10q26 Deletion Syndrome

Distal 10q monosomy: terminal and interstitial deletions of band 10q26 (10q26.11 to 10q26.3), isolated or resulting from unbalanced translocations, with a note on the EBF3-related disorder (hypotonia, ataxia and delayed development syndrome) when the deletion includes this gene.

Literature and regulatory information updated: 6 November 2026.

0. Initial Reference Table

1. Introduction

1.1 Historical overview

The first description of a partial deletion of the long arm of chromosome 10 is due to Lewandowski and colleagues, in 1978, who compared the patient with the picture of partial trisomy 10q, already known at the time [22]. A year later, Turleau and colleagues described an 11-year-old girl with a 10q26→qter deletion and proposed as characteristic features severe ID, growth retardation, microcephaly and a long, triangular face with a broad and prominent nasal root, underdeveloped nasal tip, short philtrum and flattened mandibular angles, noting that several of these features were opposite, as "type and countertype", to those of trisomy 10qter [23]. The supporting document (argumentaire) of the French PNDS attributes the first case to Turleau in 1979, but the text of the PNDS itself, OMIM and the primary literature date the first description to 1978 [2, 3, 12].

In 1985, Shapiro and colleagues brought together eight patients with deletions of different segments of 10q, of whom one had a terminal 10q26 deletion and four resulted from (8;10) translocations with a 10q26 deletion and 8q24.3 duplication, which showed early on the importance of translocation derivatives in this region [24]. Mehta and colleagues (1987) drew attention to the behavioural disturbance, describing a boy with hyperkinesis, aggressiveness, attention deficit and reduced need for sleep, alternating between provocative and affectionate behaviour [25]. Wulfsberg and colleagues (1989) compared three new patients with 15 published ones and considered the combination of a prominent "beaked" nose, large or malformed ears, severe ID, heart disease and anogenital anomalies distinctive enough to suggest the diagnosis on clinical examination, coining the term "10qter deletion syndrome" [26, 27]. Schrander-Stumpel and colleagues (1991) reviewed the psychological data of 18 survivors [28], and Wilkie and colleagues (1993) described two 46,XY infants with female or atypical external genitalia, concluding that terminal 10q deletions are strongly associated with abnormal male genital development and should be sought in the cytogenetic study of these cases [29, 30].

The largest series of the pre-microarray era is that of Irving and colleagues (2003), with 15 cases (eight familial, four de novo and three interstitial 10q25.2–q26.3) mapped by fluorescence in situ hybridisation (FISH) with yeast artificial chromosome probes; in a family with six affected individuals and a 10q26.2→qter deletion, the oldest living individual was 63 years old, which showed that the deletion may be compatible with long survival and transmission [2, 31]. Tanabe and colleagues (1999) had already reviewed 25 published patients, and Courtens and colleagues (2006), in reporting a 13-year-old girl with a de novo subterminal 10q26.2 deletion of about 6.1 Mb, reviewed 15 patients with a "pure" subterminal deletion [2, 32, 33]. From 2009 onwards, chromosomal microarray made it possible to measure deletion size accurately and to propose critical regions: Yatsenko and colleagues defined a smallest region of overlap (SRO) of about 600 kb in 10q26.2 containing DOCK1 and C10orf90, and Miller and colleagues associated the loss of HMX2 and HMX3 with sensorineural deafness and inner ear malformations [9, 34]. Between 2014 and 2025, there followed proposals of critical regions for behaviour (CALY), urinary anomalies (10q26.12–q26.13), genital anomalies (WDR11), craniosynostosis and the cognitive phenotype (INSYN2A, NPS), and the demonstration that haploinsufficiency of EBF3, in 10q26.3, causes a neurodevelopmental syndrome on its own [6, 35–40].

In November 2022, the HAS published the PNDS "Délétion 10q26", prepared by the reference centre for developmental anomalies of the Reims University Hospital Centre (CHU), based on a review of 44 publications (1975–2022) and a national cohort of 37 patients assembled between May 2020 and May 2021 in ten French genetics centres, of whom 33 were analysed [3, 12]. At the time of writing, it is the only clinical guideline dedicated to this condition found in the sources consulted.

1.2 Nomenclature and definition of the entities

The term "10q26 deletion syndrome" designates a contiguous gene deletion syndrome and not a monogenic disease; OMIM identifies it as #609625, with the alternative title "chromosome 10q26 terminal deletion syndrome" [2]. Orphanet uses "distal deletion 10q syndrome" (ORPHA:96148), with the synonyms 10qter deletion, distal 10q monosomy, 10qter monosomy and 10q telomeric deletion, and reserves ORPHA:1581 for non-distal 10q deletions [1, 14]. The literature also uses "10q26 monosomy", "10q26 microdeletion" and "10q subtelomeric deletion". The PNDS includes four types of rearrangement under the same designation: terminal deletions, interstitial deletions, complex rearrangements (for example, inverted duplication associated with deletion) and translocation derivatives with 10q26 monosomy and partial trisomy of another chromosomal segment [3].

The scope covers three situations. The first is the "pure" 10q26 deletion, terminal or interstitial, which constitutes the core of the syndrome. The second is the 10q26 deletion within a double imbalance (translocation derivative), in which the phenotype combines 10q monosomy with trisomy of the partner segment and which, for that reason, was excluded from the analysis of the French cohort when the phenotype was discordant [12]. The third is EBF3 haploinsufficiency, which may occur through a small 10q26.3 deletion or a point variant and has its own OMIM entry (#617330); it is covered mainly as a component of the phenotype of deletions that include 10q26.3 and as a differential diagnosis [4, 6]. Distal 10q duplication (trisomy 10q24→qter), described by Yunis and Sanchez in 1974, is a distinct entity and is covered in the differential diagnosis [41].

2. Molecular Genetics and Pathophysiology

2.1 Architecture of the 10q26 region

Band 10q26 is the terminal segment of the long arm of chromosome 10, more than 16 Mb long with three sub-bands (10q26.1, subdivided into 10q26.11, 10q26.12 and 10q26.13; 10q26.2; and 10q26.3), and is gene-rich [3]. OMIM places the syndrome region between positions 117,300,001 and 133,797,422 of chromosome 10 in the GRCh38 assembly [2]. Unlike recurrent microdeletion syndromes mediated by low-copy repeats (such as 22q11.2 or 7q11.23), there is no "typical" 10q26 deletion: breakpoints are distributed from 10q26.11 to 10q26.3 and size ranges from less than 1 Mb to 17.4 Mb [3, 5]. Microarray series describe deletions of 3.5 to 17.4 Mb in classic syndromic cases and deletions of 600 kb to 977 kb in the smallest cases [5, 6, 27, 39]. As published coordinates use different assemblies (many studies use GRCh37/hg19), comparison of breakpoints between studies requires conversion to the same assembly [10].

The approximate distribution of the genes with a proposed role, from proximal to distal, is as follows: EMX2 (10q26.11), WDR11 (10q26.12), FGFR2, HMX2, HMX3, CTBP2 and BUB3 (10q26.13), DOCK1, FOXI2, INSYN2A and NPS (10q26.2) and, in 10q26.3, CALY, EBF3, MGMT, GLRX3, PPP2R2D, BNIP3, JAKMIP3, TCERG1L and INPP5A [3, 39, 42–44].

2.2 Mechanisms of formation

Subtelomeric deletions affect very gene-dense regions, adjacent to the TTAGGG repeats of the telomeres and to the subtelomeric repetitive sequences, so that small losses may have a severe phenotype [19]. After the break, the end of the chromosome may be stabilised by three mechanisms: regeneration of a new telomere at the break (telomere healing), retention of the original telomere with formation of an interstitial deletion, or acquisition of another end by rearrangement, giving rise to a derivative chromosome (telomere capture) [19]. Terminal deletions may be isolated or result from unbalanced segregation of a balanced reciprocal translocation in a parent, in which case they are associated with duplication of the partner chromosome segment [19]. In the literature on the region, derivatives t(8;10), t(6;10), t(10;16), t(4;10) and t(3;10) have been described, as well as complex rearrangements with a 10q26.11–q26.2 duplication adjacent to a 10q26.2–q26.3 deletion and capture of satellite material from an acrocentric chromosome [3, 24, 29, 45–47]. The PNDS stresses that the structure of the deletion should be verified, because it may be complex (inverted duplication with terminal deletion), and that exact identification of the rearrangement determines genetic counselling [3].

Two mosaicism situations deserve mention. In the first, the mosaicism is fetal or constitutional and the prognosis may be favourable: in a 46,XY fetus with del(10)(q26.13) in 35–40% of uncultured amniocytes, the proportion of abnormal cells decreased during gestation and the newborn had a normal phenotype and development at 4 months, with 8% deleted cells in the buccal mucosa [48]. In the second, the mosaicism is maternal and low-level: 10q25→qter deletions of about 20 Mb detected by genome-wide non-invasive prenatal screening (NIPS) in eight pregnancies were not confirmed by invasive testing and corresponded to maternal mosaicism associated with expansions of the FRA10B fragile site, in 10q25 [49].

2.3 Haploinsufficiency and critical regions

The generally accepted mechanism is haploinsufficiency of one or more dosage-sensitive genes, within a contiguous gene model: patients have one intact chromosome 10 and one deleted chromosome 10, and the clinical consequences probably result from the presence of a single copy of the genes in the region [3]. Attempts to define critical regions have produced partly contradictory results, which are summarised in the table.

