP, in an Italian family with six affected individuals across three generations, with hyposensitivity to noxious heat and painless fractures without peripheral neuropathy, due to the p.Arg1913Lys variant in the homeodomain; mice with the homologous variant or lacking the gene have impaired pain sensitivity [63]. The pseudogene FAAHP1 (FAAH-OUT) is associated with insensitivity to pain with reduced anxiety; FLVCR1 with painless injuries, psychomotor delay, and anaemia; CCT5 with mutilating sensory neuropathy with spastic paraplegia; and AIFM1 with X-linked HSAN with deafness, designated DFNX5 or AUNX1, in which childhood auditory neuropathy precedes distal sensory loss by years and which is allelic with X-linked Charcot-Marie-Tooth disease type 4 and combined oxidative phosphorylation deficiency type 6 [2, 25, 26]. In the 2023 international cohort, FLVCR1 accounted for six patients, the same number as WNK1, and the authors emphasise that ATL3, FLVCR1, and NGF are rarely recognised entities [85].

2.8. Variants normalised to the MANE Select transcript

All conversions below result from validation in VariantValidator (GRCh38) and, for NGF, also in ClinVar; none was done by hand [73, 86].

The SCN9A variant historically designated I848T is p.(Ile859Thr) on the MANE transcript, because NM_001365536.1 includes an alternative exon that shifts the downstream numbering; upstream variants (p.Ile234Thr, p.Ser241Thr, p.Val400Met) keep their numbers [73]. The variants from the Brazilian cohort, those in DNMT1, and the ATL1 variants from Guelly 2011 are given in the text in the numbering of the original articles.

2.9. Allelic disorders and opposing mechanisms

Sources: [2, 9, 29, 33, 34, 67, 69, 71, 72, 74, 75, 77, 80, 89].

The association of the SPTLC1 p.(Cys133Tyr) variant with macular telangiectasia type 2 was demonstrated in nine patients from two families and in one isolated case, and Saudubray notes the same association for SPT disorders [29, 70]. CMT2B, caused by RAB7A, was defined in three extended families and three additional patients, with marked distal weakness and atrophy and a high frequency of ulcers, infections, and amputations [89, 90].

2.10. Penetrance, expressivity, and genotype–phenotype correlations

In HSAN1A penetrance is variable, and variants at codon Ser331 are associated with a severe childhood-onset sensorimotor phenotype, with muscle atrophy including the tongue, hypotonia, growth failure, intellectual disability in some, cataracts, and laryngeal involvement, generally without the ulcers of the classic form [5]. A patient with a de novo p.Ser331Phe variant, of French Romani ethnicity, had congenital insensitivity to pain, vocal cord paralysis, microcephaly, and respiratory failure; another, with the same variant, developed cataract at age 9 and complete retinal detachment at age 10 [29]. A patient with p.Ser331Tyr was included in a juvenile ALS series; the sensory involvement and toxic sphingolipids suggest that this was a severe early-onset form of HSN [5]. In HSAN2 there are no clinically relevant correlations, with inter- and intrafamilial variability [2]. In CIPA the phenotype varies even with the same two variants [7]. In familial dysautonomia no correlations have been established [6]. In the DNMT1 spectrum, the position of the variant within the TS domain separates HSN1E from ADCA-DN, with complete penetrance [9]. Among SCN9A gain-of-function variants, those that shift activation further towards hyperpolarised potentials are associated with earlier onset [69]. The p.(Ile234Thr) variant combines typical erythromelalgia pain with painless CIP injuries in different parts of the body [69].

3. Clinical Spectrum and Manifestations by System

3.1. HSAN1 due to SPTLC1 and SPTLC2

SPTLC1-related disease is an axonal sensorimotor neuropathy with prominent early sensory loss, which usually goes unnoticed until painless injuries appear; onset ranges from adolescence to the 6th decade [5]. Numbness, paraesthesias, burning, and lancinating pains lasting seconds to minutes follow, distinctive but variable; a "burning feet" sensation, relieved by cold and made worse by heat, may be the only manifestation, and restless legs are another mode of presentation [5, 29]. Unrecognised sensory loss leads to chronic ulceration of the extremities, osteomyelitis, and distal amputations, and neuropathic joints are common [5]. According to Saudubray, onset is between the 2nd and 4th decades, with slow progression, loss of pain and temperature sensation spreading from the distal limbs, spontaneous attacks of lancinating pain, and hypohidrosis [70].

Weakness begins in the distal lower limbs, spreads to the distal upper limbs and, in severe cases, to the limb girdles; weakness of the ankle flexors produces a floppy "flipper" foot rather than pes cavus; distal weakness and atrophy are present in all advanced cases, some patients have severe early motor involvement, and older patients may need a wheelchair [5]. Some patients retain or have brisk proximal reflexes, suggesting upper motor neuron involvement, but autopsy has not shown corticospinal degeneration [5]. Sensorineural hearing loss is variable and begins in mid or late adulthood; tonic or pseudo–Argyll Robertson pupils are rare, and visceral autonomic signs are uncommon, with abdominal pain, diarrhoea, and weight loss described in a single family [5]. In a French family with linkage to 9q, the mean age at onset was 34 years, all had sensory loss and distal weakness in all four limbs, four had plantar ulcers, and three had hyperhidrosis [29]. The Ser331 forms have childhood onset, a severe sensorimotor phenotype, and extraneurological manifestations (section 2.10) [5, 29]. Macular telangiectasia type 2, with parafoveal telangiectasias and bull's-eye maculopathy, may occur in carriers of p.(Cys133Tyr) [29].

HSAN1C due to SPTLC2 is an ulcero-mutilating sensory axonal neuropathy with onset in adulthood or late childhood: it begins with loss of touch and vibration in the feet and dysaesthesia and progresses to severe panmodal loss in all four limbs, with painless injuries, chronic ulcers, osteomyelitis, Charcot joints, and sometimes amputation; distal motor and autonomic involvement is variable [72]. One family with p.(Ala182Pro) had onset in the 1st decade and marked motor involvement, and demyelinating features have been described [72].

The socioeconomic impact of HSN1 was studied in the United Kingdom through an anonymous 28-item survey sent to 50 genetically confirmed patients, with 37 responses (74%): only 24% worked full time, 24% had taken early medical retirement, 46% felt the disease had harmed their career, 49% had requested workplace adjustments, 41% had lost income, 21% spent more than 1,000 pounds a year on the disease, driving was affected in 48%, and more than half had reduced their social participation [91]. Almost half felt that health professionals do not know enough about the disease [91]. These are data from a pilot study with a convenience sample, not from a population cohort.

3.2. HSN1D, HSN1E, and HSN1F

HSN1D due to ATL1 is an adult-onset axonal neuropathy with prominent sensory loss, painless injuries, delayed healing, and osteomyelitis; in the index family, most adults had trophic changes and painless ulcers with amputation of toes, feet, or more proximal segments of the leg [75]. There is overlap with spastic paraplegia: younger individuals have increased tone and older ones patellar hyperreflexia, so the authors recommend screening ATL1 in HSN type I, especially when pyramidal signs are present [56, 75]. The allelic SPG3A is an autosomal dominant hereditary spastic paraplegia.

HSN1F due to ATL3 presents with distal sensory deficit in the 2nd–3rd decade and poorly healing painless plantar ulcers that lead to osteomyelitis, destruction of the foot skeleton, and amputation; the classic description includes no autonomic involvement, spasticity, or cognitive impairment, but two Iranian families with distal weakness, one patient with hearing problems, and one biopsy showing a demyelinating-remyelinating process were later described [30, 61]. By 2023, 11 patients had been reported [30].

DNMT1-related disease forms a spectrum between HSN1E and ADCA-DN. Moderate to severe sensorineural hearing loss (70–80 dB at 4,000 Hz) begins in adolescence or the early 20s; the sensory deficit begins in the 2nd decade, distally in the lower limbs, with minimal motor involvement; sudomotor dysfunction, with loss of distal sweating, is the only autonomic dysfunction; and dementia usually appears from the mid-40s, with cognitive, executive, and behavioural decline in which irritability and personality change may precede memory loss [9]. In a cohort of 45 patients, the mean age at onset was 37.7 years, and the first manifestation was hearing loss in 36%, sensory loss with ulcers or arthropathy in 33%, cognitive decline in 7%, and gait imbalance in 7%; about half had mutilating acropathy [9]. Gait ataxia is mainly sensory, narcolepsy with cataplexy may be prominent, and there are cases with visual hallucinations, myoclonic seizures, or renal failure; PET and SPECT show medial frontal and thalamic hypometabolism, and autopsy shows diffuse neuronal loss without amyloid, tau, or α-synuclein inclusions [9, 57]. The syndrome is typically fatal in the 5th–6th decade [24].

3.3. HSAN2 (WNK1, RETREG1, KIF1A, SCN9A)

HSAN2 is characterised by progressive reduction of pain, temperature, and touch sensation, with onset at birth or, in molecularly confirmed cases, typically in the first two decades; numbness of the hands and feet is progressive and predominantly distal, with the lower limbs more affected, and eventually severely reduces all sensory function [2]. Neuropathic skin produces excess keratin, and the hyperkeratosis may be pushed into deeper layers or fissure, giving rise to ulcers and infections with spontaneous or surgical amputation of digits; osteomyelitis is common, and secondary muscle atrophy, Charcot joints, and painless fractures develop [2]. In the Newfoundland and Quebec families, the loss is in a glove-and-stocking distribution, from the elbows to the fingertips and from above the knees to the toes, with touch more affected than pain [36]. Intellectual development is usually normal but may be impaired in the KIF1A forms; sweating and tearing are generally normal, with hyperhidrosis in some, and tonic pupils and urinary incontinence with progression [2]. Italian, Austrian, and Belgian patients with truncating WNK1 variants had early mutilating acropathy without autonomic dysfunction and with preserved strength [36].

Key (adapted from GeneReviews): +++ most common; ++ less common; + rare; − not observed [2]. The first three forms are clinically very similar; autonomic dysfunction is reportedly more marked with RETREG1 and distal weakness with KIF1A [2]. HSAN2D due to SCN9A was described in two Japanese siblings and in an unrelated Japanese patient: a 50-year-old man with loss of pain and temperature sensation since childhood, which spread to the proximal limbs after age 40, with hyposmia, anhidrosis, burns, and unilateral hearing loss; his 55-year-old sister, with recurrent fractures in childhood and bone dysplasia; and a 33-year-old man with digital ulcers, hyposmia, hearing loss, occasional incontinence, and reduced fungiform papillae [40]. The phenotype varies even within families, and vibration and position sense were preserved in all [40].

3.4. Familial dysautonomia (HSAN III)

3.4.1. Overview and natural history

Familial dysautonomia affects the development and survival of sensory, sympathetic, and parasympathetic neurons; it is present from birth, and neuronal degeneration progresses throughout life [6]. The picture combines gastrointestinal dysfunction, autonomic crises (hypertensive vomiting crises), recurrent pneumonia, altered pain and temperature sensation, cardiovascular instability, hypotonia with motor delay, optic neuropathy with progressive visual loss, and a worsening wide-based ataxic gait; about 21% have developmental delay or intellectual disability [6]. OMIM summarises that only half of patients reach age 40 [38]. The following table reproduces the distribution of manifestations according to GeneReviews, adapted from Axelrod 1996.

Source: [6].

3.4.2. Neonatal period and childhood

Most are born at term after an uncomplicated pregnancy, but polyhydramnios and breech presentation are more frequent [6]. In the newborn, oropharyngeal incoordination (neurogenic dysphagia) manifests as weak sucking and swallowing, and protective airway reflexes, including cough, are diminished or absent, with a very high risk of aspiration pneumonia soon after birth; there is also difficulty maintaining temperature and indifference to pain [6]. Neurogenic dysphagia is present in all patients and is usually the presenting neonatal manifestation [92]. Axelrod and colleagues suggested suspecting familial dysautonomia in a child of Eastern European Jewish ancestry with breech delivery, meconium, weak suck, hypotonia, or hypothermia [38]. Motor milestones, from an unpublished Sheba Medical Center database, fall between 12 and 18 months for sitting unsupported, 1 to 2 years for standing, and 2 to 3 years for independent walking [6]. Verbal skills are delayed during the first nine years and then fall within the normal range for age [6].

3.4.3. Cardiovascular system and dysautonomic crises

Afferent baroreflex failure produces orthostatic hypotension without compensatory tachycardia, made worse by exercise and heat, and supine hypertension, both progressive; syncope is surprisingly infrequent and, when it occurs, usually indicates volume depletion, anaemia, or hypoxia [6]. In a trial of 22 patients with labile blood pressure, baseline blood pressure peaks averaged 164/116 mmHg, ranging from 144/92 to 213/150 mmHg [93]. Adults accumulate worsening orthostatic hypotension, supine hypertension, and sometimes bradyarrhythmias [38]. Greater blood pressure variability in childhood is associated with faster progression to end-stage kidney disease [93].

Autonomic crises, in about 40% of patients, result from stimuli that increase sympathetic outflow and cause uncontrolled catecholamine release; common triggers are emotion, intercurrent illness, abdominal discomfort, and bladder distension, but some crises are unpredictable [6]. Dopamine activates receptors in the chemoreceptor trigger zone of the area postrema and causes cyclic vomiting, or retching after fundoplication, accompanied by tachycardia, hyperhidrosis, skin blotching, irritability, and personality changes; crises may last several days [6, 84]. Among the 12 patients in the 2013 carbidopa trial, all with fundoplication, there were on average three episodes of nausea and retching per day, with 1.7 ± 1.5 hours of nausea daily, despite benzodiazepines in all and clonidine in 11 [84]. In a retrospective cohort of 192 patients from a tertiary centre (1981–2020), more than one-third had more than four crises per year [94]. Seizures with decerebrate posturing may follow breath-holding spells [38].

