Temple-Baraitser, Zimmermann-Laband, FHEIG and DOORS Syndromes

Syndromic gain-of-function potassium channelopathies (KCNH1, KCNN3, KCNK4), V-ATPase disorders (ATP6V1B2) and the TBC1D24 spectrum

Literature and regulatory information update: 6 November 2026.

0. Initial Reference Table

The entities grouped here share a recognisable clinical core — hypoplasia or aplasia of the nails and distal phalanges, gingival overgrowth, hypertrichosis, intellectual disability and epilepsy — but result from different mechanisms, which requires a gene-by-gene reading [1–3].

The Orphanet registry case numbers are counts of published patients and the prevalence classes are upper limits assigned to the lowest class, so they should not be read as population rates [5, 12].

1. Introduction

1.1 A class defined by the clinical picture and redefined by genetics

Gingival overgrowth, small or absent nails, short distal phalanges and hypertrichosis form a rare combination that, for decades, gave rise to distinct eponyms. Exome sequencing showed that several of these conditions result from variants that increase the conductance of potassium channels — KCNH1 (Kv10.1), KCNN3 (SK3) and KCNK4 (TRAAK) —, from dominant variants of the B2 subunit of the vacuolar proton ATPase (ATP6V1B2) and from biallelic variants of TBC1D24, a Rab GTPase-activating protein that regulates synaptic vesicle trafficking [1–3]. Gripp and colleagues proposed, in 2021, grouping the KCNH1, KCNK4 and KCNN3 phenotypes into a subclass of “syndromic neurodevelopmental potassium channelopathies due to dominant variants”, whose common feature is increased K+ conductance [1]. Hamilton and Suri had already termed “electrifying dysmorphology” a group of syndromes with coarse facies, gingival overgrowth, hypertrichosis and digital anomalies caused by potassium channel variants, in which they also included Cantú syndrome (ABCC9/KCNJ8) [1]. The deafness and onychodystrophy syndromes — dominant deafness-onychodystrophy syndrome (DDOD), DOORS syndrome and Zimmermann-Laband syndrome — form a second grouping, overlapping with the first, involving ATP6V1B2, TBC1D24, KCNH1 and KCNN3 [2].

1.2 Zimmermann-Laband syndrome

Zimmermann described in 1928 two patients with ectodermal anomalies, considered the first cases [13]. Laband, Habib and Humphreys published in 1964 a family from Trinidad, of Indian origin, in which a 38-year-old woman and five of her seven children had hereditary gingival fibromatosis with “tapering” of the terminal phalanges, absent or dysplastic nails, enlargement of the soft tissues of the nose and ears, joint hypermobility and splenomegaly [13, 14]. Alavandar described in 1965 five affected individuals in three generations of an Indian family [13]. The literature then accumulated isolated cases with intellectual disability of variable severity, cardiomyopathy and aortic dilatation, pericardial effusion, cataracts and sensorineural hearing loss [13]. In 2013, Castori and colleagues reviewed 50 published patients (27 female and 23 male; 14 familial in four pedigrees and 37 sporadic) and defined the phenotypic core as the association of gingival overgrowth and nail hypoplasia or aplasia, present in all [15].

1.3 Temple-Baraitser syndrome

Temple and Baraitser described in 1991 an Iranian boy aged 3.5 years with severe intellectual disability, hypotonia, seizures, generalised cerebral atrophy, small hypoplastic thumbnails and absent toenails of the halluces; radiographs showed central lucent areas in the distal phalanges of the thumbs resembling pseudoepiphyses [16, 17]. The second case was published only in 2008, by Gabbett and colleagues, and Jacquinet and colleagues added two in 2010, delineating a consistent pattern: hypo- or aplastic thumb and hallux nails, broadened and elongated first rays of tubular appearance and sporadic occurrence suggestive of de novo mutation [18, 19].

1.4 Molecular discovery and the “lumping or splitting” debate

In 2015, two groups identified de novo KCNH1 variants: Simons and colleagues in six individuals with Temple-Baraitser syndrome and Kortüm and colleagues in a considerable proportion of patients with Zimmermann-Laband syndrome, together with a recurrent ATP6V1B2 variant in two patients [20, 21]. Electrophysiological studies showed a channel gain of function in both cases [20, 21]. Bramswig and colleagues found KCNH1 variants in intellectual disability cohorts without clinical suspicion of the syndromes and showed that nail hypoplasia may be mild and develop over time, which opened the discussion of whether TMBTS and ZLS were distinct entities or expressions of a continuum [22]. Mégarbané and colleagues described a Lebanese child with a Temple-Baraitser phenotype carrying the same variant already published in a patient with Zimmermann-Laband and concluded that this was a continuum modulated by additional genetic factors [23]. The heterogeneity of ZLS was defined with ATP6V1B2 (ZLS2) in 2015 and KCNN3 (ZLS3) in 2019 [21, 24]. In 2018, Bauer and colleagues described three children with de novo KCNK4 variants and coined the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, gingival overgrowth) [25].

1.5 DOORS syndrome and the TBC1D24 spectrum

Cantwell proposed in 1975 the acronym “DOOR” for the association of congenital sensorineural deafness, onycho-osteodystrophy and intellectual disability; Qazi and Nangia added in 1984 the “S” for seizures, present in most [3, 26]. Eronen's digito-reno-cerebral syndrome (1985) and Eronen syndrome (Le Merrer, 1992) were later recognised as the same entity [27]. James and colleagues reviewed, in 2007, 32 patients from 18 publications and described a deteriorating course with death in early childhood in 32% [27, 28]. In 2014, Campeau and colleagues identified biallelic TBC1D24 variants in 9 of 18 families with the five major features, leaving other families unexplained [29]. TBC1D24 had been associated in 2010 with familial infantile myoclonic epilepsy and with a focal epilepsy syndrome with intellectual disability in an Arab-Israeli family [30, 31]. In 2021, Beauregard-Lacroix and colleagues found the recurrent truncating variant p.(Arg506*) of ATP6V1B2 in nine individuals from eight families with DOORS without a TBC1D24 variant, making ATP6V1B2 the second gene of the syndrome and reinforcing the idea of a DDOD–DOORS–ZLS spectrum [32, 33].

1.6 Definitions adopted

Temple-Baraitser syndrome is understood as the picture of severe intellectual disability, epilepsy and anomalies limited to the first rays (hypo- or aplastic thumb and hallux nails, long, proximally implanted thumbs and halluces) caused by a heterozygous KCNH1 variant [17, 23]. Zimmermann-Laband syndrome is defined by gingival overgrowth with hypoplasia or aplasia of the nails and distal phalanges, coarse facies with a bulbous nose and soft ears, hypertrichosis and joint hyperextensibility, with three genetic forms (ZLS1 KCNH1, ZLS2 ATP6V1B2, ZLS3 KCNN3) [13, 34, 35]. KCNH1-related encephalopathy designates patients with pathogenic variants without the gingival and nail features [36]. FHEIG syndrome corresponds to the KCNK4 phenotype [37]. The TBC1D24 disorders form a continuum of seven phenotypes — DOORS, FIME, progressive myoclonic epilepsy, EPRPDC, developmental and epileptic encephalopathy (DEE, including epilepsy of infancy with migrating focal seizures, EIMFS), autosomal recessive deafness DFNB86 and autosomal dominant deafness DFNA65 [3]. Epilepsy terminology follows the 2017 International League Against Epilepsy (ILAE) classification (which introduced the term developmental and epileptic encephalopathy) and the 2022 classification of epilepsy syndromes with onset in neonates and infants [38, 39]. Temple-Baraitser syndrome should not be confused with Temple syndrome (a 14q32 imprinting disorder).

2. Molecular Genetics and Pathophysiology

2.1 Overview: two groups of mechanisms

The genes of the class fall into two groups. In the first, three potassium channel genes — KCNH1, KCNN3 and KCNK4 — cause disease through dominant missense variants that increase K+ conductance; haploinsufficiency is not an established mechanism, and ClinGen assigns KCNH1 a haploinsufficiency score of 0 and has not curated dosage for KCNK4 [1, 12]. In the second group, ATP6V1B2 and TBC1D24 take part in the regulation of membrane trafficking and organelle acidification: ATP6V1B2 causes dominant disease with a mechanism that differs between truncating and missense variants, and TBC1D24 causes mainly recessive disease through loss of function [2, 3, 33].

The reference transcripts were confirmed as MANE Select in VariantValidator; KCNH1 has a short isoform (NM_002238, 962 amino acids) used in the articles on ZLS, whose numbering differs by 27 residues from the MANE isoform [40, 41].