The heterogeneity of these results has several possible explanations, discussed by Lin and colleagues: incomplete penetrance and variable expressivity of the genes in the region, the existence of several independent critical regions with an additive contribution ("two-hit" model) and an insufficient number of well-characterised patients [10]. A transcriptome study in a young adult woman with a 6.525 Mb 10q26.2→qter deletion (48 genes) without ID showed that DOCK1, C10orf90 and CALY were not dysregulated in blood, suggesting that the mechanism is more complex than simple DOCK1 haploinsufficiency [51]. Conversely, in a preterm infant with a t(4;10)(q31.22;q26.13) derivative and a 10.77 Mb 10q26.13–q26.3 deletion, expression in peripheral blood mononuclear cells was reduced for FGFR2, EMX2, WDR11, NSMCE4A, EBF3, DMBT1, CUZD1, CTBP2, CHST15, OAT and LHPP, with a mean regional decrease in expression across the deleted interval, consistent with a dosage effect [45]. Iourov and colleagues, in a boy with moderate psychomotor delay and minor dysmorphism and a 5.8 Mb interstitial 10q26.2q26.3 deletion containing 24 genes, proposed PPP2R2D and BNIP3 as candidates [52]. The PNDS considers the data supporting DOCK1 as a candidate gene for the genitourinary anomalies to be weak [3].

2.4 Genes in the region with specific evidence

EBF3. The gene for the transcription factor EBF3 (early B cell factor 3), of the COE family, takes part in neuronal differentiation and maturation and is transcriptionally repressed by ARX [16, 53]. In 2017, three independent groups showed that loss-of-function variants of EBF3 cause a neurodevelopmental syndrome with ID, ataxia, hypotonia, mild facial dysmorphism, strabismus and genitourinary anomalies [16, 53, 54]. In one family, two affected siblings inherited from a healthy mosaic mother the variant NM_001375380.1:c.625C>T, p.(Arg209Trp), validated in VariantValidator on the MANE transcript (OMIM cites it on the non-MANE transcript NM_001005463.2) [7, 8, 16]. The 600 kb deletion including EBF3, described by Lopes and colleagues at a Portuguese centre, and the Japanese and Italian series with 10q26.3 deletions confirm that loss of the whole gene reproduces the picture, supporting haploinsufficiency as the mechanism [6, 17, 20]. ClinGen assigns EBF3 a haploinsufficiency score of 3 (sufficient evidence) and a triplosensitivity score of 0 [11]. Among 41 patients with HADDS, 2 had 10q deletions disrupting EBF3, and in a review of 47 published cases another 5 had a 10q26 deletion [4, 55]. Thus, part of the hypotonia, ataxia, disproportionate motor delay and neurogenic bladder of 10q26.3 deletions is attributable to EBF3.

HMX2 and HMX3. These are homeobox genes of the NKL family, contiguous in 10q26.13 (HMX2 at 10:123,148,136–123,150,672 and HMX3 at 10:123,135,970–123,139,423, GRCh38) [43, 44]. Hmx2−/− mice have hyperactivity, head tilting, circling behaviour and dysgenesis of all three semicircular ducts; Hmx3−/− mice have severe vestibular defects; compound heterozygous Hmx2+/− Hmx3+/− mice are normal and fertile; and double knockouts lose balance completely, with spasms, involvement of the hypothalamus and anterior pituitary and death around postnatal day 5 [43, 44]. Miller and colleagues observed congenital sensorineural deafness with cochlear and vestibular malformations in the two patients whose deletion included these genes, and the headbobber mouse, with a 648 kb deletion on distal chromosome 7 and downregulation of Hmx3, Hmx2 and Nkx1.2, reproduces the absence of semicircular canals, fusion of the utricle and saccule and loss of the endocochlear potential [34, 56]. The PNDS accepts HMX2 and HMX3 as the probable explanation for the deafness and inner ear malformations, although penetrance is incomplete [3, 10]. A de novo 10q26.11–q26.13 deletion with congenital deafness and balance dysfunction indicates that the responsible gene lies in this interval [57].

DOCK1. It encodes DOCK180, a guanine nucleotide exchange factor that activates RAC (and/or CDC42) in the RhoG–ELMO–DOCK180–RAC1 pathway, involved in integrin-mediated adhesion, neurite outgrowth and phagocytosis of apoptotic cells [58]. It was proposed as the central gene of the syndrome because it lies in the 600 kb SRO, but there are no DOCK1 point variants associated with human disease in the sources consulted and Laudier's transcriptome showed no dysregulation [9, 42, 51].

WDR11. Located in 10q26.12, it is associated with hypogonadotrophic hypogonadism 14 with or without anosmia (autosomal dominant, OMIM 614858) and with an autosomal recessive disorder of intellectual development (OMIM 620237) [59]. Choucair and colleagues proposed its haploinsufficiency as the cause of the genital anomalies of 10q26.1 deletions, and Sutani and colleagues described a missense variant NM_018117.12:c.2108G>A, p.(Arg703Gln) (MANE, VariantValidator) in a boy with severe growth retardation, ventricular septal defect (VSD) and coloboma, suggesting a contribution of WDR11 to coloboma, heart disease and growth [8, 37, 60]. GenCC curation of the relationship with hypogonadism is divergent between submitters and ClinGen has not evaluated the gene [42].

FGFR2, CTBP2, CALY, INSYN2A and NPS. FGFR2 (10q26.13) has been proposed for the facial dysmorphism, renal anomalies and male sexual differentiation, but its known diseases (Apert, Crouzon, Pfeiffer) result from gain of function, a mechanism distinct from haploinsufficiency due to deletion [36, 37, 42, 61]. CTBP2 encodes a transcriptional repressor and the RIBEYE protein of ribbon synapses, and has been proposed for the renal phenotype [36, 42]. CALY (calcyon), associated with ADHD, has been proposed for behaviour [31, 35]. INSYN2A, a component of inhibitory synapses, and NPS, which encodes neuropeptide S, have been proposed for the cognitive phenotype on the basis of the smallest known 10q26.2 deletion and the 500 kb interval defined in 2025 [39, 40]. The PNDS also mentions DPYSL4 as a candidate for susceptibility to bipolar disorder and EMX2 as a gene of the region; for EMX2, the association with schizencephaly is considered limited or disputed (ClinGen Limited) and the association with hypogonadotrophic hypogonadism is recent [3, 42].

2.5 Unmasking of recessive alleles

A hemizygous deletion may unmask a recessive variant on the homologous allele. Su and colleagues identified in a fetus with VSD, intrauterine growth restriction (IUGR) and microcephaly a maternally inherited 10q26.13–q26.2 deletion, classified as likely pathogenic, which unmasked the homozygous variant c.1544A>G, p.(Tyr515Cys), of MMP21 (a recessive heterotaxy gene), classified as of uncertain significance [40]. The Oxford handbook lists unmasking of a recessive phenotype among the explanations for discordance between a carrier parent and the child [19]. Exome or genome sequencing allows copy number and point variants to be analysed simultaneously [40].

2.6 Inheritance, penetrance and expressivity

Most deletions are de novo (94% in the French cohort of 33 patients); inherited deletions come from a parent with the same deletion, often less affected, or from unbalanced segregation of a balanced translocation [3, 12]. OMIM and MedlinePlus classify transmission as autosomal dominant, because one altered copy is enough for the phenotype and the carrier transmits the deletion with a probability of 50% [2, 13]; Orphanet records the inheritance as "not applicable" or "unknown", reflecting its mostly sporadic nature [1]. Both classifications describe real aspects and do not contradict each other.

Expressivity is highly variable, even within the same family and with the same deletion [13, 27]. Documented examples are the father with hip dysplasia, anxiety and learning difficulties whose daughter had developmental delay and faltering growth with the same 5.8 Mb interstitial deletion [9]; the 29-year-old Greek Cypriot woman with a 6.3 Mb 10q26.2q26.3 deletion and almost normal development and intellect [62]; the young adult woman without ID with a 6.525 Mb deletion [51]; the mother with mild ID and the fetal son with the 860 kb deletion [39]; and the twins with autism spectrum disorder (ASD) and a 977 kb 10q26.3 deletion inherited from an asymptomatic father, one of whom also had a TRIO variant inherited from the asymptomatic mother [5]. In general terms, larger or complex deletions are associated with more severe pictures, and small terminal deletions have been associated with mild ID with hyperactivity [3, 63].

3. Clinical Spectrum and Manifestations by System

3.1 Frequency of manifestations

The available frequencies come from reviews of published cases, often with small denominators and publication bias towards severe presentations, and from the French cohort of the PNDS. There are no prospective natural history studies. The values in the table therefore describe populations of diagnosed patients and not the population of carriers.

Sources: PNDS text and argumentaire tables (reading of tables in image format, pages 20 to 23) [3, 12]. In the isolated 10q26.1, 10q26.2 and 10q26.3 subgroups of the French cohort, denominators range from 1 to 6 patients; for example, ID in 1/1, 2/2 and 3/4, behaviour in 0/1, 2/2 and 3/4 and renal anomalies in 1/1, 1/1 and 2/5, respectively [12]. The cohort had 3 fetuses, 1 child under 3 years, 11 between 3 and 12 years, 9 between 12 and 18 years and 6 adults, with a sex ratio of 0.9 [12].

In a review of 18 patients with a 10q26.12→qter deletion (11 from DECIPHER and 6 published, plus the index case; 11 female), Li and colleagues observed facial dysmorphism in 70.6%, global developmental delay in 88.9%, heart disease in 38.9%, ocular defects (strabismus, blepharophimosis, cataract) in 33.3%, ear anomalies or sensorineural deafness in 33.3%, cerebral aplasia or hypoplasia in 27.8%, renal or urinary anomalies in 27.8% and microcephaly in 22.2% [27]. In the review by Lin and colleagues of the 18 patients studied by microarray up to 2016, craniofacial dysmorphism and developmental delay were present in practically all [10].

3.2 Prenatal and neonatal period

Ultrasound signs are non-specific: small-for-gestational-age fetus or IUGR, oligohydramnios or polyhydramnios, skeletal, renal or genital anomalies (including discordance between sex on ultrasound and fetal karyotype), heart disease or brain malformation; the PNDS stresses that there are no consensual prenatal signs specifically pointing to the deletion [3]. Apparently isolated bladder outlet obstruction, particularly in female fetuses, should prompt consideration of 10qter monosomy [64]. Decreased fetal movements have been described [65].

