KBG Syndrome

Autosomal dominant neurodevelopmental disorder caused by ANKRD11 haploinsufficiency (16q24.3), with macrodontia of the upper central incisors, characteristic facial features, postnatal short stature, skeletal anomalies and auditory, neurological, cardiac and behavioural comorbidities; includes 16q24.3 deletions encompassing ANKRD11 and the genomic subtype of 16q24.3 microdeletion involving contiguous genes.

Literature and regulatory information updated: 9 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and clinical delineation

KBG syndrome was described in 1975 by Jürgen Herrmann, Philip Pallister, W. Tiddy and John Opitz, in an article whose title already listed the features that still define it today: short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies [24]. The designation follows Opitz's practice of naming syndromes after the initials of affected families' surnames [3, 25]. GeneReviews and the review by Morel Swols and colleagues attribute the letters K, B and G to the first three families [1, 26], whereas the OMIM synopsis describes two families with several affected members, with telecanthus, broad eyebrows, brachycephaly, macrodontia, short metacarpals, short femoral necks and vertebral anomalies, and father-to-son transmission in one of them [3]. The difference probably reflects how the family units in the original article were counted; only its title is available in PubMed [24].

Over the following two decades, the condition was delineated through small series. Parloir and colleagues (1977) described an extended family whose follow-up by Soekarman and colleagues (1994) showed three siblings with adult height well below the 3rd centile, arm span exceeding height by at least 9 cm and a relatively short trunk, attributed to anterior vertebral wedging and irregular vertebral endplates [3]. Fryns and Haspeslagh (1984) described two sisters and their mother, and Devriendt and colleagues (1998) a mother and daughter, the daughter with surgically repaired ventricular septal defect, chronic constipation, recurrent respiratory infections and an intelligence quotient (IQ) of 58 at 8 years, and the mother with mild ID and very broad front incisors [3]. Zollino and colleagues (1994) reported six sporadic Italian cases, with cerebellar vermis hypoplasia in two, cystic renal dysplasia in one and megalocornea in another, and outlined the first diagnostic criteria [3, 27]. Smithson and colleagues (2000) proposed including hypertelorism, macrodontia, height below the 10th centile, delayed bone maturation, skeletal anomalies and developmental delay with IQ below 80 in the criteria [3].

Three series published in 2004 established the variability of the phenotype. Tekin and colleagues described a father and two sons from central Anatolia, all with mild to moderate ID, cryptorchidism and height below the 3rd centile, confirming autosomal dominant inheritance [3]. Brancati and colleagues reviewed 29 cases from the literature and added eight Italian patients; in two families the disease was transmitted by mildly affected mothers, and the article added EEG abnormalities with or without seizures, mixed hearing loss, palatal anomalies with secondary speech disturbance, age-dependent behaviour (hyperactivity, anxiety and poor concentration) and cryptorchidism to the phenotype [3, 28]. Maegawa and colleagues described three unrelated boys and the mother of one, who was less affected than her son; the greater severity in males led these authors to consider X-linked inheritance in some families, a hypothesis abandoned after identification of the autosomal gene [3, 29]. Skjei and colleagues (2007) described male twins, reviewed published cases and proposed eight major criteria, at least four of which should be present; they noted that macrodontia, reported in more than 95% of published cases, might have that frequency because of ascertainment bias [3, 30]. The review by Brancati, Sarkozy and Dallapiccola (2006) brought together 45 patients, emphasised predominantly maternal transmission and milder severity in mothers, and noted that clinical diagnosis was generally made after eruption of the permanent upper central incisors, at 7–8 years [10].

1.2. Molecular discovery and reclassifications

In 2011, Sirmaci and colleagues, at the University of Miami, sequenced the exome of Tekin's Turkish family and identified a heterozygous splicing variant in ANKRD11 that cosegregated with the disease; the gene was subsequently analysed in nine additional probands, with truncating variants in four, including a de novo single-nucleotide deletion in a simplex case [3, 31]. As half the families studied had no identified variant, the authors considered genetic heterogeneity, without excluding changes in regulatory regions [3]. This qualification explains why the 8th edition of Smith's Recognizable Patterns of Human Malformation (2022) still states that ANKRD11 causes “some cases” and that the aetiology of most remains unknown [25]; the statement is outdated, because in current molecular series all confirmed cases have an intragenic ANKRD11 variant (approximately 80%) or a 16q24.3 deletion including the gene (approximately 20%) [1, 21].

Subsequent milestones broadened the mutational and phenotypic spectrum. In 2014, Ansari and colleagues identified ANKRD11 variants in a cohort of patients with a Cornelia de Lange syndrome (CdLS)-like phenotype, establishing the overlap between the two entities [3, 19]. In 2015 and 2016, the Dutch, British (including the Deciphering Developmental Disorders, DDD, study) and French series showed that KBG is a common Mendelian cause of developmental delay, frequently unrecognised, and that macrodontia should not be a mandatory criterion [19, 32, 33]. Novara and colleagues (2017) separated deletions removing only ANKRD11 from those including flanking genes [4]. In 2022, de Boer and colleagues demonstrated that missense variants clustered in repression domain 2 (RD2) cause the syndrome through loss of function [34], and in 2023 the epigenetic signature and deletions of the first non-coding exon were described [15, 35]. The GeneReviews version updated in June 2026 includes movement disorder among the manifestations and recommends that copy-number analysis encompass the non-coding upstream region [1].

1.3. Nomenclature and entities within scope

The eponym remains the principal designation (OMIM #148050; ORPHA:2332) [3, 7]. The dyadic approach proposed by Biesecker and colleagues suggests “ANKRD11-related neurodevelopmental disorder”, associating the gene with the phenotype and avoiding reliance on family initials [1, 2]. This article encompasses three genetic situations with the same underlying mechanism, loss of function of one ANKRD11 allele. The first is an intragenic sequence variant (truncating, splicing or missense with demonstrated loss of function). The second is a 16q24.3 deletion removing all or part of the gene, including deletions restricted to the non-coding 5′ exons and promoter region. The third is 16q24.3 microdeletion syndrome (ORPHA:261250), a designation used for larger, non-recurrent deletions that add the effects of loss of adjacent genes to the KBG phenotype [1, 4, 5]. The 16q24.3 microdeletion is treated as a genomic subtype within this article rather than as a separate entity, because its core phenotype is that of KBG and the differences concern degree and comorbidity [4, 9]. Terminal 16q24.3 deletions including GALNS and APRT without ANKRD11 fall outside the scope.

2. Molecular Genetics and Pathophysiology

2.1. The ANKRD11 gene and protein

ANKRD11 is located at 16q24.3, on the negative strand, and encodes ankyrin repeat domain-containing protein 11, also known as ANCO-1 (ankyrin repeat-containing cofactor 1) (OMIM 611192) [1, 31]. The MANE Select transcript is NM_013275.6 (equivalent to ENST00000301030.10), encoding protein NP_037407.4 [6]. In the clinical literature, “exon 9” denotes the large exon containing more than 80% of the coding sequence [19]; other authors, using different transcript numbering, call it the “last exon (exon 13)” [16]. Exon numbers cited in series are therefore not interchangeable between articles without checking the transcript used.

2.2. Molecular function and pathophysiology

ANKRD11 is a chromatin regulatory cofactor. It binds nuclear receptor complexes and the p160 coactivator complex, recruits histone deacetylases, particularly HDAC3, and factors associated with P/CAF and p300, inhibiting ligand-dependent transactivation and modulating transcriptional programmes of neurodevelopment and craniofacial and bone formation [1, 36]. In the discovery study, the protein was located mainly in neuronal nuclei and accumulated in discrete inclusions after depolarisation, suggesting a role in neural plasticity [31]. In cortical neurones, ANKRD11 regulates progenitor proliferation, neuronal migration, dendritic differentiation and synaptogenesis, partly through the brain-derived neurotrophic factor (BDNF) pathway and its receptor TrkB [1, 37]. In mice, the protein is required for intramembranous ossification, palate development and cardiac neural crest biology [1, 38]. Conditional knockout in the neural crest causes persistent truncus arteriosus, ventricular dilatation and reduced contractility through failed outflow tract septation, with changes in the mTOR, BMP and TGF-β pathways [36]; knockout in neural stem cells produces small olfactory bulbs and incomplete neuroblast migration, and two patients with KBG had anosmia with hypoplasia or agenesis of the olfactory bulbs and sulci [39].