2.2 KCNH1 and the Kv10.1 channel

KCNH1 is located at 1q32.2 and encodes Kv10.1, with predominant expression in the adult central nervous system and also in myoblasts at the start of differentiation, where it constitutes the non-inactivating K(NI) current [41]. The protein has a hydrophobic core with six transmembrane segments (S1–S6), the pore between S5 and S6, the voltage sensor in S4 and a cyclic nucleotide-binding domain downstream of S6; cryo-electron microscopy showed that the S4–S5 linker is a five-residue loop and that the segments are not domain-swapped, which suggests a distinctive mechanism of voltage-dependent opening; calmodulin binds to the channel and inhibits it [41]. Mice without functional Kv10.1 develop normally and are fertile, with mild hyperactivity, which is consistent with a human disease caused by excess rather than lack of function [41].

All the TMBTS variants studied by Simons and colleagues lowered the activation threshold and delayed deactivation in Xenopus oocytes and HEK293T cells [20]. In ZLS, Kortüm and colleagues observed marked negative shifts of activation in all mutants except p.(Gly469Arg) in the short numbering, which on co-expression with the wild-type channel forms heterotetramers with reduced conductance at positive potentials but pronounced conductance at negative potentials, still an overall gain of function [21]. In 2026, Thompson and colleagues analysed 26 disease-associated variants by automated patch-clamp, alone and co-expressed with the wild-type channel: most showed activation shifted to hyperpolarised potentials and/or accelerated kinetics, with hyperpolarisation of the resting potential; one variant from an autism cohort had the opposite behaviour, which shows that gain of function is the most common but not the exclusive mechanism [42]. Bernert and colleagues showed that p.(Gly496Glu), which alone does not form functional channels, shifts activation towards hyperpolarisation when co-expressed with wild-type Kv10.1 or Kv10.2, without affecting hERG — an explanation for the dominance of apparently “currentless” variants [43, 44].

The most discussed pathogenic hypothesis is that activation at more negative potentials stabilises the resting potential, reduces the opening of sodium and calcium channels and decreases neurotransmitter release; the paradox of a K+ channel gain of function causing epilepsy remains unresolved [45]. For the developmental anomalies, Kv10.1 controls primary cilium disassembly before mitosis and is located at the ciliary base; activating variants disturb ciliogenesis and Sonic Hedgehog signalling in fibroblasts [1, 46]. Neurons derived from patient induced pluripotent stem cells show slower repolarisation and broader action potentials, and a cell line with the recurrent variant p.(Arg357Gln) has been established [12, 47].

The variant spectrum is concentrated in transmembrane segments S4, S5 and S6 and in the S4–S5 linker, with some in the CNBHD [6, 12]. In an analysis of 30 variants in 51 patients, 49 were missense; de novo variants were associated with epileptic encephalopathy and clustered in S4 and S6, whereas inherited, mosaic or somatic variants caused isolated epilepsy or febrile seizures [6]. The two published nonsense variants do not support haploinsufficiency: p.(Arg535*) was also present in the unaffected father and sister, and p.(Arg745*) coexisted with a pathogenic CACNA1A variant [6, 48].

Mosaicism is particularly relevant in this entity: two mothers of children with TMBTS, with epilepsy and no other signs, were low-level mosaic carriers (13.6% of reads in blood for p.(Leu489Phe); 3.4–4.7% in blood, fibroblasts and saliva for p.(Gln503Arg)) [20, 41]. The same substitution p.(Val713Glu) was found in the germline in a woman with generalised epilepsy and as a somatic variant in tissue from a type IIb focal cortical dysplasia [6, 48].

2.3 KCNN3 and the SK3 channel

KCNN3 (1q21.3) encodes SK3, a homotetramer that opens in response to submicromolar concentrations of intracellular Ca2+ through constitutively bound calmodulin, in a complex with the kinase CK2 and the phosphatase PP2A [1, 24]. The de novo ZLS3 variants increase Ca2+ sensitivity and make activation faster and more complete; pretreatment with the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole revealed that wild-type and mutant channels are under basal inhibition by CK2, whereas the variant p.(Val450Leu), described in a family with portal hypertension, acts through basal constitutive activity [24]. The variants described include p.(Ser436Cys), p.(Lys269Glu) and p.(Gly350Asp) and, in 2021, NM_002249.6:c.1663G>T p.(Val555Phe), c.1616_1618del p.(Val539del) and c.859G>T p.(Ala287Ser) [1, 35, 40]. For the digital anomalies, the authors propose that excessive K+ conductance in the endothelium causes vasodilatation and increased capillary pressure at critical stages of digit development, with oedema and vascular rupture, by analogy with fetal hydantoin syndrome [1]. The association of a common intronic KCNN3 polymorphism with atrial fibrillation is a population susceptibility signal unrelated to ZLS3 [12].

2.4 KCNK4 and the TRAAK channel

KCNK4 (11q13.1) encodes TRAAK, a two-pore-domain channel expressed almost exclusively in the nervous system, whose opening is sensitive to polyunsaturated fatty acids, membrane stretch and temperature [50]. TRAAK is located at the nodes of Ranvier, where it constitutes the first identified molecular component of the nodal K+ leak conductance, maintaining a negative resting potential that maximises sodium channel availability [50]. Crystal structures show that, in the non-conducting state, a lipid acyl chain enters the cavity through the lateral fenestration and blocks the pore, and that in the conducting state rotation of transmembrane helix 4 seals that opening [50]. The FHEIG variants p.(Ala172Glu) and p.(Ala244Pro) increase basal conductance, make the channel insensitive to mechanical, lipid and voltage stimulation and act dominantly; molecular dynamics indicates sealing of the lateral fenestration [25]. Rietmeijer and colleagues showed that these variants favour the long-duration, high-conductance open state normally associated with mechanical activation, shifting the channel to a constitutively active conformation [50]. The variants were normalised as NM_033310.3:c.515C>A p.(Ala172Glu) and c.730G>C p.(Ala244Pro); the later recurrent variant c.415G>A p.(Gly139Arg) was also confirmed [10, 40, 51]. Wu and colleagues showed that p.(Ala244Pro) increases the proliferation and fibrosis of gingival fibroblasts and reduces apoptosis through activation of the MAPK/ERK1/2 pathway, which provides a mechanism for the gingival overgrowth [52]. Because the mechanism is gain of function, a truncating variant or a deletion of the gene should not be interpreted as a cause of FHEIG without new evidence [12].

2.5 ATP6V1B2 and the V-ATPase

The V-ATPase is composed of a cytosolic V1 domain (eight subunits) that hydrolyses ATP and a membrane V0 domain that transports protons; the B2 subunit is ubiquitous and the only B isoform highly expressed in osteoclasts [12, 33]. The mechanism of the ATP6V1B2 disorders is under discussion. The recurrent truncating variant NM_001693.4:c.1516C>T p.(Arg506*) has been described as impairing lysosomal acidification, and a mouse gene therapy model framed the deafness as haploinsufficiency [53, 54]. By contrast, the missense variants studied by Carpentieri and colleagues — clustered near the ADP/ATP binding site (Gly325, Tyr328, Ala332, Glu374, Gln376 and Leu398) — upregulate the V-ATPase, increase lysosomal acidification, alter lysosome morphology and distribution, and impair autophagic flux and ciliogenesis, which led the authors to classify these disorders as lysosomal diseases [33]. Both directions have been published and the mechanism probably differs between truncating and missense variants [12]. The mouse carrying p.(Arg506*) has hyperactivity, interictal epileptiform activity and a reduced seizure threshold to pentylenetetrazol, in both the heterozygous and homozygous state [55]. The emerging genotype-phenotype correlation distinguishes the deafness-onychodystrophy end, invariable with p.(Arg506*), from the neurodevelopment-epilepsy end of the missense variants [33]. Confirmed variants: c.1516C>T p.(Arg506Ter), c.1454G>C p.(Arg485Pro) (ZLS2) and c.973G>C p.(Gly325Arg) (Lennox-Gastaut syndrome) [34, 40, 56].

2.6 TBC1D24

TBC1D24 (16p13.3) has eight exons and four isoforms; isoform 1 (559 amino acids) is the most abundant in the brain [57]. The protein combines an N-terminal TBC domain, functioning as a Rab GTPase-activating protein, with a C-terminal TLDc domain, unique among the TBC/Rab-GAPs and associated with resistance to oxidative stress [3, 57]. It binds ARF6 and negatively regulates this GTPase, increasing neurite outgrowth and branching; the Drosophila orthologue, Skywalker, is a Rab35 GAP that controls endosomal sorting of synaptic vesicles and neurotransmitter release [30, 57]. The gene is expressed in the hippocampus and cortex, in the chondrocytes of the distal phalanges and in the calvaria of the mouse, and in human spiral ganglion cells and hair cells [29, 57]. Neurons with one inactivated allele have defective endocytosis, enlarged endosomes and fewer miniature excitatory currents; the mouse homozygous for the frameshift variant p.Ser324ThrfsTer3 has spontaneous seizures and dies by 3 weeks [3, 57]. Mouse models of the deafness variants have no hearing loss, which is explained by divergence of expression between species [57].

