ZTTK Syndrome (SON)

Zhu-Tokita-Takenouchi-Kim syndrome; SON-related neurodevelopmental disorder; SON haploinsufficiency syndrome

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

1. Introduction

1.1 Definition

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a neurodevelopmental disorder with multiple congenital anomalies caused by heterozygous loss of function of the SON gene, located at 21q22.11. Orphanet defines it as a rare genetic multiple congenital anomaly and dysmorphic syndrome, with developmental delay, ID and mild to moderate facial dysmorphism, associated with variable brain malformations (gyration abnormalities, ventriculomegaly, white matter anomalies, hypoplasia of the corpus callosum and of the cerebellar hemispheres), musculoskeletal anomalies (hemivertebrae, scoliosis or kyphosis, contractures and joint laxity), ocular involvement (strabismus, hypermetropia and cortical visual impairment) and hypotonia; seizures, short stature and urogenital, cardiac and gastrointestinal malformations may complete the picture [2]. The GeneReviews adds that the diagnosis is established only by identification of a heterozygous pathogenic or likely pathogenic variant in SON, because the phenotype is insufficient for a clinical diagnosis [1].

1.2 Initial description and eponym

The eponym combines the first authors of four papers published between 2015 and 2016 [1]. In 2015, Zhu et al., from Duke University, sequenced the exome of 119 trios (patient and parents) with undiagnosed genetic disorders and reached a diagnosis in 29 (24%), with an excess of damaging de novo variants in genes intolerant of variation [18]. One of the patients (trio 91) was a 5-year-old girl with a de novo frameshift variant in SON, developmental delay, epilepsy, minor dysmorphic features, macrocephaly, white matter changes, intestinal atresia and a ventricular septal defect (VSD) [5, 7, 9]. In 2016, Takenouchi et al. (Japan) described a 13-year-old boy with postnatal growth retardation and relative macrocephaly, infantile hypotonia, severe ID, congenital heart disease, long slender limbs with hyperextensible joints, smooth velvety skin and a face with prominent forehead, curly hair, sparse eyebrows, epicanthic folds, flat nasal bridge, short nose, full cheeks and prominent ears, carrying the same de novo frameshift variant, and proposed that SON haploinsufficiency defined a recognisable syndrome; as SON lies in the critical region of Braddock-Carey syndrome (congenital thrombocytopenia, ID, micrognathia and a distinctive face), they suggested that haploinsufficiency of this gene explained the ID of that deletion syndrome [9, 19]. The Japanese authors refer to 109 patients in the original exome study, a figure that differs from the 119 trios of Zhu's article [18, 19].

In the same September 2016 issue of the American Journal of Human Genetics the two series that established the phenotype appeared. Tokita et al. (Baylor and Nantes) identified, among more than 6000 patients studied by exome sequencing, mostly children with neurological disorders, six unrelated individuals with de novo truncating variants; a seventh, identified later, had two de novo missense variants in cis [9, 20]. The seven, aged 3 to 23 years, had a multisystem disorder with persistent feeding difficulties, respiratory difficulty and hypotonia from the neonatal period, developmental delay and congenital malformations, including brain, cardiac and urogenital malformations [9, 20]. Kim et al. (Radboud, University of South Alabama and the DDD study, Deciphering Developmental Disorders) brought together 20 individuals with de novo loss-of-function variants, demonstrated in patient cells reduced transcripts of genes of neuronal migration and metabolism through defective splicing, and reproduced spinal, brain and eye malformations in zebrafish with son knockdown [8, 21]. Four of these 20 individuals had the same recurrent 4 bp deletion, and the dysregulation of target genes observed in patient cells was replicated in HeLa cells with SON knockdown [9]. In zebrafish embryos, reduction of son produced short curved tails, ocular malformations, microcephaly and a deformed body axis, and those that survived longer developed spinal malformations and cerebral oedema [5, 9].

1.3 Subsequent delineation and nomenclature

In 2021, Kushary et al. (Columbia University) added 15 cases and reviewed 45 published ones, for a total of 60 [7]. In 2022, Dingemans et al., with ERN ITHACA, analysed 52 individuals (17 unpublished) and proposed surveillance recommendations [8]. Reports followed that extended the phenotype to the liver, immunity, the heart, the endocrine system and acute neurological episodes [11, 22–26]. The GeneReviews, published in September 2025, is the first management synthesis [1]. One of the authors (E.-Y. Ahn) is co-founder of the ZTTK SON-Shine Foundation and co-chair of its scientific board, and another author sits on the clinical board of the same foundation, as the review itself declares [1].

The name «SON-related neurodevelopmental disorder» follows the dyadic nomenclature (gene and phenotype) proposed by Biesecker et al. in 2021, and «SON haploinsufficiency syndrome» describes the mechanism [1, 27]. Some sources date the first description to 2015, on the basis of Zhu's case, and others to 2016, on the basis of the three publications that characterised the syndrome [8, 28]. Orphanet replaced the former descriptive name with the term «ZTTK syndrome» and withdrew the code for Braddock-Carey syndrome (ORPHA:3323), now inactive [2, 29]. In 2024, Regan-Fendt and Izumi proposed grouping ZTTK with other disorders of nuclear speckle proteins, such as NKAP-related syndrome, TARP syndrome and TAR syndrome (thrombocytopenia with absent radius), under the designation «nuclear speckleopathies» [30]. In OMIM, phenotype entry #617140, created in October 2016 and updated in 2022 with the Dingemans series, uses the name «ZTTK syndrome» (symbol ZTTKS) and keeps as alternative titles «Zhu-Tokita-Takenouchi-Kim syndrome» and the former designation «ZTTK multiple congenital anomalies-mental retardation syndrome», whose term «mental retardation» corresponds to present-day ID; the phenotype-gene relationship has mapping key 3, indicating a known molecular basis, and AD inheritance [9].

1.4 Scope

This article covers ZTTK syndrome due to sequence variants or intragenic deletions of SON and, in the differential diagnosis, the 21q22 chromosomal deletions that include SON together with neighbouring genes (21q22.11q22.12 and former Braddock-Carey syndrome; 21q21.3–q22.13 with RUNX1) and the 21q22.13 deletion that includes DYRK1A. Missense variants of SON, whose pathogenicity is uncertain, are dealt with separately [7, 8].

2. Molecular Genetics and Pathophysiology

2.1 The gene and the protein

SON spans about 34 kb at 21q22.11 and is conserved and ubiquitously expressed; the main isoform has 12 exons, of which exon 3 is long and harbours most of the variants described [4, 8]. The SON protein, of 2426 amino acids, binds RNA and DNA and has three conserved C-terminal domains: an arginine/serine-rich (RS) domain, a G-patch domain and a double-stranded RNA-binding motif [7]. ClinGen classifies SON with sufficient evidence of haploinsufficiency (score 3) and no evidence of triplosensitivity; in gnomAD, the pLI is 1.0 and the observed/expected ratio of loss-of-function variants (LOEUF) is 0.05, reflecting strong selection against loss of one allele [4, 7].

The history of the gene precedes that of the disease by almost three decades. In 1988 a fragment named Son3 was cloned from a human embryonic cDNA library, whose translation revealed short tandem repeats in the central region and homology with structural DNA-binding proteins and with oncoproteins of the MYC and MOS families; in 1994 the gene was isolated from a keratinocyte library, showed expression in several cell types and conservation in vertebrates and insects, and was assigned to chromosome 21 (21q22.1–q22.2), a location now refined to 21q22.11 [5]. The early annotations differed on the structure: an analysis of the chromosome 21 sequence predicted 10 exons in 25 kb, and targeted characterisation of the locus established 12 exons [5]. SON lies in the order GART–SON–DONSON, with SON and DONSON in tail-to-tail orientation, an organisation conserved in the mouse, whose protein shares 84.2% amino acid identity with the human one [5]. The protein localises to the interchromatin granules of the interphase nucleus, with the speckled pattern of splicing factors, and its serine/arginine-rich C-terminal domain is homologous to mRNA processing proteins [5].

2.2 Cellular functions

SON is a splicing cofactor required for correct processing of transcripts with weak (suboptimal) splice sites; it promotes the interaction between SR proteins, such as SRSF2, and RNA polymerase II [1, 4, 31, 32]. It also binds DNA at transcription start sites and represses transcription of some genes by attenuating MLL complex-mediated trimethylation of histone H3 lysine 4 (H3K4me3) [33]. With SRRM2, SON forms the structural core of nuclear speckles, compartments that supply transcription and splicing factors to sites of active transcription [34]. In HeLa cells, reduction of SON causes mitotic abnormalities, «nuclear buds» and micronuclei, linking the protein to genome stability and cell cycle progression [8, 31]. Outside neurodevelopment, SON emerged in a proteomic screen of fertility factors conserved between the nematode and mammals, carried out on spermatogenic chromatin, and in a genome-wide RNA interference screen as a host factor required for trafficking of influenza A virus to late endosomes; the sources consulted do not describe fertility or the course of influenza infections in patients with ZTTK [5].

Reduced SON produces intron retention and exon skipping, with degradation of the misprocessed RNA or unproductive translation [1, 8]. In patient cells, Kim et al. observed reduced transcripts of genes of neuronal migration and cortical organisation (TUBG1, FLNA, PNKP, WDR62, PSMD3, HDAC6) and of intermediary metabolism (PCK2, PFKL, IDH2, ACY1, ADA) through accumulation of defectively spliced transcripts, and proposed SON as a regulator of neurodevelopment [21]. ClinGen further lists targets linked to the centrosome, the mitotic spindle and DNA repair (KATNB1, TUBGCP2, AURKB, PCNT, AKT1, RAD23A, FANCG) [4].

2.3 Disease mechanism and experimental models

The mechanism is haploinsufficiency. In patients, SON transcript and protein levels are reduced relative to the parents [7]. No patients with biallelic loss-of-function variants are known, which suggests that SON is indispensable for cell survival [1]. The models confirm dose dependence. In the mouse, Son knockdown in neural progenitors causes a migration defect in corticogenesis and lower dendritic spine density; the defect is rescued by wild-type human SON and also by the truncated protein encoded by the recurrent variant, but not by a much shorter mutant, which favours haploinsufficiency as the cause independently of variant type [35]. The Son+/− mouse reproduces growth retardation, cognitive impairment, skeletal anomalies and renal agenesis, and shows leucopenia and immunoglobulin deficiency; haematopoietic stem cells are skewed towards the myeloid lineage, with compromise of the B lineage and ineffective erythropoiesis [36]. In an independent study, SON emerges as an essential target of N6-adenosine methylation (m6A) for haematopoietic stem cell fate [37]. In renal cell lines and patient cells, reduced SON alters splicing and lowers expression of known genes of congenital anomalies of the kidney and urinary tract (CAKUT), which underpins the proposal to include SON in CAKUT panels [38]. SON knockdown in neuronal and glial cell lines reduces PRRT2 mRNA through failure to remove intron 2, with a premature stop codon, without altering CACNA1A, ATP1A2 or SCN1A; SCN1A mRNA increased, which also suggests a repressor effect [26]. A 2025 preprint (bioRxiv, not peer reviewed) describes regulation of neuronal morphogenesis by the NUAK1 kinase through SON, a preliminary preclinical finding [39].