Protein abundance varies throughout the cell cycle, and the C-terminus contains proteasomal degradation signals; human truncating variants and the missense variant in the Yoda mouse affect this region, and mutant proteins accumulate abnormally [40]. The heterozygous Yoda mouse has craniofacial anomalies, a broad skull, kyphoscoliosis and reduced bone mineral density, without macrodontia [19]. Preclinical studies from 2025 and 2026 added three mechanisms. An N-terminal ANKRD11 peptide binds with high affinity to the cohesin complex, competing with CTCF, and the mouse with the Tyr347Ala substitution, which abolishes this binding, reproduces neural and craniofacial anomalies resembling KBG, providing a molecular explanation for the overlap with CdLS [41]. In neural cells, ANKRD11 deficiency reduces ribosomal RNA and translation, because ANKRD11 indirectly activates rRNA transcription through SETD5, whose variants cause a similar condition [42]. Finally, ANKRD11 forms biomolecular condensates through intrinsically disordered regions containing charge blocks, which sequester elongation factors away from RNA polymerase II and repress the most highly transcribed genes; loss in mice causes aberrant activation of developmental genes and embryonic lethality, and cells from patients with KBG have defective condensates and overactivation of these genes [43]. A 2026 study of CD8+ T lymphocytes, in which Ankrd11 suppression potentiates antiviral and antitumour responses, concerns immunotherapy rather than KBG [44].

2.3. Disease mechanism and inheritance pattern

The mechanism is loss of function of one allele, that is, haploinsufficiency [1, 26]. Inheritance is autosomal dominant, with most cases de novo in recent molecular series [1, 21]. Dosage sensitivity is consistent with the phenotypic equivalence between truncating variants and deletions removing the gene, and with the effect of deletions eliminating only the promoter and first non-coding exon, reducing expression without affecting the coding sequence [35, 45].

2.4. Variant spectrum

Sequence variants account for approximately 80% of molecular diagnoses and 16q24.3 deletions for approximately 20% [1]. In the series by Martinez-Cayuelas and colleagues, 78.5% of the 340 patients had a sequence variant, and among the 67 new patients 86.6% had one of the 44 identified variants (33 novel, 79.5% in exon 9) and 13.8% a 16q24.3 deletion [21]. Truncating variants (frameshift and nonsense) predominate: in a compilation of 583 pathogenic or likely pathogenic variants, frameshift and nonsense were the most frequent [46], and in the 2016 British series all 20 variants were truncating and located in exon 9, except for one frameshift in exon 6 and one nonsense in exon 4 [19].

Pathogenic missense variants cluster in RD2, at the C-terminus, which coincides with the degron [34, 47]. Of ten missense variants studied functionally, six reduced protein stability and one reduced proteasomal degradation, with loss of transrepression activity; both effects amount to loss of function [34]. Interpretation of missense variants is difficult, because the phenotype may be mild and variants inherited from apparently unaffected parents are increasingly found [15, 34]. In April 2022, 429 missense or in-frame ANKRD11 variants had been submitted to ClinVar, many classified as VUS [20], and in October 2026 ClinVar held 3834 gene records, with 622 pathogenic classifications, 295 likely pathogenic and 1502 VUS (counts by classification property, in which a record may have more than one) [48]. Splicing variants have been described, including that in the original family, and splicing variants with premature termination in the European cohort [31, 49].

The 16q24.3 deletions are non-recurrent; each family has its own breakpoints [1]. They range from 137 kb to 2.3 Mb in published series, and most remove the 5′ end or the entire coding region without extending to the 16q telomere, suggesting that complete distal deletion may be lethal [4, 33]. The smallest deletion described, 43 kb, removes only the first non-coding exon and was identified by genome sequencing; RNA expression was reduced [35]. Three patients with microdeletions of exon 1 and the upstream region had reduced transcript levels and global transcriptomic changes resembling KBG [45], and in a Chinese prenatal series five of seven microdeletions affected non-coding exons 1 and 2 [12]. Intragenic duplications have also been reported, including a familial duplication in three patients [1, 50].

2.5. Recurrent variants and nomenclature

The most frequent recurrent variant is NM_013275.6:c.1903_1907del, p.(Lys635GlnfsTer26), present in 34 of the 340 patients (10%) in the Spanish and international series; it is followed by c.2408_2412del p.(Lys803ArgfsTer5) in 2.9%, c.1381_1384del p.(Glu461Glnfs*48) in 2.4% and c.2398_2401del p.(Glu800AsnfsTer62) in 1.8%, together accounting for 17% of cases [21]. c.1903_1907del is classified in ClinVar as pathogenic or likely pathogenic, with criteria provided by multiple submitters without conflict (last evaluated in August 2026) [51]. Historical nomenclature included the deleted base (c.1903_1907delAAACA; c.2305delT, p.Ser769GlnfsX8), a form that the current HGVS (Human Genome Variation Society) recommendation dispenses with [1, 6, 31]. The following table presents variants normalised in VariantValidator against the MANE transcript; because the gene lies on the negative strand, genomic alleles are complementary to those in cDNA [6].

Other recurrent variants in the Spanish series, such as c.6792dup p.(Ala2265Argfs*8) in four patients from three families, c.2329_2332del, c.4384dup and c.5790C>A p.(Tyr1930*), were cited without independent normalisation [21]. No founder variants have been described; c.1903_1907del occurs in diverse populations, including 51 patients in the comparison between Chinese and non-Chinese individuals and three unrelated Turkish patients [47, 53].

2.6. Genomic subtype: 16q24.3 microdeletion involving contiguous genes

Novara and colleagues described 12 patients with 16q24.2q24.3 deletions ranging from 343 kb to 2.3 Mb, de novo in 11; 11 included ANKRD11 and one removed only upstream genes [4]. Deletions that include ZFPM1, CDH15 and ZNF778 in addition to ANKRD11 are associated with greater neurological severity and more frequent congenital heart disease, and thrombocytopenia and astigmatism distinguish 16q24.3 microdeletion syndrome from KBG [4]. The patient without ANKRD11 loss had milder psychomotor delay, heart disease, thrombocytopenia and astigmatism, implicating the flanking genes as the origin of these three findings [4]. For larger deletions, GeneReviews summarises brain anomalies in 28%, congenital heart disease in 33%, severe astigmatism in 28% and thrombocytopenia in 22%, and an association with ASD, for which ANKRD11 and ZNF778 have been proposed as candidate genes [1, 54, 55]. A familial 16q24.3 deletion involving ANKRD11 was described as a KBG-like condition [56], and partial ANKRD11 loss reproduces the KBG phenotype, distinct from that of the extended microdeletion [57–59]. In a 2026 review of 68 cases of KBG caused by 16q24.3 microdeletion, deletions restricted to ANKRD11 were associated with more triangular faces and ID [9]. In assessing expected severity, deletion size and gene content must be included in the report, requiring a technique with sufficient probe density at 16q24.3 [1].

2.7. Genotype–phenotype correlations

The reported correlations are statistical and of modest effect. In the series of 340 patients, the phenotypic index was higher with sequence variants than with CNVs, and a triangular face was more frequent with sequence variants (71.1%) than with CNVs (42.5%; p = 0.015) [21]. Short stature was more frequent with variants in exon 9 (62.5%) than outside it (27.8%; p = 0.009), and ID, ADHD or ASD were less frequent with c.1903_1907del (70.4%) than with other intragenic variants (89.4%; p = 0.012) [21]. None of the eight British patients with c.1903_1907del had hearing loss or severe otitis media, an observation suggesting, without demonstrating, a milder otorhinolaryngological phenotype [19]. Among deletions, macrodontia and comorbidities were associated with larger deletions and hand anomalies with smaller deletions [21]. Missense variants are associated with less pronounced neurodevelopmental findings [1, 60] and, in patients with epilepsy, later onset, normal magnetic resonance imaging (MRI) and better seizure control; missense variants concentrate in RD2 and truncating variants outside it [61]. The international cohort coordinated in the Netherlands found no genotype–phenotype correlation for epilepsy [62], and a Turkish series of 23 patients found no overall genotype–phenotype correlation [63]. In the Dutch radiological study, all patients with a deletion or missense variant had skeletal anomalies, compared with 83% of those with a truncating variant; statistical analysis was not possible because of the small numbers [22].

2.8. Penetrance, expressivity and sex

Expressivity varies within families, and carrier parents may have mild manifestations: in Guo's series, a carrier mother had no delay, macrodontia or short stature, and a mother with low-level mosaicism (2 of 298 reads in blood) had mild facial features, speech delay and childhood seizures [20]. The British series described intrafamilial variability and variable penetrance in several families [19]. The phenotype is typically milder in females, explaining predominantly maternal transmission in premolecular series [10, 26]. No validated genetic modifiers have been described, but additional molecular diagnoses explain part of the breadth of the spectrum, as in the series of 23 patients by Parenti and colleagues and the Italian case with an additional EHMT1 variant [11, 64].