3.4.4. Respiratory system and sudden death during sleep

The New York University (NYU) Familial Dysautonomia Patient Registry, prospective since 1970 and including 670 patients in 2016, documents upper airway obstruction in 83%, lower airway disease in 85%, and restrictive lung disease in 94% [92]. Patients have on average ten pneumonias over their lifetime, 85% have a gastrostomy, most with a Nissen fundoplication performed at the same time, chest CT shows bronchial wall thickening in 94% and bronchiectasis in 26%, 40% have chronic hypoxemia (PaO2 < 80 mmHg), and 16% daytime hypercapnia (PaCO2 ≥ 50 mmHg) [92]. Pulmonary function tests in 52 patients showed an obstructive pattern in 44% in addition to the restrictive pattern; in a small double-blind trial, half had obstruction reversible with a β-agonist and an anticholinergic [92]. Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, and Moraxella catarrhalis predominate in bronchoalveolar lavage, less often Pseudomonas aeruginosa, and 30% of cultures are negative [92].

Chemoreflex failure is the key to respiratory vulnerability. The ventilatory response to hypercapnia and acidosis, mediated by central chemoreceptors, is partially preserved, but the response to hypoxia, mediated by peripheral chemoreceptors, is almost absent; hypoxia may cause paradoxical hypotension, hypoventilation, bradycardia, and death, and rapid correction of hypoxemia with 100% oxygen causes prolonged apnoea [92]. Breath-holding spells with hypotension or syncope occur in 53% of children [92]. Sleep studies show obstructive and central apnoea in about half, a mean SpO2 nadir of 77%, and hypoventilation (peak end-tidal CO2 > 50 mmHg in children and > 55 mmHg in adults) in 60%; central apnoea is more frequent in children and obstructive apnoea in adults [6, 92]. Sleep-disordered breathing affects about 85% of adults; for children, the respiratory guideline gives 91% and Palma 2019 gives 95%, both citing the same Singh 2018 study [92, 95]. In 46% there is hypoventilation with hypercapnia without apnoeas, which justifies measuring end-tidal CO2 in every polysomnogram [95]. Acute exacerbations may involve marked hypoxemia and CO2 retention with few symptoms, little dyspnoea, and no compensatory tachycardia, and dysautonomic crises with vomiting may precede respiratory symptoms [92].

In the NYU Registry (670 patients, 327 alive, more than 99% homozygous for the founder variant, more than half living in the USA), the annual incidence of sudden unexpected death during sleep (SUDS) was 3.4 per 1,000 person-years, compared with 0.5–1 per 1,000 for sudden unexpected death in epilepsy; 32 patients with SUDS had undergone polysomnography in the preceding 18 months, the mean age at death was 29.3 ± 12.4 years, and six autopsies showed no structural cardiac pathology [95]. The independent risk factors for SUDS were fludrocortisone treatment, plasma potassium < 4 mEq/L, and untreated sleep apnoea; nocturnal noninvasive ventilation was associated with lower risk [95]. Scoliosis, in up to 90%, is typically hyperkyphotic and upper thoracic, worsens during adolescence and then stabilises, and, together with craniofacial dysmorphism, contributes to restrictive disease and upper airway obstruction [92].

3.4.5. Gastrointestinal tract, kidney, and bone

Oesophageal dysmotility and GORD are progressive [6]. In the same cohort of 192 patients (49% male, mean age at evaluation 25.3 years, range 1 to 59), 96.8% had gastrointestinal and 88.3% respiratory manifestations; the incidence of acute pancreatitis was 288.5 cases per 100,000 person-years, 8.5 times that of the general population, with no difference in classic risk factors, which led the authors to propose sphincter of Oddi dysfunction [94]. Chronic kidney disease is common and worsens with age: almost all who reach the 4th decade have a markedly reduced estimated glomerular filtration rate, some progress to dialysis, and kidney transplants have been performed; renal tubular acidosis and hyperkalemia, not always explained by renal failure, are frequent [6]. As early as 1980, glomerulosclerosis was described in patients studied at autopsy and biopsy, with no identifiable sympathetic endings in the renal vessels, and, in a review of 79 patients, elevated serum creatinine in 32% and elevated urea in 76%, with an association between hypotension and renal dysfunction [38]. Congenital renal malformations (solitary kidney, horseshoe kidney, crossed renal ectopia) are more frequent [6].

By age 20, 80% have some degree of spinal deformity [6]. In 41 patients with densitometry (2015–2023; median age at first scan, 25 years), the mean bone mineral density Z-score was −1.2 ± 1.5 at the lumbar spine and −1.3 ± 1.1 at the proximal femur, and the trabecular bone score Z-score was −1.8 ± 1.6; femoral density correlated with balance (r = 0.612), gait (r = 0.627), and ataxia (r = −0.470), and CTX was above the normal range for age in 67% [96]. Unrecognised fractures are possible because of indifference to pain [6].

3.4.6. Eye, motor function, cognition, growth, and reproduction

Recurrent corneal ulcers result from alacrima and corneal hypoaesthesia and sometimes leave permanent opacities [6]. The main cause of visual loss is optic neuropathy, which mainly affects P-type retinal ganglion cells, with axonal loss from an early age in all patients, greatest in the temporal nerve fibre layer; the accelerated damage continues until the 3rd decade and then stabilises, and visual impairment may progress to blindness, usually after the 3rd decade [6]. Strabismus is very common [6].

The wide-based ataxic gait is progressive, with difficulty in rapid movements and changes of direction; the need for walking assistance increases linearly with age: 3% at age 20, 14% at 30, 27% at 40, and 49% at 50 [6]. Cognitive function is variable, with learning and concentration difficulties being common; anxiety is the most frequent psychiatric problem, and skin and nail picking and trichotillomania occur in about 10% [6]. Dental trauma affects 60% (falls due to ataxia) and orodental self-mutilation 32%, from chewing the gums without noticing; the mandible is small, with retrognathia, malocclusion, and crowding [6].

Newborns are appropriate for gestational age, with normal head circumference, but stature falls well below the familial target: mean adult height is 158 cm in men and 150 cm in women, with low-normal IGF-I, delayed bone age, and inconclusive growth hormone (GH) stimulation tests [6]. Sexual maturation is often delayed, but sexual development is normal; women with the disease have had healthy children after uncomplicated pregnancies, and male fertility has been described, in a man with six children [6]. Stress urinary incontinence is common in adolescent and adult women, and episodic somnolence has been described [6].

3.5. CIPA due to NTRK1 (HSAN IV)

3.5.1. Anhidrosis and thermoregulation

Recurrent episodic fevers are usually the first sign, in infancy or early childhood, depending on the ambient temperature; some infants have recurrent febrile seizures, and hypothermia may occur in cold environments [7]. Anhidrosis of the trunk and upper limbs is present in 100% of cases and is more variable in other areas; intertriginous areas (neck, axillae, groin) may become slightly moist on warming, without definite sweating [7]. A Kuwaiti girl presented at 24 hours of life with fever that persisted for eight weeks, with recurrent febrile seizures and temperatures of 42 °C induced by ambient heat [39]. The Oxford Desk Reference reports death from hyperpyrexia in almost 20% of patients in the first three years of life, citing Schulman 2001 [97].

3.5.2. Pain, injuries, and self-mutilation

The absence of all pain, including visceral pain, leads to repeated injuries: oral self-mutilation (tongue, lips, buccal mucosa), biting of the fingertips, bruises, scars and skin infections, multiple fractures, many of which heal poorly, and recurrent joint dislocations with deformity [7]. Insensitivity may not be evident in early infancy, but parents recall the absence of crying during blood draws and vaccinations; tongue ulcers and finger biting begin with the eruption of the primary incisors and may lead to a bifid or absent tongue [7]. Taste buds are normal, but traumatic tongue injuries may cause secondary hypogeusia, and the reduced pain perception spares no area, including cranial nerve territories and visceral sensation [7]. Touch, vibration, position sense, motor function (barring trauma), and tendon, abdominal, and cremasteric reflexes are normal; hypotonia is common in the first years and normalises with age [7].

3.5.3. Orthopaedic complications

Orthopaedic complications are among the most characteristic and serious: multiple fractures, often with hyperplastic new bone formation, avascular necrosis, and osteomyelitis; autoamputation; limb length discrepancy; subluxation and dislocation with Charcot neuroarthropathy of the feet, ankles, knees, and hips; septic arthritis; progressive scoliosis; and amputations of digits or limbs [7]. The authors of the Latvian case cite skeletal complications in 65% of patients, 91% of fractures in the lower limbs, mostly between ages 1 and 7, and fractures that usually heal in three weeks taking six months or failing to heal [98]. In a retrospective series of four siblings (aged 3, 8, 12, and 21 years), the mean time to diagnosis was 53 months, and sports and global function, measured with the Pediatric Outcomes Data Collection Instrument, were significantly below normative values [99].

3.5.4. Eye

Neurotrophic keratitis begins as superficial punctate keratopathy and may progress to ulceration and perforation; reflex and emotional tearing is normal [7]. In 15 Bedouin children, all had absent corneal sensation, 10 (67%) had opacities, and 7 had active ulcers, which healed very slowly, some requiring lateral tarsorrhaphy, corneal grafting, or penetrating keratoplasty [39]. A 2025 systematic review (28 studies, 118 patients, mean age 7.37 years, 63.5% male) found an absent corneal reflex in 47.5% (always bilateral), corneal ulceration in 38.98%, and opacity in 27.11%, with 56 patients having bilateral manifestations; lubricants, topical antibiotics, and lateral tarsorrhaphy were the most commonly used treatments [100]. Pooled data from cases published in English are subject to publication bias, and the review excluded patients with previous eye surgery [100].

3.5.5. Cognition, behaviour, skin, infections, and blood

Most have intellectual disability of variable degree, with deficits in conceptual thinking, abstract reasoning, and social behaviour, moderate to severe emotional disturbance, and rage outbursts in some; many have severe attention-deficit/hyperactivity disorder (ADHD) [7]. Irritability, hyperactivity, impulsivity, and oppositional behaviour improve with age, and the prognosis for independent functioning is variable [7]. Cranial imaging may show mild loss of brain volume with some ventriculomegaly [97]. The skin is dry and lichenified, the nails dystrophic, and palmoplantar hyperkeratosis with fissures appears from late infancy, with deep, slowly healing heel ulcers [7]. Some patients have apparently selectively reduced immunity to S. aureus, with recurrent soft tissue infections, abscesses, and osteomyelitis; a Turkish patient with humoral immunodeficiency who responded to intravenous immunoglobulin has been described [3, 39]. In a retrospective cohort cited by the authors of the Latvian case, 48.5% of S. aureus strains were methicillin-resistant [98]. Chronic anaemia of unknown cause was present in 22 of 28 Israeli Bedouin patients [3]. Gastrointestinal dysmotility is mild or absent, and vomiting is not characteristic [7].

3.6. HSAN V due to NGF

In the northern Swedish family, severe loss of deep pain perception meant that patients did not feel fractures or joint damage, and heat perception was impaired; Charcot joint destruction began in childhood, but sweating and mental abilities were intact, and other relatives had a milder phenotype, with joint problems mainly in the feet and knees [41, 49]. Sural nerve biopsy in this family showed severe loss of unmyelinated fibres and moderate loss of small myelinated fibres, whereas the Orphanet definition describes reduced or absent small myelinated fibres with unmyelinated fibres usually spared, reflecting the heterogeneity of descriptions predating molecular genetics [16, 49]. In the Emirati Bedouin family, five siblings aged 2 to 12 years had biting of the lips, tongue, and fingers, inability to discriminate hot from cold or to detect spicy food, anhidrosis, mild intellectual disability evident by age 4, and, with age, a prematurely aged appearance with malar hypoplasia, deep-set eyes, and tooth loss [41]. Orphanet adds episodic rises in temperature, skin blotching, poor wound healing, dental, joint, and bone infections, and neurotrophic keratitis [16].

3.7. HSAN VI due to DST

The form described in 2012 is neonatal, with hypotonia, respiratory and feeding difficulties, absence of psychomotor development, labile cardiovascular function, absent corneal reflexes with scarring, areflexia, absent histamine flare, distal contractures, an immobile open-mouthed facies, and early death [6, 33, 58]. Orphanet describes a broader spectrum, with variable psychomotor delay, distal ulcers, painless fractures with amputation of digits, hypohidrosis, heat intolerance, chronic diarrhoea, pupillary abnormalities, urinary incontinence, and sensorineural hearing loss [17]. Among three adult Italian siblings, the index patient was seen at age 56 with plantar ulcers and painless fractures since age 26, persistent osteomyelitis, and disarticulations and amputations of toes; in another Italian family, three siblings had onset in childhood, normal development, reduced sweating with heat intolerance, chronic diarrhoea, and absent pupillary reflexes in two [64]. A 17-year-old Italian girl combined HSAN VI with recurrent blistering of the limbs and soles, GH deficiency, and lumbar osteoporosis [64].

3.8. HSAN VII due to SCN11A

The first two patients, a German girl and a Swedish boy, had insensitivity to pain from birth, self-mutilation, slowly healing wounds, multiple painless fractures, mild muscle weakness, motor delay, hyperhidrosis, and gastrointestinal dysfunction; sural nerve biopsy in one of them showed no axonal loss, and cognition was normal [60, 65]. The third patient, of Scottish ancestry, presented with failure to thrive due to intestinal dysmotility, with chronic constipation, mild hypotonia, ulcers mainly in the cervical region, and intolerance of moderate cold and heat, despite perceiving changes in temperature [65]. GeneReviews adds joint hypermobility, hypoperistalsis or diarrhoea, and pruritus, and severe pruritus, worse at night, was the dominant complaint of a woman with partial loss of pain [3, 65]. Hyperhidrosis, rather than anhidrosis, and pruritus point towards SCN11A [34].