At birth, there may be prematurity with respiratory distress and persistent hypotonia, with recurrent respiratory infections favoured by prematurity, resuscitation or choanal atresia; hypotonia is typically axial, with segmental hypertonia [3]. Respiratory distress with upper airway infection may occur a few months after birth and may be fatal [3]. The PNDS attributes to Wulfsberg and colleagues a neonatal mortality of 23% "in 10 patients", linked to prematurity and, in three, to heart disease; the percentage is incompatible with that denominator, and the original article is a review of 18 patients (3 new and 15 published up to 1989), so the figure should be read as an approximate proportion in a small historical series, prior to microarray and biased towards severe presentations, and not as current risk [3, 26]. Neonatal hypotonia causes sucking and feeding difficulties, sometimes requiring enteral feeding [3].

3.3 Growth, facies and skull

More than half of patients have growth retardation, frequently preceded by IUGR and aggravated by feeding difficulties; some later normalise their growth, and some develop overweight or obesity, sometimes linked to psychotropic drugs [3]. There are no specific growth charts [3]. In a young adult woman without ID, short stature from birth was the main sign [51].

The facies described in the PNDS includes microcephaly (67%), low frontal hairline (widow's peak), short or high forehead, broad nose (89%) with nostrils sometimes anteverted, large, malformed or cup-shaped ears (83%), strabismus (67%), narrow, downslanting palpebral fissures (33%), hypertelorism with or without epicanthus (44%), thin upper lip, cleft lip and palate, micrognathia, high-arched palate (28%) and a short (39%) and broad (11%) neck [3]. The triangular face with a prominent "beaked" nose and low-set, poorly hemmed ears is the most frequently cited combination since the 1980s, and facial asymmetry was one of the most consistent features in Irving's series [2, 26, 31]. Some children with facies suggestive of other syndromes have been described, such as a boy with stigmata similar to those of Noonan syndrome (short webbed neck, pectus, widely spaced nipples, cryptorchidism, trigonocephaly) and another with a phenotype similar to that of Prader-Willi syndrome in infancy [65, 66].

Cranial anomalies include a prominent metopic suture with trigonocephaly, scaphocephaly due to sagittal synostosis, plagiocephaly and lambdoid synostosis, which may require surgery from the first months [3]. Faria and colleagues, in two Brazilian patients with deletions of 13.1 and 10.9 Mb, interpreted the craniosynostosis as probably secondary to altered brain development, and not to abnormal sutural signalling [38]. Facial asymmetry on crying due to agenesis or hypoplasia of the depressor anguli oris muscle was described in a newborn girl with a 10q26.12→qter deletion [27].

3.4 Neurodevelopment, cognition and language

Developmental delay is practically constant: sitting is acquired between 8 and 10 months and independent walking between 18 months and 6 years; at 3 years there are language delay, coordination and balance disturbances, upper limb tremor and fine motor difficulties [3]. Oral-motor disorders precede dysarthria, and verbal apraxia and developmental dysphasia have been described [3]. ID is present in 95% of described patients, usually moderate to severe and global, with mean intelligence quotients of the order of 41 to 44 according to the PNDS; some patients retain limited language throughout life and social interaction may improve with augmentative and alternative communication [3, 13]. There are, however, individuals with normal or near-normal cognition [51, 62]. Schrander-Stumpel and colleagues reviewed the developmental data of 18 survivors [28].

Ataxia with coordination disturbance, difficulty with writing and saccadic ocular pursuit is described by the PNDS [3]. Lacaria and colleagues described four patients, two of them siblings, with almost identical terminal 10q26.3 deletions, ataxia, mild to moderate ID and hyperaemia of the hands and feet, without many of the usual features [67]. In deletions that include EBF3, motor delay tends to be more marked than cognitive delay (significant difference between the motor and cognitive-adaptive domains, p = 0.0016, in eight Japanese patients) and magnetic resonance imaging (MRI) shows vermis hypoplasia with a radial arrangement of the cerebellar folia ("dandelion sign") [17, 20].

3.5 Behaviour, sleep and sensory processing

More than half of patients have behavioural disorders: hyperkinesis, attention deficit, irritability, agitation, sexualised play, anxiety and aggressiveness of varying degree; families also describe excessive affection with inappropriate approaches to strangers, and some publications suggest worsening in the prepubertal period [3]. Hyperactivity and attention deficit have been associated with small terminal deletions and with patients with relatively preserved cognition [35, 63]. Autistic traits were reported in 4 of 26 children (14%) of the Unique support group, and ASD was the reason for genetic testing in the Slovak twins with a 977 kb deletion [3, 5]. The PNDS describes the 10q26 deletion as a susceptibility factor for prepubertal-onset bipolar disorder, with tics, inappropriate sexual behaviour, impaired spatial orientation, running away, oppositional behaviour and oral exploration of objects [3].

Sleep disturbances include late sleep onset, difficult waking with fatigue and, in some children, a need for only about 6 hours of sleep per night; the reduced need for sleep had already been noted in 1987 [3, 25]. Tactile and oral hypersensitivity and hyperacusis (about half of the families surveyed) frequently coexist with increased pain tolerance, so that children may not notice injuries; pain and noise may trigger behavioural changes [3]. Decreased response to pain is also characteristic of the EBF3-related disorder (95% in a series of 41 patients) [4].

3.6 Epilepsy and central nervous system

Epilepsy occurs in 31% of patients during childhood, with incomplete penetrance in families, and may manifest as febrile seizures, absences, atonic seizures, generalised tonic-clonic seizures or infantile spasms, sometimes with neonatal onset [3]. In Irving's series, four of 15 patients had seizures [2]. Brain MRI may show hypoplasia of the inferior vermis with an enlarged cisterna magna, ventricular dilatation, cerebellar hypoplasia or agenesis of the corpus callosum [3, 12].

3.7 Heart and circulation

The PNDS estimates congenital heart disease in 39 to 50% of patients, with a heterogeneous spectrum: VSD with or without pulmonary hypertension, pulmonary stenosis, patent ductus arteriosus, atrial septal defect (ASD), tetralogy of Fallot, conotruncal malformations, double outlet right ventricle with left ventricular hypoplasia, double aortic arch and cardiac hypertrophy [3]. In the French cohort, heart disease was concentrated in deletions larger than 8 Mb (5/11) and was absent in 10q26.2–q26.3 deletions (0/6) [12]. Left ventricular dilatation, postural orthostatic tachycardia in an adult woman and atrial fibrillation in a French patient have also been described [12, 62, 68]. Several families report cold extremities or Raynaud phenomenon, and Lacaria described hyperaemia of the hands and feet [3, 67].

3.8 Urinary tract, genitalia and anal region

Urinary, genital and anal anomalies, sometimes severe, are particularly associated with deletions that include 10q26.11–q26.12 and affect about 30% of patients [3]. In 46,XY individuals, hypospadias, penile curvature due to hypoplasia of the corpus spongiosum, micropenis (67%) and cryptorchidism (83 to 100%) have been described; Tanabe's review already recorded cryptorchidism in 10 of 12 males (83%) [2, 3, 32]. In 46,XX individuals, hypoplasia of the vagina and of the labia majora and minora has been described [3]. The external genitalia may be atypical to the point of preventing immediate sex assignment, particularly when anal malformations coexist (anteriorly placed anus, stenosis, imperforate anus, cloaca) [3, 29].

The published endocrine data are partial. In the only 46,XY observation with non-masculinised genitalia in which neonatal testosterone was measured, it was normal, anti-Müllerian hormone (AMH) was slightly reduced and there was a large utricle interpreted as a vagina; the PNDS interprets the whole picture, in 46,XX and 46,XY individuals, as a defect of the external genital primordia and of the urogenital sinus, without gonadal dysgenesis, and considers 46,XY gonadal dysgenesis rare in this context [3]. The case of Tosur and colleagues illustrates this: a 46,XY term newborn (3230 g), with a 0.5 cm phallus, basal meatus, no palpable gonads and imperforate anus with rectal fistula, had a distal vagina, uterine cervix and abdominal testes, normal testosterone at 24 hours and low AMH, without alteration of the AMH gene, and an 8.2 Mb interstitial 10q25.3q26.13 deletion [61]. Ogata and colleagues mapped distinct genes for urinary and genital development in distal 10q26 [50].

On the urinary side, anomalies of the urogenital sinus predominate: in 46,XY individuals, posterior urethral valves (PUV) with megacystis and hydronephrosis (1 of 18 cases investigated) or renal hypoplasia; in 46,XX individuals, bladder dysfunction that may be diagnosed prenatally [3]. Horseshoe kidney, ectopic kidneys, vesicoureteric reflux, renal hyperechogenicity and bilateral renal hypoplasia have also been described [3, 12, 31, 45]. Megacystis in girls with 10q26.2 and 10q26.3 deletions and high-output renal failure due to obstructive uropathy in an adolescent show that infravesical obstruction may have late renal consequences [12, 64]. In deletions that include EBF3, neurogenic bladder is diagnosed in infancy (median 6.5 months) and required cystostomy in seven of eight Japanese patients [17].

3.9 Limbs and skeleton

Limb anomalies include fifth finger clinodactyly (44%), clubfeet (22%), hammer toes (17%), limited elbow extension (22%), 2-3 or 4-5 toe syndactyly (22%), nail hypoplasia (22%) and single palmar crease (39%); a broad chest (22%), widely spaced nipples (28%), pectus excavatum, scoliosis, kyphosis, hyperlordosis at puberty, joint hyperlaxity, hip dysplasia and flat feet are also described [3, 9, 12, 37].