The recessive forms result from loss of function; the mechanism of DFNA65 is unknown and all dominant deafness variants are missense [3]. Truncating variants (frameshift, nonsense, splicing) are associated with the most severe forms, with drug resistance and early death, except when located in the last exon (escape from nonsense-mediated decay); missense variants in or before the TBC domain are associated with higher mortality [3, 58]. In Balestrini's series, 17 patients had at least one loss-of-function variant: 15 had drug-resistant epilepsy and 8 died by 7 years of age [58]. The same variant may give different phenotypes in different families, mainly because the second allele differs: p.(Ala500Val), for example, has been described in EIMFS, infantile myoclonic epilepsy, non-convulsive status epilepticus with ataxia and ophthalmoplegia, and EPRPDC [3, 59]. In EPRPDC, all patients had a missense variant in the TLDc subdomain between residues 500 and 511, and the variant p.(Gly501Arg) caused locomotion and vesicle trafficking defects in Drosophila that were corrected by antioxidants [59].

GeneReviews writes “c.1008delT”; the normalised form is c.1008del [40]. In DEE16, maternal uniparental isodisomy of chromosome 16 has caused homozygosity for p.(Glu148Lys) with only the mother as a carrier [57]. The 205 to 504 kb 16p13.3 microdeletion encompassing TBC1D24, ATP6V0C and PDPK1 causes, in the heterozygous state, microcephaly, developmental delay, ID and epilepsy through combined haploinsufficiencies, and the breakpoints show junctions formed by atypical homologous recombination, by microhomology-mediated or by non-homologous end joining [60, 61].

2.7 Penetrance, expressivity and modifiers

Penetrance appears high in the recessive forms of TBC1D24, with variable expressivity within the same phenotype, and DFNA65 manifests in the third decade [3]. In the dominant forms expressivity is highly variable: three patients with the same KCNH1 variant p.(Arg357Gln) had a different course with regard to epilepsy, the mother carrying the KCNK4 variant p.(Ala244Pro) had only hypertrichosis and gingival overgrowth, and the ATP6V1B2 variant p.(Arg506*) causes deafness and onychodystrophy with or without ID and epilepsy [32, 45, 62]. Additional de novo variants of uncertain significance (STK36, ZNF517) have been proposed as modifiers in the Lebanese child [23]. There are TBC1D24 heterozygotes with seizures in recessive families, without a risk estimate [3].

3. Clinical Spectrum and Manifestations by System

3.1 Common syndromic description

The phenotype uniting the class includes developmental delay or intellectual disability of variable degree, hypotonia, facies that becomes coarse with age, gingival overgrowth, hypertrichosis and, in four of the five genes, hypoplasia or aplasia of the nails and distal phalanges [1, 2]. Sensorineural hearing loss dominates at the ATP6V1B2–TBC1D24 pole and epilepsy at the KCNH1, KCNK4 and TBC1D24 poles [1–3]. A comparison of 36 individuals with variants in KCNH1 (n=27), KCNN3 (n=6) and KCNK4 (n=3) shows a constellation specific to each gene, recognisable by the clinical geneticist [1].

These figures come from individuals published up to 2021, with heterogeneous data collection and ascertainment bias towards the most severe cases; they do not represent the natural history of patients identified by sequencing without clinical suspicion [1, 36].

3.2 KCNH1 spectrum: Temple-Baraitser, Zimmermann-Laband 1 and encephalopathy

Neonatal period and infancy. Marked hypotonia is usually the first sign, sometimes with constipation, feeding difficulties and aplasia of the thumb and hallux nails noticed in the first days [22, 23]. Seizures may begin in the neonatal period or even before birth, as in a patient with myoclonus of prenatal onset [1].

Neurodevelopment. Intellectual disability is severe in more than 90% of patients with de novo variants and is frequently accompanied by absent expressive language; there is regression in some, such as a woman who lost skills after 5 years of age and developed a movement disorder with myoclonus aggravated by fever or discomfort [1]. Autistic traits, bipolar disorder with a psychotic episode, cortical visual impairment, strabismus and drooling have been described [1].

Epilepsy. In Mastrangelo's series, 7 of 9 patients had epilepsy, with generalised tonic-clonic and focal seizures, a diffusely slow electroencephalogram (EEG) background in all those with epilepsy, status epilepticus in 4 of 7, need for polytherapy in 4 of 7 and complete control in only 2 of 7 [63]. In a review of 51 patients, 42 had epilepsy; de novo variants were associated with epileptic encephalopathy and inherited, mosaic or somatic variants with isolated epilepsy or febrile seizures [6]. The spectrum includes a Dravet syndrome-like phenotype, with seizures triggered by fever or a hot bath and refractory status epilepticus, and familial febrile seizures progressing to fatal super-refractory status epilepticus in a 4-year-old child [6]. The age at onset of epilepsy is not predictable from the variant: with p.(Leu489Phe) onset was at 9 months in one patient and there were no seizures up to 4.5 years in another [45].

Limbs and nails. In classic TMBTS, the changes are limited to or predominate in the first rays: long, proximally implanted thumbs, with a bulbous tip and hypoplastic nail, long tubular halluces with absent nail; radiographs show pseudoepiphyses or fusiform ossification of the distal phalanges of the thumbs, absent proximal ossification centres of those phalanges and hypoplasia of the other terminal phalanges [17]. In ZLS1 nail involvement is generalised and accompanies hypoplasia of several distal phalanges [13, 23]. Nail hypoplasia may be mild and become evident with age, and some patients never show it [22, 36].

Face. The gestalt includes a long myopathic face, hypertelorism, epicanthic folds, a broad nasal tip, a wide open mouth with an inverted V-shaped upper vermilion and downturned corners; the face lengthens with age, with retrognathia in the adult [1, 22].

Gums and teeth. Gingival overgrowth is present in about four fifths of patients, may cover the crowns and delay eruption; in a 4-year-old boy the second deciduous molars were partially covered by thickened gingiva [1, 49].

Other systems. Scoliosis (severe in some), kyphosis, hip dysplasia, hepatomegaly or splenomegaly (mainly in classic ZLS), cardiomyopathy and progressive aortic dilatation in an adult with ZLS followed for four decades, pericardial effusion, cataracts, sensorineural hearing loss and right bundle branch block have been described [1, 13]. In the review of 50 patients with clinical ZLS, developmental delay or ID occurred in about 40% and epilepsy in 13%, lower values than in patients with a confirmed KCNH1 variant, because that series mixed different genetic forms [15, 21].

Form without syndromic features. Seven patients with ID and de novo variants detected by exome or epilepsy panel had neither gingival overgrowth nor nail hypoplasia on re-evaluation, which was associated with substitutions of Gly496 and with CNBHD variants [36].

3.3 Zimmermann-Laband 3 (KCNN3)

Patients with ZLS3 have mild to moderate developmental delay and mild ID in adulthood, without confirmed epilepsy, coarse facies with thick eyebrows, synophrys, a prominent nose with a broad tip and triangular nares, nail hypoplasia in all and hypoplasia of the distal phalanges [1, 35]. The index patient, aged 46, had marked gingival overgrowth and moderate hypertrichosis from birth; two girls had patent ductus arteriosus, and one child had hypospadias, microcolon and progressive left ventricular dilatation [1, 35]. Monozygotic twin girls with a novel variant had mild language delay, completed secondary education, are independent and have no gingival overgrowth [8].

3.4 ATP6V1B2 spectrum: DDOD, Zimmermann-Laband 2 and DOORS-ATP6V1B2

DDOD is characterised by severe to profound congenital sensorineural hearing loss and onychodystrophy, with conical teeth, selective tooth agenesis, triphalangeal or digitalised thumbs and bulbous fingertips in some families; three Chinese probands with p.(Arg506*) had aplasia of the middle phalanx of the fifth finger and language rehabilitation after cochlear implantation, without ID [53, 64]. A 12-year-old Guatemalan boy with the same variant had triphalangeal thumbs without nails and hypoplastic nails on the other fingers, without gingival overgrowth, hypertrichosis or organomegaly [64, 65]. The same variant was found in nine individuals from eight families with DOORS: all with deafness, onychodystrophy and digital anomalies; developmental delay or ID in all families but one; epilepsy in five [32]. In the pooled analysis of 20 carriers of p.(Arg506*), deafness and phalangeal hypoplasia or onychodystrophy occurred in 100%, developmental delay and ID in 40%, seizures in 35% and hypertrichosis and gingival overgrowth in 5% [33]. In the 11 missense carriers, ID and seizures occurred in 81%, deafness in 10% and onychodystrophy in 30%, with gingival overgrowth in 45% and hypertrichosis in 36% [33]. Classic ZLS2, with p.(Arg485Pro), combines almost total anonychia, very soft nasal and auricular cartilages, gingival overgrowth and variable ID [34]. A multigenerational Polish family with p.(Leu398Val) had generalised epilepsy, ID and mild gingival and nail changes, without phalangeal hypoplasia [66]. There are patients with severe epileptic encephalopathy, including Lennox-Gastaut syndrome in an 18-year-old Sicilian man and infantile-onset encephalopathy with microcephaly and profound developmental delay [56, 67].