2.9. Allelic disorders and overlap with chromatinopathies

No distinct phenotypes caused by germline ANKRD11 variants other than KBG are known [1]. The overlap with CdLS is clinical and molecular: ANKRD11 variants were found in 3 of 163 patients with a CdLS-like phenotype [19], Smith mentions five individuals with an ANKRD11 variant and non-classic CdLS phenotype [65], and 21 of 23 patients in Parenti and colleagues' series initially had a clinical diagnosis of KBG or CdLS, with evolution of the phenotype with age [64]. These observations place ANKRD11 among the chromatinopathies, and the protein's binding to cohesin provides the mechanistic basis [41, 64].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and frequency of findings

Clinical knowledge derives from cohorts of patients ascertained through clinical suspicion, exome testing in developmental delay clinics or family associations, rather than population studies [1]. Frequencies differ according to the ascertainment pathway. In Martinez-Cayuelas's series, the new cohort of 67 patients, collected by questionnaire, had less language delay (78% versus 90.5%), fewer visual problems (40.7% versus 66.2%), fewer feeding difficulties (26.8% versus 51.9%), less abnormal MRI (38.3% versus 60%) and less abnormal EEG (16.3% versus 65%) than the 273 literature cases, and more ADHD (63.3% versus 35.7%), which the authors interpreted as publication bias [21]. The British series observed a subtler phenotype in patients identified by exome testing than in those identified through clinical suspicion [19]. The following table presents the aggregate frequencies from GeneReviews and the series of 340 patients.

3.2. Prenatal and neonatal period

Pregnancy and the neonatal period are frequently complicated, although the fetal anomaly scan is often normal. In the series of 340 patients, pregnancy or perinatal complications occurred in 39.1%, intrauterine growth restriction (IUGR) in 22.4%, birthweight at or below the 3rd centile in 23.7% and length at or below the 3rd centile in 15.7% [21]. In a survey of 42 individuals, 45.2% were born by caesarean section, 33.3% had congenital heart disease, 23.8% were premature, 23.8% had been admitted to a neonatal intensive care unit (NICU), 14.3% were small for gestational age, 21.4% had feeding difficulties, 14.3% neonatal jaundice, 7.1% reduced fetal movements and 4.7% pleural effusion in utero, rates higher than in the general US population used for comparison by the authors [69]. In the European cohort of 49 patients, 28.5% had prenatal ultrasound anomalies [49]. In contrast, in the British series perinatal complications were few, the 20-week scan was generally normal, all were born at 36 weeks or later and birthweight ranged between the 2nd and 98th centiles [19].

Chinese fetal series describe the ultrasound findings leading to prenatal diagnosis. In 12 fetuses, nuchal translucency (NT) was increased in the first trimester in five; among the seven with a normal first trimester, subsequent findings were mild ventriculomegaly (four), an arachnoid cyst at 22 weeks (one), an umbilical-systemic shunt with ventriculomegaly and polyhydramnios at 24 weeks (one) and fetal growth restriction at 30 weeks (one) [70]. In 19 fetuses, fetal growth restriction occurred in 36.8%, increased NT in 26.3%, and ventricular septal defect (VSD), pericardial effusion and central nervous system and renal malformations in 15.8% each [12]. The comparison between 65 Chinese and 519 non-Chinese patients found IUGR, polyhydramnios, renal, brain and cardiovascular anomalies, prematurity and increased NT sufficiently often for the authors to recommend considering KBG in the presence of IUGR and polyhydramnios [53]. Neonatal findings that may raise suspicion include a large anterior fontanelle, wide metopic suture and early dentition, as in the infant diagnosed at 3 months in the Italian series [11].

3.3. Face and teeth

The facial gestalt is present in 62–80% and evolves with age [1, 19]. The most frequent findings are a triangular face, brachycephaly, broad thick eyebrows with synophrys, widely spaced eyes, prominent nasal bridge, bulbous nasal tip, anteverted nares, prominent ears, long philtrum and a thin vermilion of the upper lip [1]. The British series added almond-shaped palpebral fissures, prominent cheekbones and mouth corners, dysplastic helices and a low hairline with facial hypertrichosis, and noted the resemblance of the eyebrows and eyelashes to CdLS [19]. Three-dimensional stereophotogrammetry in 14 Dutch patients showed a bulbous nasal tip, broad-based upturned nose and round or triangular face [32], and a systematic review of 614 patients found a triangular face in 77%, synophrys in 43%, prominent nasal bridge in 40% and long philtrum in 20% [66]. Facial features vary with ancestry: Chinese and non-Chinese patients differed in the frequency of large ears, triangular face, anteverted nares, synophrys, long philtrum and low hairline [53], and a Colombian series of 10 patients described facial asymmetry, high forehead, nasal prominence, thick lower lip and a poorly prominent chin using two-dimensional morphometry [71]. Three-dimensional facial analysis in 2026 showed less facial consistency in KBG than in Koolen-de Vries syndrome [72].

Macrodontia of the permanent upper central incisors is the most characteristic sign, but is not mandatory. It is defined as a mesiodistal width of at least 10 mm in males and 9.7 mm in females [1], or a diameter greater than +2 standard deviations (SD) for age [19]. It was present in 80% in GeneReviews, in 23 of 27 British patients with permanent dentition and in 87% in the 2026 orofacial review [1, 19, 66]. Because it manifests only in the permanent dentition, its absence in a young child has no exclusionary value, and the French series of 39 patients concluded that macrodontia should not be a mandatory criterion [33]. Other dental anomalies include oligodontia (particularly of the upper lateral incisors), hypodontia, talon cusps, cleft or bifid teeth, shovel-shaped incisors, enamel hypoplasia and pits, supernumerary mamelons, large pulp chambers, crowding and macrodontia of other teeth [1, 25, 32]. In the European cohort, macrodontia, oligodontia and dental agenesis together occurred in 53%, a frequency close to that of skeletal anomalies [49]. The French PNDS gives macrodontia in 69–95% and adds molar-incisor hypomineralisation (MIH), enamel hypoplasia with yellowish or brownish teeth, pseudo-duplication, conical teeth and implantation anomalies; for the face, it mentions possible micro-retrognathia, a long philtrum, sometimes flat and protruding in infancy, and a long upper lip with a thin, tented lateral vermilion [18].

3.4. Growth and endocrine system

Short stature is postnatal and frequent, but not universal. In data from 18 children and 14 adults, height was below the 3rd centile in 72% of children and 57% of adults, and below −2.5 SD in 62% and 36%, with means of −2.56 and −2.17 SD, respectively; spontaneous catch-up growth after childhood was limited [73]. Among 245 patients with height data, approximately half had short stature [46], and in the Polish series of 23 patients height was between −1 and −2 SD in approximately half, with only two below −3 SD [74]. The KBG-specific growth chart, constructed from 1417 measurements in 101 individuals from the United Kingdom, Netherlands, Denmark and Spain, shows a downward shift of the 50th and 2nd centiles for height, weight and head circumference (HC) relative to the British UK-90 reference [8]. Final heights in 79 adults aged 16 or over were relatively lower than those in children, supporting postpubertal growth deceleration [8, 16]. Body mass index rises in adolescence in both sexes, a trend the authors attribute to the general population rather than the syndrome [8]. Median HC at birth was −0.88 SD and normalised with age in the European cohort [49]; microcephaly has been reported in some patients and occasional macrocephaly [8, 25].

Endocrine assessments are usually normal, and bone age may be delayed [1]. Among patients treated with recombinant human growth hormone (rhGH), 43% had growth hormone deficiency (GHD) and bone age was delayed in 81% [16]. Three of six patients with GHD and imaging had an isolated partially empty sella, a finding present in 4 of 39 patients (10.3%) in the neuroimaging series [16, 75]. Advanced or precocious puberty occurs in some patients, sometimes requiring treatment [1, 33]. The 2020 French synthesis reports height below the 3rd centile in 40–77% depending on the series, delayed bone age in 60–70% and adult height between −2 and −3 SD in very small series; it defines precocious puberty as breast development before 8 years in girls and increased testicular volume before 9 years in boys, and considers that precocious or advanced puberty worsens the height prognosis [18].

3.5. Skeleton

Skeletal anomalies are reported in 62–75% in the aggregate literature [1]. When radiographs are reviewed systematically, the frequency is higher: in the Radboudumc cohort of 38 patients (19 of each sex, median age 10 years, all Dutch except one of Chinese ancestry) assessed by a radiologist using standardised criteria, 92% had at least one anomaly [22]. The table summarises findings from that study and Peluso's series.

Source: [22]. The largest measured curvature was 22 degrees, below the surgical threshold of 40 degrees, and scoliosis or mild curvature occurred in the 5–9, 10–14, 15–17 and over-18 age groups, but not before age 5 [22]. There was no joint hypermobility or contracture, 29% had hypotonia, 18% flat feet and 50% received physiotherapy follow-up [22]. The authors compared scoliosis (28%) with a prevalence of 0.93–12% in the general population and 28.5% in neurodevelopmental disorders, and cervical ribs (32%) with 0.2–2% in the general population [22].