3.10 Hearing and vision

About 20% of patients have deafness and/or ophthalmological anomalies [3]. Bilateral congenital deafness, mainly sensorineural, occurs in 17%, is usually diagnosed in the first year, may appear later and is aggravated by chronic otitis media; the PNDS describes aided hearing thresholds of 50 to 60 dB and unaided thresholds of 75 dB in the first months [3]. Computed tomography (CT) may show bilateral Mondini malformation, with an enlarged vestibule and dilated semicircular canals [3]. Conductive deafness has been described in a 600 kb deletion including EBF3 [6].

Strabismus is the most frequent ocular finding (55 to 100%); amblyopia, moderate to severe myopia, astigmatism, hypermetropia, iris or optic disc coloboma, cataract and optic nerve hypoplasia are also described [3, 12, 68, 69]. In a 4-week-old infant with a terminal 10q26 deletion, bilateral anterior segment dysgenesis and bilateral persistent fetal vasculature were described, with microphthalmia, microcornea, corectopia, congenital cataracts and posterior embryotoxon [70].

3.11 Other systems

The PNDS describes recurrent infections (pneumonia, ear, nose and throat and urinary infections), potentially fatal in the context of hypotonia; constipation of variable degree; changes in skin appendages in rare patients (slow-growing, brittle hair, small slow-growing nails, small yellowish teeth); eczema; precocious puberty, sometimes at 8 years; and, in the French cohort, delayed puberty, pancreatic atrophy, inguinal or umbilical hernias and piriform aperture stenosis [3, 12]. Duodenal atresia has been described in a Chinese child [10] and alopecia areata in an American child [71].

3.12 Natural history and adulthood

Data on adults are scarce. The French cohort included six patients over 18 years and Irving's series a living individual aged 63 years [12, 31]. Most adults with ID live in specialised facilities, and the PNDS stresses the risk of loss of skills when follow-up and rehabilitation are interrupted at transition; in patients whose follow-up is ensured, skills are maintained [3]. Adults diagnosed through an affected child often have a mild phenotype (short stature, learning difficulties, anxiety) [5, 9, 39]. There are no life expectancy data.

3.13 EBF3-related disorder (HADDS)

In the form due to a point variant, HADDS manifests as congenital hypotonia (100% in a series of 41 patients), motor delay (98%), speech delay (>97%, with an expressive language deficit in more than 85%), ataxia (78%), incoordination (63%), hypertonia (39%), abnormal electroencephalogram (EEG) (34%), febrile seizures (20%) and unprovoked seizures (15%), decreased response to pain (95%), repetitive scratching behaviours (54%), autistic traits (68%, with formal ASD in 27%) and cerebellar abnormalities (29%) [4, 55]. Strabismus, vesicoureteric reflux, micropenis, cryptorchidism and testicular failure have been described [53, 54]. The overlap with 10q26.3 deletions is extensive and explains why these deletions may present mainly with ataxia and mild ID [20, 67].

4. Clinical Recognition and Warning Signs

4.1 General principle

The French PNDS stresses that 10q26 deletion syndrome may be suspected from a set of clinical signs, but that in most cases the diagnosis results from a genomic study requested systematically in the presence of a multiple malformation picture, with or without developmental delay or ID [3]. The most suggestive combination, described since Wulfsberg (1989), is a triangular face with a prominent nose, low-set and poorly hemmed ears, a thin upper lip and strabismus, associated with growth retardation, developmental delay and cardiac or anogenital malformations [3, 26]. None of these signs is specific, and the PNDS itself acknowledges that diagnosis is difficult without genetic analysis [3].

4.2 Prenatal period

The ultrasound signs that lead to quantitative genome analysis are non-specific: small-for-gestational-age (SGA) fetus or IUGR, oligohydramnios or polyhydramnios, skeletal anomalies, renal anomalies, genital variations or discordance between the genital appearance on ultrasound and the fetal karyotype, heart disease and brain malformation [3]. The deletion may also be found on a microarray requested for another ultrasound anomaly or on a karyotype performed because of abnormal serum markers [3]. Megacystis or another apparently isolated bladder outlet obstruction, particularly in a female fetus, justifies considering 10qter monosomy [64]. Decreased fetal movements have been reported in a patient with a 10q26.3 deletion and, in the EBF3-related disorder, as a possible prenatal sign [65, 72].

Genome-wide non-invasive prenatal screening may flag a 10q25→qter deletion that does not belong to the fetus: in eight pregnancies, the signal corresponded to low-level maternal mosaicism associated with expansion of the FRA10B fragile site, and invasive testing was normal [49]. Conversely, a mosaic fetal deletion confirmed in amniotic fluid may decrease during gestation and be associated with a newborn without abnormalities at 4 months [48].

4.3 Neonatal period

The PNDS lists as neonatal warning signs prematurity with respiratory distress, hypotonia, IUGR or SGA, the characteristic facies, microcephaly or craniosynostosis, genital variations consistent with a difference of sex development (DSD), urinary malformations, lower gastrointestinal malformations, brain, skeletal and cardiac malformations and unexplained neonatal death [3]. A 46,XY newborn with atypical or female external genitalia, particularly with an associated anorectal malformation, is a context in which a terminal 10q deletion should be sought, alongside the 9p24.3 deletion [29, 30, 61]. Facial asymmetry on crying due to hypoplasia of the depressor anguli oris muscle was the presenting sign in a preterm newborn girl with a 10q26.12→qter deletion [27].

4.4 Infant, child and any age

After the neonatal period, the signs that raise suspicion are the facies, craniofacial features, developmental delay or ID, dysarthria, heart disease, urinary, genital and lower gastrointestinal malformations, skeletal malformations, postnatal growth retardation, sensorineural deafness, myopia, coloboma or cataract, behavioural disorders and the combination of epilepsy, ataxia and brain malformation [3]. Severe infantile hypotonia, with sucking difficulties and hypogenitalism, may resemble Prader-Willi syndrome, and the combination of a short webbed neck, pectus, widely spaced nipples and cryptorchidism may resemble Noonan syndrome [65, 66]. In small 10q26.3 deletions, the presentation may be mainly neurological, with ataxia, mild to moderate ID and hyperaemia of the hands and feet, or dominated by neurogenic bladder with recurrent urinary tract infections when EBF3 is included [17, 67, 72].

4.5 Adults

Adults are diagnosed mainly in two situations. The first is the study of the parents of an affected child, which may reveal the same deletion in a parent with a mild phenotype, such as short stature, learning difficulties, anxiety or mild ID [5, 9, 39]. The second is the study of a couple with affected offspring or with reproductive difficulties, which may reveal a balanced translocation involving 10q26 in a parent without clinical manifestations [3, 19].

4.6 Warning signs and urgent situations

The PNDS includes an emergency card in appendix 5, intended to accompany the patient [3]. The situations requiring rapid action, according to the PNDS and published series, are summarised in the table.

4.7 Newborn screening

There is no newborn screening for the 10q26 deletion. In the newborn girl described by Li and colleagues, newborn hearing screening was normal, which is consistent with the frequently late or progressive nature of the deafness described in the PNDS and indicates that a normal screen does not obviate subsequent audiological assessment [3, 27].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

There are no formal clinical criteria. The diagnosis is cytogenomic and corresponds to the demonstration of a copy number loss involving 10q26 (breakpoints between 10q26.11 and 10q26.3), terminal, interstitial, complex or within a translocation derivative [3]. The deletion should be classified according to the technical standards of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen), which assign points to gene content, overlap with established dosage-sensitive regions or genes, number of genes, literature and segregation, and classify the copy number variant (CNV) into one of five categories, from benign to pathogenic, separating the classification of the variant from its implications for the individual [73]. ClinGen has no curated terminal 10q26 region; of the genes in the region, EBF3 has a haploinsufficiency score of 3 and EMX2 a score of 1, so deletions including EBF3 obtain a high score through overlap with an established haploinsufficient gene [11, 73].

5.2 Diagnostic algorithm

Appendix 4 of the PNDS proposes the following sequence: in case of suspicion, referral to a reference centre for "developmental anomalies and malformation syndromes", a genetics clinic and a paediatric neurology clinic; request for chromosomal microarray (chromosomal microarray analysis, ACPA, or array comparative genomic hybridisation, aCGH) or targeted FISH; after confirmation, referral to care services (early medico-social action centre, CAMSP; medico-educational institute, IME); and a further genetics clinic appointment for counselling and possible prenatal diagnosis [3].

5.3 Available tests and their limitations

The International Standards for Cytogenomic Arrays (ISCA) consensus, based on 33 studies with 21,698 patients, showed that chromosomal microarray has a diagnostic yield of 15–20% in patients with developmental delay, ID, ASD or multiple congenital anomalies, versus about 3% for the karyotype, and recommended it as the first-line test, reserving the karyotype for obvious chromosomal syndromes, a family history of chromosomal rearrangement or multiple miscarriages [18]. The Oxford handbook adopts the same recommendation and points out that the G-banded karyotype has a resolution of about 5 to 10 Mb [19]. In a Brazilian series of 5778 patients with neurodevelopmental disorders or congenital anomalies studied by microarray, 1024 had a pathogenic result, and 10q26 deletion syndrome was identified in 3 patients [15].

Coordinates should be stated with the genome assembly used. Many reports and publications prior to 2015 use GRCh37/hg19 and more recent ones use GRCh38, so the same deletion has different coordinates; OMIM places the syndrome on GRCh38, between positions 117,300,001 and 133,797,422 of chromosome 10 [2, 10, 27]. The report should include the international cytogenomic nomenclature, the size, the list of OMIM genes included (in particular EBF3, HMX2, HMX3, WDR11, FGFR2 and DOCK1), the ACMG/ClinGen classification and, when the parents have been studied, the origin [73]. EBF3 point variants are described in Human Genome Variation Society (HGVS) nomenclature on the MANE transcript NM_001375380.1, and not on the transcript NM_001005463.2 used in OMIM [7, 8].