3.5 FHEIG syndrome (KCNK4)

The three original children had significant generalised hypertrichosis and a distinctive facial gestalt: hypotonic facies, bitemporal narrowing, micrognathia, deep-set eyes, thick eyebrows, long eyelashes, low-set ears, a short deep philtrum, prominent upper and lower vermilions and an everted upper lip [25, 37]. Development ranged from absence of milestones at 11 months to a developmental quotient of 85 on the Griffiths scale at 5 years; two had early focal and generalised seizures controlled with medication and one had a disorganised EEG without seizures, with a thin corpus callosum [37]. Nystagmus with optic hypoplasia, hyperreflexia, brachydactyly and developmental dysplasia of the hip have been described in individual patients [37]. In the 2024 review, 8 of 10 patients had epilepsy, with a mean onset at 1.8 years and focal seizures progressing to bilateral tonic-clonic seizures in 5 of 8; severity ranged from benign epilepsy to epileptic encephalopathy, with drug-resistant nocturnal seizures and peripheral nerve hyperexcitability in one patient [10]. A subgroup has neither facial dysmorphism nor generalised hypertrichosis, and there are patients with rolandic epilepsy or with genetic epilepsy with febrile seizures plus and hypertrichosis, which led to neurodevelopment and epilepsy being considered the core of the phenotype [10, 51, 68]. Atrial fibrillation and joint laxity have been described in an Egyptian boy [62]. There are no nail anomalies in the published series [1].

3.6 TBC1D24 spectrum

The table reproduces the GeneReviews frequencies, calculated on the published cases of each phenotype [3].

DOORS. The hearing loss is frequently profound and prelingual; the nails are small or absent and the terminal phalanges hypoplastic in the hands and feet, with a triphalangeal thumb in about one third; ID is frequently severe, with greater motor and language delay [3]. Seizures usually begin in the first year, are mainly generalised tonic-clonic but also myoclonic, partial, absences and infantile spasms, and may be difficult to control, with status epilepticus and death [3, 29]. Other manifestations include microcephaly (about one third), sagittal craniosynostosis, trigonocephaly, dental anomalies, congenital heart defects (double outlet right ventricle, atrial septal defect, complete atrioventricular block), renal anomalies (hydronephrosis, nephrocalcinosis, cystic dysplastic kidneys), hypothyroidism, visual impairment and optic atrophy, peripheral neuropathy, microcytic anaemia and T2 hyperintensity in the cerebellar hemispheres and frontal regions [3, 27]. Urinary 2-oxoglutaric acid may be raised and fluctuate between normal and raised in the same patient; Rajab and colleagues associated raised 2-oxoglutarate with a more severe and frequently lethal phenotype [3, 27]. The facies is coarse, with a large nose, broad bridge, bulbous tip, anteverted nares, long philtrum and downturned mouth corners [28]. Polyhydramnios is frequent in a pregnancy with an affected fetus [3].

TBC1D24 epilepsies. In a series of 48 patients from 30 families, 38% had myoclonic epilepsy, 25% focal epilepsy, 25% early epileptic encephalopathy, 4% generalised, 2% multifocal and 6% unclassified; the mean age at seizure onset was 7 months (from 1 hour after birth to 8 years), 79% had status epilepticus or prolonged seizures, 19 patients had seizures triggered by fever or infection and 30 were drug-resistant [58]. In the Italian FIME family, eight members had normal development over a mean follow-up of 52 years [3, 58]. Arab-Israeli FIME combined focal epilepsy, dysarthria, mild to moderate ID and selective cerebellar atrophy with signal change in the ansiform lobule [3, 31]. EPRPDC begins in childhood with focal motor seizures, often hemifacial, and paroxysmal forearm dystonia triggered by sustained exertion or stress that makes writing scrawled and then impossible within a few minutes; the seizures remit, and the dystonia persists less frequently into adulthood, with postural tremor and mild nystagmus [3, 59]. DEE combines myoclonic epilepsy with episodic dystonia, hemiparesis, autonomic signs and lethargy, progression to chronic dystonia, progressive cerebral atrophy and early death; EIMFS begins in the first six months with seizures that migrate between hemispheres, refractory, with regression [3]. Parkinsonism, alternating hemiplegia of childhood, epilepsia partialis continua, multifocal polymyoclonus and paroxysmal dyskinesia with episodic ataxia have also been described [3].

Non-syndromic hearing loss. DFNB86 is a profound prelingual hearing loss with thresholds above 90 dB at all frequencies; DFNA65 is progressive, begins in the third decade and affects the high frequencies first [3].

3.7 Natural history and treated disease

The available descriptions mix natural history and course under antiseizure medications and rehabilitation, and no prospective cohort has been published for any of these entities [1, 3]. In the TBC1D24 series, 9 of 48 patients (19%) died, at a mean age of 37 months (6–96), from infection, respiratory failure, status epilepticus associated with pulmonary infection or probable sudden unexpected death in epilepsy [58]. In the review of 32 patients with DOOR from before the molecular era, 32% died in early childhood from seizures or respiratory distress [27]. Survival data for the KCNH1, KCNN3 and KCNK4 forms are limited to isolated cases, some followed into adulthood (46 years in ZLS3; 37 years in classic ZLS) [13, 35].

4. Clinical Recognition and Red Flags

4.1 When to suspect

In the newborn, the combination of marked hypotonia with absent or small nails on the thumbs and halluces should lead to consideration of the KCNH1 spectrum, especially if the first rays are long and proximally implanted [17, 23]. Hypoplastic nails on all digits with hearing loss detected on newborn hearing screening point towards ATP6V1B2 or TBC1D24 [3, 64]. In the infant and young child, early-onset epilepsy associated with global developmental delay, especially with a slow EEG background, recurrent status epilepticus or seizures triggered by fever, justifies including KCNH1, KCNK4, TBC1D24 and ATP6V1B2 in the panels [10, 56, 58, 63]. Gingival overgrowth in a child not taking phenytoin, ciclosporin or calcium channel blockers, especially with hypertrichosis and late tooth eruption, should prompt examination of the nails and development [49, 69]. Balestrini and colleagues recommend testing TBC1D24 in any patient with myoclonic seizures, ID and an extra-neurological finding (facial, cranial, acral or of another organ) [58].

4.2 Clues on physical examination

The examination should include inspection of all fingernails and toenails, the thumbs (length, implantation, tip), the halluces, the gums and the hair distribution, palpation of the nasal and auricular cartilages and a search for hepatosplenomegaly and joint hyperextensibility [13, 69, 70]. Targeted questions should cover the age of tooth eruption, nail growth, hearing and seizures [70]. The parents should be examined, because a mother who is a mosaic carrier of KCNH1 may have only epilepsy and a mother carrying a KCNK4 variant only hypertrichosis and gingival overgrowth [20, 62].

4.3 Red flags and emergencies

The recommended actions are based on case reports and on the general rules for managing status epilepticus, not on guidelines specific to these entities [13, 49, 58, 62, 71, 72].

4.4 Newborn screening

There is no biochemical newborn screening for these entities. Universal newborn hearing screening may identify the congenital hearing loss of DDOD, DOORS and DFNB86, and the aetiological diagnosis follows the general recommendations for the genetic evaluation of hearing loss [3, 73].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

There are no validated formal diagnostic criteria for any of these syndromes. The diagnosis of TBC1D24 disorders is established in a proband with suggestive findings and biallelic pathogenic variants (recessive forms) or a heterozygous variant (DFNA65) [3]. For the KCNH1, KCNN3, KCNK4 and ATP6V1B2 forms, the diagnosis is exclusively molecular, through identification of a heterozygous pathogenic variant; electrophysiology in oocytes or HEK293T cells demonstrates the gain of function but is a research technique [12, 20]. Campeau and colleagues included in their study patients with at least three of the five features of the DOORS acronym, and recommend testing TBC1D24 even in the absence of deafness and seizures [29].