Peluso's series, with skeletal imaging in 40 patients, confirmed scoliosis, coccygeal anomalies and cervical ribs and described greater delay in carpal ossification than in the metacarpals and phalanges [75]. Other reported findings are brachydactyly (particularly of the 1st, 3rd and 5th fingers), 5th-finger clinodactyly, small hands, cutaneous syndactyly between the 2nd and 3rd toes, a wide gap between the 1st and 2nd toes, short broad feet, a short webbed neck, pectus excavatum, short femoral necks, hip dysplasia or Perthes disease, sternal anomalies, wormian bones, clavicular pseudarthrosis and osteopenia [1, 19, 25, 76]. A large anterior fontanelle with delayed closure occurred in 22% of British and 56% of Polish patients; in one British child it remained open at 4.5 years, and five were referred with suspected craniosynostosis without suture fusion [19, 74]. Osteopenia or osteoporosis was described at 15–20 years in one patient [20], and the Bone Health Index was within 2.5 SD in all 28 patients assessed in the Dutch cohort [22]. The French PNDS estimates skeletal anomalies at 75%, almost always minor, but also lists, as clinically relevant, hip dysplasia, hemivertebrae, scoliosis, kyphosis and a prominent caudal (sacral) appendage, as well as poor mineralisation and diffuse joint stiffness [18].

3.6. Development and cognition

More than 90% have developmental delay, particularly in language; cognition ranges from normal to moderate ID, and most have mild ID [1]. Walking begins at a mean age of 21 months and first words between 25 and 36 months; the voice may be hoarse [1]. The French PNDS describes delay in 91–100% of cases from 0 to 36 months, mostly global and moderate (63%), with mild hypotonia in infancy, first motor concerns around 1 year and no subsequent motor disability; between 3 and 6 years, a specific oral language disorder and dyspraxia may appear, and from 6 to 12 years school difficulties are almost constant (94%), owing to mild ID (IQ 55–70), rarely moderate ID (IQ 40–55), or specific learning disorders without ID (dyslexia, dysorthographia, dyscalculia) [18]. In Guo's series, walking began at a median age of 22 months (12.5–36) and speech at 30 months (19–36), three patients had selective mutism or absent speech, and mean IQ in eight patients was 73 ± 4.84 (64–80) [20]. In the European cohort, 82% had ID, mild to moderate in most and severe in two [49]. In the Polish series, psychomotor hyperactivity (86%), speech delay (81%) and a hoarse voice (56%) were useful signs [74]. In the British series, all patients walked (the latest at 3 years and 2 months), there was no regression, and learning difficulties were almost universal, sometimes very mild [19].

The cognitive profile tends to favour verbal skills. Among 24 Italian children, 17 had ID, six borderline intellectual functioning and one no deficit, and the verbal comprehension index exceeded those for perceptual reasoning, working memory and processing speed; adaptive functioning was homogeneous across domains [77]. GeneReviews reports verbal IQ frequently exceeding performance IQ [1]. Two patients with ANKRD11 variants studied in 2013 had ID, severe impairment of communication skills, executive function and working memory deficits and anxious traits [78]. Compared with 17 controls with other genetic diseases and similar IQ, 18 Dutch patients did not differ in overall IQ or subtests [79], but had poorer sustained attention, cognitive flexibility and visuoconstruction, and better visual memory, social cognition and emotion recognition [80]. In 39 individuals from 11 countries assessed with the Vineland-3 scale, the adaptive composite was below the population mean, with some individuals above the mean; epilepsy was associated with lower scores across all domains, reaching significance only in written communication [81]. Adult cognitive decline has been reported in two individuals, one aged 76 with suspected dementia, without evidence that it is frequent [1, 82].

3.7. Behaviour and mental health

Behavioural problems affect at least half of patients and range from poor concentration and restlessness to severe obsessions and decompensation with changes in routine; anxiety and shyness are common, and many have difficulty understanding social situations [1]. GeneReviews indicates known or suspected ADHD in 45% and ASD in approximately 30% [1]; in the Spanish cohort ADHD symptoms reached 63.3% and ASD 41.5% [21], whereas in Guo's series ADHD was 24% and ASD 28% [20] and in the British series eight patients (25%) had a formal ASD diagnosis [19]. The French series considered autism less frequent than previously described [33]. The Dutch neuropsychological profile showed more attention problems, hyperactivity and oppositional behaviour than in genetic controls and fewer social functioning difficulties, which the authors interpret as impulsivity resulting from executive function deficits, without impaired social cognition [80]. Among 17 Italian children, 10 had repetitive paper handling behaviour, resembling obsessive-compulsive hoarding or ordering, with intense emotional reactions when interrupted [83]. The French PNDS places ADHD between 11% and 50%, recommends systematic screening for ASD and describes temper outbursts, impulsivity, opposition and frustration intolerance linked to executive function deficits, generalised or performance anxiety, obsessive-compulsive traits, depressive episodes and delusional phenomena, and notes that psychiatric disorders may appear in adolescence and young adulthood [18]. Sleep disorders occurred in six British patients, most resistant to melatonin [19]. Smith describes significant childhood behavioural problems that in most diminish in adulthood, with calm, friendly adults [25]; more recent adult data, however, show psychiatric or behavioural comorbidities in 26 of 36 adults [82].

3.8. Epilepsy and EEG abnormalities

EEG abnormalities, with or without seizures, occur in approximately half [1], and epilepsy in 24.6% of the series of 340 patients and 26.5% of the European cohort [21, 49]; in the British series 14 of 32 (43%) had seizures [19]. In the international cohort of 75 patients, 26 had epilepsy, with median onset at 4 years (12 months to 20 years); 57.7% had generalised-onset seizures, tonic-clonic seizures were the most common (23.1%), and epilepsy type was generalised in 42.9% and combined generalised and focal in 42.9%, without a defined electroclinical syndrome [62]. Moderate to severe ID was more frequent with epilepsy (42.3% versus 9.1%; relative risk 4.6; 95% confidence interval [95% CI] 1.7–13.1), 50% had been seizure-free for at least one year and 26.9% were drug-resistant, defined by failure of two or more antiseizure medications (ASMs) [62]. In an Italian series of 11 patients, mean onset was at 67 months, with focal epilepsy in five, generalised epilepsy in four and developmental and epileptic encephalopathy in two, and epilepsy responded well, sometimes following a self-limiting course [84]. The French PNDS estimates seizures at 25–43%, mainly generalised tonic-clonic seizures or absences, rarely myoclonus or infantile spasms, with onset in early childhood or adolescence and a good response to usual ASMs, and states that there is no specific EEG pattern [18].

Two 2026 reviews expanded these numbers. In a systematic review of 163 individuals with ANKRD11 variants and epilepsy, median onset was at 4.0 years (interquartile range 1.5–8.0), focal and generalised seizures had similar proportions, absences accounted for 22.8%, MRI was abnormal in 45.9% of cases with data, 63.2% became seizure-free and 36.8% were drug-resistant [61]. In a scoping review of 54 studies and 233 patients, 89.7% had delay or ID; median onset was at 4 years (1 month to 51 years); generalised seizures occurred in 73.9% and focal seizures in 37.9%, with generalised tonic-clonic seizures in 38.2% and absences in 26.6%; focal discharges predominated on interictal EEG (24.6% versus 15%); approximately 70% were seizure-free after a mean follow-up of 9.9 years and 22.6% were drug-resistant, and focal impaired-awareness seizures were associated with a lower likelihood of remission [85]. GeneReviews counts 7 drug-resistant cases among 23 individuals with epilepsy described and reports rare cases of infantile spasms or epileptic encephalopathy [1, 86]. The differences between 22.6% and 36.8% drug resistance reflect different definitions and denominators. Electrical status epilepticus in sleep and febrile seizures have been described [21], as have absences precipitated by hyperventilation and photic stimulation in a boy with a missense variant [3], and additional paediatric cases [87].

3.9. Movement disorders and other neurological manifestations

Approximately 26% (33 of 126) of reported patients have movement disorder symptoms: dystonia, tremor, ataxia and parkinsonism [1]. Early-onset parkinsonism [88, 89], a tremor-predominant movement disorder [90] and unilateral paroxysmal dystonia from age 7 in a child with global delay, ASD, sensorineural hearing loss (with additional CDH23 variants) and spastic diplegia have been reported [91]. In the British series, four patients had a movement disorder, one with Tourette-like tics [19]. Among 75 patients with neurological data in the epilepsy review, hypotonia occurred in 30.7%, sleep disorders in 20%, ataxia in 18.7%, migraine in 8.3% and stereotypies in 6.7% [85]. In Guo's series, migraine affected 24% and abdominal migraine 20%, with one case of cyclical vomiting, and four patients had a high or absent pain threshold [20]. Tethered cord syndrome was diagnosed in 11% of a paediatric survey and was under investigation in a further 24%, without a predictive clinical sign; affected boys had more coordination problems and global delay [92]. Anosmia with olfactory bulb hypoplasia was described in two patients [39].