3.9. HSAN VIII due to PRDM12

In a series of five adults (aged 23 to 57 years; four from the same consanguineous family), all had reduced tear production and an absent corneal reflex, with a greater risk of corneal injury, keratitis, and scarring than in any other form of CIP; two had no useful vision in one eye, and in one of them several corneal grafts failed [66]. Insensitivity was present from birth but was diagnosed only after age 3, and could be non-global, limited to the limbs and head; three had autoamputation of the tip of the tongue and three had fractures; intelligence and neurological examination were normal, with fine touch, pressure, vibration, itch, and tickle preserved, and crude temperature detection was retained, without recognition of noxious extremes [66]. Four of the five had normal sweating and thermoregulation, and none had Charcot joints, unlike patients with SCN9A or NTRK1, who, according to the authors, have at least one by mid-adolescence and several after age 20 [66]. S. aureus infections are frequent [3]. A 2-year-old Indian boy with a homozygous splice variant also had global developmental delay, dolichocephaly, frontal bossing, and deep-set eyes [3].

3.10. HSAN IX due to TECPR2

The disease combines developmental delay and intellectual disability, mostly moderate to severe, behavioural abnormalities, hypotonia, sensory neuropathy with hyporeflexia or areflexia and ataxic gait, and autonomic dysfunction with central hypoventilation, apnoea, gastrointestinal dysmotility, dysphagia, and GORD with recurrent aspiration [8]. The frequencies in GeneReviews, with the denominator of patients assessed for each feature, are shown in the table.

Source: [8].

Independent walking is delayed and apraxic-ataxic, with possible regression in the 2nd decade; speech is severely impaired and some patients are nonverbal [8]. In late childhood and adolescence, lower limb spasticity, dystonia, dyskinesia, rigidity, and crouch gait appear; epilepsy is uncommon [8]. Daytime and nocturnal central hypopnoea and apnoea, hypercapnia, dysphagia with aspiration and choking, temperature and blood pressure instability, hyperhidrosis, and electrolyte disturbances weigh on morbidity and mortality, and there are anecdotal reports of disproportionate depression of consciousness with intercurrent illness or antihistamines [8]. Respiratory infections begin in the 1st year, sometimes with laryngeal clefts or laryngomalacia, and progress to chronic lung disease with bronchiectasis [8]. Dysmorphic features include brachycephaly, synophrys, thick eyebrows, hypotelorism, epicanthus, a round or triangular face, a short neck with retrocollis, and dental crowding; kyphosis, scoliosis, and barrel chest appear in the 2nd decade [8]. In an international collaboration of 28 patients, the corpus callosum was thin in 52% of the MRI scans reviewed [35].

3.11. SCN9A-related CIP and other CIPs

SCN9A-related CIP causes an inability to perceive pain from birth for any noxious stimulus, including inflammation and heat; infants bite their fingertips and oral cavity, with loss of the tip of the tongue, damage to the teeth and gums, and tooth avulsion, and they sustain cuts, bruises, and burns [3]. They distinguish large temperature differences but do not feel that something is too hot or too cold [3]. In older individuals, painless fractures and joint damage are common, and Charcot joints, especially of the ankles, hips, and lumbar spine, are almost universal; Charcot spine may present with progressive deformity or new motor or sensory deficits [3]. Anosmia is complete, patients cannot detect body odour or rancid food, and the corneal reflex and tear production are normal [3, 40]. The Pakistani index case performed street shows with knives and burning coals and died at age 14 after jumping from a roof; all affected individuals had lip or tongue injuries from biting in the first four years of life [40]. Some patients with CIP have neuropathic pain, which does not limit activities, and emotional tears are present [3]. Many parents are suspected of child abuse [3].

CLTCL1-related CIP combines complete insensitivity to pain, absence of response to light touch, and severe nonprogressive cognitive delay, with normal strength and preserved perception of heat and cold [21]. Marsili-type CIP due to ZFHX2 is a non-global insensitivity (low back pain, headaches, and labour pain are perceived), with normal intellect, scant sweating, low sensitivity to capsaicin, fainting, and vomiting [3, 63]. The entity ORPHA:217399 combines congenital insensitivity to pain, hyperhidrosis, and absence of cutaneous sensory innervation, with no gene identified [101].

3.12. Clinically ascertained genetic cohorts

The largest molecularly solved international cohort of CIP and HSAN (a retrospective, cross-sectional study including patients from underrepresented countries and the Genomics England PanelApp pain syndromes panel) identified 80 novel pathogenic or likely pathogenic variants in 78 patients from 73 families, distributed across 12 genes: SCN9A (22 patients), NTRK1 (21), SPTLC2 (8), WNK1 (6), FLVCR1 (6), ATL3 (3), PRDM12 (3), DST (2), NGF (2), RAB7A (2), SPTLC1 (2), and KIF1A (1) [85]. Detailed clinical data were missing for some cases, and the distribution reflects referred patients, not population frequency [85]. The first Brazilian cohort of hereditary sensory neuropathies, with genome sequencing in 23 unrelated families, solved five families (21.7%; 12 patients): heterozygous ATL3 c.575A>G p.(Tyr192Cys) and SPTLC2 c.529A>G p.(Asn177Asp), with sensory deficits, neuropathic pain, and recurrent ulcers, and three unrelated probands with CIP due to biallelic SCN9A loss of function, with the combinations c.2106G>A p.(Trp702Ter) and c.2908G>T p.(Trp970Ter), and c.3319-1G>A and c.2690G>A p.(Glu897Ter), in the authors' numbering [102]. Most Brazilian cases remained unexplained, and the authors consider the epidemiology of these neuropathies in Brazil to be unknown [102].

4. Clinical Recognition and Red Flags

4.1. Newborn and infant

In the newborn, the combination of weak sucking and swallowing, early aspiration, hypotonia, difficulty maintaining temperature, and indifference to pain should raise the possibility of familial dysautonomia, especially with breech delivery or meconium and Ashkenazi Jewish ancestry, although the absence of such ancestry does not exclude the diagnosis [6, 38]. The absence of overflow tears with emotional crying can only be assessed after 3 months of age, and the smooth, pale tongue without fungiform papillae is visible early [6]. Unexplained fever from the first weeks, without sweating and dependent on ambient heat, is often the initial manifestation of CIPA and of HSAN V due to null alleles, more so in hot climates [3, 7]. A newborn with severe intestinal hypomotility and no reaction to pain should be tested for SCN11A first [3, 34]. Hypotonia with central hypoventilation, apnoea, GORD, and aspiration in the first year suggests HSAN IX [8]. The neonatal form of HSAN VI adds contractures, an immobile facies, and absence of psychomotor development [6, 58].

Parents recall that the infant with CIPA did not cry during vaccinations or blood draws [7]. The most typical red flag is biting of the tongue, lips, or fingertips beginning with the eruption of the first teeth [3, 7].

4.2. Child

In the child, repeated trauma (bruises, fractures, painless dislocations), neurogenic arthropathy of the knees and ankles, unrecognised burns, absence of withdrawal or emotional change in response to painful stimuli, absence of pain on moving injured joints, altered visceral pain, and consistent errors between hot and cold wet substances point to CIP or CIPA [7]. Anhidrosis with recurrent fevers, intellectual disability, and ADHD point towards NTRK1 and NGF; anosmia with normal intellect towards SCN9A; corneal anaesthesia with early abrasions (before age 8) and normal intellect and smell towards PRDM12; and hyperhidrosis with pruritus towards SCN11A [3, 34, 66]. In familial dysautonomia, the child has vomiting crises, recurrent aspiration pneumonia, extreme blood pressure variability with postural hypotension, hypotonia, diminished or absent reflexes, and reduced taste [6]. Early sensory deficit in all modalities, with ulcers of the hands and feet and acral mutilation, especially with affected siblings or consanguineous parents, suggests HSAN2, but the absence of a family history does not exclude it [2].

4.3. Adolescent and adult

In the adult, a neuropathy that is initially sensory and evolves into an axonal sensorimotor neuropathy, with painless injuries of the feet and hands, ulcers, Charcot joints, sometimes amputations, typical lancinating pains, distal weakness spreading proximally, variable sensorineural hearing loss, and a dominant family history suggests HSAN1 due to SPTLC1 or SPTLC2 [5]. The presence of pyramidal signs points towards ATL1 [75]. The triad of sensory neuropathy, hearing loss, and dementia before age 50, with loss of distal sweating, ataxia, and narcolepsy or cataplexy, suggests DNMT1 [9]. Adult-onset paroxysmal dry chronic cough and gastro-oesophageal reflux preceding the neuropathy correspond to the phenotype described as HSAN1B, with cough triggered by odours, fumes, dry food, lying down, or stimulation of the external auditory canal [12].

4.4. Suspected child abuse

CIP is a mandatory differential diagnosis of nonaccidental injury: painless fractures, bruises, cuts, and corneal ulcers may be interpreted as abuse, and many parents of these children have been suspected of maltreatment [3, 97]. The distinction rests on the response to pain, which is normal in nonaccidental injury, and on a pattern of injuries that, in abuse, is not proportionate to the child's size and development [3]. Molecular confirmation is what definitively settles the question and enables recessive counselling [67]. Diagnostic delay can be long: in a series of siblings with HSAN IV, a mean of 53 months elapsed before diagnosis, with unnecessary use of health care before it [99].

4.5. Emergency signs

Emergencies include hyperpyrexia in a child with anhidrosis, potentially fatal without cooling, and hypothermia in a cold environment [3, 7]. Joint swelling, limping, or refusal to use a limb in a child who does not feel pain requires radiography and inflammatory markers, because these may reflect a fracture, septic arthritis, or osteomyelitis [3]. In familial dysautonomia, a respiratory exacerbation may present with significant hypoxemia and hypercapnia without dyspnoea or tachypnoea, and dysautonomic crises are often the initial manifestation; rapid correction of hypoxemia with 100% oxygen may cause prolonged apnoea [6, 92]. An adrenergic crisis that does not respond to home treatment, defined in the NYU series by nausea or vomiting, skin blotching, and agitation with blood pressure ≥ 140/90 mmHg and heart rate ≥ 100/min, led to hospital admission and, in severe cases, to intensive care [6, 103]. In HSAN IX, choking from aspiration of solid food and nocturnal central apnoea are the most common causes of death [8]. In CIP, postoperative tachycardia and hypertension should suggest inadequate sedation, because the child may move and become injured [3].

4.6. Newborn and carrier screening

The sources consulted describe no newborn screening programmes for any of these diseases. The American College of Obstetricians and Gynecologists (ACOG, 2017) recommends offering familial dysautonomia carrier screening to individuals of Jewish ancestry, and ELP1 is included in the screening panels targeted at the Ashkenazi population [6, 104].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Clinical examination and bedside tests

There are no consensus clinical criteria for CIP; diagnosis requires visible evidence of absent nociception in a conscious individual with normal intellectual capacity, which is more difficult when intellectual disability is present [3]. Many children are wrongly considered insensitive after an insufficient stimulus, and techniques that injure before causing significant pain, such as sternal rubbing, should be avoided; pressure of 5 to 10 kg with a pen over the nail bed, until it blanches for a few seconds, is a reliable test [3]. The rest of the neurological examination is typically normal in CIP (touch, vibration, position sense, motor function, reflexes), and smell should be tested whenever age permits, because anosmia points towards SCN9A; below age 5, smell is difficult to assess [3, 66].

Three specialised tests are used in familial dysautonomia. The Schirmer test is valid only after 6 months of age: a 5 × 35 mm strip of filter paper placed in the lateral portion of the lower eyelid that is moistened less than 10 mm at 5 minutes indicates diminished basal and reflex tear secretion [6]. Intradermal histamine produces no axon flare [6]. Conjunctival instillation of 2.5% methacholine or 0.0625% pilocarpine does not affect the normal pupil but causes miosis after about 20 minutes in almost all patients, owing to denervation hypersensitivity [6]. If the histamine or pilocarpine test is normal or equivocal in a newborn, it should be repeated after 6 weeks of age [38]. In SCN9A-related CIP, the histamine flare is normal, which distinguishes it from the HSAN [40].

5.2. Clinical criteria for familial dysautonomia

In 1984, Axelrod and Pearson defined five cardinal criteria: absence of fungiform papillae on the tongue; absence of a flare after intradermal histamine; diminished or absent deep tendon reflexes; absence of overflow emotional tears; and Ashkenazi Jewish ancestry [6]. The last criterion was refuted by the discovery of rare variants in non-Jewish patients [6]. A 1983 version replaced ancestry with miosis after methacholine [38]. The diagnosis is currently established by suggestive findings together with biallelic pathogenic or likely pathogenic variants in ELP1 [6].

5.3. Neurophysiology, biopsies, and autonomic testing

In CIP, nerve conduction studies and electromyography are typically normal, nerve biopsy is not routine, and some centres perform skin biopsy in adults to measure intraepidermal nerve fibre density and autonomic innervation [3]. In HSAN1A, electrophysiology is initially normal and is of no use for early detection; sensory potentials decrease only late, and motor conduction velocities remain normal until amplitudes fall [5]. Sural nerve biopsy shows nonspecific axonal degeneration, with loss of unmyelinated fibres greater than that of small myelinated fibres, and of the latter greater than that of large myelinated fibres, up to loss of ganglion cells [5]. In HSAN2, sensory potentials are reduced or absent, motor conduction is preserved or reduced, and sural nerve biopsy shows a marked absence of myelinated fibres and a reduction of unmyelinated fibres [2]. In HSN1E, there is length-dependent sensory axonal loss of both small and large fibres, with normal motor conduction; QSART (quantitative sudomotor axon reflex test) and the thermoregulatory sweat test show postganglionic sudomotor dysfunction, with cardiovagal and adrenergic function spared [9]. In CMT, a motor conduction velocity above 45 m/s defines the axonal form [89]. In HSAN VII, motor and sensory conduction may be mildly reduced with normal amplitudes [65].

5.4. Biomarkers

In HSAN1 due to SPTLC1 or SPTLC2, elevated plasma 1-deoxysphinganine and 1-deoxymethylsphinganine, measured by liquid chromatography–mass spectrometry (LC-MS), constitute strong biochemical evidence and appear to correlate with severity [70]. The marker helps demonstrate variant pathogenicity, falls with L-serine, and is used as a pharmacodynamic marker, but it supports rather than replaces molecular diagnosis: it is also elevated in other conditions, and the opposite pattern (elevated ceramides) accompanies the ALS variants; it is a specialised laboratory assay, not a routine clinical chemistry test [72]. In the L-serine trial, baseline values correlated with the CMTNS (r = 0.50), but changes on treatment did not correlate with clinical changes [105].