5.4 Interpretation of small deletions and inherited deletions

The interpretation of small deletions is the most difficult part of the diagnosis. A 600 kb deletion that includes EBF3 is pathogenic, because it reproduces the haploinsufficiency of a gene with sufficient evidence [6, 11]. An 860 kb deletion in 10q26.2 containing DOCK1, INSYN2A, NPS and FOXI2, found in a fetus with IUGR and in the mother with mild ID, suggests an effect of the interval, but the evidence comes from a single family [39]. A 977 kb deletion in 10q26.3, with 28 genes, inherited from an asymptomatic father in twins with ASD, did not allow causality to be concluded and was interpreted as a possible contribution to a combined genetic burden, together with a TRIO variant in one of the twins [5]. Inheritance from a parent without an apparent phenotype is not sufficient to classify the deletion as benign, given the variable expressivity documented in this region, and a mild phenotype in the parent should be actively sought [9, 10, 19].

The Oxford handbook lists the explanations for discordance between a carrier parent and a child with the same CNV: unmasking of a recessive variant on the other allele, imprinting, incomplete penetrance, complex inheritance and amplification or extension of the CNV on transmission [19]. In the 10q26 region, the unmasking of a homozygous MMP21 variant by a maternal 10q26.13–q26.2 deletion illustrates the first possibility, and justifies sequencing of the remaining allele when the phenotype includes signs that the deletion does not explain, such as heterotaxy [40].

5.5 Mosaicism

Mosaicism is rare, but has diagnostic and prognostic consequences. In a fetus with mosaic del(10)(q26.13), the proportion of deleted cells varied between techniques and tissues (about 35% in uncultured amniocytes by aCGH, 29.8% by FISH in amniocytes, 16 of 40 and later 4 of 26 cells in fetal blood, 6 of 40 in cord blood and 8% in the buccal mucosa at 4 months), with a normal karyotype in the placenta and cord; the child had no abnormalities at 4 months [48]. In another fetus, a der(10)t(3;10) derivative in 20% mosaicism in amniotic fluid, with 3q26.32–q29 duplication (17%) and 10q26.12–q26.3 deletion (18%), proved to be de novo, with normal parental karyotypes and microarrays and FISH of paternal sperm without imbalance [46]. The Oxford handbook states that the SNP-array is more sensitive than aCGH for mosaicism, but quantifies the percentage poorly, so interphase FISH in several tissues is useful [19, 48]. Low-level maternal mosaicism, as in the false positives of non-invasive screening associated with FRA10B, should be considered when a parent appears to carry a large deletion without a phenotype [49].

5.6 Additional assessment at confirmation

The PNDS recommends, at diagnosis, a complete multidisciplinary clinical examination with targeted complementary investigations [3]. Cardiovascular assessment includes a paediatric cardiology consultation with a systematic echocardiogram, even without symptoms [3]. Urogenital and anal assessment includes a paediatric clinical and laboratory examination, supplemented by paediatric surgery and paediatric endocrinology, abdominal and pelvic ultrasound, possible abdominopelvic CT, assessment of renal function and pelvic ultrasound follow-up at 3 and 5 years [3]. Endocrine assessment comprises examination of the external genitalia at birth; measurements at 24 hours of life of growth hormone (GH), testosterone, AMH and thyroid hormones; repeat testosterone and AMH at 1 month, which may be normal; plasma 17-hydroxyprogesterone (17-OHP), which may be slightly elevated and normalise after 4 months; a 24-hour urinary steroid profile and gonadotrophins; and, when indicated, study of the somatotrophic axis with basal insulin-like growth factor 1 (IGF-1) and binding protein 3 (IGFBP-3) and a possible GH stimulation test [3]. Study of the androgen receptor, when performed, showed normal binding and thermolability [3]. Sensory assessment includes otoacoustic emissions and auditory evoked potentials or audiometry, CT of the petrous bones when there is deafness, and ophthalmological examination; neurological assessment includes examination of tone, EEG in the presence of seizures and brain MRI to look for malformations [3]. Developmental assessment and, when there are signs, referral to an autism resource centre complete the initial assessment [3].

5.7 Prenatal and preimplantation diagnosis

In the presence of ultrasound signs, microarray on chorionic villi or amniocytes is the test that establishes the diagnosis, and the finding of a 10q26 deletion during pregnancy should lead to study of the parents [3]. Non-invasive screening results should be confirmed by invasive testing, because maternal mosaicism associated with FRA10B may produce false positives [49]. A discrepancy between cultured and uncultured amniocytes, or between amniocytes and fetal blood, suggests mosaicism and justifies studies in more than one tissue [48]. The prognosis of a fetus with a non-mosaic 10q26 deletion is difficult to individualise, because size and gene content correlate only partially with severity; the PNDS relies on ID in 95% of described cases to consider admissible, in France, a request for termination of pregnancy for medical reasons after the opinion of the multidisciplinary prenatal diagnosis centre (CPDPN) [3]. Preimplantation genetic diagnosis applies mainly to carriers of a deletion or of a balanced translocation [3].

6. Differential Diagnosis

6.1 Approach

The PNDS considers that diagnosis is difficult without genetic analysis, because the phenotype, sometimes not very specific, resembles that of other chromosomal rearrangements with non-specific signs [3]. In practice, the differential diagnosis is resolved by chromosomal microarray, which distinguishes the 10q26 deletion from other deletion or duplication syndromes, and by exome or genome sequencing when the microarray is normal and the picture suggests a monogenic syndrome [3, 18]. The differential diagnoses of greatest practical interest fall into three groups: imbalances of the long arm of chromosome 10 itself, terminal deletion syndromes of other chromosomes with an overlapping phenotype and monogenic syndromes that reproduce part of the picture.

6.2 Comparative table

6.3 Main differential diagnoses

The closest differential diagnosis is the EBF3-related disorder. A 10q26.3 deletion that includes EBF3 may produce a picture dominated by hypotonia, disproportionate motor delay, ataxia, mild to moderate ID and neurogenic bladder, without the growth retardation, heart disease and genital anomalies of larger deletions [17, 20, 67]. In a child with hypotonia, non-progressive congenital ataxia and vermis hypoplasia with radially arranged cerebellar folia, the exome detects EBF3 point variants and the microarray detects deletions, so the two tests are complementary [20, 72].

Terminal deletion syndromes of other chromosomes share with the 10q26 deletion the combination of ID, dysmorphism and multiple malformations, and some share particular signs: the 9p deletion is associated with trigonocephaly and ambiguous genitalia in males, and the 1p36 deletion with heart disease, epilepsy and severe language impairment [30, 76, 77]. The clinical overlap is broad enough for the diagnosis to rest on the microarray and not on the facies [3].

The similarities with Prader-Willi syndrome are limited to the first year (hypotonia, sucking difficulties, hypogenitalism); in adolescence, the patient with a 10q26.3 deletion described by Lukusa and Fryns developed hyperactivity and destructive behaviour, without hyperphagia or obesity [65, 79]. Similarities with Noonan syndrome (short webbed neck, pectus, widely spaced nipples, cryptorchidism) have been described in a boy with a small terminal deletion [66, 78].

In the context of 46,XY DSD, the terminal 10q deletion should be sought alongside the 9p24.3 deletion, which contains the DMRT1 and DMRT2 genes and is associated with gonadal dysgenesis; in the 10q26 deletion, the available data point to a defect of the external genital primordia and of the urogenital sinus, with normal neonatal testosterone and without gonadal dysgenesis in most cases [3, 30, 61]. Loss of Fgfr2 causes partial XY sex reversal in the mouse, which made FGFR2 a candidate for 46,XY cases with undermasculinised genitalia [12, 61].

Distal 10q duplication is the reciprocal imbalance of the same region and was described by Turleau as the "type" of which 10qter monosomy would be the "countertype", with opposite facial features; it is distinguished by a gain, and not a loss, of copy number, and by the greater severity of duplications starting at 10q24 [23, 41]. In translocation derivatives, the picture combines the effects of 10q26 monosomy and trisomy of the partner segment, which explains why the French cohort excluded from analysis the three derivatives with a discordant phenotype [12, 45].

The entities in the differential diagnosis include the 1p36 deletion, Noonan syndrome, Prader-Willi syndrome, juvenile polyposis associated with 10q23 deletions, split hand-foot malformation, hypogonadotrophic hypogonadism, FGFR2-related craniosynostoses and DSD.

7. Treatments and Risk Management Strategies

7.1 Principles and organisation of care

There is no specific treatment for the 10q26 deletion; treatments are symptomatic and depend on the organs affected [3]. The PNDS recommends a multidisciplinary approach with regular follow-up, early diagnosis and access to personalised rehabilitation aimed at motor development, cognition, communication and social skills [3]. Coordination is the responsibility of a physician at the reference or competence centre, working with the attending physician and with hospital and community professionals: geneticists, paediatric neurologists, paediatric cardiologists, paediatric surgeons, ear, nose and throat specialists, ophthalmologists, paediatric gastroenterologists and endocrinologists, orthopaedic surgeons, rehabilitation physicians, child psychiatrists, dentists and orthodontists, physiotherapists, psychomotor therapists, speech and language therapists, hearing aid specialists, orthoptists, occupational therapists, specialised educators, psychologists, social workers and special education teachers [3]. The PNDS assigns to the attending physician referral for diagnostic confirmation at a reference or competence centre, verification that follow-up is carried out by an experienced team and follow-up of complications in coordination with that team [3].