5.2 Molecular tests in order

1. Exome or genome (preferably as a trio) is the most efficient approach when the phenotype is not unequivocal, because most patients with KCNH1 variants were identified by exome, genome or epilepsy panel without prior clinical suspicion [12, 22, 36].
2. Multigene panels for epilepsy, ID or hearing loss should include KCNH1, KCNK4, KCNN3, ATP6V1B2 and TBC1D24; the composition varies between laboratories [3].
3. Sequencing of TBC1D24 followed by deletion/duplication analysis, when the DOORS picture is complete; sequencing detects more than 90% of pathogenic variants and targeted deletion/duplication analysis less than 10% [3].
4. Chromosomal microarray or low-coverage genome when a 16p13.3 deletion including TBC1D24, ATP6V0C and PDPK1 is suspected (microcephaly, ID, epilepsy) [3, 60].

5.3 Biomarkers and ancillary investigations

Urinary 2-oxoglutaric acid, measured in organic acid analysis, may be raised in DOORS, but it fluctuates in the same patient, is absent in some cases (6 of 11 in Campeau's series) and is also raised in 2-ketoglutarate dehydrogenase deficiency (OGDH), combined D-2- and L-2-hydroxyglutaric aciduria (SLC25A1) and, occasionally, in 3-methylcrotonyl-CoA carboxylase 1 deficiency [3, 12, 27]. Its absence helps distinguish DOORS from Coffin-Siris, Zimmermann-Laband, Temple-Baraitser, Mabry, Nicolaides-Baraitser and Kaufman syndromes, but does not exclude the diagnosis [3]. The EEG shows a diffusely slow background in KCNH1 epilepsy, centrotemporal spikes in EPRPDC and migrating ictal patterns in EIMFS [3, 63]. Brain magnetic resonance imaging (MRI) is abnormal in about half of TBC1D24 DEE cases (diffuse cerebral and cerebellar atrophy) and in 18% of FIME cases [3]. Radiographs of the hands and feet document hypoplasia of the distal phalanges, pseudoepiphyses of the thumbs and the triphalangeal thumb [3, 17]. Audiological assessment (auditory brainstem responses, otoacoustic emissions, behavioural audiometry) and temporal bone imaging precede the decision on cochlear implantation [12].

5.4 Algorithm

The algorithm summarises the guidance of GeneReviews and the published series; it is not a prospectively validated algorithm [1, 3].

5.5 Limits of the tests

Exome or panel sequencing does not reliably detect low-level mosaicism; the mothers who were mosaic carriers of KCNH1 had 3.4–13.6% variant reads, values that may escape the usual calling filters [41]. An apparent homozygote for a TBC1D24 variant may have, in trans, an undetected deletion of one or more exons, or uniparental isodisomy [3, 57]. A negative TBC1D24 result does not exclude DOORS, because half of the families with the five major features had no variants in this gene, some of them later explained by ATP6V1B2 [29, 32]. The percentage of variants detectable by sequencing (more than 90% in TBC1D24) is not the clinical sensitivity of the test, which depends on the genetic heterogeneity of the phenotype [3]. For KCNK4, the 231 ClinVar records of uncertain significance, against 11 pathogenic and 7 likely pathogenic, illustrate the risk of overinterpretation; for KCNH1 and KCNK4, truncating variants or deletions do not correspond to the established mechanism [6, 12].

5.6 Report content and classification

The report should state the gene, the MANE transcript with version (NM_172362.3 for KCNH1, NM_002249.6 for KCNN3, NM_033310.3 for KCNK4, NM_001693.4 for ATP6V1B2, NM_001199107.2 for TBC1D24), the nucleotide and protein HGVS nomenclature, the zygosity, the read fraction when mosaicism is suspected, the parental origin when studied and the class according to the ACMG/AMP criteria [3, 40]. For KCNH1 variants published with the short isoform, the report should give both numberings [41]. A variant of uncertain significance neither confirms nor excludes the diagnosis; parental segregation, de novo status and location in the functional domain (S4–S6 in KCNH1; M3–M4 helices in KCNK4; ADP/ATP binding site in ATP6V1B2) are the main arguments for reclassification [3, 6, 33, 50].

5.7 Prenatal and preimplantation diagnosis

Polyhydramnios is frequent when the fetus has DOORS, and in one family a subsequent affected pregnancy was terminated because of a nuchal translucency of 5.1 mm at 12 weeks [3]. No specific ultrasound signs have been described for the KCNH1, KCNK4 or KCNN3 forms, except polyhydramnios in a patient with ZLS3 and in a patient with classic ZLS [1, 13]. Once the familial variants have been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible [3].

6. Differential Diagnosis

6.1 Comparative table

The table brings together the differential diagnoses from GeneReviews, the reference textbooks and the published series [1, 3, 27, 60, 69, 70, 74, 75].

6.2 Main differential diagnoses

Within the class. The distinction between KCNH1 and KCNN3 rests on the degree of ID, the presence of epilepsy, the broad thumbs and the gestalt; FHEIG is distinguished by generalised hypertrichosis and normal nails [1]. ATP6V1B2 DDOD differs from TBC1D24 DOORS in its dominant inheritance and the frequent absence of ID, but the same allele p.(Arg506*) can cause both pictures, and the family excluded from Campeau's study had a DDOD phenotype [29, 32]. TMBTS and ZLS1 may result from the same variant, so the clinical label should not determine the choice of gene [23].

Cantú syndrome. It shares the hypertrichosis, coarse facies and thickening of the alveolar ridge and also results from hyperactivity of a K+ channel (K-ATP channels); cardiomegaly due to increased muscle mass, recurrent pericardial effusion, ductus arteriosus (58%) and skeletal changes (broad ribs, platyspondyly) point to Cantú, and nine individuals with ABCC9 variants had signs overlapping with ZLS [1, 74, 76]. Minoxidil, a K-ATP channel agonist, reproduces part of the phenotype [74].

BAFopathies. Coffin-Siris syndrome has nail hypoplasia predominantly of the fifth digit, sparse hair and seizures, and some forms have gingival overgrowth; Nicolaides-Baraitser syndrome combines sparse hair and swollen interphalangeal joints [3, 70].

Iatrogenic and teratogenic causes. Gingival overgrowth and hypertrichosis are recognised adverse effects of phenytoin; ciclosporin and nifedipine also cause gingival overgrowth; fetal exposure to hydantoin causes nail and distal phalangeal hypoplasia [1, 49]. A drug history is therefore mandatory, and a child with epilepsy treated with phenytoin may have gingival overgrowth from two causes [1].

Myoclonic epilepsies and encephalopathies. In FIME and PME, the differential diagnosis includes the neuronal ceroid lipofuscinoses, Unverricht-Lundborg disease (CSTB), Lafora disease, MERRF, and POLG, PRICKLE1, SCARB2, SCN1A and SLC25A22 disorders; DEE involves more than one hundred genes [3]. The Dravet-like phenotype of KCNH1 enters the differential diagnosis of SCN1A [6].

Syndromic hearing loss. Congenital hearing loss with abnormal nails should be investigated according to the general principles of aetiological evaluation of hearing loss, including panels that contain ATP6V1B2 and TBC1D24 [70, 73].

7. Treatments and Risk Management Strategies

7.1 Principles

There is no treatment that corrects the mechanism of any of these diseases, no drug approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for these indications, and no published clinical guideline; GeneReviews states that there are no clinical practice guidelines for TBC1D24 disorders [3, 12]. Management is symptomatic and multidisciplinary — paediatric neurology and epileptology, otorhinolaryngology and audiology, dentistry and periodontology, genetics, rehabilitation and social support — and the following recommendations combine those of GeneReviews, those of the published series and those of the official drug labels [1, 3]. The French Haute Autorité de Santé has not published a PNDS (French National Diagnosis and Care Protocol) for any of these entities.

7.2 Initial evaluation after diagnosis

The table adapts the GeneReviews recommendations for TBC1D24 and adds the organs affected in the other entities [1, 3, 12, 13, 62].