3.10. Neuroimaging

The frequency of brain malformations is not accurately known, because MRI was not performed systematically in the large cohorts [1]. In Peluso's study, with central nervous system imaging in 44 patients, incomplete hippocampal inversion occurred in 63.4% and posterior fossa malformations in 65.9%, compared with 1.1% and 24.7% in the earlier literature; a patulous internal auditory canal was described for the first time, and ventriculomegaly, brain cysts, empty sella and a low-lying conus medullaris recurrently, without correlation with epilepsy or ID [75]. The European cohort found brain anomalies in 56% and considered them the second most relevant finding for suspicion in childhood [49], whereas the Spanish cohort had abnormal MRI in 38.3% (enlarged cisterna magna in 9%, leukoencephalopathy and abnormal cerebellum in 4.5% each) [21]. Other reported findings include vermian hypoplasia, Chiari I malformation, periventricular nodular heterotopia, mild periventricular leukomalacia, pineal, arachnoid and choroid plexus cysts, dysgenesis or agenesis of the corpus callosum, colpocephaly, calcifications, optic nerve hypoplasia, subdural haemorrhage and a small pituitary gland [1, 20]. Smith states that patients with a structural brain defect on MRI had severe ID [25], an observation from older series that Peluso's cohort did not confirm [75].

3.11. Hearing, ear and palate

Hearing problems affect 25–31% [1]. In a French multicentre series of 32 patients, hearing loss was typically conductive (71%), bilateral (81%), mild to moderate (84%) and stable (69%), and computed tomography was abnormal in 55%, with ossicular chain abnormalities in 67%, stapes footplate fixation in 33% and inner ear malformations in 33% [67]. One third of Dutch patients had conductive hearing loss [32]. Chronic or recurrent otitis media is frequent and causes hearing loss in some: in the British series, eight had permanent conductive hearing loss, all with recurrent otitis or perforation treated with ventilation tubes, and another seven had recurrent otitis without hearing loss; sensorineural hearing loss occurred in one patient with a maternal history [19]. Enlarged vestibular aqueduct and choanal stenosis or atresia have also been described [20]. Palatal anomalies occurred in 8 of 32 British patients (four with submucous cleft, two with bifid uvula, one with velopharyngeal incompetence and one with a short palate; two underwent pharyngoplasty), and the authors acknowledge possible underestimation [19]; the European cohort recommends actively looking for submucous cleft [49]. The French PNDS estimates hearing loss at no less than 30%, conductive, sensorineural or mixed, congenital or acquired, warns of the complications of otitis media with effusion (tympanic perforation and retraction, cholesteatoma) and gives velar insufficiency, ranging from a non-functional soft palate to bifid uvula and submucous or overt cleft palate, in 20–74% of patients, with an indication for early screening [18].

3.12. Eyes

In a group of 43 patients recruited through a US association, 40 of whom had a pathogenic variant, strabismus occurred in 22.5%, astigmatism in 27.5%, myopia in 15.0% and hypermetropia in 20.0%, with anisometropia, amblyopia and nystagmus, prevalences higher than in the literature and possibly influenced by recruitment method [93]. In the Spanish series, 42.6% had visual problems, of which 81.8% were refractive errors and 18.4% strabismus [21]. Bilateral congenital cataract, high myopia, megalocornea, ptosis and visual impairment have also been described [1, 25]. Severe astigmatism is more characteristic of extended deletions [4]. The French PNDS reports visual anomalies in 55% and considers cerebral visual (neurovisual) disorders frequent and early, with an impact on learning [18].

3.13. Heart and vessels

Congenital heart disease is reported in 10–26% [1]. In the Bambino Gesù Hospital series, 15 of 40 patients (38%) with an intragenic variant had heart disease, mainly left ventricular outflow tract obstruction (9 of 15) and subaortic or muscular VSD (5 of 15), with dextrocardia in one; the only patient with a 16q24.3 deletion and heart disease, among six, had a complete atrioventricular septal defect (AVSD) with aortic coarctation [3, 68]. In the combined review, septal defects accounted for 44%, left outflow tract obstructions for 31% and AVSD for 18%, and septal defects occurred in 78% of patients with deletions; left-sided valvular anomalies were frequent, and AVSD was proposed as a diagnostic marker in young children [68]. In the British series, heart disease occurred in 4 of 32 (patent ductus arteriosus, AVSD and two small VSDs) and second-degree atrioventricular block with a structurally normal heart in a 6-year-old child [19]; in Guo's series, surgically repaired tetralogy of Fallot and mitral valvuloplasty were described [20]. Among adults, two of 36 had ascending aortic dilatation [82]. The French PNDS gives heart disease in 15–26% (VSD, atrial septal defect, pulmonary valve stenosis, atrioventricular canal and minor valvulopathies found on systematic screening), reports two aortic dilatations and considers the incidence of secondary valvulopathy higher than in the general population [18].

3.14. Gastrointestinal tract and feeding

Feeding problems predominate in infancy: vomiting, constipation and gastro-oesophageal reflux disease (GORD) [1]. Six British patients (19%) had significant feeding difficulties; one child required a nasogastric tube (NGT) until age 4 and another was gastrostomy-dependent at 4.5 years, and there was severe constipation, drooling and, in one adult, chronic diarrhoea with absent thirst and two admissions for dehydration [19]. The Polish series recorded failure to thrive in 61% [74]. Severe feeding difficulties requiring prolonged gastrostomy are rare, and cyclical vomiting is a recognised rare finding [8]. A mother's account in the growth-chart publication illustrates how an undiagnosed child with KBG was labelled as having “failure to thrive” for not following generic charts [8]. The French PNDS adds sucking and swallowing difficulties, delayed introduction of lumpy foods, oral feeding disorders aggravated by cleft palate and retrognathia, and food selectivity in patients with ASD [18].

3.15. Genitourinary tract and kidney

Cryptorchidism occurs in 25–44% of boys [1]. The French PNDS gives testicular ectopia in 18–35%, hypospadias in 6% and malformative uropathies in approximately 10% (vesicoureteral reflux, single kidney, megaureter) [18]. Shawl scrotum, hypogonadism, duplication of the collecting system, recurrent urinary tract infections, enuresis, cystic renal dysplasia and renal fusion have been described [3, 11, 20, 21, 25, 52]. Renal anomalies are also among prenatal findings [12, 53].

3.16. Skin, appendages, immunity and other findings

Hyperpigmentation, ichthyosis, hypertrichosis, abnormal hair whorls, dystrophic nails (6 of 32 British patients), keloids, lymphoedema and cutis marmorata have been described [1, 19]. Recurrent respiratory infections without identified immune deficiency occurred in 6 of 32 [19]; autoimmune diseases in four of 36 adults [82] and juvenile idiopathic arthritis in two patients in an Italian series [3]. Parents in Guo's series reported immunodeficiency, recurrent infections and allergies as frequent, without reported laboratory confirmation [20].

3.17. Neoplasms

A paratesticular rhabdoid tumour was described in a boy with a 16q24.3 microdeletion, with uncertain association [1, 94], and the French series reported one malignancy [33]. Cancer predisposition is not established, and tumour screening is not recommended [1].

3.18. Adulthood

Life expectancy appears normal; approximately 200 adults have been described, the oldest alive at 76 years, and many adults are probably undiagnosed [1]. In the clinician-reported natural history study, 36 adults from 31 families had mild or borderline ID in 22, motor difficulties in 15, psychiatric or behavioural comorbidities (aggression, anxiety, attention deficit, autistic traits) in 26, absent verbal language in three, seizures in 10, ophthalmological comorbidities in 20, cognitive regression in one, ascending aortic dilatation in two and autoimmune disease in four; the accompanying systematic review found 154 adults in the literature [82]. In the co-produced questionnaire with 91 responses from people aged 16–86 years, the proportion with independent living skills (driving, shopping) was higher in the 45–54 group than in younger groups, no participant with active seizures lived independently, and psychiatric, sleep, visual, auditory, dental, skeletal, cardiovascular and gastrointestinal comorbidities were frequent [95]. More than half of reported adults were employed and self-sufficient; completing mainstream secondary education without support appears rare, some completed vocational education, and some affected women had children whom they raised with help from a spouse or family [1]. In the British series, two parents diagnosed after their children lived independently, and another five adults lived with their parents [19]. The age of 86 years in the questionnaire is the maximum age of a respondent, not an estimate of longevity [95].

3.19. Particular features of the 16q24.3 microdeletion

Deletions including ANKRD11 reproduce the KBG phenotype and, when they encompass flanking genes, add greater neurological severity, congenital heart disease, thrombocytopenia, astigmatism and brain abnormalities, particularly of the corpus callosum [1, 4]. Septal defects were particularly frequent in patients with deletions (78%) [68]. In the series of 340 patients, triangular face and the phenotypic index were lower with CNVs than with sequence variants [21]. In the review of 68 cases, a prominent nasal root (50%) and prominent forehead (45.45%) were described in non-Chinese patients, and a Cupid's-bow lip, prominent ears and thick eyebrows in Chinese patients [9]. The French series observed that 16q24.3 deletions involving ANKRD11 never extend to the telomere [33].