In familial dysautonomia, a whole-blood ELP1 radioimmunoassay in 59 homozygotes and 66 carriers gave 244 ± 75 pg/mL in patients and 2,210 ± 1,031 pg/mL in carriers, with stability across replicates and after one year; values below 492 pg/mL were strongly indicative of disease [106]. This is an exploratory study, proposed as a target-engagement marker for gene-targeted therapies and not as a validated diagnostic test [106].

5.5. Genetic testing strategy by entity

Sources: [2, 3, 5–7, 9, 31, 35]. These percentages are the proportion of known pathogenic variants that each method detects, not the clinical sensitivity of the test in a patient with suspected disease.

5.6. Algorithm for congenital insensitivity to pain

GeneReviews proposes a phenotype-driven order, feasible mainly after age 5, because intellect, sweating, temperature, and autonomic function are difficult to assess in infants; the exception is SCN11A, which is tested first in a newborn with severe intestinal hypomotility [3]. With normal intellect and anosmia, SCN9A is tested first. With normal intellect, staphylococcal infections, and hypohidrosis, PRDM12 is tested and, if negative, NTRK1 and NGF, because some patients have minimal learning difficulties. With learning difficulties or developmental delay, staphylococcal infections, and hypohidrosis, NTRK1 and NGF are tested first; unexplained fever due to anhidrosis is characteristic and often the first sign [3]. In current practice, a multigene panel that includes the CIP and HSAN genes, or exome or genome sequencing, often replaces the gene-by-gene approach [2, 3]. In familial dysautonomia, exome or genome sequencing is reserved for atypical phenotypes or patients without known Ashkenazi ancestry [6].

5.7. Test limitations, VUS, and unsolved cases

A negative result does not exclude the disease. When no variant is found in a dominant gene (SCN11A, ZFHX2) or only one variant is found in a recessive gene, deletion or duplication analysis should be performed, because whole-gene deletions have been described in NGF- and SCN9A-related CIP [3]. In the 2023 international cohort, the 1.3-kb intragenic deletion in NTRK1, the 3.8-kb and 3.4-kb deletions, and the 322-kb deletion spanning the entire SCN9A locus were all in compound heterozygosity with a point variant; the 3,421-bp deletion of SCN9A exon 20 was sized only by long-read sequencing [85]. The deep intronic NTRK1 variants frequent in Asia fall outside the usual coverage of exon sequencing, and variants in the WNK1 HSN2 exon may be filtered out as intronic if the analysis is limited to the MANE transcript [7, 73]. Apparent homozygosity may result from uniparental isodisomy of chromosome 1 in CIPA, which makes testing of both parents mandatory [7]. A VUS, or a pathogenic variant together with a VUS in a recessive gene, neither establishes nor excludes the diagnosis [3, 6, 7]. In ATL3 and TECPR2 the proportion of VUS among missense variants is high, and in the 2023 cohort many missense variants remained VUS despite segregation, predictions, heterologous expression, and metabolic testing [30, 35, 85]. In the Brazilian cohort, only 21.7% of families were solved by genome sequencing, which gives a measure of the unexplained cases [102].

The report should state the gene, the versioned transcript (MANE Select and, for WNK1, also the isoform containing the HSN2 exon), the HGVS description of the variant at the DNA and protein levels, zygosity, phase when there are two variants, the ACMG/AMP class, and the technical limitations of the region analysed; when phase is unknown, parental testing is the next step [7, 73]. Family segregation, phenotype, and, in HSAN1, plasma deoxysphingolipids help reclassify a VUS [72].

5.8. Evaluations after diagnosis

In familial dysautonomia, GeneReviews recommends assessing growth; sensory ataxia, proprioception, Romberg sign, and reflexes, with MRI if ataxia worsens and an electroencephalogram if seizures are suspected; development and cognition with standardised tests; anxiety; dysphagia by a multidisciplinary team with videofluoroscopic swallow study; blood pressure instability with 24-hour ambulatory blood pressure monitoring (ABPM) and orthostatic testing; the skin, for decubitus and pressure ulcers; sleep by full laboratory polysomnography with end-tidal CO2, even without symptoms, because transcutaneous CO2 may be unreliable; the upper airway by awake flexible laryngoscopy and, if there is no anatomical obstruction, drug-induced sleep endoscopy; the lower airway by pulmonary function tests, cultures, and bronchoscopy with lavage; restrictive disease by plethysmography or nitrogen washout; the eye by corrected acuity, cornea, fundus, and optical coherence tomography (OCT) with mean retinal nerve fibre layer thickness and macular ganglion cell–inner plexiform layer thickness; motor function and orthotics; the spine and feet; and oral health [6]. The 2018 respiratory guideline adds chest radiography in acute deterioration (1C), noncontrast chest CT at paediatric dose in unexplained deterioration or suspected bronchiectasis (1C), videofluoroscopy if aspiration is suspected (1C), oesophageal impedance with manometry for poorly explained symptoms (1D), bronchoscopy with lavage in purulent disease and deteriorations (1D), annual pulmonary function tests in all who are able (1C), laryngoscopy in patients with noisy breathing, snoring, stridor, or obstructive apnoea (1D), and laboratory polysomnography with end-tidal CO2 at diagnosis and annually (1C), recommending against home polysomnography (1D) [92].

In CIP and CIPA, evaluations include the skin (dry skin, palmoplantar hyperkeratosis with fissures), history of hyperthermia or hypothermia, whole-body examination (bruises, cuts, burns, bites, infections), orthopaedics (fractures, avascular necrosis, septic arthritis, osteomyelitis, subluxation, Charcot joints, limb length discrepancy, scoliosis; baseline radiographs of the lumbar spine, hips, knees, and ankles if the child walks), the mouth, ophthalmology (punctate keratopathy, ulcer, perforation, infection), neurodevelopment (CLTCL1, NGF, NTRK1, SCN11A), behaviour and ADHD (especially NTRK1), smell (SCN9A), genetic counselling, and family support [3, 7]. In HSAN1A, the skin of the feet, ankles, and hands, Charcot joints, strength, loss of sweating, and patchy compensatory hyperhidrosis are examined [5]. In HSAN2, the extent of sensory loss and autonomic and motor involvement are assessed [2]. In HSN1E, audiometry, QSART, the thermoregulatory sweat test, and tilt-table testing are performed [31].

5.9. Prenatal diagnosis and preimplantation genetic testing

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing (PGT) are possible for all entities [2, 3, 6–8]. Before the gene was identified, familial dysautonomia was diagnosed prenatally using CA-repeat markers linked to the 9q31-q33 locus, with accuracy above 98% in six of eight pregnancies, and CIPA in Israeli Bedouins in eight cases, two by linkage and six by direct variant testing [38, 39].

6. Differential Diagnosis

6.1. Comparison table

Sources: [2, 3, 5–7, 29, 42, 69, 97, 107–111]. PEPD denotes paroxysmal extreme pain disorder, CIDP chronic inflammatory demyelinating polyneuropathy, and CSF cerebrospinal fluid.

6.2. Nonaccidental injury and paediatric differentials

The most delicate question is that of nonaccidental injury, because the painless fractures, bruises, cuts, and corneal ulcers of SCN9A-related CIP and CIPA mimic abuse [97]. In CIPA, the skeleton shows fractures, deformities, dislocations, osteomyelitis, avascular necrosis, and acro-osteolysis [97]. The Oxford Desk Reference also includes in the differential of nonaccidental injury osteogenesis imperfecta, Ehlers-Danlos syndrome, brittle cornea syndrome (ZNF469, PRDM5), hypophosphatasia (ALPL), and, for subdural haematoma, glutaric aciduria and Menkes disease [97]. Self-mutilating behaviour similar to that of the congenital HSAN occurs in Lesch-Nyhan syndrome and untreated phenylketonuria, but pain is present in these conditions [2]. The Oxford Desk Reference describes the combination of anhidrosis with insensitivity to pain as a recessive disorder of the peripheral cholinergic nerves affecting structurally normal sweat glands and pain sensation, with frequent distal injuries [112]. Anhidrosis without insensitivity to pain points to hypohidrotic ectodermal dysplasia, and the combination of dysautonomia with bowed long bones, camptodactyly, and hyperthermic episodes, present from prenatal ultrasound with oligohydramnios, points to Stüve-Wiedemann syndrome [3, 107].

6.3. Distinguishing the forms of CIP from one another

Three features separate the most frequent forms. SCN9A-related CIP has anosmia, Charcot joints, and normal corneal reflex and tear production; HSAN VIII due to PRDM12 has an absent corneal reflex, reduced lacrimation, normal smell, and no Charcot joints; CIPA due to NTRK1 has anhidrosis, recurrent fevers, hypothermia in the cold, and variable intellectual disability, and may also have an absent corneal reflex [3, 66]. The GeneReviews chapter on CIP states, in its management table, that all individuals with congenital corneal anaesthesia seen by the authors had SCN9A-related CIP, which contradicts its own Table 1 and the primary series of patients with PRDM12; congenital corneal anaesthesia is characteristic of PRDM12-related CIP, and this is the interpretation adopted here [3, 66]. Clinically, NGF-related and NTRK1-related CIPA cannot be reliably distinguished [7]. The distinction between congenital HSAN and clinically similar CIP is inconsistent in the literature, and genetic testing is what determines the classification [2].

6.4. Differential diagnosis of juvenile- or adult-onset HSAN

In the dominant forms, the main differential lies among the HSAN1 genes (SPTLC1, SPTLC2, ATL1, ATL3, DNMT1) and with CMT2B due to RAB7A, a sensorimotor neuropathy with severe sensory loss and foot ulcers, in which distal weakness and atrophy are often the first and most prominent manifestations and there are no lancinating pains [5, 6]. CMT2I/J due to MPZ p.Thr124Met is almost identical to HSAN1A, with severe sensory loss and lancinating pains, but without ulceration [5]. HSN1E is distinguished by hearing loss, dementia, and narcolepsy, and its dementia may resemble frontotemporal dementia [6, 9]. Painful diabetic neuropathy has a similar phenotype but no family history [5]. Charcot-Marie-Tooth disease in general and HNPP are also part of the differential, and the acquired neuropathies to exclude include alcoholism, vitamin B12 deficiency, thyroid disease, diabetes, HIV, vasculitis, leprosy, neurosyphilis, amyloidosis, occult neoplasia, heavy metals, and CIDP [42].

6.5. Metabolic differential diagnosis

Saudubray points out that painful small fibre neuropathy may correspond to Fabry disease, Tangier disease, GM2 gangliosidosis, HSAN1, or porphyria; that bone crises occur in Fabry disease, Gaucher disease type I, and the HSAN; and that an inborn error should be suspected when neuropathy is accompanied by incongruent neurological or systemic signs [108, 111]. Treatable metabolic causes of neuropathy include vitamin E deficiency, Refsum disease, cerebrotendinous xanthomatosis, acute porphyria, serine deficiency, and SORD deficiency [108]. 3-Phosphoserine phosphatase (PSPH) deficiency has been described in nine patients from three families; in one adult, with contractures and severe axonal neuropathy with a nonhealing foot ulcer, oral serine for four months reduced neuropathic pain and allowed the ulcer to heal; and a man with PHGDH deficiency was diagnosed at age 31 with a severe axonal sensorimotor polyneuropathy with a CMT2 phenotype [109]. The L-serine doses used in these synthesis defects (500–700 mg/kg/day in six divided doses in PHGDH deficiency and 100–150 mg/kg/day in the mild forms) do not apply to HSAN1 [109]. In deficiency of dopamine β-hydroxylase, which converts dopamine to noradrenaline at postganglionic sympathetic synapses, the differential includes pure autonomic failure, familial dysautonomia, and central autonomic failure [110].

6.6. Erythromelalgia and small fibre neuropathy: the other side of SCN9A

Gain-of-function SCN9A variants produce the opposite phenotype to CIP. Erythromelalgia causes recurrent bilateral episodes of intense burning pain with redness, warmth, and sometimes oedema, mainly in the feet, triggered by heat and relieved by cold; paroxysmal extreme pain disorder begins in the neonatal period or infancy with flushing, harlequin colour change, nonepileptic tonic attacks, and syncope with bradycardia, followed by episodes of rectal, ocular, or submandibular pain; small fibre neuropathy causes stocking-and-glove pain in adults, with autonomic manifestations [69]. Penetrance is 100% in families with erythromelalgia and paroxysmal extreme pain disorder and incomplete in small fibre neuropathy [69]. In a series of 28 rigorously selected adults with idiopathic small fibre neuropathy, 8 had an SCN9A missense variant, a yield in a selected population that should not be read as prevalence [81]. Erythromelalgia secondary to essential thrombocythaemia and other myeloproliferative disorders accounts for up to 25% of secondary cases [81]. A Brazilian boy with intense paroxysmal lower limb pain since early childhood, triggered by heat and relieved by prolonged immersion in cold running water, with autonomic dysfunction, loss of dermal and epidermal small fibres, and marked loss of small myelinated fibres in the sural nerve, had the de novo variant NM_001365536.1:c.701T>C p.(Ile234Thr) and achieved more than 90% pain improvement with carbamazepine [73, 113].

7. Treatment and Risk Management Strategies

7.1. Framework: no approved therapy and the evidence base

No drug is approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) with a specific indication for any HSAN or CIP; all drugs used are off-label, and L-serine and kinetin are investigational [105, 114, 115]. The only formal guideline identified for the entities in this article is the 2018 respiratory care guideline for familial dysautonomia; for HSAN1, HSAN2, CIPA, SCN9A-related CIP, HSAN VII, and the remaining forms, management rests on case series, GeneReviews, and expert opinion [2, 3, 7, 92]. Treatment is supportive, provided by paediatric or neurology, orthopaedic, dental, ophthalmology, and dermatology teams at a centre with integrated care [3, 7].