7.2 Communication of the diagnosis

The PNDS recommends that the diagnosis be communicated in a dedicated consultation; when the person who requested the analysis is not a geneticist, the communication should be made jointly with a medical geneticist or, if this is not possible, a genetics appointment should be scheduled within no more than 1 to 2 weeks, to limit family anxiety and inappropriate internet searches [3]. The presence of a psychologist is strongly recommended [3]. In prenatal diagnosis, the information includes the characteristics of the disease, the possibilities of care and follow-up, the possibility of obtaining the opinion of other specialists, the mode of transmission and the options regarding the pregnancy: welcoming the child, palliative care in the presence of an incurable malformation (particularly cardiac), anonymous birth with relinquishment for adoption, foster care without loss of parental rights or termination of pregnancy for medical reasons after discussion at the CPDPN [3]. In postnatal diagnosis, the information includes the disease and prognosis, transmission and genetic counselling, the care plan, screening for complications and the social framework, with the long-term condition (ALD) care protocol and applications to the Maison Départementale des Personnes Handicapées (MDPH) and the Caisse d'Allocations Familiales (CAF) for the daily parental presence allowance [3]. A second consultation a few weeks later allows the information to be revisited and the team to be introduced, including the social worker; a letter is sent to the physicians following the child and psychological support is offered to parents and siblings [3].

7.3 Rehabilitation, development and schooling

Early intervention, in France through the CAMSP, combines psychomotor therapy, physiotherapy, speech and language therapy with training in augmentative and alternative communication (AAC), occupational therapy, psychology and specialised education [3]. Physiotherapy begins as soon as hypotonia is recognised and supports head control, sitting, transfers, crawling, standing and walking, with muscle strengthening when there is scoliosis, kyphosis or orthopaedic problems [3]. Psychomotor therapy and speech and language therapy work on oral-motor function, buccofacial praxis, sucking and swallowing, gross and fine motor skills and language acquisition; AAC uses sign language, the Makaton method (signs and pictograms), the PECS system or other systems, and the ISAAC association is indicated as a resource [3]. Occupational therapy supports daily autonomy and adaptation of the home and school; in the presence of motor coordination disorder, the PNDS recommends introducing keyboard writing early, with later transition to a tablet [3]. Children usually attend pre-school education with the support of an assistant (AESH, accompagnant d'élève en situation de handicap) and are then directed to special education and home care services (SESSAD) or to an IME, with a child psychiatry day hospital when there is a behavioural disorder [3]. Community integration (nursery, school, leisure centres, adapted holidays) should be encouraged, and the PNDS reports benefit from animal-assisted therapy (therapeutic horse riding, donkey-assisted therapy) for anxiety [3]. The general approach to ID and ASD follows the specific recommendations for those conditions.

7.4 Behavioural disorders

The PNDS recommends behavioural management techniques and behavioural, cognitive and cognitive-behavioural therapies for managing frustration, anger outbursts, impulsivity and self-directed and other-directed aggression, parental guidance and child psychiatric follow-up, supplemented by occupational therapy [3]. For some children, psychotropic drugs were the only effective approach, in particular low-dose risperidone, and the PNDS also accepts the strategies used in ASD [3]. Before intensifying drug treatment of a behavioural crisis, pain, noise or intercurrent illness should be sought, given the increased pain tolerance and hyperacusis; the PNDS refers to adapted pain assessment scales (Pédiadol, Evadol, EVS, San Salvadour) [3].

The PNDS does not give doses. The reference dose is therefore that of the label, and the European indication closest to the use described in the PNDS is that of the Summary of Product Characteristics (SmPC) approved in Portugal by INFARMED: short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder in children from 5 years and adolescents with subaverage intellectual functioning or mental retardation, as part of a comprehensive treatment programme and prescribed by a specialist [80]. The United States Food and Drug Administration (FDA) label approves risperidone for irritability associated with autistic disorder between 5 and 17 years, with a different titration schedule [81]. Use in the 10q26 deletion outside these indications is off-label use.

In the controlled paediatric trials in autistic disorder supporting the FDA label (risperidone 0.5–4 mg/day, n = 107, versus placebo, n = 115), the most frequent adverse effects were fatigue (31% versus 9%), vomiting (20% versus 17%), nasopharyngitis (19% versus 9%), constipation (17% versus 6%), dry mouth (10% versus 4%), weight gain (8% versus 2%) and sialorrhoea (7% versus 1%) [81]. The labels warn of persistent hyperprolactinaemia, significant weight gain, orthostatic hypotension, extrapyramidal symptoms and tardive dyskinesia, neuroleptic malignant syndrome and leucopenia or neutropenia [80, 81]. In the 10q26 deletion, the PNDS adds a specific risk: antipsychotics aggravate constipation and hypotonia, which may lead to intestinal obstruction and aspiration; monitoring of adverse effects by all carers, more regular follow-up, adjustment of treatment and information for the family and institutions are required [3]. Weight gain should be monitored, because the PNDS reports overweight and obesity linked to behavioural treatments, requiring dietetic support [3, 80].

The PNDS further describes the 10q26 deletion as a susceptibility factor for prepubertal-onset bipolar disorder, with worsening at puberty, to be treated by child psychiatry according to the nature of the symptoms, for example with antipsychotics and day hospital care [3].

7.5 Sleep disorders

The PNDS indicates that sleep disorders may require melatonin or an anxiolytic, after a neurology or child psychiatry opinion and with follow-up at a specialised centre, without specifying drug or dose; the anxiolytic is not specified [3]. The melatonin formulation with a European centralised authorisation for paediatric insomnia is Slenyto® (prolonged-release melatonin, 1 mg and 5 mg), authorised in the EU on 20 September 2018 for insomnia in children and adolescents aged 2 to 18 years with ASD and/or Smith-Magenis syndrome. The Commission decision of 26 August 2024 extended the indication to neurogenetic disorders with aberrant diurnal melatonin secretion and/or nocturnal awakenings, and that of 17 March 2025 added insomnia from 6 to 17 years with ADHD, whenever sleep hygiene measures are insufficient [82]. The 10q26 deletion is a neurogenetic condition that may fall within this indication when the label conditions are met; in other situations use is off-label.

7.6 Epilepsy

Treatment of epilepsy depends on the type and frequency of seizures and is managed by a paediatric neurologist, who adjusts therapy with growth on the basis of the clinical picture and EEGs; the PNDS does not recommend a preferred antiepileptic drug or specific doses for the 10q26 deletion [3]. The choice of drug and its dosage follow the recommendations for the type of seizure or epilepsy syndrome identified. Before starting an antiepileptic drug, individual contraindications should be excluded, and interaction with other treatments should be considered [3].

7.7 Growth and endocrinology

Growth is followed on the usual reference charts, because there are no specific charts; many patients are born SGA or with IUGR and have feeding difficulties, and some catch up spontaneously [3]. The PNDS makes no recommendation on growth hormone: the decision rests with the paediatric endocrinologist, after study of the somatotrophic axis with basal IGF-1 and IGFBP-3 and a possible stimulation test [3]. Outside demonstrated GH deficiency, the European indication applicable to some of these children is that for children born SGA without catch-up growth: the Omnitrope® (somatropin) label approves treatment when birth weight and/or length are below −2 standard deviations (SD), current height is below −2.5 SD, height adjusted for mid-parental height is below −1 SD and growth velocity in the last year was below 0 SD at 4 years or later, with a usual dose of 0.035 mg/kg/day (1 mg/m² of body surface area per day) until final height; treatment is stopped after the first year if growth velocity is below +1 SD [83]. The same label recommends excluding other causes of growth retardation, measuring fasting insulin and blood glucose before starting and annually, measuring IGF-1 before starting and twice a year, not starting treatment close to puberty and not using somatropin when there is evidence of active tumour [83]. Application of this regimen to the 10q26 deletion is an extrapolation, with no published efficacy or safety data in this condition in the sources consulted.

For penile hypoplasia, the PNDS states that testosterone enanthate may be used, without giving the dose [3]. The reference dose is, by extrapolation, that for micropenis of other causes described in a paediatric endocrinology review: four doses of 25 mg of testosterone cypionate or enanthate in oil, intramuscularly, every 3 weeks for 3 months (Guthrie regimen: 25 mg of depot testosterone every 3 weeks for 3 months); as a topical alternative, 2.5% dihydrotestosterone gel at a daily dose of 0.2–0.3 mg/kg for 3–4 months [84]. The same review states that there is no consensus on dose, route and duration, and that adverse effects are minimal, although treatment may transiently accelerate growth velocity and bone maturation [84]. The case of Tosur and colleagues shows the response in a 46,XY newborn with a 10q25.3q26.13 deletion: the phallus increased from 0.5 cm to 1.5 cm with testosterone [61]. In DSD, the PNDS recommends monitoring and adaptation of hormonal treatments, and precocious puberty, which may appear at around 8 years, requires specialist follow-up [3]. Thyroid hormones are measured every 2 years [3].

7.8 Urogenital, anal and renal anomalies

Surgical assessment should be early, following the model of congenital anomalies of the kidney and urinary tract (CAKUT), often on the basis of a prenatal diagnosis [3]. PUV in 46,XY children are treated according to the French PNDS dedicated to PUV [3]. A surgical opinion is mandatory in the process of civil sex assignment and in all anomalies of the external genitalia, including cryptorchidism, hypospadias and testicular ectopia [3]. As gonadal dysgenesis appears rare in this context, the PNDS does not indicate prophylactic gonadectomy without a formal diagnosis of gonadal dysgenesis [3]. When the genitalia do not allow sex to be assigned with confidence, French bioethics law allows civil registration of sex to be deferred beyond 5 days, up to a maximum of 3 months, on the opinion of a specialised reference centre, after informing the parents and with possible support from associations [3]. The approach to DSD follows the general recommendations for those conditions. In Tosur's case, bilateral orchidopexy and posterior sagittal anorectoplasty were performed at 11 months and rudimentary Müllerian remnants were found [61]. In deletions that include EBF3, neurogenic bladder required cystostomy in seven of eight patients in a Japanese series [17]. Renal function, urine dipstick and albumin/creatinine ratio in the first morning urine are monitored annually, and blood pressure is measured systematically when there is heart disease or renal malformation [3].