2.4 Inheritance

Inheritance is autosomal dominant. In the Dingemans series, 49 of the 52 individuals had a proven de novo variant and 3 had undetermined inheritance; in the Kushary series, all variants were de novo when both parents were tested [7, 8]. The sources consulted do not describe transmission from an affected parent or proven parental mosaicism [1, 7, 8].

2.5 Variant spectrum

Truncating variants predominate. Among the 52 individuals of Dingemans there were 40 frameshift, 5 nonsense, 2 in-frame deletions, 3 missense and 2 whole-gene deletions; all sequence variants were in exon 3, distributed along it, except one in exon 4, without clustering in domains [8]. Among the 48 unique variants reviewed by Kushary there were 33 frameshift (69%), 6 nonsense (13%), 1 splice site (2%), 6 missense (13%) and 2 in-frame deletions (4%); all loss-of-function variants were absent from gnomAD v2.1.1 [7]. Whole-gene deletions and large intragenic deletions are detected by microarray or CNV analysis and account for about 1% of the variants recorded in HGMD (Human Gene Mutation Database), according to the GeneReviews [1, 8].

The most frequent variant is NM_138927.4:c.5753_5756del, p.(Val1918GlufsTer87), a 4 bp deletion in the RS domain of exon 3 predicted to undergo nonsense-mediated decay (NMD). It was present in 13 of the 52 individuals (25%) of Dingemans and in 10 of the 60 cases (17%) pooled by Kushary [7, 8]. The GeneReviews rounds it to 20–25% of reported pathogenic variants and writes it on NM_032195.3, which is not the MANE transcript; the genomic coordinate is the same, NC_000021.9:g.33554984_33554987del [1, 6]. The same deletion is described as ENST00000356577.4:c.5751_5754delAGTT in the original article by Zhu et al. and as c.5751_5754delAGTT in an Italian report, because it lies in a repeated sequence [5]; normalisation to the most 3′ position gives c.5753_5756del [6, 22]. Other recurrent variants, in two individuals each, are p.(Val629AlafsTer56), p.(Met1284IlefsTer2), p.(Val2004TrpfsTer2) and p.(Arg1112Ter) [8].

The articles use earlier versions of the same transcript (NM_138927.2 and NM_138927.3); for the variants in the table, the c. positions coincide with those of the current MANE version [6–8]. The last six rows of the table correspond to the allelic variants selected by OMIM from the founding series, all de novo, identified by exome sequencing and absent from ExAC or from more than 2000 controls; normalisation in VariantValidator kept the original positions [5, 6]. In the report by El-Said et al., the variant of the second case appears as «p.R10X or c.27dupT», two notations that do not describe the same change; it cannot be normalised from the article [25].

2.6 Missense variants

The role of missense variants is uncertain. The three individuals with missense variants in the Dingemans series, p.(Thr579Ser) de novo, p.(Ser1843Tyr) and p.(Ser223Leu), had no brain anomalies (0/3, against 90% in individuals with loss of function); one had severe ID, another had no ID and the third only motor delay, and one had osteochondroma and haemangiomas [8]. The p.(Thr579Ser) variant did not alter splicing of the known targets (ACY1, PNKP, TUBG1, WDR62, PFKL, PSMD3) or the expression of ADA and HDAC6, and the three were classified as variants of uncertain significance (VUS); the gnomAD missense Z score is only 1.54, indicating little constraint on this class [8]. Kushary described the missense p.(Arg1072Cys), present once in gnomAD, in a patient with regression after encephalitis, classified as VUS, and the comparison of 6 missense or in-frame deletions with 54 loss-of-function variants showed more abnormal neuroimaging, genitourinary anomalies and growth failure in the latter [7]. Tokita described an individual with two de novo missense variants in cis, p.(Thr1637Ser) and p.(Ser1843Tyr), with ID, hypotonia, gallbladder agenesis, left pulmonary agenesis and multiple heart defects [7]. A boy of consanguineous parents with the homozygous missense p.(Ala557Val), medulloblastoma and café-au-lait macules, whose parents had the same macules without neoplasia, was cited without conclusions [8]. SON missense variants may therefore correspond to another mechanism or to a distinct overlapping entity, and should not be interpreted by loss-of-function criteria [8].

2.7 Genotype-phenotype correlation, penetrance and modifiers

The GeneReviews does not recognise clinically useful genotype-phenotype correlations [1]. Variability is wide even among the 13 carriers of the recurrent variant in the Dingemans series [8]. Kushary observed heart disease in 5 of 8 carriers of the recurrent variant (63%) against 19 of 37 of the others (24%), a difference based on small numbers, and found no relationship between variant type and severity of neurodevelopmental involvement [7]. Penetrance of truncating variants appears complete for developmental delay in the published series, which are biased towards patients with ID [7, 8]. There are reports of dual diagnosis or modification: a patient with IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X-linked) due to a FOXP3 variant and a pathogenic variant in SON, with both conditions atypical, and a patient with ZTTK in whom blood RNA sequencing identified a second relevant gene, CEP120 [43, 44]. The GeneReviews accepts that genetic background, environmental and nutritional factors or modifiers may explain part of the variability [1].

2.8 Allelic disorders and contiguous deletions

No other germline phenotypes associated with SON are known [1]. Chromosomal deletions that include SON and neighbouring genes produce overlapping pictures, with components specific to the other genes lost, such as thrombocytopenia when RUNX1 (21q22.12) is included; they are covered in the differential diagnosis [15, 17, 25].

2.9 Bibliographic problem in the GeneReviews

The GeneReviews attributes large intragenic deletions of SON to four papers, among them Luo et al. 2023 [1]. That article is a haematopoietic stem cell biology study on SON as a target of m6A methylation, and neither its title nor the journal in which it appeared (Cell Stem Cell) indicates a description of patients with ZTTK; the citation appears inappropriate and should not be used as a source for deletions in patients [37].

3. Clinical Spectrum and Manifestations by System

3.1 Data sources and their limits

Clinical knowledge rests on three partially overlapping series. The Dingemans et al. (2022) series brought together, by systematic review of the literature up to August 2020 and by contacts through GeneMatcher, 52 individuals (35 published and 17 unpublished), half female, with a median age at examination of 6 years and 8 months (1 year and 9 months to 34 years), from several European countries and the United States; the frequencies of the series refer to the 49 with a loss-of-function variant [8]. The Kushary et al. (2021) series described 15 new individuals and pooled 60 cases with 45 previously published, including nine from DECIPHER [7]. The GeneReviews combined these two series and the review by Tang et al. (2023) in a frequency table without denominators per item [1, 45]. The published cases are mostly children and adolescents under 20 years of age, longitudinal data are scarce and the series tend to include the most severely affected patients, who reach sequencing earlier [1, 8]. The percentages describe cohorts of diagnosed cases, not the population of carriers.

The table uses P3 for the 3rd centile and GH for growth hormone. The GeneReviews describes the delay as mild to profound and the ID as moderate to severe in the same table, whereas the Dingemans series found mild ID in 21% [1, 8].

3.2 Development and cognition

Developmental delay is present in all individuals described. Generalised infantile hypotonia delays head control, sitting, crawling and walking [1]. In the 60 cases of Kushary, independent walking appeared between 24 months and 9 years, a quarter of the individuals with documented language were non-verbal and half of these also did not walk; comprehension was better than expression [7]. Developmental regression occurred in 3 of 7 individuals of Tokita and in 2 of 15 of Kushary, in one of them after encephalitis with intractable seizures [1, 7]. Behavioural problems include sleep disturbance, autism spectrum disorder (ASD), emotional dysregulation and aggression [1, 8]. In the Tokita et al. series, 3 of the 7 individuals had ASD [9]. A report from Turkey described obsessions, insomnia and self-injury in an 11-year-old boy [46]. In adults, autism was more frequent (2 of 4) than in those under 18 years (3 of 41, 7%), a finding that suggests late manifestation or late recognition, with small numbers [8].

3.3 Brain malformations

Among the 41 individuals of Dingemans with neuroimaging, 37 had anomalies: ventriculomegaly in 24 (59%), corpus callosum anomalies in 18 (44%), of which hypoplasia in 7, cortical dysplasia in 7 (17%), white matter changes in 6 (15%) and cerebellar changes in 6 (15%) [8]. In the founding series, neuroimaging was abnormal in 89% of the 20 individuals of Kim et al. (abnormal gyration patterns, ventriculomegaly, arachnoid cysts, hypoplasia of the corpus callosum and cerebellum, periventricular white matter loss) and in 5 of 6 of those of Tokita et al. (enlarged ventricles, thin corpus callosum, arachnoid cysts, periventricular leucomalacia) [9]. The GeneReviews adds periventricular nodular heterotopia, subependymal grey matter heterotopia, polymicrogyria or simplified cortex and enlarged subarachnoid space [1]. Halliday et al. described, in 7 individuals (5 identified on the basis of periventricular nodular heterotopia), a pattern they consider characteristic: periventricular nodular heterotopia, elongated pituitary stalk, enlarged cerebellum with abnormal posterior fossa, rounded caudate nuclei, hippocampal malformations and polymicrogyria or dysgyria [47]. A 2-year-old boy had septo-optic dysplasia, with partial agenesis of the corpus callosum and of the septum pellucidum, optic nerve hypoplasia and a small pituitary with a thin stalk, nystagmus, congenital hypothyroidism and growth retardation [41]. Hydrocephalus has also been described [46].

3.4 Epilepsy

The GeneReviews places seizure onset between infancy and 6 years; in the cases pooled by Kushary, onset ranged from 6 months to 8 years [1, 7]. In the Kim et al. series, about half of the 20 individuals had seizures with onset between 1 and 6 years [9]. Focal impaired awareness seizures, complex febrile seizures, generalised tonic-clonic and focal seizures have been described [1]. Of the 31 patients with seizures pooled by Kushary, 5 (16%) had status epilepticus and 8 (26%) febrile seizures [7]. In the new Kushary series, 5 of the 9 children with seizures had fever-triggered seizures and the seizures were generally controlled with levetiracetam, carbamazepine or clobazam [7]. The electroencephalogram (EEG) was abnormal in 11 of 48 individuals of Dingemans [8].

3.5 Acute neurological episodes: hemiplegic migraine, confusional migraine and stroke-like episodes

Langford et al. described a North American boy with recurrent episodes of altered consciousness, headache and transient right hemiparesis after minor head injuries from 2 years and 11 months of age, interpreted as hemiplegic migraine; in the most severe episode there was status epilepticus, left hemispheric cortical oedema and asymmetric slowing on EEG, with imaging resolution within 4 months [26]. The authors linked the picture to the reduction of PRRT2 induced by SON deficiency and propose studying SON in recurrent hemiplegic migraine of unknown cause [26]. In Spain, a child was described in 2026 with episodes of acute confusional migraine (transient confusion and agitation, non-specific EEG, normal laboratory tests and neuroimaging), which, given the limited communication, may be mistaken for epileptic seizures [48].