4. Clinical Recognition and Warning Signs

4.1. Why the diagnosis is missed

KBG is underdiagnosed because many findings are mild and none is mandatory [3, 33]. Facial features are subtle at early ages and become evident only with age, macrodontia is observed only in the permanent dentition, short stature is not universal and vertebral anomalies require radiography [19, 49]. In the British series, facial features were recognisable in approximately half and the diagnosis was easily missed [19]. Clinical diagnosis was traditionally made at 7–8 years, after eruption of the upper central incisors [10]. Today most diagnoses are made through exome testing or developmental delay panels, and many adults remain undiagnosed because they have never had access to genomic testing [1, 19].

4.2. When to suspect the condition, by age

Prenatally, suspicion may arise with IUGR, polyhydramnios, increased NT, mild ventriculomegaly, VSD or renal anomalies, particularly if CMA is normal [12, 53, 70]. The European cohort recommends that sequencing performed after prenatal ultrasound anomalies include ANKRD11 [49].

In newborns and infants, warning signs are a large anterior fontanelle with delayed closure, wide metopic suture, feeding difficulty with failure to thrive, axial hypotonia, congenital heart disease (particularly AVSD), cryptorchidism and early dentition [11, 19, 68]. The large fontanelle sometimes prompts suspicion of craniosynostosis or cleidocranial dysostosis [19]. The French PNDS stresses that, in infancy, growth delay, feeding difficulties, ENT problems and postural delay predominate, and that the dysmorphism should be assessed by a clinical geneticist to guide testing [18]. In the European cohort, brain anomalies were considered the second most relevant finding for suspicion in childhood, when short stature and dental and vertebral anomalies are still indistinct [49].

In preschool and school-age children, the combination of language delay, hyperactivity, ASD or learning difficulties with postnatal short stature, recurrent otitis media with conductive hearing loss, submucous cleft or velopharyngeal insufficiency, brachydactyly and suggestive facial features should prompt consideration of KBG [1, 21]. Eruption of broad upper central incisors, around age 7, is the classic point of recognition [10]. A hoarse voice and psychomotor hyperactivity have been described as useful signs [74].

In adolescents and adults, suspicion almost always arises retrospectively, after a child's diagnosis, in a mildly affected parent with macrodontia, short stature or learning difficulties [1, 10]. Early-onset parkinsonism or tremor in an adult with mild ID and broad incisors also warrants consideration of the diagnosis [88, 89].

4.3. Warning and emergency signs

No KBG manifestation is in itself a frequent emergency, but some require prompt assessment. Seizures beginning in infancy, infantile spasms or epileptic encephalopathy and electrical status epilepticus in sleep require referral to paediatric neurology [1, 21]. Heart disease with left outflow tract obstruction, AVSD with coarctation and tetralogy of Fallot may require surgery in the first months [20, 68]. Severe failure to thrive, aspiration and repeated respiratory infections suggest swallowing dysfunction [1]. Motor regression, coordination or sphincter control problems in a child with a sacral dimple should prompt investigation for tethered cord [20, 92]. Progressive enlargement of a posterior fossa arachnoid cyst was described in an isolated case and treated by shunting, with subsequent cognitive improvement [96]. Diarrhoea with absent thirst and dehydration, described in an adult, warrants hydration monitoring [19].

4.4. Newborn screening

The sources consulted describe no newborn screening or biochemical marker for KBG, whose diagnosis is molecular [1]. Newborn hearing screening may be normal because hearing loss is mainly conductive and associated with otitis, as in the infant in the Italian series with normal neonatal otoacoustic emissions and mild conductive hearing loss at 3 years and 6 months [11, 67].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no consensus clinical criteria; the proposed sets guide test requests and do not replace molecular diagnosis [1]. Criteria have evolved from lists of major findings to algorithms combining neurodevelopment with physical features and comorbidities, as molecular cohorts showed that macrodontia, short stature and costovertebral anomalies are absent in some patients [3, 19, 21].

Absence of a family history does not exclude the diagnosis [1]. The case described by Geckinli and colleagues, without costovertebral anomalies or short stature, led the authors to propose revising the classic major findings [3]. The 2020 French PNDS adopts the Low 2016 criteria, which predate the 2023 proposal [18].

5.2. Genetic testing strategy

Diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic ANKRD11 variant, or a heterozygous 16q24.3 deletion including ANKRD11 [1]. The two classes, pathogenic and likely pathogenic, are equivalent for clinical decision-making under the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) framework [1, 97].

When the phenotype suggests KBG, GeneReviews proposes targeted testing: ANKRD11 sequencing first, for missense, nonsense, splicing variants and small insertions or deletions, followed by targeted deletion and duplication analysis if sequencing is negative; CMA detects larger 16q24.3 deletions, and a multigene panel including ANKRD11 and differential diagnosis genes is an alternative [1]. The British series recommended ANKRD11 sequencing and array-CGH for the microdeletion when sequencing is normal [19]. When KBG has not been considered, comprehensive genomic testing, generally exome and sometimes genome, is the most frequent route; ACMG and the American Academy of Pediatrics (AAP) recommend exome or genome as first- or second-line testing in children with global developmental delay, ID or multiple congenital anomalies [1, 13, 14]. Because approximately one fifth of cases result from deletions, CNV analysis must accompany sequencing [1, 47]. The detection of 19.4% deletions in a Turkish series of 36 patients illustrates this point [47].

The table values, based on the series of 340 patients and HGMD (Human Gene Mutation Database), represent the proportion of pathogenic alterations found by each method among confirmed cases, rather than the clinical sensitivity of testing in a suspected case [1, 21, 98]. qPCR denotes quantitative PCR and MLPA multiplex ligation-dependent probe amplification.

5.3. Test limitations

A negative result does not exclude KBG. Deletions removing only the promoter and non-coding 5′ exons escape coding-region sequencing and CNV analyses that do not include the upstream region [1, 35, 45]. Low-level somatic mosaicism may not be detected in blood, as in the parent with 2 of 298 reads [20], and gonadal mosaicism is not detectable in leucocytes [1]. Interpretation of non-coding CNVs benefited from transcriptome analysis [45]. Missense variants require caution because many are VUS and some are inherited from apparently unaffected parents [15, 34]. Finally, a patient with an ANKRD11 variant may have a second molecular diagnosis explaining part of the presentation [11, 64].

5.4. Adjunctive tests: episignature, transcriptome and assisted phenotyping

The peripheral blood DNA methylation signature, developed in 21 individuals with ANKRD11 variants, two with a 16q24.3 microdeletion and 28 controls, identified 95 differentially methylated CpG sites, validated in an independent set of seven; the model classified four VUS, assigned an intermediate value to a missense variant inherited from a mother without clinical signs and transmitted to an affected son, and showed indistinguishable profiles in microdeletions [15]. GeneReviews indicates the episignature when clinical suspicion exists without a variant identified by sequencing, CNV or genomic testing, and when an ANKRD11 VUS is present [1]; it thus serves as an adjunctive test for inconclusive results and does not replace identification of the genetic alteration. Transcriptome analysis documented reduced expression in exon 1 deletions [45].

Facial phenotyping by computational image analysis has moderate performance. In Guo's series, DeepGestalt (Face2Gene) ranked KBG first in 28% and among the top five possibilities in 80%, GestaltMatcher among the top ten in 60%, and PEDIA, combining facial features with exome data, ranked ANKRD11 first in 72% (18 of 25) [20]. Unrecognised patients included a family with a missense variant of doubtful pathogenicity, older adults and the mosaic parent, and alternative diagnoses proposed by the algorithm were CdLS, Williams-Beuren, Rubinstein-Taybi, Angelman and mucopolysaccharidosis [20]. PhenoScore, an open-source tool combining facial recognition with Human Phenotype Ontology (HPO) terms, trained on 79 individuals with truncating variants, distinguished six patients with functionally confirmed pathogenic missense variants with an area under the curve (AUC) of 0.95; it outperformed REVEL and complemented AlphaMissense, and the authors propose using it as evidence for ACMG/AMP criterion PP4 [99]. The Indian series reported high Face2Gene concordance [100].