7.2. Protecting the insensate limb: common measures

The measure common to all HSAN is education in caring for the painless limb. Foot ulcers result mainly from the breakdown of calluses, so sources of pressure must be eliminated, calluses softened with moisturising and lipid-based ointments, and routine podiatric care provided as for the diabetic foot; diabetic foot and diabetes education clinics are a good source of advice [2, 5]. Daily foot inspection, appropriate footwear and socks, insoles, gloves for cooking and handling hot objects, cleaning and protecting wounds with antiseptic, and early treatment of infection prevent osteomyelitis and amputation [2, 30]. Wounds of neuropathic limbs heal if they are kept clean and protected and the limb is rested, and the surgical principles are those of leprosy surgery [5]. Foot drop is treated with ankle-foot orthoses, worn with a sock or "second skin" to prevent abrasion, and Charcot joints may require arthrodesis [5]. When osteomyelitis is suspected, imaging and targeted antibiotic therapy are the rule [30]. Siblings at risk of HSAN2 should be evaluated so that preventive measures can be started early [2].

7.3. HSAN1: lancinating pain, wounds, and L-serine

7.3.1. Symptomatic treatment

Lancinating pains are difficult to treat, and relief is only partial with carbamazepine, gabapentin, pregabalin, or amitriptyline, or with the combination of an antiepileptic and an antidepressant; GeneReviews gives no doses for this indication [5]. The same source considers opioids contraindicated, because this is a chronic disease [5]. Measures for HSAN1C follow, by analogy, those for HSAN1A [72].

7.3.2. L-serine: rationale and randomised trial

L-serine supplementation aims to shift mutant SPT back to its canonical substrate and reduce deoxysphingolipid formation. In a 10-week pilot study, 200 or 400 mg/kg/day reduced plasma deoxysphingolipids, and dietary serine had the same effect in a mouse model and in 14 patients [70, 116]. The trial by Fridman and colleagues (Massachusetts General Hospital and University of Massachusetts, registration NCT01733407, IND 110957) was double-blind and placebo-controlled (dextrose), with 1:1 parallel groups for one year, followed by a one-year open-label extension in which all participants received L-serine [105]. The dose was 400 mg/kg/day in three divided doses, in adults, as powder dissolved in water, with no maximum dose defined in the source; it was chosen on the basis of the pilot study and because higher doses had caused reversible adverse effects (nausea, vomiting, nystagmus, myoclonus) in children with serine synthesis defects [105].

Between August 2013 and April 2014, 18 adults with HSAN1 confirmed by an SPTLC1 variant were enrolled (9 L-serine, 9 placebo; 16 completed), with a mean age of 47.8 years, 67% women, a mean symptom duration of 24.7 years, a baseline CMTNS of 22.6, and previous ulcers in all [105]. The primary outcome, the proportion with worsening of more than 1 point on the CMTNS (Charcot-Marie-Tooth Neuropathy Score, version 2, 0–36) at one year, was negative: 1/9 (11%) with L-serine versus 2/9 (22%) with placebo (p = 1.0) [105]. In the mixed-model analysis, at one year the CMTNS was 1.5 units lower with L-serine (95% CI −2.8 to −0.1; p = 0.03), while the placebo group worsened by 1.1 points (p = 0.02); in the second year, the relative difference was −1.4 (95% CI −3.6 to 0.76; p = 0.19), and the article abstract gives −0.77 (CI −1.67 to 0.13; p = 0.09) [105]. 1-Deoxysphinganine fell by 60% with L-serine and rose by 9% with placebo (p < 0.001), 1-deoxysphingosine fell by 41% (p = 0.001), and canonical sphingolipids did not change; the article abstract gives −59% versus +11% [105]. Epidermal nerve fibre density in the distal leg increased with L-serine (median +8 versus 0 fibres/mm², p = 0.014), with no difference at the thigh; nerve conduction, autonomic tests, pain, and quality of life (SF-36) did not differ [105].

Adverse events in the 1st year occurred in 89% with L-serine and 100% with placebo, with no related serious events; localised infection (6/9 versus 4/9), methicillin-resistant S. aureus infection (1/9 versus 0), osteomyelitis with amputation (2/9 versus 0), and abdominal pain or dyspepsia (2/9 versus 0) were more frequent with L-serine, and ulcers did not decrease [105]. The authors rate the evidence as class I but point out the small sample, the advanced disease at enrolment, the lack of validation of the CMTNS in HSAN1 (in a natural history study the CMTNS did not change over one year), and the uncertainty about the optimal dose and the benefit of early treatment [105]. L-serine is not approved in the USA or the EU for any neurological indication, has no FDA or EMA orphan designation for HSAN1, and was used in the USA under an IND [105, 114, 115]. Before considering it outside a trial, the genotype must be a deoxysphingolipid-producing variant; for the childhood ALS variants of SPTLC1 or SPTLC2 the rationale is reversed [72].

7.3.3. SENSE trial (United Kingdom)

The phase 2 SENSE trial compared L-serine with dextrose monohydrate in adults with HSN1 due to SPTLC1 or SPTLC2, at a single centre (National Hospital for Neurology and Neurosurgery, London), sponsored by University College London and funded by the Charcot-Marie-Tooth Association [117, 118]. The dose is 400 mg/kg/day (total daily dose) in three divided doses for 12 months, as powder dissolved in water [117]. The primary outcome is the difference in change in lower limb muscle fat fraction on MRI at 12 months; secondary outcomes include the CMTNS and CMTES, the CMT Health Index, and the DN4, NPSI, and BPI neuropathic pain questionnaires, and the ClinicalTrials.gov record adds neurofilament light chain, deoxysphingolipids, and thigh nerve fibre density [117, 118]. Inclusion required a CMTES ≤ 26 and the ability to undergo MRI without sedation, and excluded diabetes, nephrolithiasis, and recent or planned foot surgery [117]. The ISRCTN17106427 record, edited on 5 June 2026, lists the trial as completed, with 29 of the 50 planned participants enrolled between 1 August 2023, and 30 August 2024, and completion on 30 September 2025; the NCT06113055 record still shows the status "UNKNOWN," with its last update in 2023 [117, 118]. As of 18 October 2026, no results had been published [117].

7.4. HSAN2, ATL1, ATL3, and DNMT1

There are no published guidelines for HSAN2, and treatment is symptomatic, by a neurology, orthopaedic, and physiotherapy team, with training in care of the insensate limb and foot self-examination [2]. The same measures apply in HSN1F due to ATL3, with monofilament assessment [30]. For HSN1D due to ATL1 with spasticity, GeneGuidance summarises the sequence in the SPG3A GeneReviews chapter: oral baclofen or tizanidine, then botulinum toxin, and finally an intrathecal baclofen pump, with intensive physiotherapy, orthoses, and anticholinergics for urinary urgency, avoiding dantrolene because of the risk of irreversible weakness; onabotulinumtoxinA (BOTOX®, USA) is indicated for spasticity from age 2, and use of rimabotulinumtoxinB (MYOBLOC®, USA) for spasticity is off-label [75]. There is no cure for DNMT1-related disease; treatment includes education about the sudomotor deficit and injury prevention, hearing aids and augmentative communication, sedatives or antipsychotics for extreme restlessness, wandering, delusions, and hallucinations of dementia, and caregiver support; the feet should be protected with appropriate socks and footwear and not exposed to hot water [9]. In CMT2B, the priorities are foot care and avoiding obesity and neurotoxic drugs such as vincristine, according to the CMT guidelines [89].

7.5. Familial dysautonomia

7.5.1. Dysautonomic crises

GeneReviews recommends written instructions for home management of crises, with fluids and medication via gastrostomy, and clear criteria for going to the emergency department; dehydration and electrolyte imbalances should be monitored, and refractory crises call for a search for the cause [6]. Avoidable triggers (heat, full bladder, long journeys, fatigue, emotional stress, visceral pain) are part of prevention [6].

Benzodiazepines reduce retching and vomiting but may suppress ventilation; GeneReviews recommends noninvasive ventilation as a precaution and reserves intravenous benzodiazepines for the emergency department or the intensive care unit (ICU), because of the risk of prolonged apnoea [6]. Tolerance to benzodiazepines with escalating doses and the associated respiratory depression were already known, and diazepam has been associated with respiratory arrest [84, 93]. In the intranasal dexmedetomidine series, the home regimens described were diazepam 10 mg every 12 hours with clonidine 0.1 mg every 4 to 6 hours via gastrostomy in one patient, and rectal diazepam up to 40 mg over 12 hours, without resolution, in another [119]. These are individual regimens from a single report, not recommended doses. Clonidine, a central α2 agonist, reduces sympathetic activity and can be given via gastrostomy, sublingually, or transdermally, but causes sedation, hypotension, and rebound hypertension [6, 84, 93]. Metoclopramide is associated with tardive dyskinesia and is unsuitable for long-term therapy, and pregabalin is only moderately effective [84].

Dexmedetomidine, another α2 agonist, was given intranasally to three adults (aged 20, 43, and 26 years) with an adrenergic crisis: 2 µg/kg, half in each nostril, a dose derived from paediatric preprocedural sedation; symptoms, blood pressure, and heart rate returned to previous values within 8 to 17 minutes, but the effect was short-lived: in one patient the dose was repeated three more times, for a total of 344 µg over 17 hours, in another a second dose was needed after 20 minutes, and all three were eventually admitted on intravenous dexmedetomidine [119]. There were no adverse effects; the authors recommend monitoring for ileus and the nasal mucosa and do not define an optimal dose [119]. In refractory adrenergic crisis, a retrospective review of 9 patients and 14 admissions at NYU described usual initiation at 0.1–0.2 µg/kg/h, titration every 30 minutes to blood pressure < 140/90 mmHg, and a maximum generally of 1.4 µg/kg/h, without boluses; in the series, the median starting dose was 0.4 µg/kg/h, the median maximum dose 0.8 µg/kg/h (interquartile range 0.5–1.4), and the median duration 58 hours [103]. One hour after initiation, systolic pressure fell from 160 ± 7 to 122 ± 7 mmHg, diastolic pressure from 103 ± 6 to 65 ± 8 mmHg, and heart rate from 112 ± 4 to 100 ± 5/min; there was a median of one adverse event per admission, mainly rate reduction for hypotension or bradycardia, and one paradoxical hypertensive response [103]. The median admission was 9 days, 7 of them in the ICU, and 79% of patients had received benzodiazepines with or without clonidine in the preceding 72 hours [103]. GeneReviews restricts intravenous dexmedetomidine to the ICU [6].

Carbidopa, an aromatic L-amino acid decarboxylase inhibitor that blocks dopamine synthesis outside the brain, was studied in 12 patients aged 12 to 36 years (mean 18), homozygous for the founder variant, all with fundoplication and refractory cyclic nausea and retching [84]. In the open-label phase, the dose started at 12 mg and was increased by 25 mg/day on alternate days, over a mean of 38 days; adults were titrated to 600 mg/day (three 200-mg doses every 6 hours, orally or via gastrostomy), and in paediatric patients under 50 kg the dose was adjusted using the Lack and Stuart-Taylor formula [84]. One patient withdrew because of constipation, and the remaining 11 reached the maximum tolerated dose, a mean of 480 mg/day (325–600), maintained for four weeks without electrocardiographic changes or renal or hepatic toxicity; the composite nausea score fell from 14 ± 5 to 9 ± 2 (p < 0.01) [84]. In the double-blind crossover phase, completed by 8 patients, there was less nausea (p < 0.03) and less retching (p < 0.02) than with placebo, a lower need for extra doses of benzodiazepines and clonidine (p < 0.01), and lower urinary dopamine (147 ± 32 versus 222 ± 41 µg/g creatinine, p < 0.05) [84]. The authors rate the evidence as class II and were unable to define the best dose; they acknowledge that high doses may cross the blood–brain barrier and suggest adding domperidone in patients who remain symptomatic [84].

7.5.2. Baroreflex failure, orthostatic hypotension, and hypertension

The therapeutic goal is not to normalise blood pressure but to reduce its variability [93]. In the double-blind crossover trial of carbidopa in afferent baroreflex failure (NCT02553265), 22 patients aged 12 to 59 years with labile systolic pressure received three 4-week periods (600 mg/day, i.e., 200 mg three times daily; 300 mg/day, 100 mg three times daily; and placebo), with doses every 6 hours, orally or via gastrostomy, and 4 days of tapering and washout between periods [93]. Both co-primary outcomes were met: the standard deviation of daytime systolic pressure was 17 ± 4 mmHg with the low dose and 18 ± 5 mmHg with the high dose, versus 23 ± 7 mmHg with placebo (p = 0.0013), and the maximum systolic pressure peak was reduced (p = 0.0015); the morning surge also decreased (p = 0.0007) [93]. The two doses were equivalent, and the authors conclude that 300 mg/day (100 mg three times daily) is sufficient; there was no measurable worsening of orthostatic hypotension, mean 24-hour diastolic pressure fell by 6 mmHg, and adverse effects were loose stools in 3 and near-syncope in 3, one of them on 600 mg/day and three additional antihypertensives [93]. One patient died suddenly during screening, before receiving the drug [93]. A 2025 review of carbidopa outside Parkinson disease concludes that the evidence is limited, although doses up to 600 mg/day did not cause bothersome effects in some familial dysautonomia trials [120].

The US label for carbidopa alone (Lodosyn®, 25-mg tablets) restricts the indication to Parkinson disease, in combination with levodopa, and states that the maximum daily dose should not exceed 200 mg because of a lack of experience with higher doses [121]. The doses used in the familial dysautonomia trials, 300 to 600 mg/day, exceed this maximum and constitute off-label use, supported by the trials and accompanied by monitoring of blood pressure and orthostatic symptoms [93, 121]. The EMA database does not include carbidopa alone, only levodopa-carbidopa combinations for Parkinson disease (for example, Onerji®, European Commission decision of 27 April 2026, and Hopledo®, of 20 August 2026); national authorisations were not searched [122].