El-Said et al. reported two girls aged 11 and 12 years with acute left hemiplegia and restricted diffusion on magnetic resonance imaging (MRI) not respecting vascular territories, termed «metabolic stroke» (stroke-like episode) [25]. The first had a 589 kb deletion at 21q22.11 that included SON and six other genes, encephalopathy, gaze deviation, lateralised periodic activity on EEG and plasma lactate up to 3.0 mmol/L; study of the mitochondrial genome and the nuclear mitochondrial gene panel were negative and she recovered within 2 weeks. The second recovered within 1 week without treatment [25]. The authors cite a 10-month-old infant with hemiplegia, status epilepticus and infarcts in multiple territories, with recovery within 2 months, and stroke was described in the Turkish boy mentioned above [25, 46]. The proposed link is the role of SON in splicing of energy metabolism genes; the mechanism of these episodes is not established [25].

3.6 Movement disorders

Dystonia and tremor have been described, without systematic characterisation [1]. An adult with childhood onset developed cervical dystonia and dystonic limb posturing with progressive worsening and functional disability, as well as intention tremor, and was diagnosed in adulthood on the basis of the motor picture [49]. In three of the 60 pooled cases, the initial hypotonia progressed to spasticity [7].

3.7 Face and skull

About 95% of individuals have some combination of facial features: downslanting palpebral fissures (52%), nasal bridge changes (56%), short or smooth philtrum (54%), low-set ears (53%), midface retrusion (34%), horizontal eyebrows (32%), facial asymmetry (30%), deep-set eyes (27%), epicanthic folds (20%), posteriorly rotated ears (15%), thin upper lip (13%), ptosis, prominent forehead, bifid uvula and high palate [1, 8]. Reports add curly hair, long eyelashes and a triangular face [10, 11, 19]. Despite this list, computerised facial analysis of 26 photographs did not distinguish patients from matched controls with ID (p = 0.37): there is no consistent facial gestalt [8]. Craniosynostosis (metopic, sagittal or coronal) has been described in 6 individuals, about 10% [1, 26].

3.8 Musculoskeletal system

Skeletal anomalies affect 83% of the individuals of Dingemans: joint hypermobility in 35%, foot anomalies in 40%, flat feet in 23%, digit anomalies in 23%, skull anomalies in 21% and abnormal spinal curvature in 15% (7 of 48) [8]. The 60 cases of Kushary include hemivertebrae in 3, scoliosis in 3 and lumbar hyperlordosis in 1, as well as clinodactyly or syndactyly, pes planovalgus, pes cavus and clubfoot [7]. Thumb agenesis, rib fusions, contractures of small and large joints, hyperextensibility of the interphalangeal joints and elbows and delayed bone age have been described [1]. In the 5 adults of Dingemans, spinal curvature was present in 3 of 4 and contractures in 2 of 4 [8]. A 7-year-old Czech boy required spinal fusion for neuromuscular scoliosis with a Cobb angle of 95° [28].

The GeneReviews estimates the combined frequency of scoliosis and kyphosis at 6%, based on Kim 2016 and Tokita 2016 [1]. This figure does not agree with the Dingemans series (15% at all ages and 3 of 4 adults) or with the progression described in adults, and appears to underestimate the problem; spinal surveillance should take into account the higher frequency and its increase with age [1, 8].

3.9 Eyes and hearing

Strabismus, childhood-onset hypermetropia and cortical visual impairment are the most frequently described ocular manifestations [1]. In the Dingemans series, hypermetropia was present in 19% and cortical visual impairment in 11% [8]. In the Kim et al. series, 15 of the 20 individuals had visual problems (cortical visual impairment, hypermetropia, optic atrophy and strabismus), and in that of Tokita et al. convergent and divergent strabismus, nystagmus, visual loss and optic atrophy were described [9]. Nystagmus and optic nerve hypoplasia in the setting of septo-optic dysplasia, and congenital amblyopia, have been described [40, 41]. Hearing loss affects about 15%: 3 of 7 individuals of Halliday (one with conductive hearing loss), a child with bilateral hearing loss at 4 years and another with congenital bilateral hearing loss; the age at onset is generally unknown [1, 7, 8]. Recurrent otitis media occurred in 13% [8].

3.10 Growth, feeding and endocrine system

Growth failure often begins before birth: 27 of 49 individuals had prenatal or birth anomalies, 13 were born preterm and 12 of 36 had a birth weight below P3 [8]. After birth, 64% have feeding difficulties, 56% low weight, 54% short stature and 28% small head circumference, with no parameter above P97 [8]. Feeding difficulties contribute to failure to thrive [1]. A 2023 Chinese review recorded short stature in about 29% of cases, and the accompanying case had malnutrition [11, 45]. Final adult height is not documented [1].

GH deficiency was documented in 6 of 43 individuals of Dingemans and in two Chinese reports (peaks of 7.37 ng/mL at 13 years and 8.1 ng/mL at 11 years, with a cut-off of 15 ng/mL) [1, 7, 42, 50]. That cut-off is higher than the current British one, below 6.7 ng/mL (20.1 mIU/L), a difference that depends on the immunoassay and the protocol and makes diagnoses poorly comparable between studies [11]. Hypopituitarism with hypothyroidism, congenital hypothyroidism associated with septo-optic dysplasia, premature adrenarche and, in adults, early-onset arterial hypertension (2 of 4, at 23 and 34 years) have been described [8, 11, 28, 41]. Metabolic disturbances were recorded in 22% and dental changes, mainly of the enamel, in 17% [8].

3.11 Kidney and genitourinary tract

Renal anomalies are present in about 38%: horseshoe kidney (13%), renal cysts (13%), single kidney, unilateral or bilateral renal hypoplasia or dysplasia and duplex kidney [8, 24, 38]. In the Kim et al. (2019) series, 8 of 14 patients had renal anomalies and some had recurrent urinary infections, electrolyte disturbances and hypertension [38]. In the 60 cases of Kushary, vesicoureteric reflux appeared in 3 of 18 assessed, and prenatal pyelectasis and echogenic medullary pyramids were described [7]. Genital anomalies include chordee, cryptorchidism, inguinal hernia, shawl scrotum and hypoplastic labia majora [1]. Recurrent urolithiasis has been described [46].

3.12 Heart

Congenital heart disease affects about one third: in the Dingemans series, 15 of 46, mainly atrial septal defect (ASD, 6) and VSD (4), and a dysplastic aortic valve and anomalous position of the carotid arteries were described [1, 7, 8]. A review of 51 published cases in 2026 found heart disease in 11 (22%): isolated ASD in 4, VSD in 1, ASD with VSD in 2, tetralogy of Fallot in 1, hypoplastic left heart syndrome in 1, recurrent myocardial injury in 1 and unspecified in 1; septal lesions account for 64% and the same article described the first Shone complex (supravalvular mitral membrane, parachute mitral valve, subaortic stenosis and coarctation) [24]. The most severe published form is that of a Japanese newborn with a hypoplastic left heart variant diagnosed at 34 weeks, palliated with septostomy, pulmonary artery banding and ductal stenting, who died suddenly on day 168 [10]. In China, a 7-year-old girl had three episodes of myocardial injury after respiratory infections over three years, with raised cardiac enzymes and T-wave changes, which raises the hypothesis of myocardial susceptibility [40]. As a hypothesis, Coleman et al. point to abnormal splicing of IDH2 and PCK2, genes of cardiomyocyte metabolism [24].

3.13 Blood and immunity

Thrombocytopenia and deep vein thrombosis have been described in about one third [1]. In the Dingemans series, 15 of 46 had immunological abnormalities, mainly IgA and IgG deficiency, with recurrent respiratory and urinary infections and otitis [1, 8]. In the Tokita et al. series, 3 of the 7 individuals had reduced IgA or IgG and 2 had coagulation abnormalities, of unspecified type in the OMIM synopsis [9]. Van Stechelman et al. published hypogammaglobulinaemia in two children, and a British child had severe bronchiolitis requiring invasive ventilation at 3 months and 8 admissions for respiratory infections over 2 years [11, 23]. The Son+/− mouse reproduces the leucopenia and immunoglobulin deficiency [36]. No neoplasms were recorded in 46 individuals with loss-of-function variants [8].

3.14 Digestive system and liver

In addition to feeding difficulties, intestinal malrotation, duodenal or intestinal atresia, gastro-oesophageal reflux disease, chronic diarrhoea, recurrent vomiting, constipation and gallbladder agenesis have been described [1, 7]. Taking all digestive abnormalities together, the Dingemans series recorded gastrointestinal abnormalities in 71% of individuals with loss of function; the difference from the 22% with structural malformations indicates that this category includes functional abnormalities, such as feeding difficulties [8, 9]. An Italian patient with the recurrent variant had chronic liver disease with micro- and macronodular cirrhosis, and the diagnosis of ZTTK was made only during investigation of the liver disease; the authors recommend screening the liver from the first years of life [1, 22].

3.15 Skin, nails and teeth

Skin, hair or nail abnormalities were recorded in 41% [8]. Retronychia of the toenails and dental anomalies, absence of the nails of the 4th and 5th toes, slow nail growth, microdontia, delayed tooth eruption, facial capillary malformation and a café-au-lait macule have been described [11, 24, 51].

3.16 Adults and natural history

The natural history in adulthood is poorly known. The five adults of Dingemans had ID (severe in 3), brain anomalies, musculoskeletal abnormalities with spinal curvature in 3 of 4, autism in 2 of 4 and hypertension in 2 of 4 [8]. The adult of Indelicato et al. had progressive dystonia [49]. The available data come almost entirely from children observed under usual supportive care (physiotherapy, tube feeding, antiseizure medicines, cardiac surgery), and there is no description of the course without that care or of any disease-modifying treatment.

4. Clinical Recognition and Warning Signs

4.1 Principle

ZTTK syndrome has no pathognomonic sign or face recognisable by computerised analysis, and a clinical suspicion must always be confirmed by molecular testing [1, 8]. Suspicion arises from the combination of developmental delay with malformations in several organs, especially when structural brain anomalies (ventriculomegaly, heterotopia, corpus callosum anomalies), feeding difficulties, short stature, renal anomalies, septal heart disease and immunological or haematological abnormalities occur together [1, 8]. Before diagnosis, Kushary's patients had been assessed for RASopathy, tuberous sclerosis and Coffin-Siris syndrome, and all had undergone karyotype, microarray and methylation studies for Angelman and Prader-Willi without result [7].