5.5. Report content and VUS interpretation

The report should state the gene, versioned transcript (NM_013275.6), variant in HGVS nomenclature at cDNA and protein levels, zygosity, ACMG/AMP classification and, for CNVs, genomic coordinates with the reference genome version, size and included genes [1, 6, 97]. For deletions, the gene list allows anticipation of comorbidities associated with flanking genes [4]. For a VUS, assessment includes parental segregation studies, careful carrier phenotyping, the episignature, RD2 location for missense variants, functional evidence when available and tools such as PhenoScore [15, 34, 99]. A VUS neither establishes nor excludes the diagnosis [1]. The French PNDS requires reverse phenotyping before the disclosure consultation when the variant arises from a genome-wide test without prior suspicion, and requires missense variants to be classified at a clinical-laboratory meeting, with study of the phenotype of the proband and of the carrier parent, because ANKRD11 missense variants are frequent and mostly non-pathogenic; if the presentation is not suggestive, the diagnosis should not be retained and investigation continues [18].

5.6. Practical algorithm

For a child with developmental delay or ID and suggestive findings, the first step is genomic testing (exome or genome) with CNV analysis or, if suspicion is specific, ANKRD11 sequencing with CNV analysis including the 5′ region [1, 13]. If the result is negative and suspicion persists, consider high-density CMA at 16q24.3, genome, episignature and, in a research setting, transcriptome [1, 15, 45]. If a VUS is found, follow the steps in subsection 5.5. Once the diagnosis is confirmed, test the parents and, for deletions, perform parental karyotyping [1]. The decision tree of the French PNDS has two entry points: with clinical suspicion (neurodevelopmental disorder with growth delay, ENT problems, malformations and typical dysmorphism), targeted ANKRD11 sequencing or a panel and, if negative, CMA or exome sequencing depending on the centre; without suspicion, CMA followed by exome or genome sequencing. A pathogenic or likely pathogenic variant with a typical phenotype confirms the diagnosis; a variant of uncertain interpretation leads to re-examination of the phenotype, parental studies and discussion at a multidisciplinary meeting; absence of a variant leads to reassessment of the differential diagnosis and consideration of genome sequencing [18].

5.7. Prenatal diagnosis

Prenatal diagnosis uses CMA and fetal exome following ultrasound findings; in a Chinese series, CMA identified seven 16q24.3 microdeletions and exome 12 ANKRD11 variants in 19 fetuses [12]. In a family with a known variant, prenatal testing and preimplantation genetic testing (PGT) are possible [1]. The fetal phenotype is non-specific, and postnatal severity cannot be predicted from the variant [1, 70].

6. Differential Diagnosis

6.1. Comparative table

AD and AR denote autosomal dominant and autosomal recessive inheritance; ICR1 is imprinting control region 1 and UPD7 uniparental disomy of chromosome 7.

6.2. Main differential diagnoses

The most important differential is CdLS, because of overlapping thick eyebrows, synophrys, long eyelashes, growth restriction, cryptorchidism and hearing loss, and shared molecular pathways; in classic CdLS, microcephaly and more severe ID guide diagnosis, and ANKRD11 was found in 3 of 163 patients with a CdLS-like phenotype [1, 19]. Among 23 patients with ANKRD11 variants, almost all initially had a clinical diagnosis of KBG or CdLS, and reassessment at another age showed evolution towards the other entity's phenotype [64]. ANKRD11 binding to cohesin provides a molecular basis for this overlap [41]. CdLS panels should therefore include ANKRD11, and patients with a non-classic CdLS phenotype without a variant in cohesin genes should be tested for ANKRD11 [19, 65].

Faciogenital dysplasia (Aarskog-Scott) and SATB2-associated syndrome share large or prominent upper incisors; normal cognition and shawl scrotum favour the former, and frontal bossing and midface hypoplasia the latter [1]. Shawl scrotum has, however, been described in an infant with KBG, so the sign is not exclusive [11]. Silver-Russell syndrome shares the triangular face and growth restriction, but has body asymmetry and 11p15 methylation abnormalities [1]. SETD5 variants produce a similar presentation, with more severe ID and less frequent dental anomalies (9/32, 28%, including macrodontia of the upper central incisors) [104], and ANKRD11 acts upstream of SETD5 in ribosomal RNA regulation [1, 42].

The French PNDS groups the differential diagnosis into three presentations: early growth delay and feeding difficulties with dysmorphism (22q11.2 deletion, CdLS and other cohesinopathies and transcriptomopathies, Silver-Russell, Floating-Harbor, Noonan and other RASopathies); mild delay or learning difficulties with dysmorphism (22q11.2, mild CdLS, other cohesinopathies); and ENT disease with cleft palate or velar insufficiency (22q11.2, Floating-Harbor). It also notes that many children with mild ID, ADHD or ASD and subtle dysmorphism remain undiagnosed despite genome-wide testing [18].

Within the KBG spectrum, distinguishing a deletion restricted to ANKRD11 from an extended microdeletion affects surveillance: thrombocytopenia, severe astigmatism and more frequent heart disease justify targeted blood counts, ophthalmology and echocardiography when the deletion includes ZFPM1, CDH15 or ZNF778 [1, 4]. A large fontanelle with delayed closure prompted referral for suspected craniosynostosis in five British patients and evokes cleidocranial dysostosis [19]. Finally, additional molecular diagnoses explain part of the breadth of the spectrum, such as the EHMT1 variant in the Italian patient, and should be considered when the phenotype exceeds expectations [11, 64].

7. Treatments and Risk Management Strategies

7.1. Principles and evidence base

There is no cause-directed treatment or drug approved for KBG; management is supportive, multidisciplinary and guided by each patient's manifestations [1, 16]. No clinical practice guideline has been published by scientific societies or ERN-ITHACA, and the GeneReviews recommendations are based on the authors' experience [1]. The only national protocol is the French PNDS of the Haute Autorité de Santé (HAS), published in December 2020 by the developmental anomaly reference centres of Rouen and Marseille (AnDDI-Rares network) using the 2012 HAS method; in the absence of high-level evidence, the recommendations and surveillance intervals rest on the consensus of the network's experts [18]. The PNDS considers that treatment of complications does not differ from that in the general paediatric population and that the specificity lies in multidisciplinary coordination [18]. The remaining proposals come from author groups: the recommendation table in the 2016 British series, reproduced by Radboudumc's Human Disease Genes portal, recommendations by Guo and colleagues (2022), growth hormone recommendations by Aukema and colleagues (2025) and skeletal recommendations by van der Leij and colleagues (2026) [16, 19, 20, 22, 105]. The British series proposed coordination by a hospital or community paediatrician for children and a general practitioner for adults [19].

7.2. Assessment after diagnosis

The table integrates the GeneReviews initial assessment with the recommendations of other authors and of the French PNDS; differences are identified.

The recommendation for a full blood count in extended microdeletions follows from the frequency of thrombocytopenia described by Novara and colleagues and is not an explicit recommendation in the sources [4].

7.3. Development, language and rehabilitation

Early intervention should start as soon as delay is identified [1, 10]. In the USA, GeneReviews describes the early intervention programme until age 3 (occupational therapy, physiotherapy, speech and feeding therapy, infant mental health, specialist educators and sensory impairment specialists), developmental preschool from 3 to 5 years with an individualised education programme (IEP) reviewed annually, and an adolescent transition plan [1]; the organisation of these services varies between countries. Families in Guo's series reported benefit from physiotherapy, occupational therapy and speech therapy at least once weekly [20]. Physiotherapy aims to maximise mobility and reduce later orthopaedic complications such as contractures, scoliosis and hip dislocation, and occupational therapy addresses fine motor skills [1]. Regular assessment by a physiotherapist allows detection of postural changes and initiation of targeted training to prevent kyphosis or lordosis [22].

The French PNDS recommends motor physiotherapy once or twice weekly followed by psychomotor therapy for hypotonia and postural delay, early speech and language therapy and AAC (PECS, Makaton) without delay if the oral language deficit persists beyond age 3, and formal neuropsychological assessment at age 5, before primary school, at 10–11 years, before transition to the next school stage, and in secondary school, for vocational guidance [18]. The approach is tailored to developmental level rather than to the diagnosis; school placement ranges from a mainstream class with individual support to an inclusion unit for mild ID (IQ 50–70) and a specialised establishment when IQ is below 50 or behavioural disorders predominate, and should be reviewed if the child is struggling [18]. In France, the pathway uses early medico-social action centres (CAMSP) before age 6, special education and home care services (SESSAD), localised school inclusion units (ULIS) and medico-educational institutes (IME) or therapeutic, educational and teaching institutes (ITEP), with an application to the Maison départementale des personnes handicapées (MDPH) and the education allowance for a child with a disability (AEEH) to fund non-reimbursed psychomotor therapy [18].

Oromotor function should be assessed at each appointment; choking, poor weight gain, frequent respiratory infections or feeding refusal indicate clinical swallowing assessment or videofluoroscopy, with feeding therapy, modification of food texture and temperature and, in severe cases, NGT or gastrostomy [1]. Language should be assessed early, and augmentative and alternative communication (AAC), from picture exchange to voice devices, may be introduced by an experienced speech and language therapist without detriment to speech development [1]. Velopharyngeal insufficiency may require surgery or speech therapy [1, 19].