For orthostatic hypotension, GeneReviews recommends physical countermanoeuvres and lower limb strengthening; midodrine is effective for short periods, when needed, before physical activity, and hydration helps only for short periods, owing to the altered osmopressor response [6]. The US midodrine label indicates it for symptomatic orthostatic hypotension in patients who are severely limited despite nonpharmacological measures, at 10 mg three times daily during the period when the patient is upright, at intervals of about 4 hours (or as short as 3), never after the evening meal or less than 4 hours before bedtime; single doses of 20 mg caused severe and persistent supine hypertension in about 45%, total doses above 30 mg/day have not been studied, in renal impairment treatment is started with 2.5-mg doses, dosing in children has not been adequately studied, and blood pressure should be measured supine and standing [123]. The boxed warning notes that the indication rests on a surrogate marker, standing systolic pressure at 1 minute [123]. Droxidopa (Northera®, USA) is indicated for symptomatic neurogenic orthostatic hypotension in adults, including nondiabetic autonomic neuropathy, at 100 mg three times daily, titrated in increments of 100 mg three times daily up to 600 mg three times daily, with the last dose at least 3 hours before bedtime, and no dosing recommendation for a glomerular filtration rate below 30 mL/min; efficacy beyond 2 weeks has not been established, and the label carries a boxed warning about supine hypertension [124]. The sources consulted include no data on droxidopa in familial dysautonomia, and the European orphan designations for L-threo-3,4-dihydroxyphenylserine have been withdrawn [114, 124].

Fludrocortisone, used since the 1990s, sometimes at doses up to 0.6 mg/day, was independently associated with sudden death during sleep, left ventricular hypertrophy, and renal failure, and it worsens hypoventilation through metabolic alkalosis; the NYU Registry authors recommend reducing or discontinuing fludrocortisone, monitoring potassium over the following two weeks because of the risk of hyperkalemia [6, 92, 95]. For hypertension, the precipitating factors should be addressed rather than resorting to antihypertensives, given the blood pressure lability; sleeping with the head of the bed raised by 20° to 40° reduces supine hypertension and nocturnal pressure natriuresis and increases morning intravascular volume, and the hypertension of chronic kidney disease is treated according to the usual standards [6]. Calcium channel blockers have caused symptomatic hypotension and syncope [93]. Bradyarrhythmia with syncope or cardiac arrest warrants a pacemaker [6].

7.5.3. Respiratory disease: recommendations of the 2018 guideline

The respiratory care guideline is the product of a multidisciplinary panel convened in January 2016, a systematic review (PubMed, EMBASE, and Google Scholar, 1949–2017; 61 articles found and 25 included), and NYU Registry data; it uses the GRADE system (1 = strong, "we recommend"; 2 = weak, "we suggest"; evidence A to D), applies to children and adults, and most recommendations have level D evidence [92]. The table lists all the recommendations in the document.

Source: [92]. AHI denotes apnoea-hypopnoea index and PCR polymerase chain reaction. High-frequency chest wall oscillation was evaluated in a one-month study in 15 patients, with improvement in SpO2, forced vital capacity, and peak expiratory flow and, in the long term, fewer pneumonias, admissions, and antibiotic courses [92]. The recommendations against routine fundoplication and against nocturnal oxygen alone, the reduction of fludrocortisone, and noninvasive ventilation even in mild sleep-disordered breathing depart from historical practice, in which gastrostomy was almost always accompanied by Nissen fundoplication [6, 92, 95]. The 2021 GeneReviews chapter still keeps a low threshold for gastrostomy with fundoplication in neurogenic dysphagia, a divergence that should be resolved in favour of the more specific guideline [6, 92]. Spinal surgery also lacks established guidance; a 2025 report of a 45-year-old woman who underwent several operations highlights the higher incidence of kyphoscoliosis and osteomyelitis [125].

7.5.4. Nutrition, gastrointestinal tract, kidney, bone, eye, growth, and oral health

In neurogenic dysphagia, infants benefit from thickened feeds and nipples of different shapes, under the guidance of a feeding team [6]. GORD is treated with upright positioning during meals, prokinetics, H2 antagonists and proton pump inhibitors, and gastrostomy with or without fundoplication, after confirming reflux by oesophageal impedance and manometry; the respiratory guideline restricts empirical antacids [6, 92]. Renal tubular acidosis is treated with bicarbonate and hyperkalemia with a low-potassium diet, and blood pressure control protects the kidney [6]. Corneal ulcers are treated with methylcellulose artificial tears 3 to 6 times daily, normal body hydration, and moisture chambers on spectacles; soft contact lenses may promote healing, tarsorrhaphy is reserved for refractory cases, and corneal transplantation has limited success [6]. Chronic blepharitis responds to combined antibiotic-corticosteroid ointment, early surgical correction of strabismus may help, and optic neuropathy benefits from low-vision aids [6]. Growth hormone may be effective and should be considered according to height, growth velocity, and skeletal maturation criteria; in an open-label study, growth velocity increased in 12 of 13 treated patients, stimulation tests may be unreliable, and the spine should be monitored because it worsens during accelerated growth [6]. Anxiety sometimes responds to selective serotonin reuptake inhibitors, psychotherapy, and behavioural techniques, and cognitive behavioural therapy has been studied in a registered trial [6, 118]. Sensory ataxia is managed with occupational therapy and physiotherapy, footwear with good ankle support, and orthoses for foot drop; many adults use a walker or wheelchair outside the home [6]. Spinal braces are ineffective and may cause pressure ulcers [6]. Dental plaque and calculus require cleaning by a hygienist every six months, and oral self-mutilation calls for a search for hidden mucosal biting and planned extractions when necessary [6]. Caregiver support includes respite, home nursing, coordination of appointments, and equipment [6].

7.6. CIPA and congenital insensitivity to pain

7.6.1. Temperature

In a child with anhidrosis, temperature should be monitored so that hyperthermia and hypothermia can be addressed promptly; hyperthermia is treated by direct cooling in a bath or with a cooling blanket, and control of ambient temperature is essential; hypothermia is treated with a blanket [3, 7]. Hot or cold environments, foods, showers, and baths, as well as electric blankets, are avoided, especially in the perioperative period [3]. Molecular identification of at-risk infants in a family with known variants allows hyperpyrexia and febrile seizures to be monitored for and prevented from birth [7].

7.6.2. Orthopaedics

Fractures receive standard treatment, but with careful, regular review, on the assumption that union may not occur, and with a low threshold for repeat imaging until normalisation; external fixators may lead to serious infectious complications [3]. The inability to achieve adequate immobilisation delays healing, and orthoses and invasive procedures increase the risk of infection [7]. Deformities are treated by corrective osteotomy with prolonged, intensive monitoring, limb length discrepancy by shoe lifts or epiphysiodesis, considering a nonsurgical approach, and foot ulcers by standard treatment, with appropriate footwear, ankle support, and periods of non–weight bearing [3]. Prolonged infections require extensive surgical debridement [3]. The authors of the Latvian case cite as adjuncts, without trials, hyperbaric oxygen for healing and infection control, described in one case, and intravenous pamidronate for one year in a patient with recurrent fractures, with fewer fractures and no adverse effects at five years of follow-up [98]. These are individual reports and do not support routine use.

7.6.3. Mouth and teeth

Injuries to the lips, mucosa, tongue, and teeth are prevented by extraction or filing of sharp incisal edges and by dental splints or mouth guards [3, 7]. To prevent osteomyelitis of the jaw, caries and periodontal disease are treated early, with regular dental examinations and restriction of sweets [3].

7.6.4. Eye

Corneal ulceration, perforation, and infection are treated in the standard way, with regular review; corneal transplants have a higher risk of failure, presumably because of the lack of nociceptive innervation of the new cornea and conjunctiva, and surgical treatment of neurotrophic keratitis has not been successful [3]. Dry eye is treated with lubricants, and neurotrophic keratitis requires routine eye care, infection prevention, and daily observation of the ocular surface [3, 7]. In PRDM12-related CIP, the 2016 series recommends ophthalmological assessment at least annually, lubricants day and night, eye protection in wind or dust, and avoidance of irritants such as bleach, onions, and fumes [66]. Artificial tears are especially useful in the PRDM12 form [3].

7.6.5. Skin and infections

Untreated dry skin leads to infections, cellulitis, and osteomyelitis, so daily topical moisturiser prevents hyperkeratosis, palmoplantar fissures, and secondary infection [3, 7]. Susceptibility to S. aureus, which affects the NTRK1, NGF, CLTCL1, and PRDM12 forms, is prevented with hand hygiene, antiseptic soaps, and early topical antibiotics; a swollen joint, limping, or underuse of a limb should be investigated with radiography and C-reactive protein [3]. In the PRDM12 form, staphylococcal infections without an external cause are treated with early topical antibacterial creams until resolution; septic osteomyelitis and arthritis are difficult to diagnose, and most significant infections required intravenous antibiotics [66].

7.6.6. Primary and secondary injury prevention

Patients learn that others feel pain and simulate it in appropriate situations [3]. The scarcity of men with CIP over age 20 correlates with risk-taking behaviour, and jumping, impact and contact sports, and occupations involving severe bone or joint trauma should be avoided [3].

7.6.7. Neurodevelopment and behaviour

The developmental delay and intellectual disability of the CLTCL1, NGF, NTRK1, and SCN11A forms benefit from early intervention between 0 and 3 years of age (occupational, physical, speech, and feeding therapy), specialised preschool, and an individualised education programme, following the US model described in GeneReviews, with transition planning from age 12 [3]. Irritability, hyperactivity, impulsivity, and oppositional behaviour tend to improve with age, and the family benefits from social support and parent networks [3].

7.6.8. Pharmacological hypotheses

Naloxone may temporarily relieve the analgesia of CIP, according to a study cited by GeneReviews, and could help locate an injury, but it may unmask generalised pain from accumulated injuries; this is a hypothesis, not an established use [3]. Efficacy of naloxone in CIPA had already been described in 1978, interpreted as an excess of brain endorphins [39]. In the sources consulted, there are no gene therapies, NGF-pathway agonists, or targeted approaches under human study for CIPA, and GeneReviews lists no trials [7, 67]. A 2024 systematic review of congenital insensitivity to pain, with an emphasis on CIPA, concludes that the available information is limited and that early diagnosis, education of families and professionals, and appropriate nursing care are essential, without identifying specific treatments [126]. The authors of the Latvian case mention gene therapy, nerve growth factor administration, and stem cells as experimental approaches, without clinical trials [98].

7.7. HSAN VII, HSAN VIII, and HSAN IX

In HSAN VII, in addition to the CIP measures, severe intestinal dysmotility in the newborn requires nutritional support, and pruritus is typical [3, 65]. In HSAN VIII, annual skeletal MRI is not recommended, because these patients do not develop Charcot joints, unlike SCN9A-related CIP, for which the same authors recommend it [66]. In HSAN IX there is no disease-modifying treatment, and supportive care aims to reduce apnoea and choking, the two most common causes of death: ankle-foot orthoses; antacids, H2 antagonists, or proton pump inhibitors for GORD; gastrostomy with or without fundoplication and feeding precautions for aspiration, avoiding solid foods that could lodge in the trachea; chest physiotherapy and cough-assist devices for chronic lung disease; continuous nocturnal oximetry and nocturnal noninvasive ventilation for central hypopnoea and apnoea; and adenotonsillectomy for obstructive apnoea [8]. Drugs that lower consciousness and cause hypopnoea and CO2 retention, such as benzodiazepines and antihistamines, should be avoided; if they are needed, low doses are used with close monitoring [8]. The 2021 international collaboration published recommendations for evaluation, surveillance, and treatment, noting the lack of prospective natural history studies [35].

7.8. Comparative regulatory status and dosing

Sources: [105, 114, 115, 121–124, 127–129].

The US Precedex® label specifies, for sedation of adults in intensive care, a loading dose of 1 µg/kg over 10 minutes followed by maintenance at 0.2 to 0.7 µg/kg/h, by continuous infusion not exceeding 24 hours; the usual maximum rate of 1.4 µg/kg/h and the median duration of 58 hours in the NYU series exceed these values [103, 127].

The Igalmi® label, in DailyMed version 4 of 25 November 2025, describes a starting dose of 120 µg for mild or moderate agitation and 180 µg for severe agitation, with up to two additional half doses, separated by at least two hours, and daily maximums of 240 µg and 360 µg; patients with hepatic impairment and those aged 65 years or older receive lower starting doses and maximums, and additional doses are not given to patients with systolic pressure below 90 mmHg, diastolic pressure below 60 mmHg, heart rate below 60 per minute, or significant postural drop [129]. In the registration studies, orthostatic hypotension at two hours occurred in 18% with 180 µg, 16% with 120 µg, and 9% with placebo, and somnolence in 23% and 22% versus 6% [129]. These figures form the safety framework for any use in dysautonomic crisis, which would be off-label and without paediatric data.

None of the following doses is approved for any HSAN or for familial dysautonomia; the doses from trials and series describe what was administered, not an approved regimen.

For carbamazepine, gabapentin, pregabalin, and amitriptyline in HSAN1, baclofen, tizanidine, and botulinum toxin in HSN1D, glycopyrronium for sialorrhea, metoclopramide, growth hormone, and pamidronate, the sources consulted give no doses for these entities [5, 6, 75, 84, 92, 98].

7.9. Clinical trials

These trials are not comparable with one another: they differ in disease, population, design, and outcomes, and relative effects should be read alongside the corresponding absolute rates. The L-serine trial missed its primary outcome, and the favourable difference in the mixed model is a secondary analysis in a sample of 18 patients; osteomyelitis with amputation occurred in two patients in the active arm and in none in the placebo arm [105]. Negative results and trials that were withdrawn (dronabinol) or have no published results (phosphatidylserine, kinetin) are part of the overall picture. For CIPA, HSAN VIII, HSAN VII, HSAN2, and HSAN VI, there were no interventional trials registered on ClinicalTrials.gov at the time of the search [118].