4.2 By age and setting

4.3 Warning signs and urgent situations

Status epilepticus occurred in 16% of patients with seizures [7]. An acute focal neurological deficit (hemiparesis, gaze deviation, encephalopathy) may correspond to hemiplegic migraine, a stroke-like episode or a postictal state and requires urgent assessment with neuroimaging and EEG; in the cases described, recovery occurred within 1 week to 4 months [25, 26]. Episodes of confusion and agitation may be confusional migraine and be mistaken for seizures [48]. Heart failure in the newborn with complex left-sided heart disease was fatal in the only published case, and recurrent post-infectious myocardial injury presented with fatigue and palpitations [10, 40]. Severe or recurrent infections suggest hypogammaglobulinaemia [1, 23]. Easy bruising or bleeding should prompt a full blood count, because thrombocytopenia is one of the haematological manifestations described [1]. Choking, food refusal, frequent respiratory infections or poor weight gain suggest dysphagia with risk of aspiration [1]. A limp or hip or knee pain during somatropin treatment may correspond to slipped capital femoral epiphysis [52].

4.4 Newborn screening

ZTTK syndrome is not part of any newborn screening programme in the sources consulted, and there is no biochemical biomarker of SON deficiency [3].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

There are no formal clinical criteria. The GeneReviews defines suggestive findings (developmental delay with occasional regression, ID, hypotonia and feeding difficulties in infancy, skeletal, ophthalmological, craniofacial and brain anomalies, failure to thrive, behavioural changes, epilepsy, movement disorder, genitourinary and renal anomalies, thrombocytopenia or thrombosis, heart disease, immunodeficiency, digestive malformations and GH deficiency) and establishes the diagnosis in a proband with those findings and a heterozygous pathogenic or likely pathogenic variant in SON [1]. Pathogenic and likely pathogenic variants have the same clinical value under the standards of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP); a VUS neither confirms nor excludes the diagnosis [1, 53]. A deletion that includes the whole SON gene has the same diagnostic meaning as a truncating variant, given the ClinGen haploinsufficiency score of 3, but the phenotype of a larger deletion depends on the neighbouring genes lost [4, 17, 25].

5.2 Testing algorithm

In a child with developmental delay or an older individual with ID, the first-line test is exome or genome sequencing [1, 54]. The 2021 ACMG evidence-based guideline strongly recommends considering exome or genome as a first- or second-tier test in paediatric patients with congenital anomalies with onset before 1 year or with developmental delay or ID with onset before 18 years, because of its higher yield compared with conventional tests [13]. A Dutch study showed the performance of genome sequencing as a first-tier test in neurodevelopmental disorders [55]. Chromosomal microarray detects whole-gene deletions and contiguous 21q22 deletions; brain malformation, ID, ASD or epilepsy panels identify the cause after a negative microarray, provided they include SON, which not all commercial panels do [1]. Sequencing targeted only at SON is rarely useful and is not recommended [1].

These percentages, based on HGMD, describe the proportion of known variants that each method detects and not the clinical sensitivity of the test [1].

5.3 Limits of testing

A negative exome does not exclude the syndrome. Langford's patient had an initially negative clinical trio exome and the diagnosis emerged only on reanalysis in an undiagnosed diseases programme [26]. The patient of Lee et al. had a normal microarray and normal ID and developmental disorder panels and was diagnosed only by genome sequencing at 10 years [11]. Exomes have reduced sensitivity for mosaicism; the laboratory in the Irish case stated sensitivity above 99% for single nucleotide variants and small indels with coverage above 20-fold, but limited capacity for mosaicism [24]. Deep intronic variants and balanced structural rearrangements may escape the exome; blood RNA sequencing, in a Canadian study of 134 children already assessed by genome sequencing, added diagnostic information in a patient with ZTTK [44]. SON missense variants call for caution, as they have a different phenotype and mechanism [8]. The authors of the GeneReviews offer to review VUS in SON and families without an identified causal variant [1].

5.4 Content of the report

The report should state the gene, the transcript and its version (NM_138927.4, MANE Select), the variant in HGVS nomenclature with the protein consequence (for example, NM_138927.4:c.5753_5756del, p.(Val1918GlufsTer87)), zygosity (heterozygous), origin when the parents are tested (de novo or inherited) and the ACMG/AMP classification with the criteria used [6, 53]. When the laboratory uses NM_032195.3, as the GeneReviews does, or earlier versions of NM_138927, genomic equivalence should be confirmed before comparison with databases [1, 6]. For deletions, the report should state the genomic coordinates, the reference genome version and the genes included, especially RUNX1 and DYRK1A [15, 16, 25].

5.5 Complementary assessment and extent of disease

No non-molecular investigation is diagnostic; brain MRI, EEG, spinal radiographs, renal ultrasound, audiological and ophthalmological assessment, echocardiogram, full blood count, immunological and endocrinological assessment define the extent of the disease [3]. The assessment recommended after diagnosis is summarised below [1, 7, 8, 22].

5.6 Prenatal diagnosis

The first published prenatal diagnosis was made by trio exome in a pregnancy with early fetal growth restriction, dysgenesis of the corpus callosum, cortical anomalies and digestive malformations, according to the description by Lee et al. of the work of Carmant et al.; the latter proposes agenesis of the corpus callosum, malformations of cortical development, duodenal atresia and fetal growth restriction as prenatal markers [11, 12]. The Japanese newborn with left-sided heart disease had fetal growth restriction and breech presentation, and the karyotype and fluorescence in situ hybridisation (FISH) for 22q11.2 were normal before the postnatal exome [10]. When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible [1].

6. Differential Diagnosis

6.1 Approach

Because the phenotype is not specific, the differential covers all disorders with developmental delay and ID without other distinguishing findings, including the OMIM phenotypic series of autosomal dominant, autosomal recessive and X-linked, syndromic and non-syndromic ID [1]. In practice, exome or genome sequencing with CNV analysis resolves most of these differentials in a single test [1, 13]. The differentials of greatest clinical interest are the 21q22 deletions, because they share SON or neighbouring genes with consequences of their own.

6.2 21q22 deletions that include SON

SON lies at 21q22.11, upstream of RUNX1 (21q22.12) and DYRK1A (21q22.13) [1, 15, 16]. Interstitial deletions of this region have variable breakpoints and the phenotype depends on the size and the genes lost [15]. Braddock-Carey syndrome was delineated as a 21q22 contiguous gene syndrome that includes RUNX1, with Pierre Robin sequence, agenesis of the corpus callosum, dysmorphism, ID, enamel hypoplasia and congenital thrombocytopenia [15]. Takenouchi et al. proposed that loss of SON explains the ID of these patients and loss of RUNX1 the thrombocytopenia [19]. Orphanet deactivated the code for Braddock-Carey syndrome and keeps 21q22.11q22.12 microdeletion syndrome, with growth retardation, ID with severe language delay, thrombocytopenia and dysmorphism [14, 29]. In a Moroccan boy with an 8.2 Mb de novo deletion at 21q21.3–q22.13 that included SON and RUNX1, the picture comprised global delay, microcephaly, epilepsy and passive hydrocephalus [17]. The 589 kb deletion at 21q22.11 in El-Said's patient included SON and six other genes (TMEM50B, GART, DONSON, CRYZL1, ITSN1, ATP5O), without RUNX1, and the phenotype was that of ZTTK with a stroke-like episode [25].

Inclusion of RUNX1 changes follow-up. With germline RUNX1 variants, the lifetime risk of haematological malignancy is 25–50%, mainly acute myeloid leukaemia and myelodysplastic syndrome, with a median onset at 33 years [15]. The RUNX1 GeneReviews did not include contiguous deletions in that calculation; applying the same risk to a 21q22 deletion with RUNX1 is an extrapolation, but justifies referral to haematology and the surveillance proposed for RUNX1-FPDMM (clinical examination every 6–12 months and full blood count with differential every 3–4 months) [15]. The thrombocytopenia described in ZTTK due to an intragenic SON variant does not imply this risk, and no neoplasms were recorded in 46 individuals with SON loss of function [8].

6.3 DYRK1A syndrome and 21q22.13 deletion

DYRK1A syndrome results from haploinsufficiency of DYRK1A due to a truncating variant, deletion or translocation and accounts for 0.1–0.5% of people with ID or autism [16]. 21q22.13 deletions that include DYRK1A are rare and produce a similar phenotype, with developmental delay, poor language, ataxic gait, short stature, low weight, seizures and a distinctive face; larger deletions, extending to other bands, may be more severe [16]. Compared with ZTTK, microcephaly is constant and cardinal in DYRK1A syndrome and present in only 28% of patients with ZTTK; DYRK1A syndrome has hypertonia and gait abnormality, whereas ZTTK mainly has hypotonia; and the face of DYRK1A syndrome (deep-set eyes, prominent ears, slightly upslanting fissures, short nose with broad tip and retrognathia) is more recognisable than that of ZTTK [8, 16]. Frequent structural brain malformations, renal anomalies and immunological abnormalities weigh in favour of ZTTK [8]. The distinction is made by exome or microarray [16]. DYRK1A syndrome is part of the differential.

6.4 Other differentials

In the newborn with complex left-sided heart disease and dysmorphism, the main differential is 22q11.2 deletion syndrome; hypermobility, a prominent forehead and curly hair should prompt consideration of ZTTK [10]. In episodes of transient hemiparesis, the absence of variants in CACNA1A, ATP1A2, SCN1A and PRRT2 in a patient with syndromic ID should lead to including SON in the analysis [26]. In stroke-like episodes, the negative mitochondrial study in El-Said's patient separates this picture from MELAS [25, 57]. The nuclear speckleopathies share developmental delay and the general mechanism of altered RNA processing, and TAR syndrome is distinguished by thrombocytopenia with absent radius [30].

7. Treatments and Risk Management Strategies

7.1 Principles and framework

There is no treatment acting on SON deficiency and no specific clinical practice guideline [1, 3]. Treatment is supportive, multidisciplinary and guided by the manifestations, with the aim of preserving function and quality of life and preventing complications [1]. The available syntheses are the 2025 GeneReviews and the surveillance recommendations of the Dingemans et al. series, which are expert opinion based on case series [1, 8]. The published cardiological and anaesthetic reviews confirm the absence of specific recommendations [24, 28]. All doses in this article are therefore those of the official labels for the closest indication or for analogous conditions, and their use in ZTTK is off-label when the corresponding approved indication is absent (for example, proven GH deficiency or focal epilepsy).

7.2 Treatment by manifestation

7.3 Development, rehabilitation and behaviour

The GeneReviews describes the North American organisation, which varies between countries: early intervention from 0 to 3 years (occupational therapy, physiotherapy, speech and feeding therapy, infant mental health and special education), developmental preschool from 3 to 5 years and, at all ages, an individualised education plan reviewed annually, with a transition plan in adolescence [1]. Physiotherapy aims to maximise mobility and reduce late orthopaedic complications (contractures, scoliosis, hip dislocation), with wheelchairs, walkers, orthoses and other equipment [1]. Occupational therapy works on fine motor skills for feeding, hygiene and dressing [1]. Dysphagia is assessed at every visit and, in the presence of choking, poor weight gain, frequent respiratory infections or food refusal, justifies a clinical or radiological swallowing assessment [1]. Because a substantial proportion of patients do not speak, augmentative and alternative communication should be assessed by a speech and language therapist, from picture exchange systems to speech-generating devices; its use does not hinder speech development [1, 7]. For ASD, behavioural intervention is recommended, including applied behaviour analysis (ABA, applied behavior analysis), and the developmental paediatrician guides behavioural strategies and medication when needed [1]. Adapted sport is part of support for participation [1].