7.9 Heart disease

Treatment of heart disease depends on the lesion and is the responsibility of paediatric cardiology; complex congenital heart defects are operated on in specialised surgical centres, and the PNDS refers to the French PNDS on tetralogy of Fallot, pulmonary atresia with ventricular septal defect and absent pulmonary valve with ventricular septal defect [3]. In the case described by Li and colleagues, the ASD, patent foramen ovale and patent ductus arteriosus, associated with pulmonary hypertension of about 74 mmHg at 5 months, were treated by percutaneous closure and ligation of the ductus arteriosus [27].

7.10 Hearing, vision and ear, nose and throat

Hearing correction includes hearing aids, tympanostomy tubes and cochlear implants, prescribed by specialists according to clinical assessment, with preventive treatment of otitis media with effusion, repeated checks and speech and language therapy; CT of the petrous bones and MRI focused on the auditory canals are performed according to progression [3]. Genetic deafness and inner ear malformations are not developed here. Strabismus may be corrected surgically at around 3–4 years; amblyopia is treated with occlusion of the healthy eye or alternating optical penalisation, and myopia is monitored [3].

7.11 Feeding, gastroenterology and nutritional status

The sucking and feeding difficulties of the hypotonic newborn may require nasogastric tube feeding, with rehabilitation of oral-motor function, the buccofacial sphere and swallowing through psychomotor therapy and speech and language therapy [3]. Constipation, of variable degree, appears later and is aggravated by antipsychotics [3]. Overweight associated with behavioural treatments may require dietetic support, and vitamin deficiencies should be monitored [3].

7.12 Orthopaedics, skull and skin

Hyperlaxity and the spine should be monitored, because scoliosis may be early and hyperlordosis appears mainly at puberty; treatment includes physiotherapy, rehabilitation, orthoses and surgery [3]. Craniosynostoses may be operated on from the first months of life [3]. Nail dystrophy and eczema flares are treated symptomatically [3].

7.13 Oral health

Usual oral hygiene, with toothbrushing, and regular follow-up from 3 years aim to prevent caries; when behavioural or language disorders require it, care may be provided through an oral health network for people with disabilities, which in France is the Handident network [3].

7.14 Agents to avoid, anaesthesia and surgery

The PNDS does not identify specifically contraindicated drugs, but requires that individual contraindications of each treatment (antiepileptic drugs, antipsychotics, hormonal and cardiological treatments) be excluded and that, before any surgery, anaesthetic or surgical contraindications be excluded [3]. Antipsychotics deserve particular monitoring because of worsening constipation and hypotonia [3]. Somatropin is contraindicated in the presence of evidence of active tumour [83].

7.15 Pregnancy and lactation

The sources consulted do not describe pregnancies in women with the 10q26 deletion other than those that resulted in transmission of the deletion, as in the families of Irving and Cherik [31, 39]. A female carrier transmits the deletion with a probability of 50% in each pregnancy, which justifies a genetics consultation before conception [3]. Regarding the drugs used, the risperidone SmPC reports a lack of adequate data in pregnancy and a risk of extrapyramidal or withdrawal symptoms in the newborn exposed in the third trimester, and the Slenyto® label recommends, as a precaution, avoiding melatonin in pregnancy [80, 82].

7.16 Transition to adulthood

The PNDS recommends organising the transition to adult services at the end of adolescence, to avoid interruption of follow-up and loss of skills [3]. Most patients go on to live in adult medico-social facilities (foyer d'accueil médicalisé, FAM, or maison d'accueil spécialisé, MAS), which have little knowledge of the syndrome and little coordination of medical follow-up with the reference centres, which is of concern in risk situations (cardiac, behavioural and drug contraindication) [3]. Physiotherapy, psychomotor therapy, occupational therapy, speech and language therapy and psychological or psychiatric support should continue after a prior assessment, also when the adult lives with their parents [3]. When dialogue between the family and the institution is difficult, the PNDS proposes recourse to a mediator, to the reference teams for rare disabilities (ERHR) or to a social worker, and lists support resources for families, such as the 360 communities, the rare disease expertise platforms and the Orphanet booklets on rights and benefits; follow-up may take place in a multidisciplinary day hospital, coordinated by a reference paediatrician, every 6 months [3]. In patients whose follow-up is ensured, skills are maintained [3].

7.17 Organisation of care in France

The PNDS was prepared by the reference centre for developmental anomalies and malformation syndromes of the East inter-region (Reims CHU), within the AnDDI-Rares network, at the request of families through the Valentin APAC association [3, 12]. Patients are referred to the reference and competence centres of the AnDDI-Rares or DéfiScience networks, and the PNDS serves as the reference for the care protocol with exemption from patient co-payment under an ALD outside the list [3]. Therapeutic patient education is offered at the annual follow-up [3].

7.18 Regulatory status of the drugs used

No medicinal product has an approved indication for the 10q26 deletion. The table compares the status of the drugs that the PNDS mentions or that apply by extrapolation.

7.19 Clinical trials

ClinicalTrials.gov had, in November 2026, no study registered for the 10q26 deletion; the only registration related to a gene in the region is Simons Searchlight (NCT01238250), an observational registry of genetic neurodevelopmental disorders that includes EBF3 [85]. Efficacy data for the drugs used come from trials in analogous populations, none with identified patients with the 10q26 deletion.

These trials did not include identified patients with the 10q26 deletion, and their results cannot be transposed directly: the deletion combines hypotonia and constipation, which the PNDS considers to be aggravated by antipsychotics, and the sleep profile described (late sleep onset, reduced need for sleep) has not been specifically studied [3]. In the risperidone trials, the label presents statistical significance without confidence intervals, and the low-dose trial was negative, which shows that doses much lower than those on the label are not distinguishable from placebo [81]. Comparisons between trials of different drugs are not valid, because of differences in population, outcome and duration.

7.20 Targeted therapies and recent developments

There is no therapy targeting the cause. Since this is a deletion of dozens of contiguous genes, single-gene replacement gene therapy strategies are not applicable to the overall picture, and no preclinical or clinical programmes of gene therapy or expression modulation targeting genes in the region were identified in the sources consulted, including for the EBF3-related disorder [85]. Research on the region focuses on genotype-phenotype correlation and transcriptomics [40, 45].

7.21 PNDS recommendations and divergences between sources

The HAS PNDS is the only dedicated guideline; the remaining sources are cytogenomic consensus statements, drug labels and primary literature. The divergences identified are summarised in the table.

8. Reproductive Options and Family Counselling

8.1 Genetics consultation and family study

The PNDS considers genetic counselling indispensable for all parents and urgent when there is a current pregnancy or a planned pregnancy; its content includes transmission and recurrence risk after the family study, the disease, complications and prognosis, the possibilities of prenatal and preimplantation diagnosis and information for relatives [3]. Study of both parents is intended to confirm whether the deletion is de novo or inherited and to look for a balanced or unbalanced rearrangement [3]. The Oxford handbook stresses the special importance of this study in subtelomeric rearrangements, because of the possibility of a cryptic balanced translocation in a parent, and points out that microarray is normal in a balanced carrier, so parental study should use karyotype, FISH or genome sequencing [19].

8.2 Recurrence risks by scenario

Balanced translocations are not rare: the PNDS estimates that 1 in 500 people carries one [3]. The balanced carrier usually has no clinical manifestations, because there is no relevant loss or gain of genetic material, but may have fertility difficulties [3]. Translocation derivatives described in the region include t(8;10), t(6;10), t(10;16), t(4;10) and t(7;10), and the children of a carrier may inherit the derivative chromosome 10, with 10q26 monosomy and partial trisomy of the partner segment [3, 12, 24, 29, 45].

8.3 Cascade testing and relatives

When a parent carries a deletion or a balanced translocation, the study should be extended to relatives at risk, according to the rearrangement observed; the PNDS schedule provides for genetic counselling of relatives during paediatric follow-up and in adulthood [3]. Variable expressivity within families means that a relative with the deletion and without ID may have more severely affected offspring, as in the families of Irving, Yatsenko and Cherik [9, 31, 39].

8.4 Prenatal diagnosis

Prenatal diagnosis consists of chromosomal analysis of a chorionic villus biopsy or amniotic fluid, depending on gestational age [3]. When a parent is a carrier, the Oxford handbook recommends offering prenatal diagnosis if the deletion is considered the cause of the anomaly, with caution in cases of variable penetrance, and with adequate time and consent when the parent has learning difficulties [19]. In de novo cases, prenatal diagnosis may be offered for reassurance [19]. Non-invasive prenatal screening does not replace invasive diagnosis, because of the risk of false positives due to maternal mosaicism associated with FRA10B [49].

8.5 Preimplantation genetic diagnosis

Preimplantation diagnosis requires in vitro fertilisation with intracytoplasmic sperm injection and analysis of one or two cells of the embryo between day 2 and day 5 of development, to exclude imbalance of the chromosomes involved; only embryos balanced for the regions analysed are transferred [3].

8.6 Psychosocial aspects and minors

The PNDS recommends psychological support for parents and siblings, information about patient associations and continuous support at each stage of development [3]. Adults with the deletion and mild ID, or diagnosed through a child, should receive information adapted to their abilities, with adequate time and consent [19]. Testing asymptomatic minor siblings to determine their carrier status for a balanced translocation does not alter their health in childhood, and the sources consulted do not define the age at which it should be offered; the PNDS refers counselling of relatives to the context of the rearrangement observed [3].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

There are no population studies of the prevalence or incidence of the 10q26 deletion. The PNDS gives an incidence below 1/10,000 births and fewer than 200 published patients, and its argumentaire fewer than 150 [3, 12]. Orphanet places the worldwide point prevalence in the class below 1/1,000,000 and records about 40 cases or families, and MedlinePlus reports at least 100 published cases [1, 13]. These figures describe published cases or upper limits, not the true frequency, which includes carriers with a mild phenotype who have never been studied [5, 51, 62]. The sex ratio in the French cohort was 0.9, with a slight female predominance, and in Li's review 11 of 17 patients with a 10q26.12→qter deletion were female [3, 27].