7.10. Research in the past twelve months

The level of evidence is stated explicitly in each line: preclinical, registered trial, published result, press release, or regulatory decision.

In HSAN1, a preclinical study published in 2026 tested allele-specific antisense oligonucleotides against the SPTLC1 p.Ser331Phe transcript in a heterozygous knock-in mouse: a single subcutaneous injection in neonates or adults silenced more than 90% of the mutant transcript in the liver and dorsal root ganglia, and weekly injections of GalNAc-conjugated oligonucleotides were more effective than unconjugated ones, without affecting the normal transcript and reducing the deoxysphingoid bases in blood [131]. This is proof of concept in an animal model, without a human trial. For the childhood ALS variants of SPTLC1, there is only in vitro normalisation with allele-specific siRNAs [74].

In familial dysautonomia, a 2025 review describes three lines of research: small molecules derived from kinetin, gene therapy, and antisense oligonucleotides, and notes that an N-of-1 clinical trial is under way with an intrathecal antisense oligonucleotide to correct the splicing defect in one individual [132]. That single-patient trial has no locatable registration on ClinicalTrials.gov and no published results, and the supplementary information comes from the patient organisation's website, which is not peer-reviewed [118, 133]. In animal models, adeno-associated virus serotype 2–mediated intravitreal delivery of an exon-specific U1 snRNA increased inclusion of exon 20, rescued the loss of retinal ganglion cells, and improved visual function, and gene supplementation with AAV2.U1a.hELP1 (5.4 × 10⁸ vg) restored structure and function in a retina-specific model [134, 135]. Another preclinical study showed rescue of peripheral neuron phenotypes by adeno-associated virus–mediated gene therapy [136]. In HEK293 cells with a minigene, prime editing of the c.2204+6T>C variant increased exon 20 inclusion from 19 ± 2% to 48 ± 3% (PE2) and 60 ± 3% (PE3), with about 10% genomic editing efficiency, and an alternative approach targeting the ESS2 silencer restored inclusion to 50 ± 4%; the authors point out that modest increases in ELP1, of 5 to 10% of normal, greatly attenuate the disease in mouse models [137]. In the transgenic mouse carrying the exon 20 variant, oral kinetin started soon after birth improved sensorimotor coordination, prevented spinal deformities, and increased the survival of proprioceptive neurons [38]. The whole-blood ELP1 radioimmunoassay has been proposed as a target-engagement marker for these therapies [106].

None of these approaches has reached approval, and the three US orphan designations for familial dysautonomia remain unapproved for the orphan indication [115].

7.11. Agents and circumstances to avoid

7.12. Pregnancy, perioperative care, and transition

Women with CIP become pregnant and have children normally; labour progresses normally but is painless, with stretch and touch intact, so the obstetric team must be informed, and a delay in detecting postpartum pelvic fractures has been described [3]. Pregnancy in women with CIPA has rarely been reported [7]. In familial dysautonomia, pregnancy is high-risk because of the abrupt swings in blood pressure, and the hypertension of the disease is difficult to distinguish from preeclampsia; attention to hypovolemia and hypotension is needed, without reflex tachycardia; the visceral pain of contractions is perceived normally, and analgesia should be provided, with epidural analgesia preferable because of the blood pressure lability with general anaesthesia or subarachnoid block [6].

In the perioperative care of CIP, sedation must be adequate, because insufficient sedation allows unexpected movements with secondary injury, and postoperative tachycardia and hypertension should raise that possibility; temperature should be monitored closely [3]. A child with CIPA who underwent internal fixation for a femoral neck fracture was operated on with an ultrasound-guided femoral nerve block combined with a lateral femoral cutaneous nerve block and dexmedetomidine sedation, without opioids, with stable vital signs and discharge on day 5; the authors note that general and neuraxial anaesthesia are the approaches usually described and that autonomic dysfunction makes them challenging [138]. This is an isolated case, not a recommendation. In familial dysautonomia, sedatives and drugs that induce metabolic alkalosis worsen hypoventilation, and the described complications of scoliosis surgery include refractory hypertensive-emetic crisis, pain, pancreatitis, and paraplegia [92].

Transition to adult care should be planned from age 12 in the forms with intellectual disability, following the model described by GeneReviews, and adults with familial dysautonomia develop more marked orthostatic hypotension and supine hypertension, chronic kidney disease, and greater dependence on walking aids, which requires continuity of care at a reference centre [3, 6, 38].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by inheritance pattern

Most of these diseases are autosomal recessive: HSAN2 (WNK1, RETREG1, KIF1A, SCN9A), familial dysautonomia, CIPA, HSAN V, HSAN VI, HSAN VIII, HSAN IX, and CIP due to SCN9A and CLTCL1 [2, 3, 6–8]. The parents are obligate asymptomatic heterozygous carriers, with the exception of one report of increased sensitivity to thermal stimuli in heterozygotes for WNK1 variants [2]. For the siblings of a patient, the risk is 25% of being affected, 50% of being carriers, and 25% of having no variant; the proband's offspring are obligate carriers, unless the partner is affected or a carrier, and aunts and uncles have a 50% chance of being carriers [3, 7]. Clinical variability among affected siblings can be considerable, especially in HSAN2 and CIPA [2, 7].

The dominant forms are HSAN1 (SPTLC1, SPTLC2, ATL1, ATL3), HSN1E due to DNMT1, HSAN VII due to SCN11A, and Marsili-type CIP due to ZFHX2 [3, 5, 9]. In HSAN1A, most probands have an affected parent, the proportion of de novo cases is unknown, and the risk to siblings is 50% if a parent is a carrier, although they may be unaffected because of reduced penetrance, and about 1% if the variant is not found in the leukocytes of either parent, because of the theoretical possibility of germline mosaicism [5]. Siblings who are asymptomatic at age 30 are no longer considered to be at increased risk, because clinical and electrophysiological findings do not appear after that age; offspring have a 50% risk [5]. An apparently negative family history may be due to lack of recognition, reduced penetrance, early death, or late onset, and nonmedical explanations should be explored when the variant appears to be de novo [5]. In HSAN VII due to SCN11A, the variant may be de novo or inherited, and the frequency of de novo cases is poorly known [3]. In ZFHX2, with a single family described, the risk to siblings is estimated at 1% if the variant is not detected in the parents, and offspring have a 50% risk [3]. In HSN1E, most probands have an affected parent, and offspring have a 50% risk [9].

8.2. Mechanisms that alter the calculation

When only one parent is a carrier in a recessive disease, three explanations must be considered: a large deletion on the other allele, uniparental disomy, or a de novo variant, whose rate is low but appreciable [2, 7]. Uniparental isodisomy of chromosome 1 has been described in families with CIPA and makes testing of both parents mandatory; when it is present, the risk to siblings falls to that of the general population, and half will be carriers [7]. Isodisomy has also been described in a child with HSAN2 due to RETREG1, a situation in which siblings have a 50% chance of being carriers and less than 1% of being affected [2]. In familial dysautonomia, if only one parent is a carrier and biological parentage is confirmed, the possibilities are a de novo variant in the proband or postzygotic mosaicism in a parent [6]. Germline mosaicism has not been described in HSAN1A, but it is possible [5].

8.3. Familial dysautonomia: figures for counselling

The incidence of familial dysautonomia among Ashkenazi Jews is 1 in 3,703 live births, corresponding to a carrier frequency of about 1 in 32 to 1 in 36 [6, 38]. In an Israeli study, 34 carriers among 1,100 individuals of full Ashkenazi ancestry gave 1 in 32, with 11 in 195 (1 in 18) in the subgroup of full Polish origin and 3 in 298 (1 in 99) in those of non-Polish origin [6]. A commercial screening panel cited by the Oxford Desk Reference found, among 2,385 people tested of Ashkenazi ancestry, a carrier frequency of 1 in 41.8 (95% CI 1 in 33 to 1 in 57), versus 1 in 31 in the literature; this is commercial screening, not a population study [104]. For the offspring of a patient, the risk of an Ashkenazi partner being a carrier is 1 in 32, which gives a risk of about 1.5% of having an affected child; with a non-Ashkenazi partner, the carrier risk is less than 1 in 150 and the risk in the offspring less than 1 in 300 [6]. ELP1 testing should be offered to the partner regardless of ancestry [6].

In HSAN IX, the estimated carrier frequency of pathogenic TECPR2 variants is 1 in 1,221 in the general population and 1 in 155 among Ashkenazi Jews; the carrier frequency of the Bukharan founder variant is 1.33% and that of the Ashkenazi variant at least 0.65% [8, 35]. In HSAN2A, the regional carrier frequency of the two founder variants in Quebec was estimated at 1 in 116 for Q315X and 1 in 260 for 918insA (historical numbering, = NM_213655.5:c.3301C>T p.(Gln1101Ter) and NM_213655.5:c.3276dup p.(Ser1093IlefsTer13)) [36]. In CIPA, carrier frequencies are not available, and about half of the patients reported are the children of consanguineous parents [7].

8.4. Carrier testing, predictive testing, and testing of minors

Carrier testing in at-risk relatives requires that the familial variants be identified [2, 3, 7]. In HSAN1A, predictive testing is possible once the variant has been identified, with formal counselling, but predictive testing in asymptomatic minors is considered inappropriate because this is an adult-onset disease with no benefit from early treatment, according to the positions of the National Society of Genetic Counselors and of the American Academy of Pediatrics with the American College of Medical Genetics and Genomics; symptomatic minors should be tested at any age [5]. The position is different in CIPA, where molecular testing of at-risk infants in a family with known variants allows hyperpyrexia, febrile seizures, and injuries to the tongue, lips, and teeth at the time of tooth eruption to be monitored for and prevented, so the immediate benefit justifies testing [7]. In HSAN2, evaluation of at-risk siblings identifies who will develop sensory loss and benefit from preventive measures [2]. When there is no molecular diagnosis, storing DNA for future analysis is recommended [3, 7].

8.5. Population, prenatal, and preimplantation screening

Since 2017, ACOG has recommended offering familial dysautonomia carrier screening to individuals of Jewish ancestry, and ELP1 is included in the panels targeted at the Ashkenazi population [6]. Prenatal diagnosis and preimplantation genetic testing are possible for all entities once the familial variants have been identified, and preconception counselling is the appropriate time to discuss the options [2, 3, 6–8].

8.6. Content of counselling

Counselling should explain the inheritance pattern and the numerical risks, the clinical variability within the same family, the difference between the proportion of variants detectable by a method and the clinical sensitivity of the test, the meaning of a VUS and the possibility of reclassification, the technical limitations that affect specific regions (the WNK1 HSN2 exon, deep intronic NTRK1 variants, CNVs), the availability of cascade testing, and the reproductive options [3, 7, 73]. In families in which the child was initially suspected of being a victim of abuse, molecular confirmation also has a reparative role and should be documented in the record [67]. Social support and contact with patient organisations and, above all, with affected adults are part of the plan [3].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

There is no validated global prevalence for the HSAN as a whole, and Orphanet classifies HSAN1, HSAN IV, and HSAN VII as "unknown" and assigns the class below 1 per 1,000,000 to HSAN V, HSAN VIII, HSAN IX, and CLTCL1-related CIP [11, 15, 16, 18–21]. The available figures are of different kinds: counts of reported patients, authors' estimates from their own practice, diagnostic yields in selected series, and, in a few cases, population incidences.

The UK estimate of about 1 per 1,000,000 for CIP applies to the genes as a whole and is probably an underestimate [34]. The Japanese prevalence of CIPA should not be applied to populations without founder variants [67]. The yield of a series of patients referred to a specialised centre, such as the 73 families of the international cohort or the 23 Brazilian families, measures the genetic composition of the solved cases, not the frequency in the population [85, 102].

9.2. Founder populations

Consanguinity is a factor common to the recessive forms: half of the reported patients with CIPA and about half of the patients with HSAN IX have consanguineous parents [7, 8].

9.3. North America, Europe, Portugal, and Brazil

The most robust North American data come from the NYU Familial Dysautonomia Patient Registry, prospective since 1970, with 670 patients registered and 327 alive in 2019, more than 99% homozygous for the founder variant and more than half living in the United States; it is the basis for the respiratory natural history, the incidence of sudden death during sleep, and the 2018 guideline [92, 95]. In Israel, the National Center for Familial Dysautonomia at the Sheba Medical Center follows its own cohort, and the cohort of 192 patients followed between 1981 and 2020 at a tertiary centre documented the gastrointestinal burden and pancreatitis [6, 94]. The European HSAN1 data include the British socioeconomic study of 37 patients and the SENSE trial, both conducted in the United Kingdom [91, 117]. The international cohort of 73 families with CIP and HSAN was recruited from a German centre, with participation from underrepresented countries [85].

No Portuguese prevalence data or cohorts of HSAN or CIP were found in the sources consulted; the only Portuguese reference identified in the source material is a prevalence study of ataxias and spastic paraplegias, which concerns SPG3A rather than these neuropathies [75]. The absence of data in the sources consulted does not demonstrate the absence of published data. In Brazil, the first cohort of hereditary sensory neuropathies solved 5 of 23 families by genome sequencing, with variants in ATL3, SPTLC2, and SCN9A, and the authors conclude that the Brazilian epidemiology is unknown and that most cases remain unexplained [102]. A second Brazilian contribution, in collaboration with the United Kingdom, describes a patient with a gain-of-function SCN9A variant who responded to carbamazepine [113].

9.4. Special populations

Children bear the brunt of the morbidity of the congenital forms: the anhidrosis and hyperpyrexia of CIPA are most dangerous in the first years and in hot climates, the skeletal complications cluster between ages 1 and 7, and mortality from hyperpyrexia was estimated at almost 20% in the first three years [3, 97, 98]. In familial dysautonomia, mortality before age 5 is currently below 12%, and scoliosis worsens in adolescence [92]. Adults with familial dysautonomia accumulate chronic kidney disease, supine hypertension, visual loss, and dependence on walking aids [6]. In the adult-onset forms, HSAN1 compromises occupational and social activity [91]. Familial dysautonomia affects both sexes equally, and the CIPA ophthalmology series had 63.5% male patients, which reflects the published cases [100].