7.3 Epilepsy

Choice of antiseizure medication. No drug has demonstrated efficacy specifically for any of these diseases; the choice follows the seizure type and electroclinical phenotype, by a neurologist with expertise in epilepsy [3, 45]. The available information comes from series and case reports:

• KCNH1 spectrum. Control has been described with sodium channel blockers (carbamazepine, lamotrigine, phenytoin), benzodiazepines, phenobarbital, levetiracetam and valproate; in a survey of 34 patients, 58% responded to drugs and 29% became seizure-free, and only 19% of carriers of de novo variants became seizure-free [45]. In Mastrangelo's series, only 2 of 7 patients became seizure-free and 4 required polytherapy [63]. Documented individual responses include valproate with zonisamide, levetiracetam, phenytoin with valproate, and valproate, clobazam and levetiracetam in combination; a patient with a Dravet-like phenotype became seizure-free on valproate; there was drug resistance with the variant p.(Leu379Val) and a partial response to cannabidiol in a woman with p.(Val713Glu) [6].
• FHEIG. Sodium channel blockers and valproate were effective in most patients with seizures, but 3 of 8 were drug-resistant; a patient with drug-resistant nocturnal seizures improved with the carbonic anhydrase inhibitor sulthiame; carbamazepine/oxcarbazepine and valproate were considered potentially effective in another series [10, 68].
• TBC1D24 spectrum. Thirty of 48 patients were drug-resistant; the Italian FIME family became free of tonic-clonic seizures on valproate or phenobarbital; there were responses to phenytoin with clobazam, to zonisamide, to topiramate and to the combination of oxcarbazepine with sulthiame [58]. In EPRPDC, focal seizures respond to carbamazepine or oxcarbazepine without relapse in adulthood, and lamotrigine, benzodiazepines and carbidopa/levodopa may be effective for dystonic attacks or seizures; acetazolamide, flunarizine, valproate and levetiracetam have been reported as ineffective [3]. A patient with DOORS received oxcarbazepine, clobazam, levetiracetam, valproate, lamotrigine, sulthiame, diazepam, clonazepam, midazolam, zonisamide and corticosteroid pulses without lasting success [29].
• ATP6V1B2 spectrum. The epilepsy of the missense forms is frequently drug-resistant, including Lennox-Gastaut-type presentations [12, 56].

Dosage. As there are no doses defined for these diseases, the doses below are those of the official label for the epilepsy indication in the age group; use in a rare genetic syndrome follows the seizure type and constitutes extrapolation. The reference doses in the FDA labels may differ from those in the European summary of product characteristics (SmPC); in Portugal, the choice of presentation should follow the national SmPC.

Sodium valproate has been subject to European restrictions since the European Commission decision of 31 May 2018: it is contraindicated in girls and women of childbearing potential unless a pregnancy prevention programme is followed, with assessment, pregnancy tests, contraception and annual specialist review, and it should not be started in prepubertal girls if a suitable alternative exists; in January 2024 the Pharmacovigilance Risk Assessment Committee (PRAC) recommended precautionary measures for children of treated men [79]. In the KCNH1 forms with planned gingival surgery, valproate may contribute to haemorrhage through its effect on platelets, without this in itself justifying its withdrawal [49].

Drugs to weigh up. Phenytoin causes gingival overgrowth and hypertrichosis, which would aggravate cardinal manifestations of these syndromes; avoiding it in patients with gingival fibromatosis is an inference from the adverse effect profile and not a guideline recommendation [1, 49]. In women of childbearing age, phenytoin and valproate are teratogenic (fetal hydantoin syndrome, valproate embryopathy) [1, 79].

Rescue of prolonged seizures and status epilepticus. The operational definition of convulsive status epilepticus considers treatment from 5 minutes [71]. The American Epilepsy Society guideline classifies intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital as established in initial therapy (level A) and rectal diazepam and intramuscular, intranasal and buccal midazolam as probably effective (level B); fosphenytoin is preferable to phenytoin and second-line therapy is less effective than first-line [72]. For use by carers, midazolam oromucosal solution (Buccolam®, authorised by the EMA on 5 September 2011 and marketed in Portugal) is dosed by age: 3–6 months 2.5 mg (hospital setting only), >6 months–<1 year 2.5 mg, 1–<5 years 5 mg, 5–<10 years 7.5 mg, ≥10 years to adults 10 mg, as a single dose, calling for help if the seizure does not stop within 10 minutes [86]. In the USA, nasal diazepam (Valtoco®) is dosed at 0.5 mg/kg (2–5 years), 0.3 mg/kg (6–11 years) or 0.2 mg/kg (≥12 years), with a second dose at least 4 hours later, no more than two doses per episode, no more than one episode every 5 days and five per month [87]. Because seizures in the TBC1D24 forms are frequently precipitated by fever or infection and status epilepticus is common, all families should have a written rescue plan [3, 58].

7.4 Movement disorders (EPRPDC and other TBC1D24 forms)

Trihexyphenidyl may be effective for tremor in adults with EPRPDC, and carbidopa/levodopa, lamotrigine and benzodiazepines for dystonic attacks [3]. Patients learn to limit fatigue and prolonged exercise to reduce episodes [3]. In the absence of published doses for this indication, the trihexyphenidyl label for adult parkinsonism provides for 1 mg on the first day and increases of 2 mg every 3–5 days up to 6–10 mg/day in divided doses, with gradual withdrawal to avoid worsening and neuroleptic malignant syndrome, and with anticholinergic effects (dry mouth, constipation, confusion) [88]. The carbidopa/levodopa label (Sinemet®, authorised in Portugal) provides for starting with one 25/100 mg tablet three times daily, with increases of one tablet daily or on alternate days up to eight tablets, and recommends assessing vitamin B6 before and during treatment because of the risk of deficiency and seizures [89]. Both are off-label uses with doses extrapolated from adult parkinsonism. Ubidecarenone, tried at 30 years in one patient, was of no benefit [3].

7.5 Hearing

Hearing aids or cochlear implants are indicated according to the degree of deafness; cochlear implantation at around 1 year of age was beneficial in patients with DOORS [3, 29]. In DDOD due to ATP6V1B2, three Chinese probands achieved language rehabilitation after unilateral implantation, and a child with sequential bilateral implants (1 and 4 years) improved in hearing, communication and cognition, with 95% on the Parents' Evaluation of Aural/Oral Performance of Children (PEACH) scale at the last follow-up, although language was still delayed [53, 90]. Counselling on the expected results of implantation must take the neurodevelopmental comorbidities into account, which makes molecular diagnosis before surgery useful [12]. Carriers of DFNA65 should avoid excessive ambient noise [3]. Communication with deaf people should use a sign language interpreter when necessary and neutral terminology [3, 73].

7.6 Gingival hyperplasia and oral health

Gingival hyperplasia is not merely cosmetic: it may cover the crowns, prevent eruption, compromise chewing and speech and hinder hygiene [49, 62]. Do and colleagues proposed a stepwise protocol for KCNH1 patients: myofunctional rehabilitation and speech therapy to stimulate biting and chewing (chewing toys and tubes placed between the molars), followed, if insufficient, by gingivoplasty, which in their patient was performed under general anaesthesia with an electric scalpel and an external bevel, with gentle luxation of the deciduous molars to exclude ankylosis [49]. The postoperative course included heavy bleeding and prolonged pain for more than two weeks, with admission for analgesia, toothbrushing and chlorhexidine gel twice daily; at 12 months the gingiva had healed, without recurrence, and chewing was adequate [49]. Recurrence after gingivectomy in paediatric syndromic fibromatoses is around 34% and the risk increases at the change of dentition, with poor hygiene and with drugs that induce hyperplasia [49]. In the Egyptian family with FHEIG, dental management restored the boy's chewing, smile and psychological well-being [62]. Regular periodontal review, parent-supervised oral hygiene and gingivectomy when hyperplasia compromises feeding, speech or eruption are recommended [12, 49]. Anaesthetic planning must take into account the risk of perioperative seizures and the antiseizure medication [49].

7.7 Neurodevelopment, rehabilitation and other organs

Early intervention (occupational therapy, physiotherapy, speech and feeding therapy), the individualised education plan and augmentative and alternative communication, which does not hinder the development of speech, apply to all the entities [3]. Physiotherapy reduces the risk of contractures, scoliosis and hip dislocation [3]. Nail and phalangeal anomalies are managed conservatively or by hand surgery when there is functional impairment [12]. Hypertrichosis may be treated by hair removal methods, once characterised, with dermatological support [69]. Cardiac, renal, endocrine, ophthalmological and orthopaedic abnormalities receive standard treatment; palpitations or syncope in a patient with a gain-of-function K+ channelopathy justify an electrocardiogram [3, 12]. In families with severely affected children, palliative care, home nursing and carer respite should be considered [3].

7.8 Regulatory status

[77–79, 83–87, 91]

7.9 Clinical trials and treatment studies

The search of ClinicalTrials.gov on 6 November 2026 for TBC1D24, KCNH1, KCNK4, KCNN3, ATP6V1B2, DOORS syndrome, Zimmermann-Laband and Temple-Baraitser identified no trial directed at these entities [91]. The therapeutic evidence comes from case series and preclinical studies.

[10, 42, 45, 54, 58, 59, 63, 92]

None of these studies has a control group, randomisation or a calculable confidence interval for efficacy; the response proportions come from published patients, with publication bias in favour of severe cases or of those with a notable response, and do not allow drugs to be compared with one another [10, 58, 63]. The results in animal and cellular models do not establish efficacy or safety in humans [54, 92].