7.4 Growth: somatropin

Drug and mechanism. Somatropin is recombinant human growth hormone (rhGH), administered subcutaneously; the labels consulted were that of Genotropin® in the United States and that of Omnitrope®, centrally authorised in the European Union since 12 April 2006 [52, 58].

Indication in ZTTK. In proven GH deficiency, described in about 14% of patients, somatropin is used under the approved indication of GH deficiency [1, 8]. Outside deficiency, ZTTK is not among the indications of the European label or of NICE appraisal TA188 (GH deficiency, Turner syndrome, Prader-Willi, chronic renal insufficiency, child born small for gestational age with growth failure at 4 years or older, SHOX deficiency) [58, 59]. In the United States there is an indication for idiopathic short stature (height ≤ −2.25 standard deviations, SD, with a growth velocity that does not allow normal adult height, open epiphyses and other causes excluded), which does not exist in the European Union; a child with ZTTK does not have idiopathic short stature, because the cause is known [52, 58]. Some children with ZTTK were born small for gestational age (birth weight below P3 in 12 of 36) and may meet the criteria for that indication, a decision for the endocrinologist in each case [8, 58].

Data in ZTTK. Dingemans reports three children with GH deficiency and another three in whom somatropin improved short stature, without quantitative data; a 15-year-old girl was treated with a response described as adequate, without published measurements [7, 8]. A conference abstract described a 5-year-old child with GH deficiency with minimal response after 5 years of high-dose treatment (0.05 mg/kg/day), with height from −4.05 to −3.98 SD [11]. The most complete report is that of Lee et al. (2026): in a girl without GH deficiency (peak GH of 7.2 ng/mL on arginine stimulation, above the British cut-off) and with a height of −4.16 SD, a 12-month trial of 0.6 mg/day (0.035 mg/kg/day), then 0.7 mg/day to maintain the weight-based dose, increased growth velocity from 4.3 to 7.2 cm/year and height from −4.16 to −3.40 SD over 2 years, still at breast pubertal stage 1, without adverse effects [11]. It is a single uncontrolled case, and the result cannot be generalised; the authors propose a supervised 12-month trial in children with ZTTK and severe short stature [11].

Monitoring and discontinuation. NICE recommends that treatment be started and monitored by a paediatrician with expertise in GH disorders and discontinued if growth velocity increases by less than 50% over baseline in the first year, if final height is approached (velocity below 2 cm/year), if there are insurmountable adherence problems or if final height is reached [59]. The European label, for the small for gestational age indication, requires discontinuation after the first year if growth velocity is below +1 SD, and discontinuation when velocity is below 2 cm/year with a bone age above 14 years in girls or 16 years in boys [58]. In the absence of response in the first year, the US label requires assessment of adherence, hypothyroidism, malnutrition, advanced bone age and anti-GH antibodies, and somatropin is discontinued when the epiphyses close [52]. Lee's case was monitored with insulin-like growth factor 1 (IGF-1), thyroid function, fasting glucose and glycated haemoglobin [11].

Contraindications and adverse effects. Somatropin is contraindicated with active tumour, for growth promotion with closed epiphyses and in acute critical illness after cardiac or abdominal surgery, multiple trauma or acute respiratory failure [58]. The US label describes intracranial hypertension (exclude papilloedema before starting), glucose intolerance, hypothyroidism that may appear or worsen, hypoadrenalism, fluid retention, slipped capital femoral epiphysis (assess if limping or hip or knee pain), pancreatitis, lipoatrophy, injection site reactions, headaches and progression of pre-existing scoliosis [52]. This last point matters in ZTTK, in which spinal curvature is frequent: scoliosis should be documented before starting and monitored during treatment [8, 52]. In patients with hypopituitarism, concomitant treatment with levothyroxine and hydrocortisone requires adjustment and stress cover, as in the spinal fusion case described in 7.9 [28, 52].

7.5 Epilepsy: levetiracetam and other antiseizure medicines

No antiseizure medicine has demonstrated efficacy in ZTTK, and the GeneReviews recommends standardised treatment by an experienced neurologist [1]. In the reports, seizures were generally controlled with levetiracetam, carbamazepine or clobazam; an Irish child with generalised tonic-clonic status epilepticus at 1 year was controlled with levetiracetam monotherapy; a boy with hypopituitarism was receiving vigabatrin; and the patient with hemiplegic migraine and status epilepticus continued lacosamide after resolution with lorazepam and fosphenytoin [7, 24, 26, 28]. Levetiracetam is the drug most often mentioned and, for that reason, the only one whose label dosing is detailed; its choice in a particular child depends on seizure type and comorbidities.

Sources: FDA label and European SmPC of Keppra® [60, 61]. For primary generalised tonic-clonic seizures, the US label approves adjunctive use from 6 years, from 10 up to 30 mg/kg twice daily [60]. The dose is adjusted to renal function, in paediatric patients using the Schwartz formula [60, 61]. Withdrawal is gradual: above 50 kg, reductions of 500 mg twice daily every 2–4 weeks; between 6 months and 50 kg, reductions of no more than 10 mg/kg twice daily every 2 weeks; below 6 months, 7 mg/kg twice daily every 2 weeks [61]. The most frequent adverse effects in children are fatigue, aggression, nasal congestion, decreased appetite and irritability; in paediatric trials, 38% of treated children had non-psychotic behavioural symptoms, against 19% with placebo [60]. The label also includes suicidal ideation, somnolence, severe skin reactions, drug reaction with eosinophilia and systemic symptoms (DRESS), coordination difficulties and withdrawal seizures if stopped abruptly [60]. As ZTTK involves behavioural disturbance in more than half of patients, behaviour should be recorded before and after starting [8, 60].

In status epilepticus, management follows general protocols; the 2026 European consensus on MELAS refers to the 2024 ERN consensus on status epilepticus and recommends treating suspected seizures even without EEG confirmation, but these recommendations concern mitochondrial disease and apply to ZTTK only by analogy [57].

7.6 Spasticity and dystonia: baclofen, tizanidine and botulinum toxin

The GeneReviews states that hypertonia and dystonia should be treated by specialists with baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs or orthopaedic procedures, without doses [1]. The following doses are those of the US labels, for spasticity, and their use in ZTTK is an extrapolation; the Portuguese SmPCs of these drugs were not consulted and their European authorisations are national, without a centralised EMA procedure [62–64].

In ZTTK, baseline dysphagia and hypotonia increase the risk of worsening swallowing and breathing with botulinum toxin or sedating muscle relaxants, and baclofen is used with caution in patients with epilepsy, because its abrupt withdrawal can trigger seizures [1, 62, 64]. No doses were found in the sources for the antiparkinsonian drugs mentioned by the GeneReviews, nor any description of their use in patients with ZTTK [1].

7.7 Immunodeficiency: prophylactic antibiotics and immunoglobulin

Infections should be treated early and immunodeficiency managed by an immunologist, with prophylactic antibiotics, targeted therapy and possible IVIG [1]. The GeneReviews recommends irradiated blood products in patients with immunodeficiency, which should be recorded in the notes for planned transfusions and surgery [1]. There is no published IVIG dose for ZTTK; the analogous condition is primary humoral immunodeficiency. In the US label of Privigen®, the replacement dose in primary immunodeficiency is 200–800 mg/kg (2–8 mL/kg) every 3–4 weeks, with infusion started at 0.5 mg/kg/min and increased up to 8 mg/kg/min as tolerated, adjusted by clinical response and IgG levels [65]. The most frequent adverse reactions (above 5%) in primary immunodeficiency were headache, fatigue, nausea, chills, vomiting, back pain, fever, abdominal pain, diarrhoea, cough, urticaria and dizziness [65]. The sources on ZTTK do not specify a particular prophylactic antibiotic or regimen.

7.8 Acute neurological and cardiac episodes: what the reports did

In hemiplegic migraine, mild episodes were treated with diphenhydramine, an antiemetic and a non-steroidal anti-inflammatory drug (ibuprofen or ketorolac), and the severe episode with status epilepticus required lorazepam, fosphenytoin, intubation and intensive care [26]. In stroke-like episodes, one patient received L-arginine, ubiquinol and levocarnitine, as is done in MELAS, and the other recovered without treatment [25]. The analogy with MELAS does not support a regimen: the 2026 consensus of ERN EURO-NMD, the Mitochondrial Medicine Society and MetabERN reached a strong negative consensus against routine administration of IV L-arginine in the acute phase of stroke-like episodes, considered its efficacy unproven, although it may be used case by case because it is safe, and recognised no benefit of prophylactic oral L-arginine, L-citrulline, coenzyme Q10 and analogues, or vitamins and supplements [57]. Moreover, ZTTK is not a primary mitochondrial disease, and the mitochondrial study of the treated patient was negative [25]. For these reasons, this article gives no dose of L-arginine. The same consensus advises against propofol in status epilepticus in MELAS or limits it to short infusions, a recommendation that has not been studied in ZTTK [57].

In the girl with recurrent post-infectious myocardial injury, treatment was anti-infective therapy and oral metoprolol, and IV coenzyme Q10 was also mentioned, without published doses [24, 40]. Structural heart disease was treated according to standard paediatric practice; Coleman et al. suggest considering assessment for mitochondrial dysfunction in symptomatic cardiac cases, without evidence of therapeutic benefit [24].

7.9 Anaesthesia and the perioperative period

The only published anaesthetic description is that of a 7-year-old Czech boy weighing 14.5 kg with 95° neuromuscular scoliosis, repaired tetralogy of Fallot, hypopituitarism and epilepsy, who underwent a 5.5-hour spinal fusion [28]. Anaesthesia was total intravenous, with propofol (5–7 mg/kg/h) and remifentanil (0.4–0.5 µg/kg/min) guided by a bispectral index of 40–60, cisatracurium at induction and recovery of train-of-four above 90% before motor evoked potential monitoring; he received perioperative hydrocortisone on endocrinological advice [28]. Intubation was easy, but there was stridor and desaturation after extubation, treated with oxygen and hydrocortisone 50 mg, and metabolic alkalosis with hypokalaemia for 10 days; analgesia used paracetamol, metamizole 15 mg/kg IV 6-hourly and piritramide 0.1 mg/kg subcutaneously 6-hourly [28]. The authors recommend, with no basis other than this case, avoiding volatile anaesthetics and suxamethonium (malignant hyperthermia is unlikely, but the risk of rhabdomyolysis is unknown), considering rocuronium with sugammadex acceptable, monitoring neuromuscular blockade because of hypotonia, testing for myoglobinuria postoperatively, preparing for a difficult airway (facial asymmetry, midface retrusion, small mouth and high palate), using ultrasound-guided vascular access, positioning carefully because of osteoporosis, contractures and hypermobility, and monitoring for postoperative respiratory failure [28]. Coleman et al. add preoperative cardiac assessment and individualised airway planning [24]. In patients with immunodeficiency, blood products should be irradiated [1]. Somatropin should not be started or continued without reassessment in acute critical illness after cardiac or abdominal surgery, according to the European label [58].