9.5. Reference networks, centres, and patient organisations

The relevant European reference network is EURO-NMD, whose peripheral nerve disease working group covers the hereditary sensory and autonomic neuropathies; the network has a patient advisory board, a cross-border consultation system, an educational academy, and a recommendations and consensus section [4]. In the United States, the Dysautonomia Center at NYU Langone Health sees adults and children with genetic and sporadic autonomic disorders, maintains the international patient registry, and has been supported for more than 40 years by the Familial Dysautonomia Foundation; referral requires a letter from the attending physician with supine and standing blood pressure and heart rate, and the first visit includes the selection of autonomic tests [139]. In Israel, the National Center for Familial Dysautonomia operates at the Sheba Medical Center [6].

The Familial Dysautonomia Foundation funds research (small molecules derived from kinetin, adeno-associated virus serotype 2 gene therapy, and antisense oligonucleotides), a genetic screening programme, mental health support, oxygen rental, and informational materials [133]. There is also the Familial Dysautonomia Now Foundation [6]. For CIPA, the Japanese patient organisation "Tomorrow" is the identified resource, and the authors of the CIP GeneReviews chapter maintain a clinical and counselling service in the United Kingdom [3, 7]. The Charcot-Marie-Tooth Association, which funded the SENSE trial, provides resources on neurotoxic drugs to avoid, management of neuropathic pain, foot care, orthotics, and foot surgery, also useful in these neuropathies [117, 140]. The Norton & Elaine Sarnoff Center for Jewish Genetics and MedlinePlus Genetics complete the information resources [3, 6]. Two references that appeared in older lists no longer belong to the original entities and should not be used.

10. Illustrative Clinical Case

The following case was published in 2025 and represents the first documented patient with CIPA in Latvia [98].

A 3-year-old girl, the daughter of nonconsanguineous parents, was seen at the Ventspils regional hospital in July 2023. She had carried a diagnosis of CIPA since the age of 2 months. The parents described absence of pain and sweating, self-mutilating behaviour with tearing off the skin of the fingers and injuries to the buccal mucosa and tongue, slowly healing wounds, frequent skin, oral, and genitourinary infections, and frequently elevated body temperature; there was a history of osteomyelitis of the hand bones treated with antibiotics. Language development was delayed, with a bilingual vocabulary and no complete sentences, and hearing was normal. The child was sensitive to bright light and wore sunglasses, without any prior ophthalmological evaluation.

Genetic testing identified two heterozygous NTRK1 variants, in the article's notation NM_001012331.2:c.2188-11G>A, intronic, of maternal origin, likely pathogenic, and previously described in a single patient, and NM_001012331.2:c.2109C>A p.(Asp703Glu), missense, of paternal origin, likely pathogenic, and novel [98]. On the MANE Select transcript, these correspond to NM_002529.4:c.2206-11G>A and NM_002529.4:c.2127C>A p.(Asp709Glu) [73].

About a month before admission, the child fell at a playground without complaining; only days later did she refuse to walk, and a fracture of the left tibia was identified, immobilised in a circular cast for six weeks. In the fifth week of immobilisation, a fever of about 40 °C developed, refractory to antipyretics. Follow-up radiography, performed after cast removal under sedation, and computed tomography showed marked sclerotic hyperostosis in the soft tissues, nonunion of the midshaft tibial fracture, and an angular deformity of about 15°; these images appear in the article's first figure [98]. Inflammatory markers were elevated, with C-reactive protein of 150 mg/L, procalcitonin of 19 ng/mL, and 16,000 leukocytes/µL. Blood and tissue cultures grew Staphylococcus aureus susceptible to methicillin, resistant to penicillin, and susceptible to erythromycin, clindamycin, ciprofloxacin, tetracycline, gentamicin, and cotrimoxazole.

With no improvement in the 24 hours after transfer to the university paediatric hospital, partial tibial resection was performed with cavity cleaning and application of an external fixator, with drainage of about 500 mL of pus; histology confirmed acute osteomyelitis. The child spent a week in intensive care, received intravenous oxacillin 1,000 mg six times daily and negative-pressure therapy, and the wound was then closed with gastrocnemius and soleus musculocutaneous flaps. Five admissions followed over nine months: dislodgement of the external fixator with purulent drainage; osteotomy with resection of the pseudarthrosis and a vascularised fibular graft with a locking plate, complicated by a 40 °C fever that necessitated a switch to piperacillin-tazobactam; fractures of the lateral and medial malleoli with a new focus of osteomyelitis in the distal femur and isolation of Staphylococcus epidermidis; and a final episode with elevated C-reactive protein, negative cultures, and a response to vancomycin, cefotaxime, and oxacillin.

Given the extent of the radiographic changes and the duration of the disease, a panel of surgeons and radiologists judged reconstruction unfeasible and recommended amputation; the parents declined. At one month of follow-up, the child had left knee valgus and hip flexion, with a persistent wound on the lateral aspect of the thigh, documented in the article's fifth figure; passive ankle range of motion was normal and that of the foot and knee was increased, and the marked valgus during walking caused recurrent inflammation, so a rigid knee-ankle-foot orthosis was recommended [98].

The case illustrates the principles of section 7 and their difficulties: the fracture went unnoticed because it did not hurt, prolonged immobilisation of an insensate limb preceded the infection, the external fixator was complicated by infection, just as GeneReviews warns, and union did not occur within the usual timeframe [3, 98]. The management described is that of an isolated report and does not constitute a protocol; in particular, there are no established guidelines for reconstructive surgery in CIPA, and the authors emphasise the need for a multidisciplinary team with orthopaedics, paediatrics, pain specialists, psychology, and rehabilitation [98]. The authors also cite, as background with indirect attribution, a reported survival from 6 months to 33 years, with mortality from septic shock or postoperative cardiac arrest associated with dysautonomia, more than 500 functional variants described in NTRK1, of which at least 105 are associated with CIPA, and post-traumatic stress disorder in up to 16% of children and 23% of parents after paediatric surgery [98].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis by entity

In HSAN1A the prognosis is one of slow progression over decades: distal weakness and atrophy are present in all advanced cases, and older patients may need a wheelchair; chronic ulcers, osteomyelitis, and distal amputations are the complications that determine disability [5]. In the L-serine trial, the 18 patients had a mean of 24.7 years of symptoms and a CMTNS of 22.6, already in the severe range of the scale, and all had had ulcers [105]. The disease compromises the occupational and social life of a high proportion of patients [91]. In HSN1E, the course is degenerative, and death typically occurs in the 5th or 6th decade [24]. In HSAN2 sensory function ends up severely reduced, with recurrent amputations and osteomyelitis, without any documented reduction in life expectancy in the sources consulted [2].

In familial dysautonomia, the disease is potentially fatal, with high mortality and a high incidence of sudden death; half of patients do not reach age 40 [6, 38]. The causes of death described by Axelrod in 2002 were pulmonary in 26%, unexplained in 38%, possibly due to unopposed vagal stimulation, and sepsis in 11% [6]. The respiratory guideline, with NYU Registry data, attributes 24% of deaths to aspiration pneumonia, 23% to sudden death during sleep, 17% to non-aspiration pneumonia, and 5% to respiratory failure, respiratory and sleep events together accounting for 53% of deaths; mortality before age 5 is currently below 12%, and acute pulmonary exacerbations accounted for 54% of admissions in 2016 [92]. The mean age at sudden death during sleep was 29.3 ± 12.4 years [95]. As for quality of life, children have a greater physical than psychosocial burden, young adults are at the mean on the physical and mental dimensions, self-esteem is problematic but improves with age, and physical quality of life declines with age [6].

In CIPA, reported survival ranges from 6 months to 33 years, with mortality from hyperpyrexia in the early years, septic shock, and postoperative cardiac arrest; morbidity is dominated by orthopaedic and corneal complications and by intellectual disability [7, 97, 98]. In HSAN IX, the disease is progressive, with reduced life expectancy; several patients died in the 1st or 2nd decade, and the oldest known patient lived to age 19, the main causes of death being choking from aspiration of solid food, nocturnal central apnoea, and complications of chronic lung disease [8]. In HSAN VI, the neonatal forms may be lethal in infancy, whereas the late-onset forms reach the sixth decade with acral mutilation [17, 64].

11.2. Surveillance table

The intervals in this table are the same as those applied to treatment in section 7: annual pulmonary function tests and polysomnography with end-tidal CO2, chest CT every 3 to 5 years, polysomnography 6 to 8 weeks after starting growth hormone and 6 weeks to 3 months after adenotonsillectomy, ophthalmological assessment at least annually in CIP, and dental examination every six months [3, 6, 92].

11.3. Markers of progression

In familial dysautonomia, densitometry showed mean Z-scores of −1.2 at the lumbar spine and −1.3 at the proximal femur and a trabecular bone score Z-score of −1.8, with a correlation between femoral density and balance, gait, and ataxia, which links bone health to motor function [96]. The loss of retinal axons accelerates until the 3rd decade and then stabilises, which gives meaning to follow-up by optical coherence tomography [6]. Acute pancreatitis is 8.5 times more frequent than in the general population and should be considered in the face of persistent abdominal pain [94]. The need for walking assistance increases from 3% at age 20 to 49% at 50 [6]. In CIPA, the mean diagnostic delay of 53 months and the global function significantly below normative values document the cumulative burden of injuries [99]. In HSAN1, the CMTNS progresses little over one year, which limits its usefulness as a short-term measure of progression and explains the choice of muscle fat fraction on MRI as the primary outcome of the SENSE trial [105, 117].

12. Summary and Concluding Remarks

The hereditary sensory and autonomic neuropathies bring together diseases with three distinct mechanisms and different clinical consequences. When nociceptor and sympathetic neuron development fails, through loss of NGF-TrkA signalling (NTRK1, NGF), failure of nociceptive lineage specification (PRDM12), or disruption of ELP1 splicing, the deficit is present from birth, is complete, and does not progress: the child does not feel pain, does not sweat, or does not produce tears, and the disease manifests through the consequences of that absence. When the defect is in a channel, loss of function of Nav1.7 or sustained depolarisation due to gain of function of Nav1.9 silences structurally intact nociceptors, with normal nerve conduction. When the defect is metabolic or in cellular trafficking, as in the deoxysphingolipids of serine palmitoyltransferase, the atlastins, axonal transport, or autophagy, the degeneration is length-dependent and begins later. The mechanism determines the age at onset, the progression, and what can be expected from an intervention.

The clinical picture is organised around a few axes. Loss of pain produces ulcers, osteomyelitis, Charcot joints, painless fractures, and acral mutilation, and protection of the insensate limb, with daily inspection, podiatric care on the diabetic foot model, appropriate footwear, and early treatment of wounds, is the intervention with the greatest effect in all entities. Dysautonomia determines the risk to life: in familial dysautonomia, chemoreflex failure, aspiration, and sleep-disordered breathing explain more than half of deaths, and nocturnal noninvasive ventilation, even in mild disorder, is the only guideline recommendation with level B evidence. Corneal abnormalities, from anaesthesia or alacrima, threaten vision and require at least annual evaluation. Intellectual disability accompanies some forms and not others, and is one of the features that guide genetic testing.

Diagnosis rests on objective demonstration of the deficit and on molecular confirmation. The five criteria of Axelrod and Pearson still guide the suspicion of familial dysautonomia, with the histamine, Schirmer, and pilocarpine tests, but the criterion of Ashkenazi ancestry has fallen away. In congenital insensitivity to pain, demonstrating the absence of nociception requires an adequate and safe stimulus. At the molecular level, three pitfalls recur: the WNK1 HSN2 exon does not exist in the MANE transcript and its variants appear as intronic; two NTRK1 variants frequent in Asia are deep intronic and fall outside the usual coverage; and sequencing that finds only one variant in a recessive disease makes it necessary to look for deletions, which in the largest international cohort even spanned the entire SCN9A locus. The historical notations need verification: the Swedish NGF variant is p.(Arg221Trp) and not p.Arg211Trp, the Bedouin NTRK1 founder variant is p.(Pro621SerfsTer12) and not Ter21, and the SCN9A variant known as I848T is p.(Ile859Thr) on the current transcript.

There is no approved therapy for any of these diseases, and all drugs in use are used off-label. In HSAN1 due to deoxysphingolipid-producing variants, L-serine reduced the biomarker by more than half and increased epidermal nerve fibre density but missed the primary outcome of the only completed randomised trial, and the British trial that used muscle fat fraction on MRI ended in 2025 without published results; the rationale does not apply to the variants of the same genes that cause childhood amyotrophic lateral sclerosis. In familial dysautonomia, carbidopa reduced nausea and retching and blood pressure variability in two crossover trials, at doses above the US label maximum, and dexmedetomidine, intranasal or intravenous, treats the adrenergic crisis in small series; high-dose fludrocortisone should be reduced, because it is independently associated with sudden death during sleep. Gene-targeted therapies remain preclinical, with the exception of a single-patient trial of an antisense oligonucleotide without public registration, and the three US orphan designations for familial dysautonomia correspond to no approval.

The gaps are substantial and should be stated. There is no validated prevalence for the HSAN as a whole, and the available figures measure different things, from case counts to incidences in founder populations. There are no guidelines for HSAN1, HSAN2, CIPA, SCN9A-related CIP, or the remaining forms, and the only formal guideline located covers only respiratory care in familial dysautonomia. No Portuguese data were found in the sources consulted, and the Brazilian data are limited to a cohort of 23 families and one case. The classification of missense variants remains an open problem in ATL3, TECPR2, and other genes, and the management recommendations in the sources contain errors that should not be repeated, such as the attribution of congenital corneal anaesthesia to the SCN9A form, which belongs to the PRDM12 form. Early recognition, genetic testing that settles the suspicion of abuse, protection of the insensate limb, respiratory and ophthalmological surveillance, and referral to a centre with integrated care remain what most changes the trajectory of these patients.

13. References

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