7.10 Targeted and gene therapies under investigation

Kv10.1 modulators. As all the characterised KCNH1 variants shift activation towards hyperpolarised potentials, Sundman and colleagues argue that an allosteric modulator shifting activation in the depolarising direction would restore normal function, whereas pore blockers (astemizole, imipramine, IC50 1800 nM) suppress function instead of correcting it [45]. Tarantula venom peptides (Ap1a, IC50 236 nM; Aa1a, IC50 640 nM) induce depolarising shifts of +17 to +18 mV and are 13 to 35 times more selective for Kv10.1 than for hERG, but the most severe mutants have shifts that may exceed −90 mV [45]. The central obstacle is selectivity over Kv11.1 (hERG), with 49% identity, whose blockade prolongs the QT interval; all known small-molecule modulators also act on hERG, and astemizole was withdrawn from the market in 1999 for that reason [45]. Thompson and colleagues observed differences in blocking potency between variants for imipramine and for the experimental blocker LY97241, which suggests repurposing opportunities, as yet without clinical study [42]. Level of evidence: preclinical.

Gene therapy for ATP6V1B2. The strategy tested is additive: an adeno-associated virus vector with inner ear tropism (AAV-ie) and a promoter enhancer (Eh3) expressing murine Atp6v1b2, given once into the scala media between postnatal days 0 and 2, in a mouse with inactivation of the gene in hair cells [54]. The treatment prevented hair cell degeneration, normalised lysosomal morphology and rescued auditory and vestibular function for at least 24 weeks [54]. The limitations are substantial: the model reproduces a loss of function, whereas the human missense variants act by upregulation of the V-ATPase, for which gene addition is not rational; the murine neonatal window does not correspond to human cochlear development; and there are no safety, immunogenicity or human trial data [33, 54]. Level of evidence: preclinical.

Modulation of lysosomal pH. The cAMP analogue CPT-cAMP restored lysosomal acidification in cells with p.(Arg506*), crossed the blood-brain barrier and, at 20 mg/kg intraperitoneally, reduced seizures, improved cognitive performance and restored autophagic flux in homozygous mice [92]. For the missense variants that increase acidification, Carpentieri and colleagues propose the opposite rationale, molecules that reduce V-ATPase function [33]. Level of evidence: preclinical.

Other pathways. Antioxidants corrected the defects of the Drosophila model of TBC1D24 p.(Gly501Arg) [59]. Inhibition of ERK1/2 reduced the proliferation of gingival fibroblasts with KCNK4 p.(Ala244Pro), suggesting a future pharmacological complement to surgery [52]. Both are preclinical results.

7.11 Developments in the last 12 months

Between November 2025 and November 2026 there were published a review of the molecular basis of KCNH1 encephalopathy and the therapeutic challenges (Sundman, Brain 2026), the functional characterisation of 26 KCNH1 variants with pharmacological blocking data (Thompson, Brain 2026), the demonstration of the dominant interaction between mutant Kv10.1 and Kv10.2 subunits (Bernert, 2026), the ERK1/2 mechanism of gingival fibromatosis associated with KCNK4 (Wu, 2026) and the modulation of lysosomal pH by cAMP in ATP6V1B2 models (Zheng, 2026) [42, 43, 45, 52, 92]. In 2025 there were published the gingivoplasty protocol for KCNH1 patients, bilateral cochlear implantation in DDOD, AAV gene therapy in the mouse and the mapping of the breakpoints of the 16p13.3 deletions [49, 54, 61, 90]. None corresponds to a clinical trial, results announcement, regulatory application or authorisation.

7.12 Special situations

Pregnancy. In women with KCNH1 epilepsy (including mosaic mothers) or with mild FHEIG, preconception planning should review the antiseizure medicine, avoiding valproate where there is an alternative and following the European pregnancy prevention programme [20, 79]. Phenytoin and carbamazepine in pregnancy may cause teratogenic phenotypes with nail hypoplasia that are confused with these syndromes, as noted in the second TMBTS case, whose epileptic mother took carbamazepine [1, 17]. Pregnancy with a fetus with DOORS is frequently associated with polyhydramnios [3].

Perioperative care. Gingival and dental surgery is usually performed under general anaesthesia in patients with ID; antiseizure medication should be continued, prolonged analgesia planned and the effect of valproate on haemostasis considered [49]. In patients with classic ZLS with cardiomyopathy, aortic dilatation or pericardial effusion, cardiac assessment precedes anaesthesia [13].

Transition to adulthood. Patients with ZLS and FIME reach adulthood; in EPRPDC, seizures remit but exertional dystonia and tremor persist; in classic ZLS, cardiomyopathy and aortic dilatation appeared in the fourth decade [13, 58, 59]. Transition should ensure continuity of epileptology, audiology, dentistry and cardiovascular surveillance in the phenotypes in which these have been described [3, 13].

8. Reproductive Options and Family Counselling

8.1 Autosomal dominant forms (KCNH1, KCNN3, KCNK4, ATP6V1B2)

Most variants arise de novo, but the recurrence risk for the parents of a proband is not negligible, for three documented reasons. First, parental mosaicism: two mothers with isolated epilepsy were low-level mosaic carriers of KCNH1 variants that caused TMBTS in their children [20, 41]. Second, variable expressivity: a mother carrying KCNK4 p.(Ala244Pro) had only hypertrichosis and gingival overgrowth, and relatives of patients with clinical ZLS had minimal forms (mild hypertrichosis, thick nose, ears and lips) [13, 62]. Third, dominant transmission in families with ATP6V1B2 (DDOD over several generations; Polish family with p.(Leu398Val)) and with inherited KCNH1 variants associated with febrile seizures or isolated epilepsy [6, 64, 66]. Testing and examining both parents (nails, gums, hair pattern, seizure history) is therefore recommended, and deep sequencing or sequencing of another tissue should be considered when the variant is not detected in the parents but mosaicism is suspected [12, 41]. An affected carrier has a 50% risk of transmission in each pregnancy, with severity not predictable from the variant [45, 62]. In clinical ZLS, Castori and colleagues concluded that segregation was incompatible with recessive inheritance and that the most likely hypothesis was a dominant mutation with a high mutation rate and rare germline mosaicism [15].

8.2 Autosomal recessive forms (TBC1D24)

The parents of a proband are presumed heterozygous, and molecular testing of both is recommended; each sibling has, at conception, a 25% risk of being affected, a 50% risk of being a carrier and a 25% chance of inheriting neither variant [3]. If only one parent is a carrier, with confirmed parentage, a de novo variant in the proband or parental post-zygotic mosaicism should be considered; if the proband appears homozygous, an undetected deletion and uniparental isodisomy, described for chromosome 16, should be excluded [3, 57]. The siblings of each parent have a 50% risk of being carriers [3]. Heterozygotes are usually asymptomatic, but carriers with seizures (including absences in childhood) and untested relatives with hearing loss have been described, without a risk estimate [3]. Patients with DOORS, PME and DEE have not reproduced in the published series; the children of patients with FIME or DFNB86 are obligate carriers [3]. DFNA65 is transmitted dominantly with a 50% risk [3]. In consanguineous families, such as the Pakistani families with DFNB86 or DOORS families with related parents, carrier screening may be extended to the wider family [27, 57].

8.3 Cascade testing, minors and prenatal diagnosis

Cascade testing of the asymptomatic siblings of a TBC1D24 patient is appropriate to start treatment of seizures and hearing loss early [3]. In minors, testing is justified when it has clinical consequences (seizures, hearing loss); carrier status is mainly of reproductive interest, and counselling on risks and reproductive options should be offered to young adults who are affected, carriers or at risk [3]. Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible; the discussion should take place before pregnancy and respect different perspectives, including those of members of the Deaf community who do not regard deafness as a disease [3]. In a pregnancy at risk of DOORS, increased nuchal translucency and polyhydramnios have been described [3]. In the de novo dominant forms, the residual risk from germline mosaicism justifies offering prenatal diagnosis in subsequent pregnancies, although there is no published risk estimate for these genes [15, 20].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

There is no measured population prevalence estimate for any of these entities. The Orphanet registry counts 9 cases of TMBTS, 52 of ZLS, about 50 cases or families with DOORS, 22 with DDOD and 4 with FHEIG, all in the prevalence class below 1 per million, which is an upper limit and not a measurement [4, 5, 7, 9, 11]. These counts are out of date relative to the literature: in 2021, 27 patients with syndromic KCNH1 variants had been described and, in 2023, 51 with KCNH1 variants and neurological detail; in 2024, up to 10 patients with KCNK4 variants; and GeneReviews refers to at least 200 individuals with TBC1D24 variants [1, 3, 6, 10]. Because many KCNH1 and KCNK4 patients are identified by sequencing in ID or epilepsy cohorts without syndromic suspicion, the real number of carriers exceeds that of clinically recognised syndromes [12, 36]. The proportion of epilepsy attributable to TBC1D24 is unknown and appears small [3].