7.10 Regulatory status

7.11 Available evidence

There are no clinical trials in ZTTK; a search of ClinicalTrials.gov on 28 October 2026 with «ZTTK» and «Zhu-Tokita-Takenouchi-Kim» returned no studies, and the GeneReviews acknowledges that there may be no trials for this disease [1, 66]. The intervention evidence is limited to case reports.

None of these data have a control group, confidence intervals or power to estimate efficacy. The response to somatropin in one case does not predict the response of other children, and the conference abstract describes a minimal response with a higher dose; recovery from stroke-like episodes with and without treatment shows that the spontaneous course may be favourable and that the outcome cannot be attributed to treatment [11, 25].

7.12 Developments in the last 12 months

Between November 2025 and October 2026, all published developments are case reports or reviews with a low level of evidence: the case of response to somatropin without GH deficiency (October 2026), the first Shone complex with a cardiac review of 51 cases (2026), acute confusional migraine (August 2026, early online publication), sudden death on day 168 in a newborn with left-sided heart disease (2026), the Turkish case with stroke and urolithiasis (2026) and the 8.2 Mb deletion with SON and RUNX1 (November 2025) [10, 11, 17, 24, 46, 48]. At the preclinical level, the preprint on NUAK1 and SON (October 2025, not peer reviewed) joins the 2024 Son+/− mouse model [36, 39]. No clinical trial, regulatory application, orphan designation or company announcement was identified; a negative search does not demonstrate that no projects are under way, and the GeneReviews mentions therapy-oriented research in the group of E.-Y. Ahn, without details [1].

7.13 Agents to avoid, pregnancy, lactation and transition

There are no drugs specifically contraindicated in ZTTK. As a precaution, Hudec et al. suggest avoiding suxamethonium and volatile anaesthetics [28]. Somatropin requires scoliosis surveillance and is contraindicated in the situations described in 7.4 [52, 58]. Abrupt withdrawal of baclofen, tizanidine or levetiracetam should be avoided [60, 62, 63]. There are no data on pregnancy or lactation in women with ZTTK, because most patients have not reached reproductive age [1]. The baclofen label describes omphaloceles in fetuses of rats exposed to about 13 times the maximum human dose, with no studies in pregnant women [62]. Transition to adult care should begin in adolescence, with an educational and care transition plan; US educational services extend up to 21 years of age [1]. In adulthood, blood pressure measurement, surveillance of dystonia and the spine, and reassessment of autism are added [8, 49].

7.14 Convergences and divergences between sources

The GeneReviews and the Dingemans series agree on neurological, ophthalmological, cardiac, renal and feeding assessment after diagnosis [1, 8]. The GeneReviews adds haematological, immunological, audiological and endocrinological assessment, irradiated blood products and annual renal ultrasound and audiology; Dingemans adds repeated surveillance for autism and hypertension in adulthood, without intervals; Kushary recommends renal ultrasound for all and audiology after diagnosis; and Pietrobattista recommends early liver screening, which none of the syntheses includes [1, 7, 8, 22]. On somatropin outside deficiency, the GeneReviews does not take a position, NICE does not include ZTTK and Lee et al. propose a supervised 12-month trial [1, 11, 59].

8. Reproductive Options and Family Counselling

8.1 Mechanism of transmission

ZTTK syndrome is transmitted in an autosomal dominant manner, but almost all cases result from a de novo variant [1, 7, 8]. Testing both parents for the proband's variant is recommended, which also makes it possible to confirm de novo origin and strengthen the classification of the variant [1, 53].

8.2 Recurrence risks

The figure of about 1% is a general estimate of the risk of parental germline mosaicism based on the study by Rahbari et al. on human germline mutation, and not an empirical rate measured in families with ZTTK; the sources consulted describe no recurrence in siblings [1, 8, 67]. Parental leucocyte DNA may not detect low-level somatic mosaicism and does not detect mosaicism confined to the gonads [1]. There are no data on reproduction in people with ZTTK, who generally have moderate to severe ID and have not yet reached reproductive age [1, 8].

8.3 Testing of relatives, prenatal and preimplantation testing

Extended cascade testing is not indicated when the variant is de novo; the GeneReviews refers relatives for genetic counselling and does not propose surveillance of asymptomatic relatives [1]. The appropriate time to discuss the risk and the options of prenatal diagnosis or preimplantation genetic testing is before pregnancy, and counselling should be offered to the parents of an affected child [1]. Once the variant is identified, prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation testing are possible; attitudes to the use of prenatal diagnosis vary between professionals and families and the decision is personal [1]. In a subsequent pregnancy with a de novo variant in the previous child, the risk of about 1% justifies offering targeted prenatal testing. On ultrasound, early fetal growth restriction, agenesis of the corpus callosum, cortical malformations, duodenal atresia and left-sided heart disease are findings that may lead to fetal exome sequencing in a pregnancy without a family history [10, 12]. Early molecular diagnosis also guides neonatal critical care and counselling on recurrence [10].

8.4 Minors and other situations

Testing of asymptomatic minor siblings is of no use when the parents are not carriers, because there is no late-onset phenotype that would justify predictive testing; in a sibling with developmental delay, the test is diagnostic. Assessment of a symptomatic sibling or of a parent with mild ID and suggestive features should include the familial variant, given the variability described, including mild ID in 21% of cases [8]. As SON missense variants are VUS, they should not be used for reproductive decisions without reclassification [8, 53].

9. Special Considerations: Population Diversity and Epidemiology

9.1 What is known about frequency

There is no population-based estimate of prevalence or birth incidence. Orphanet assigns a worldwide point prevalence of less than 1 per 1 000 000, a class that the sources consulted do not link to any population-based study [2, 3]. Case counts have increased with the spread of exome sequencing: about 45 published and 60 known in 2021, 52 in the 2022 European series, about 79 published up to 2023 according to the GeneReviews, about 80 according to Lee et al. and about 100 according to a 2026 Japanese letter [1, 7, 8, 10, 11]. The ZTTK SON-Shine Foundation reported to the GeneReviews an estimate of 450 to 500 people identified worldwide in May 2025, and its patient census, cited by Lee et al. in December 2025, indicates more than 300; these are figures from a patient association, not published in a peer-reviewed journal and not equivalent to prevalence [1, 11]. The difference between published cases and those identified by the association shows that most diagnosed patients are not described in the literature.

9.2 Geographical distribution and populations

The published cases cited in this article come from the United States (Baylor, Columbia, Utah, Alabama), several European countries (the Netherlands, France, Spain, Italy, Ireland, the United Kingdom and Czechia), Japan, China, Turkey and Morocco [7, 8, 11, 17, 19–22, 24, 26, 28, 40, 46, 51]. The distribution reflects access to exome sequencing and not differences in frequency. Because it is a disease of de novo variants, founder populations or relevant ethnic variation in frequency are not expected, and none has been described. The recurrent variant c.5753_5756del arises de novo in patients of various origins; it lies in a repeated sequence, which explains the two notations under which it has been published, and the sources do not describe a founder haplotype [6, 8, 22]. The sources consulted do not include cases from Portugal or Brazil, which does not demonstrate their absence.

9.3 Special populations

Most patients described are under 20 years of age, and data on adults are limited to five individuals of Dingemans and isolated cases [1, 8, 49]. There are no data on pregnancy in affected women [1]. Interpretation of GH deficiency depends on national cut-offs for the stimulation test, which range from 6.7 ng/mL in the United Kingdom to 15 ng/mL in the Chinese reports [11, 42]. In patients with a deletion that includes RUNX1, the haematological surveillance described in 6.2 applies [15].

9.4 Reference networks, registries and associations

ERN ITHACA (rare congenital malformations and rare intellectual disability) took part in the 2022 European series, which also involved the Solve-RD project [8]. Phenotypic data and variants are brought together on the Human Disease Genes platform (humandiseasegenes.nl/son) and in the SON LOVD database (databases.lovd.nl/shared/genes/SON) [8]. The ZTTK SON-Shine Foundation (zttk.org) aims to accelerate research into treatments, support the community and raise awareness, and maintains a patient census; the RARE-X Registry (Global Genes) has a data collection programme for ZTTK [1, 11]. The group of E.-Y. Ahn (University of South Alabama, later the University of Alabama at Birmingham) develops cellular, zebrafish and mouse models [21, 26, 36, 38].

10. Illustrative Clinical Case

10.1 Severe short stature treated with somatropin without GH deficiency (Lee et al., 2026)

A British girl of Congolese origin, born to non-consanguineous parents, had a muscular VSD and asymmetric ventriculomegaly in the prenatal period [11]. She was born at 39 weeks and 3 days weighing 2.65 kg (−1.55 SD) and spent 3 weeks in hospital with pulmonary hypertension and respiratory difficulty, with continuous positive airway pressure, nasogastric tube feeding and hypotonia with a normal electromyogram [11]. At 3 months she had severe bronchiolitis requiring invasive ventilation, followed by eight admissions for respiratory infections over two years; the VSD closed spontaneously [11]. She achieved head control at 8 months, sat at 11, walked after 3 years and did not develop expressive language [11]. At 23 months she measured 72.7 cm and weighed 7.3 kg (both −4.0 SD), despite high-calorie tube feeding of up to 160 mL/kg/day [11]. She had a prominent forehead, triangular face, low-set ears, flat nasal bridge, prominent eyebrows, long curly eyelashes, a short fifth finger and absent nails on the 4th and 5th toes [11]. Full blood count, renal, liver and thyroid function, bone profile, inflammatory markers and coeliac disease screening were normal; IGF-1 at 3.6 years was 91 ng/mL (11.9 nmol/L) [11]. At 5.4 years, the arginine stimulation test gave a peak GH of 7.2 ng/mL (21.6 mIU/L), above the British cut-off for deficiency, and the short tetracosactide test (Synacthen®) gave a cortisol of 1600 nmol/L [11]. MRI showed grey matter heterotopia with a normal midline [11]. Microarray and ID and developmental disorder panels were normal; at 7.9 years she had premature adrenarche and, at 10 years, genome sequencing identified the de novo variant NM_138927.4:c.2107del, p.(Val703Ter) [6, 11].

Source: Lee et al., table 1 [11]. B, A and P denote the Tanner stages for breast, axillary and pubic development; the IGF-1 reference ranges were 77.2–235.6 ng/mL at stage 1, 120.8–449 at stage 2 and 180.5–522.4 at stage 3.