9.2 Data by region

No founder populations have been described, which is consistent with the non-recurrent nature of the deletions, which are not mediated by low-copy repeats [3]. The geographical distribution of published cases reflects access to microarray and the publication activity of centres, not differences in frequency between populations. The sources consulted do not describe Portuguese series other than the case of Lopes, nor Brazilian data other than the Krepischi series and the Faria cases [6, 15, 38].

9.3 Special populations

Adults are a poorly described population: six in the French cohort, one aged 63 years in Irving's family, and several carrier parents with a mild phenotype [9, 12, 31, 39]. Fetuses with a mosaic deletion may have a favourable course [48]. 46,XY individuals with atypical genitalia require decisions on sex assignment and surgical interventions that the PNDS frames within French legislation and multidisciplinary meetings, possibly national, acknowledging the debate on the definition of gender [3, 12]. People with severe ID, limited communication and increased pain tolerance need active pain assessment and adapted oral health care [3].

9.4 European networks and patient associations

The relevant European reference network is ERN ITHACA, dedicated to rare congenital malformations and rare ID [21]. In France, patients are followed at the reference and competence centres of the AnDDI-Rares network (developmental anomalies and malformation syndromes) and the DéfiScience network (rare neurodevelopmental disorders) [3]. There is no specific French association; the PNDS recommends systematically offering contact with the Valentin APAC association (Association de Porteurs d'Anomalies Chromosomiques, Éragny) [3]. The British support group Unique (Rare Chromosome Disorder Support Group) publishes guides for families on 10q25 and 10q26 deletions, in English and French, and its families provided data on behaviour and sensory processing cited in the PNDS [3, 19, 86]. Orphanet and MedlinePlus have information pages on the condition [1, 13]. The sources consulted did not identify specific associations in Portugal or Brazil.

10. Illustrative Clinical Case

10.1 Presentation

Li and colleagues described, in 2021, a Chinese newborn girl, the first child of healthy, non-consanguineous 24-year-old parents, with no family history of ID, behavioural disorder or malformations [27]. The pregnancy, naturally conceived, was complicated by complete placenta praevia and fetal growth restriction diagnosed at 28 weeks; trisomy 21 screening and the oral glucose tolerance test were normal, nuchal translucency at 11 weeks was 1.5 mm and subsequent ultrasound scans showed no anomalies, and no prenatal genetic testing was performed [27]. She was born by caesarean section at 34 weeks, weighing 1480 g (below the 3rd centile), 40 cm long (3rd to 10th centiles) and with a head circumference of 28 cm (3rd centile), and Apgar scores of 8 and 9 [27].

10.2 Findings

On examination, the face was symmetrical at rest and asymmetrical on crying, with inferolateral deviation of the right labial commissure, a picture of asymmetric crying facies; she also had pallor, thick and overfolded helices bilaterally, deep-set orbits, a small mouth opening and a high-arched palate [27]. Figure 1 of the article, which was consulted, shows the child at rest and crying at 15 days and 6 months, documenting the asymmetry of the mouth on crying and symmetry at rest (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278754/figure/Fig1/) [27]. There were weak and uncoordinated sucking and swallowing, hypotonia and weak primitive reflexes; on day 2, haemoglobin was 100 g/L and platelets 17 × 10⁹/L [27]. Newborn hearing screening and thoracoabdominal radiography were normal; the echocardiogram showed a 3 mm ASD, a 2 mm patent foramen ovale and a 2.5 mm patent ductus arteriosus; brain MRI showed abnormal signal in the periventricular white matter and a focal haemorrhage in the left cerebellar hemisphere [27].

10.3 Genetic diagnosis

The child's G-banded karyotype (400–550 bands) was 46,XX,del(10)(q26), and the parents' karyotypes were normal [27]. aCGH (CGX 8 × 60 K, GRCh37/hg19 coordinates) showed a 10q26.12→qter deletion between positions 122,119,070 and 135,403,394, with 106 RefSeq genes, of which 62 were OMIM genes, including WDR11 and FGFR2 [27]. The article gives 13.49 Mb in the text and 13.28 Mb in the abstract and table for the same interval; the difference between the two coordinates corresponds to about 13.28 Mb. The authors considered the deletion probably de novo, but acknowledged that, without FISH in the parents, they could not exclude a parental balanced translocation [27].

10.4 Management and course

The child was admitted to neonatal intensive care because of prematurity and irregular breathing, received packed red cells, plasma and oxygen, was fed by nasogastric tube until adequate intake was achieved and was discharged on day 18 [27]. At about 5 months, the echocardiogram showed a 2.1 mm ASD, a 1.4 mm foramen ovale, a 4 mm ductus arteriosus and a pulmonary artery pressure of about 74 mmHg, and the child underwent percutaneous closure of the ASD and foramen ovale and ligation of the ductus arteriosus [27]. At 8 months, the cerebellar lesion had disappeared on MRI and myelination corresponded to 5–6 months; she could not sit, did not roll and held her head up only briefly, and the Gesell assessment at 31 weeks of life showed gross motor skills equivalent to 4 weeks, fine motor skills to 13 weeks, adaptive behaviour to 9 weeks, language to 8 weeks and social skills to 12 weeks [27]. She started physiotherapy aimed at head control, sitting and crawling, with improvement in head control, as well as occupational therapy and speech and language therapy [27].

10.5 Comment

The case brings together several frequent elements of the extensive 10q26 deletion: IUGR, prematurity, hypotonia with feeding difficulties, dysmorphism, heart disease and global delay, here with a rarely described sign, asymmetric crying facies [3, 27]. Management corresponds to the PNDS recommendations regarding echocardiography, surgical treatment of heart disease and early rehabilitation, but parental study was limited to the karyotype, whereas the PNDS and the Oxford handbook recommend FISH or another method capable of detecting a cryptic balanced translocation, which determines the recurrence risk [3, 19]. Neonatal thrombocytopenia is not a manifestation described in the series of the syndrome, and its relationship with the deletion is not discussed by the authors [27].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

The prognosis depends mainly on the size and content of the deletion, the presence of heart disease and urogenital malformations and the severity of ID [3]. Larger or complex deletions are associated with more severe pictures; in the French cohort, deletions larger than 8 Mb concentrated severe short stature (6/15) and heart disease (5/11), whereas 10q26.2–q26.3 deletions had mainly ID and behavioural disorder, without heart disease [3, 12]. ID is present in 95% of described patients, usually moderate to severe, but there are adults with normal or near-normal cognition and deletions of 6.3 to 6.5 Mb [3, 51, 62]. Early mortality is linked to prematurity, respiratory infections in the context of hypotonia and heart disease; the figure of 23% neonatal death that the PNDS draws from the 1989 review (18 published patients, with an inconsistent denominator in the PNDS) belongs to the pre-microarray era and reflects the selection of severe cases [3, 26]. Survival into adulthood is documented, with an individual aged 63 years, but there are no life expectancy data [3, 31]. Dependence in adulthood is the rule in patients with moderate to severe ID, and the PNDS identifies interruption of follow-up and rehabilitation as a cause of loss of skills [3].

11.2 Frequency of consultations

The PNDS recommends two multidisciplinary consultations per year in the first years, depending on symptoms, later spaced to one per year, with attending physician consultations in between [3]. Paediatric follow-up is monthly until 6 months and then at 9, 12, 18 and 24 months; in childhood there is an annual consultation at a reference centre; in adulthood, assessment annually or every 2 to 3 years depending on progress, and a consultation at the reference centre every 3 years [3]. Non-medical follow-up (early childhood services, CAMSP) is continuous at least during the first 6 years [3].

11.3 Surveillance table

12. Summary and Final Considerations

10q26 deletion syndrome results from the loss of a terminal or interstitial segment of the long arm of chromosome 10, from less than 1 Mb to 17.4 Mb, without recurrent breakpoints, and is a contiguous gene syndrome with haploinsufficiency of several genes, of which EBF3, HMX2 and HMX3 have the most consistent evidence for ataxia and hypotonia and for deafness with inner ear malformation [3, 11, 34]. Most deletions are de novo, but about 6% are inherited, from a carrier parent with an often milder phenotype or from a parental balanced translocation, which makes study of the parents by a method capable of detecting balanced rearrangements indispensable [12, 19].

The clinical picture combines a triangular face with a prominent nose and dysplastic ears, growth retardation, microcephaly, ID in 95% of described cases, behavioural disorders in more than half, heart disease in 39 to 50%, urogenital and anal anomalies in about 30%, deafness in 17% and epilepsy in 31%, with highly variable expressivity and adults with near-normal cognition [3, 51, 62]. Deletions larger than 8 Mb concentrate heart disease and severe short stature, and 10q26.3 deletions that include EBF3 resemble the disorder related to this gene, with hypotonia, ataxia and neurogenic bladder [12, 17].

Diagnosis rests on chromosomal microarray, supplemented by FISH or karyotype for the structure and by study of the parents; genome sequencing combines detection of CNVs and point variants and allows unmasking of recessive alleles to be identified [3, 18, 40]. Treatment is supportive and multidisciplinary, according to the 2022 HAS PNDS: systematic echocardiogram, neonatal urogenital and endocrine assessment, early rehabilitation with augmentative communication, hearing and ophthalmological surveillance, treatment of epilepsy according to seizure type, behavioural management with low-dose risperidone when necessary and monitoring for worsening constipation and hypotonia, and melatonin for insomnia [3, 80, 82]. The recurrence risk is below 1% for de novo deletions and 50% when a parent is a carrier, with a higher risk for balanced translocations, and prenatal and preimplantation diagnosis are available in these situations [3]. Transition to adulthood should avoid interruption of follow-up, because loss of skills is associated with interruption of rehabilitation [3].

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