9.2 Geographical diversity and founder populations

TBC1D24 variants have been described in Moroccan, Pakistani, Czech, Chinese, Brazilian, Polish and northern European populations [3]. In Pakistani families with DFNB86, the variant p.(Asp70Tyr) has a founder effect, and in three Moroccan families recessive TBC1D24 variants were described as frequent in non-syndromic hearing loss [3, 57]. In DOORS, the variant p.(Arg242Cys) was found in the homozygous state in families from the USA, India and Brazil [57]. The in-frame deletion p.(Ile81_Lys84del) of TBC1D24, associated with EPRPDC in two Chinese patients, has a frequency of 1.2 × 10−3 in East Asian individuals [57]. ZLS has been described in India, Trinidad, Mexico and Europe, and TMBTS in Iranian, Algerian, Chinese, Turkish, Lebanese, North American and Hispanic patients [13, 17, 23].

9.3 Portugal and Brazil

In Portugal, the first cohort of hereditary sensorineural hearing loss studied by exome with a 158-gene panel (71 probands, after GJB2/GJB6 screening) identified a cause in 21.1% and a presumptive cause in 8.5%, including TBC1D24 [93]. In Brazil, three cases of DOORS in unrelated children (Felix, 2002), one with congenital heart disease and none with organic acid abnormalities, a DOORS family with homozygous p.(Arg242Cys), TBC1D24 variants in recessive and dominant hearing loss (Quaio, 2022) and a case of ZLS with mild ID, limb asymmetry and hypertrichosis (de Pina Neto, 1988) have been published [3, 13, 27, 57]. The sources consulted do not describe Portuguese patients with KCNH1, KCNK4, KCNN3 or ATP6V1B2 variants, which reflects the sources and not an absence of patients.

9.4 European networks and patient associations

The relevant European Reference Networks are ERN EpiCARE, for rare and complex epilepsies, and ERN ITHACA, for rare congenital anomalies and intellectual disability [94, 95]. The Cure KCNH1 Foundation, founded by parents in the USA, supports research, a patient registry and meetings of families and researchers [96]. The TBC1D24 Foundation, created by two mothers, funds research on natural history, seizures and treatment, with grants awarded through the Orphan Disease Center of the University of Pennsylvania (103,546 dollars in 2022 and 86,962 dollars in 2023) [97]. The Human Disease Genes portal, from Radboudumc, collects and disseminates information on KCNH1 and TBC1D24 for families and professionals [98]. GeneReviews also lists general epilepsy and deaf people's associations [3].

10. Illustrative Clinical Case

Mégarbané and colleagues described in 2016 a Lebanese boy, the third child of healthy non-consanguineous parents, with no relevant family history [23]. He was born at 36 weeks, after a pregnancy in which the mother received drugs for contractions at 32 weeks, weighing 2700 g (60th centile), 48 cm long (75th centile) and with a head circumference of 33 cm (60th centile) [23]. In the first two to three days, marked hypotonia, constipation and absent nails on the thumbs and halluces were noted [23]. At 9 months (9750 g, 71.5 cm, head circumference 42.7 cm, 10th centile) he had a flat occiput, frontal bossing, large ears, mild hypertelorism, epicanthic folds, a broad depressed nasal bridge, a short columella, a long philtrum, a wide mouth with downturned corners, a high-arched palate and full cheeks; the thumbs were adducted, terminally broad and without nails, and the halluces were broad, long and without nails; there was no hirsutism, hypoplasia of the distal phalanges of the other digits or hypermobility [23]. At 15 months the delay was marked — he could not stand or walk with support, nor respond to simple commands —, the face was myopathic, with little eye contact, an open mouth and mild gingival overgrowth; radiographs showed almost absent distal phalanges of the thumbs and halluces, very small femoral and humeral epiphyses and osteosclerosis of the anterior arch of the right tenth rib (figure 1, photographs at 9 and 15 months: https://pmc.ncbi.nlm.nih.gov/articles/PMC4901505/figure/Fig1/; figure 2, radiographs: https://pmc.ncbi.nlm.nih.gov/articles/PMC4901505/figure/Fig2/) [23]. Brain MRI, abdominal and cardiac ultrasound, auditory brainstem responses, EEG, full blood count, biochemistry, thyroid, liver and renal function, comparative genomic hybridisation and chromosomal microarray were normal [23]. Trio genome sequencing identified the de novo KCNH1 variant c.1042G>A p.(Gly348Arg) in the short isoform numbering, corresponding to NM_172362.3:c.1123G>A p.(Gly375Arg) in the MANE transcript, confirmed by Sanger, and two de novo variants of uncertain significance in STK36 and ZNF517 [23, 40]. The child had no seizures at the time of publication [23].

The case illustrates four points. The clinical picture corresponded to TMBTS (anomalies limited to the first rays, without hypertrichosis), but the same variant had been described in a patient with ZLS, which supports the continuum between the two labels [21, 23]. The absence of epilepsy at 15 months does not allow the course to be predicted, because the patient with ZLS carrying the same variant began to have seizures in adolescence and three patients with the same variant p.(Arg357Gln) had different courses [23, 45]. Gingival overgrowth may be absent or mild in the first years and warrants dental surveillance, as shown by the case of a 4-year-old boy with p.(Arg357Gln) who required gingivoplasty for blocked eruption of the deciduous molars (figure 1 of the intraoral examination: https://pmc.ncbi.nlm.nih.gov/articles/PMC12220361/figure/Fig1/; figure 12 of the proposed protocol: https://pmc.ncbi.nlm.nih.gov/articles/PMC12220361/figure/Fig12/) [49]. Finally, genome sequencing was decisive when the array was normal, and the role of the additional STK36 and ZNF517 variants as modifiers remains hypothetical; the management described in the report is descriptive and does not replace formal recommendations, which do not exist [23].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

The prognosis depends mainly on the severity of the epilepsy and the intellectual disability. In the KCNH1 forms with de novo variants, ID is severe in more than 90% of patients, epilepsy occurs in about nine in ten and only a minority become seizure-free; there are adult survivors with ID and active epilepsy, and patients who lose skills [1, 45]. In ZLS3 and in part of FHEIG, ID is mild and there are independent adults [8, 10]. In DDOD, cognitive development may be normal and the functional prognosis depends on auditory rehabilitation [53, 90]. In the TBC1D24 spectrum, the prognosis ranges from FIME with normal development over decades to DEE with death in childhood; 19% of the patients in one series died, at a mean age of 37 months, and loss-of-function variants in at least one allele were associated with drug resistance and death by 7 years of age [58]. In classic ZLS, follow-up of an adult over four decades revealed cardiomyopathy, aortic dilatation and pericardial effusion [13].

11.2 Surveillance

The annual intervals (hearing, teeth, thyroid) are those of GeneReviews for TBC1D24; for the other entities there are no published recommendations and the table applies them by analogy, adjusted to the phenotype [3, 12].

12. Summary and Final Considerations

Temple-Baraitser, Zimmermann-Laband, FHEIG and DOORS syndromes are rare, share nail and phalangeal hypoplasia, gingival overgrowth, hypertrichosis, intellectual disability, hearing loss or epilepsy in different combinations, and result from five genes with two main mechanisms. KCNH1, KCNN3 and KCNK4 cause dominant disease through gain of function of potassium channels; ATP6V1B2 causes dominant disease ranging from deafness-onychodystrophy to intellectual disability with epilepsy, with a mechanism that differs between truncating and missense variants; TBC1D24 causes a recessive spectrum of epilepsies and hearing loss through loss of function, whose syndromic end is DOORS. TMBTS and ZLS1 are expressions of the same KCNH1 spectrum, which includes patients with intellectual disability or epilepsy without syndromic features and mosaic mothers with isolated epilepsy. The diagnosis is molecular, preferably by trio exome or genome, because the phenotype may be incomplete, nail hypoplasia may appear late and genetic heterogeneity is the rule; urinary 2-oxoglutarate is an inconsistent marker of DOORS. There is no targeted treatment or specific guideline: epilepsy is treated according to seizure type, with a high frequency of drug resistance and status epilepticus, a home rescue plan and caution with drugs that aggravate gingival overgrowth; hearing loss benefits from early cochlear implantation; gingival overgrowth requires periodontal surveillance and surgery when it compromises function. The therapies under investigation — allosteric Kv10.1 modulators, adeno-associated virus gene therapy for the inner ear and modulation of lysosomal pH — are at the preclinical stage. Genetic counselling should take into account parental mosaicism and variable expressivity in the dominant forms and the 25% risk in the recessive forms.

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