After a multidisciplinary team decision, she began a 12-month trial of somatropin 0.6 mg/day (0.035 mg/kg/day), then 0.7 mg/day to maintain the weight-based dose, chosen as a conservative starting dose within the NICE range because baseline IGF-1 was at the upper limit and the response was uncertain [11]. Growth velocity rose from 4.3 to 7.2 cm/year (+67%), which corresponds to a good response by the NICE criterion, and height went from −4.16 to −3.40 SD over 2 years, without onset of breast development; IGF-1, thyroid function, fasting glucose and glycated haemoglobin remained normal, without adverse effects, and the family reported better stamina and participation [11, 59]. Figure 1 of the article shows the height curve on the UK-WHO reference, with referral, the start of somatropin and the mid-parental target height (https://pmc.ncbi.nlm.nih.gov/articles/PMC13579057/figure/luag247-F1/; legend consulted) [11].

The case shows several characteristics of ZTTK: delayed molecular diagnosis despite repeated testing, severe growth failure that does not correct with nutrition, severe respiratory infections and subtle cardiac and brain malformation. The use of somatropin without GH deficiency is off-label, rests on a single uncontrolled patient and is not routine practice; it corresponds to a proposal for a supervised trial with defined stopping criteria [11, 59].

10.2 Shone complex and epilepsy (Coleman et al., 2026)

An Irish girl born at term weighing 3.03 kg had cyanosis and lethargy at 30 minutes of life and required continuous positive airway pressure for a week; the echocardiogram showed Shone complex, monitored without intervention, and she also had a left duplex kidney, a facial capillary malformation and a café-au-lait macule [24]. At 1 year she had generalised tonic-clonic status epilepticus, with left posterior temporal focal slowing on EEG, controlled with levetiracetam monotherapy; at 6 years she had absence seizures [24]. Brain MRI and microarray were normal; she had exotropia, global delay (2 to 3 words and crawling at 4 years; walking with an aid at 6 years), dysmorphism, microdontia, delayed tooth eruption, slow nail growth and hypermobility [24]. Trio exome sequencing identified the de novo variant NM_138927.4:c.4723_4729del, p.(Arg1575TyrfsTer46), classified as pathogenic [6, 24]. Figures 1 to 3 of the article show the face at 1 and 4 years and the profile (https://pmc.ncbi.nlm.nih.gov/articles/PMC13583451/figure/fig-0001/, fig-0002 and fig-0003; legends consulted) [24]. The case illustrates that a normal MRI does not exclude the syndrome and that obstructive left-sided heart disease is part of the spectrum.

11. Prognosis and Long-term Follow-up

11.1 Prognosis

On current data, life expectancy does not appear to be shortened in most patients: several adults have been described, and the Dingemans series included five adults with a maximum age of 34 years [1, 8]. The GeneReviews mentions an individual alive at 50 years citing Dingemans, but that article describes no one of that age; one of the five adults is «individual 50», a study number, which suggests that the identification number was misread as an age [1, 8]. Three children have died according to the ZTTK SON-Shine Foundation, without documented causes, and a sudden death on day 168 has been published in a newborn with complex left-sided heart disease and heart failure [1, 10]. Complex heart disease, status epilepticus, severe infections in immunodeficiency and aspiration due to dysphagia are the described situations with the greatest risk to life [1, 7, 10, 11]. The functional prognosis is dominated by ID, moderate or severe in about 78–79% of cases, with a quarter of patients without verbal language and independent walking generally achieved between 2 and 9 years [7, 8]. The course is variable: some patients have had neurological or behavioural regression or progression and others have not, with no known explanation, and the GeneReviews stresses that the molecular diagnosis does not imply a uniformly severe prognosis [1]. In adulthood, progressive dystonia, scoliosis, autism and arterial hypertension may appear [8, 49].

11.2 Surveillance

There are no validated surveillance intervals. The table brings together the surveillance of the GeneReviews, the recommendations of Dingemans and the additions of Kushary and Pietrobattista; where no source defines the interval, this is stated [1, 7, 8, 22].

The annual surveillance frequencies for renal ultrasound and audiology come from the GeneReviews and are the same as those in section 7; the others are «at every visit» or depend on the specialist, because the series do not define intervals [1, 8].

12. Summary and Final Considerations

ZTTK syndrome results from haploinsufficiency of SON, a splicing cofactor and structural component of nuclear speckles required for processing transcripts with weak splice sites, many of them linked to neuronal migration, the cell cycle, metabolism and renal and haematopoietic development [21, 34, 36, 38]. Almost all cases result from de novo truncating variants, concentrated in exon 3, with one recurrent variant, NM_138927.4:c.5753_5756del, p.(Val1918GlufsTer87), in 17–25% of patients [6–8]. The picture combines developmental delay and ID in all cases with brain malformations, hypotonia, epilepsy, feeding difficulties, short stature and skeletal, ocular, renal, cardiac and immunological anomalies, without a recognisable facial gestalt [1, 8]. Diagnosis is made by exome or genome sequencing with CNV analysis, and a negative test may require reanalysis, genome or RNA sequencing [13, 26, 44]. 21q22 deletions that include SON enter the differential, and inclusion of RUNX1 adds thrombocytopenia and, by extrapolation, a risk of haematological malignancy that justifies dedicated haematological surveillance [15, 17]. There is no targeted treatment or clinical trial; care is supportive, with doses taken from the labels of the closest indications, and somatropin outside GH deficiency, L-arginine in stroke-like episodes and anaesthetic management rest on isolated reports [1, 11, 28, 57]. The GeneReviews contains inaccuracies worth knowing: a non-MANE transcript, underestimated scoliosis, a citation without patients and a 50-year-old adult who does not appear in the source [1, 8, 37]. The recurrence risk for siblings is about 1% when the parents are not carriers, and surveillance focuses on development, the spine, growth, the kidney, hearing, the heart, immunity and, in adults, blood pressure and movement [1, 8].

13. References

1. Mori M, Lemaire M, Raines G, Stone BS, Ahn EY. Zhu-Tokita-Takenouchi-Kim syndrome. 2025 Sep 25. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. PMID: 40991760. Available from: https://www.ncbi.nlm.nih.gov/books/NBK618356/
2. Orphanet. ZTTK syndrome (ORPHA:500150). Available from: https://www.orpha.net/en/disease/detail/500150
3. GeneGuidance. SON (SON DNA and RNA binding protein): curation of the gene and of the condition ZTTK syndrome (OMIM 617140; ORPHA:500150), with Orphadata data. Version of 2026-09-26. Local project database.
4. ClinGen Dosage Sensitivity Curation. SON (ISCA-18088; CCID:007916). Last evaluated 2019 Apr 24. Available from: https://search.clinicalgenome.org/kb/gene-dosage/SON
5. OMIM® Online Mendelian Inheritance in Man. *182465 SON DNA-BINDING PROTEIN; SON. Johns Hopkins University; last edited 30/11/2022. https://omim.org/entry/182465. Accessed 28 October 2026.
6. VariantValidator. GRCh38 (MANE Select NM_138927.4). Available from: https://variantvalidator.org/
7. Kushary ST, Revah-Politi A, Barua S, Ganapathi M, Accogli A, Aggarwal V, et al. ZTTK syndrome: clinical and molecular findings of 15 cases and a review of the literature. Am J Med Genet A. 2021;185(12):3740-53. doi:10.1002/ajmg.a.62445
8. Dingemans AJM, Truijen KMG, Kim JH, Alaçam Z, Faivre L, Collins KM, et al. Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON. Eur J Hum Genet. 2022;30(3):271-81. doi:10.1038/s41431-021-00960-4
9. OMIM® Online Mendelian Inheritance in Man. #617140 ZTTK SYNDROME; ZTTKS. Johns Hopkins University; last edited 08/01/2024. https://omim.org/entry/617140. Accessed 28 October 2026.
10. Okamoto K, Nakato D, Kataoka K, Nakagawa N, Takenouchi T. Hypoplastic left heart syndrome variant with unexpected early sudden death in a newborn infant with ZTTK syndrome. Congenit Anom (Kyoto). 2026;66(1):e70059. doi:10.1002/cga.70059
11. Lee SC, Muflihi Y, Mohammed Z, Kinning E, Dias RP. Growth outcomes following recombinant human growth hormone therapy in Zhu-Tokita-Takenouchi-Kim syndrome. JCEM Case Rep. 2026;4(10):luag247. doi:10.1210/jcemcr/luag247
12. Carmant LS, Miller E, Chong K, Chitayat D, Shinar S. Agenesis of corpus callosum, malformations of cortical development, duodenal atresia and fetal growth restriction: prenatal markers for Zhu-Tokita-Takenouchi-Kim syndrome. Prenat Diagn. 2024;44(11):1416-9. doi:10.1002/pd.6658
13. Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(11):2029-37. doi:10.1038/s41436-021-01242-6
14. Orphanet. 21q22.11q22.12 microdeletion syndrome (ORPHA:261323). Available from: https://www.orpha.net/en/disease/detail/261323
15. Deuitch N, Broadbridge E, Cunningham L, Liu P. RUNX1 familial platelet disorder with associated myeloid malignancies. 2021 Mar 4 [Revised 2025 Dec 4]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK568319/
16. van Bon BWM, Coe BP, de Vries BBA, Eichler EE. DYRK1A syndrome. 2015 Dec 17 [Updated 2021 Mar 18]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK333438/
17. Jouali F, El Haddoumi G, Antra I, Benhida R, Ben Itto A, Fekkak J. A case report: identification of a pathogenic microdeletion at chromosome 21q21.3q22.13 using whole-exome sequencing and CNV analysis in a Moroccan child with global developmental delay. Genes (Basel). 2025;16(11):1280. doi:10.3390/genes16111280
18. Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu YF, McSweeney KM, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med. 2015;17(10):774-81. doi:10.1038/gim.2014.191
19. Takenouchi T, Miura K, Uehara T, Mizuno S, Kosaki K. Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: possible contribution to Braddock-Carey syndrome phenotype. Am J Med Genet A. 2016;170(10):2587-90. doi:10.1002/ajmg.a.37761
20. Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Küry S, et al. De novo truncating variants in SON cause intellectual disability, congenital malformations, and failure to thrive. Am J Hum Genet. 2016;99(3):720-7. doi:10.1016/j.ajhg.2016.06.035
21. Kim JH, Shinde DN, Reijnders MRF, Hauser NS, Belmonte RL, Wilson GR, et al. De novo mutations in SON disrupt RNA splicing of genes essential for brain development and metabolism, causing an intellectual-disability syndrome. Am J Hum Genet. 2016;99(3):711-9. doi:10.1016/j.ajhg.2016.06.029
22. Pietrobattista A, Della Volpe L, Francalanci P, Figà Talamanca L, Monti L, Lepri FR, et al. The expanding phenotype of ZTTK syndrome due to the heterozygous variant of SON gene focusing on liver involvement: patient report and literature review. Genes (Basel). 2023;14(3):739. doi:10.3390/genes14030739
23. Van Stechelman P, Wilson B, Grebe TA, Jaffery S, Bauer CS. Hypogammaglobulinemia in 2 children with Zhu-Tokita-Takenouchi-Kim syndrome. Ann Allergy Asthma Immunol. 2024;133(1):109-10. doi:10.1016/j.anai.2024.04.005
24. Coleman J, Shakerdi AL, Dvorakova V, Kenny J. ZTTK syndrome expanding the cardiac phenotype: a case of Shone's complex with a novel SON variant and focused review of the cardiac manifestations in ZTTK syndrome. Case Rep Genet. 2026;2026:3473063. doi:10.1155/crig/3473063
25. El-Said A, Morales JL, Rossi G, Longani N. Metabolic stroke as a clinical manifestation of Zhu-Tokita-Takenouchi-Kim syndrome: a case series. Neurol Genet. 2023;9(3):e200072. doi:10.1212/NXG.0000000000200072
26. Langford J, Vukadin L, Carey JC, Botto LD, Velinder M, Mao R, et al. SON-related Zhu-Tokita-Takenouchi-Kim syndrome with recurrent hemiplegic migraine: putative role of PRRT2. Neurol Genet. 2023;9(3):e200062. doi:10.1212/NXG.0000000000200062
27. Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, et al. A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet. 2021;108(1):8-15. doi:10.1016/j.ajhg.2020.11.013
28. Hudec J, Kosinova M. Anesthesia of the patient with Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome: a case report. Children (Basel). 2022;9(6):869. doi:10.3390/children9060869
29. Orphanet. Braddock-Carey syndrome (ORPHA:3323; inactive status). Record of 2026-07-02. Available from: https://www.orpha.net/en/disease/detail/3323
30. Regan-Fendt KE, Izumi K. Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins. Hum Genet. 2024;143(4):529-44. doi:10.1007/s00439-023-02540-6
31. Ahn EY, DeKelver RC, Lo MC, Nguyen TA, Matsuura S, Boyapati A, et al. SON controls cell-cycle progression by coordinated regulation of RNA splicing. Mol Cell. 2011;42(2):185-98. doi:10.1016/j.molcel.2011.03.014
32. Sharma A, Markey M, Torres-Muñoz K, Varia S, Kadakia M, Bubulya A, et al. Son maintains accurate splicing for a subset of human pre-mRNAs. J Cell Sci. 2011;124(Pt 24):4286-98. doi:10.1242/jcs.092239
33. Kim JH, Baddoo MC, Park EY, Stone JK, Park H, Butler TW, et al. SON and its alternatively spliced isoforms control MLL complex-mediated H3K4me3 and transcription of leukemia-associated genes. Mol Cell. 2016;61(6):859-73. doi:10.1016/j.molcel.2016.02.024
34. Ilik İA, Malszycki M, Lübke AK, Schade C, Meierhofer D, Aktaş T. SON and SRRM2 are essential for nuclear speckle formation. eLife. 2020;9:e60579. doi:10.7554/eLife.60579
35. Ueda M, Matsuki T, Fukada M, Eda S, Toya A, Iio A, et al. Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities. Mol Brain. 2020;13(1):80. doi:10.1186/s13041-020-00622-4
36. Vukadin L, Park B, Mohamed M, Li H, Elkholy A, Torrelli-Diljohn A, et al. A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis. JCI Insight. 2024;9(5):e175053. doi:10.1172/jci.insight.175053
37. Luo H, Cortés-López M, Tam CL, Xiao M, Wakiro I, Chu KL, et al. SON is an essential m6A target for hematopoietic stem cell fate. Cell Stem Cell. 2023;30(12):1658-73.e10. doi:10.1016/j.stem.2023.11.006
38. Kim JH, Park EY, Chitayat D, Stachura DL, Schaper J, Lindstrom K, et al. SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes. Kidney Int. 2019;95(6):1494-504. doi:10.1016/j.kint.2019.01.025
39. Kerkhofs M, Meyer-Dilhet G, Polvèche H, et al. The AMPK-related kinase NUAK1 regulates neuronal morphogenesis through the RNA splicing co-factor SON [preprint]. bioRxiv. 2025. doi:10.1101/2025.10.10.681550
40. Na J, Cui L, Zhen Z, Chen X, Li Q, Gao L, et al. Recurrent myocardial injury in a de novo SON mutation ZTTK syndrome patient: a case report. BMC Pediatr. 2024;24(1):232. doi:10.1186/s12887-024-04703-4
41. Pasca L, Politano D, Cavallini A, Panzeri E, Vigone MC, Baldoli C, et al. A novel de novo heterozygous mutation in the SON gene associated with septo-optic dysplasia: a new phenotype. Neuropediatrics. 2024;55(3):191-5. doi:10.1055/a-2114-4387
42. Yang Y, Xu L, Yu Z, Huang H, Yang L. Clinical and genetic analysis of ZTTK syndrome caused by SON heterozygous mutation c.394C>T. Mol Genet Genomic Med. 2019;7(11):e953. doi:10.1002/mgg3.953
43. Kylat RI, Stanley K, Simon S, Erickson RP. Immune dysregulation, polyendocrinopathy and enteropathy, X-linked (IPEX) syndrome due to a mutation in FOXP3, modified by a pathogenic variant in SON (SON DNA-binding protein). J Appl Genet. 2023;64(1):141-4. doi:10.1007/s13353-022-00728-6
44. Hou H, Yuki KE, Costain G, Szuto A, Barnes S, Ramani AK, et al. Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing. NPJ Genom Med. 2025;10(1):51. doi:10.1038/s41525-025-00505-4
45. Tang S, You J, Liu L, Ouyang H, Jiang N, Duan J, et al. Expanding the mutational spectrum of ZTTK syndrome: a de novo variant with global developmental delay and malnutrition in a Chinese patient. Mol Genet Genomic Med. 2023;11(8):e2188. doi:10.1002/mgg3.2188
46. Ates K, Ozturk M, Esener Z, Sigirci A, Tekedereli I. A novel SON gene variant associated with rare clinical features in ZTTK syndrome: a case report and literature review. Mol Syndromol. 2026;17(2):142-53. doi:10.1159/000546621
47. Halliday BJ, Baynam G, Ewans L, Greenhalgh L, Leventer RJ, Pilz DT, et al. Distinctive brain malformations in Zhu-Tokita-Takenouchi-Kim syndrome. AJNR Am J Neuroradiol. 2022;43(11):1660-6. doi:10.3174/ajnr.A7663
48. Zapata-Aldana E, Argemi JP, Ares MJV, Ruiz-Nello A, Spataro N, Martínez-Glez V. Expanding the neurological phenotype of ZTTK syndrome: a case of recurrent acute confusional migraine. Am J Med Genet A. 2026 Aug 5. doi:10.1002/ajmg.a.70269
49. Indelicato E, Zech M, Amprosi M, Boesch S. Untangling neurodevelopmental disorders in the adulthood: a movement disorder is the clue. Orphanet J Rare Dis. 2022;17(1):55. doi:10.1186/s13023-022-02218-8
50. Yang L, Yang F. A de novo heterozygous variant in the SON gene is associated with Zhu-Tokita-Takenouchi-Kim syndrome. Mol Genet Genomic Med. 2020;8(11):e1496. doi:10.1002/mgg3.1496
51. Quintana Castanedo L, Sánchez Orta A, Maseda Pedrero R, Santos Simarro F, Palomares Bralo M, Feito Rodríguez M, et al. Skin and nails abnormalities in a patient with ZTTK syndrome and a de novo mutation in SON. Pediatr Dermatol. 2020;37(3):517-9. doi:10.1111/pde.14113
52. Pfizer. GENOTROPIN (somatropin) for injection. Prescribing information. BLA020280. Revised 2026-08-04 (set id ffebf88b-d257-4542-9808-74d9b7167765). Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffebf88b-d257-4542-9808-74d9b7167765
53. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. doi:10.1038/gim.2015.30
54. Rodan LH, Stoler J, Chen E, Geleske T; Council on Genetics. Genetic evaluation of the child with intellectual disability or global developmental delay: clinical report. Pediatrics. 2025;156(1):e2025072219. doi:10.1542/peds.2025-072219
55. van der Sanden BPGH, Schobers G, Corominas Galbany J, Koolen DA, Sinnema M, van Reeuwijk J, et al. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur J Hum Genet. 2023;31(1):81-8. doi:10.1038/s41431-022-01185-9
56. Orphanet. DYRK1A-related intellectual disability syndrome due to 21q22.13q22.2 microdeletion (ORPHA:268261). Available from: https://www.orpha.net/en/disease/detail/268261
57. Mancuso M, Bellusci M, Carelli V, de Coo I, Diodato D, Distelmaier F, et al. Diagnostic criteria and management of MELAS and stroke-like episodes: consensus-based statements. Eur J Neurol. 2026;33(4):e70588. doi:10.1111/ene.70588
58. European Medicines Agency. Omnitrope (somatropin): EPAR — product information. Initial authorisation 2006-04-12. Available from: https://www.ema.europa.eu/en/documents/product-information/omnitrope-epar-product-information_en.pdf
59. National Institute for Health and Care Excellence. Human growth hormone (somatropin) for the treatment of growth failure in children. Technology appraisal guidance TA188. London: NICE; 2010. Available from: https://www.nice.org.uk/guidance/ta188
60. UCB. KEPPRA (levetiracetam) tablets and oral solution. Prescribing information. NDA021035/NDA021505. Revised 2026-01-28 (set id 3ca9df05-a506-4ec8-a4fe-320f1219ab21). Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ca9df05-a506-4ec8-a4fe-320f1219ab21
61. European Medicines Agency. Keppra (levetiracetam): EPAR — product information. Initial authorisation 2000-09-29; renewal 2015-08-20. Available from: https://www.ema.europa.eu/en/documents/product-information/keppra-epar-product-information_en.pdf
62. Baclofen tablets USP. Prescribing information. ANDA209102. Revised 2025-01-28. Available from: https://dailymed.nlm.nih.gov/ (openFDA query of 2026-10-28)
63. Zanaflex (tizanidine hydrochloride) tablets and capsules. Prescribing information. NDA020397/NDA021447. Revised 2025-05-05. Available from: https://dailymed.nlm.nih.gov/ (openFDA query of 2026-10-28)
64. Allergan. BOTOX (onabotulinumtoxinA) for injection. Prescribing information. BLA103000. Revised 2023-11-18. Available from: https://dailymed.nlm.nih.gov/ (openFDA query of 2026-10-28)
65. CSL Behring. PRIVIGEN (immune globulin intravenous [human], 10% liquid). Prescribing information. Revised 2026-05-06. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e5649da-75be-4a42-8eeb-4aeba562c401
66. ClinicalTrials.gov. Search for the terms «ZTTK» and «Zhu-Tokita-Takenouchi-Kim» (API v2), 2026 Oct 28. Bethesda (MD): National Library of Medicine. Available from: https://clinicaltrials.gov/
67. Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48(2):126-33. doi:10.1038/ng.3469