7.4. Behaviour, ADHD and mental health

Interventions for ASD include applied behaviour analysis (ABA) delivered by a certified behaviour analyst, and the developmental paediatrician guides behavioural strategies and, if necessary, medication, for example for ADHD [1]. The neuropsychological profile, with attention and executive function deficits and relatively preserved social cognition, suggests that interventions should target attention regulation and impulsivity [80]. Repetitive paper handling and the intense reaction to interruption should be recognised to avoid confrontation [83]. Strategies promoting healthy habits in adolescence should be adapted to learning difficulties and sensory needs [8].

Methylphenidate has no demonstrated efficacy specifically in KBG; the N-of-1 trial registry states that caregivers reported a good effect in a previous survey [17]. When used, the ADHD indication applies rather than a KBG indication. The US label for the modified-release formulation Ritalin LA® (methylphenidate, extended-release capsules) indicates it for ADHD in ages 6–12 and does not recommend it below age 6; the initial dose is 20 mg once daily in the morning (10 mg when appropriate), with weekly increments of 10 mg, and doses above 60 mg daily are not recommended [106]. Before initiation, the label requires assessment for heart disease (personal history, family history of sudden death or ventricular arrhythmia and physical examination) and tics or Tourette syndrome [106]. This assessment is particularly relevant in KBG because of the frequency of congenital heart disease and reported tics [19, 68], and the ongoing trial excludes patients with haemodynamically significant heart disease, a family history of sudden cardiac death and uncontrolled epilepsy [17]. In Portugal, the equivalent formulation (modified-release capsules with approximately 50% immediate release and 50% released about 4 hours later, for example Metilfenidato Ciclum®) is indicated for ADHD from age 6 and in adults; in children, the starting dose is 20 mg once daily in the morning (10 mg when appropriate) and the maximum dose 60 mg/day, and in adults the starting dose is 20 mg, with weekly increments of 20 mg, up to a maximum of 80 mg/day; treatment is discontinued if symptoms do not improve after one month of titration [107]. The Portuguese SmPC also requires prior cardiovascular assessment, with blood pressure, heart rate and family history of sudden death, and recording of blood pressure, pulse, height, weight and psychiatric status at each dose adjustment and at least every 6 months [107]. Use in adults with KBG falls within the European adult ADHD indication, but not within the US Ritalin LA® label, which is limited to ages 6–12 [106, 107].

In the Italian report, an 18-year-old patient with externalising behaviour disorder was receiving aripiprazole 10 mg daily as an oral solution; this was an individual management decision described in the case and not a recommendation for the syndrome [11]. Aripiprazole has no indication for externalising behaviour disorder: in the EU it is authorised for schizophrenia from age 15 and for manic episodes of bipolar I disorder from age 13, with a recommended dose of 10 mg/day in adolescents (starting at 2 mg with titration), and in the USA also for irritability associated with autistic disorder from 6 to 17 years, starting at 2 mg/day, with a dose of 5–15 mg/day and a maximum of 15 mg/day [108, 109]. The dose in the case lies within the labelled range, but its use falls outside the conditions of the European label [11, 109]. Sleep disorders were resistant to melatonin in most British patients [19].

For ASD, the French PNDS proposes assessment by a regional diagnostic support team or an autism resource centre, using the ADI-R, ADOS and CARS-2; for ADHD, psychotherapy, remediation and parent training as first line, with a stimulant or non-stimulant prescribed by a paediatric neurologist or child psychiatrist if these are insufficient; and systematic child psychiatric follow-up for behavioural disorders, which weigh most heavily in adolescence and in the transition to adulthood [18].

7.5. Epilepsy

Epilepsy is treated with ASMs selected by an experienced neurologist; many ASMs are effective and none has been studied specifically in KBG [1]. Most respond to treatment: 50% seizure-free for at least one year in a cohort of 26 patients and approximately 70% seizure-free after a mean follow-up of 9.9 years in a review of 233 patients, with drug resistance between 22.6% and 36.8% depending on the series [61, 62, 85]. Some patients enter remission after adolescence [84]. GeneReviews recommends educating parents and caregivers about seizure presentations [1]. Guo and colleagues' suggestion of early detection and seizure “prophylaxis” is unsupported by trials and does not constitute established practice [20]. The Italian patient with seizures from age 12 was taking oral levetiracetam 1000 mg daily in two divided doses, an individual dose reported in the case [11]. Epilepsy is associated with poorer development and lower adult independence, reinforcing seizure control as an objective [62, 95]. The French PNDS describes epilepsy as usually drug-responsive and without specific treatment, and requests paediatric neurology or neurology consultation for abnormal movements or any sign suggestive of seizures [18].

7.6. Growth and growth hormone

Short stature should be assessed using KBG-specific charts, showing the centile shift relative to the reference population, and population charts; growth velocity, bone age and GHD may be investigated in children meeting short-stature criteria [8]. GeneReviews recommends considering growth hormone [1]. Somatropin has no approved indication for KBG; use in a child with KBG without GHD is off-label, whereas a child with KBG and proven GHD has an indication through GHD [16, 110].

The largest treated series combined 6 new patients and 18 from the literature (baseline cohort 24): median pretreatment height was −2.9 SD (standard deviation score, SDS), 86% had short stature, median starting age was 6 years, bone age was delayed in 81% and GHD (total, partial or unspecified) was present in 9 of 21 (43%) [16]. In the 20 patients with at least two measurements, after a median duration of 5.0 years (interquartile range 3.1–7.6), height increased from −3.0 to −1.8 SDS, with a median change in height SDS (ΔHSDS) of +0.9 (0.5–1.5); in patients without GHD who were not small for gestational age (median 4.5 years), the change was from −3.0 to −1.7 SDS [16]. At 12 months (n = 13), median ΔHSDS was +0.4 and 6 of 13 (46%) responded (ΔHSDS ≥0.5), rising to 12 of 13 (92%) after a median follow-up of 5.8 years (ΔHSDS +1.2); first-year response was similar with and without GHD (+0.4 in both) [16]. Among eight patients treated for at least one year with adult height data, three were within the normal range and five of seven with a known target height were within 2 SDS of target [16]. Doses were heterogeneous, in different units depending on country, and there is no recommended KBG dose [16].

Smaller series point in the same direction. In Reynaert and colleagues' series, two children gained +0.6 and +1 SDS in one year, one also receiving a gonadotrophin-releasing hormone (GnRH) agonist for medical need [73]; eight Chinese patients increased their height without significant adverse effects [53]; two children with microdeletions gained +1.66 and +0.68 SD [9]; one Chinese child received long-acting somatropin for 20 months with improved height and no adverse reactions [111]; and in Guo's series a child treated from 3.5 to 5.7 years reached the 13th centile [20]. In a compilation of 245 patients, most treated patients responded, although numbers were limited [46].

These data have important limitations: they are retrospective, without a control group, with different national protocols and missing target and adult heights; ΔHSDS may overestimate the effect if delayed bone age accelerates; first-year response was comparable to or lower than that described in children born small for gestational age, Turner syndrome and idiopathic GHD; and GHD diagnosis is subject to false positives [16]. The 2026 chart emphasises the lack of data on the effect on final adult height [8]. Aukema and colleagues recommend prospective studies with a minimum dataset (variant, pregnancy and birth, anthropometry and treatment), use of specific charts, monitoring of bone age, scoliosis, apnoea, blood glucose and insulin-like growth factor 1 (IGF-1), dose studies with and without GHD, and inclusion of patients with height below −2.0 or −2.5 SDS according to local criteria, irrespective of GHD [16]. Two parents reported increased muscle tone and strength during treatment, and data on scoliosis progression are only anecdotal [16].

The 2020 French PNDS is more restrictive: it recommends measuring height and growth velocity every 6 months on a standard chart, assessing bone age by left hand and wrist radiography (Greulich and Pyle method) and referring to paediatric endocrinology if height is −2 SD or lower; growth hormone is considered in persistent short stature after IUGR or in proven deficiency, with stimulation tests in a day hospital, information for parents about the uncertain benefit and systematic prior brain MRI to look for a hypothalamic-pituitary anomaly [18]. Prior MRI is consistent with the partially empty sella found in patients with GHD [16, 75].

The table presents the labelled somatropin (Genotropin®) doses in the USA and in Portugal for approved indications; none corresponds to KBG.

Source: Genotropin® label effective 4 August 2026 [110]. The label also includes adult GHD [110]. In the Netherlands, reimbursed indications are GHD and children born small for gestational age without catch-up [16]. The Portuguese Genotropin® SmPC also includes chronic renal insufficiency (0.045–0.050 mg/kg/day) and adult GHD, and does not include idiopathic short stature [112]. Doses in KBG series that exceed these dosing schedules, or treatment without GHD, fall outside the conditions of the label [16, 110, 112].

7.7. Advanced or precocious puberty

Advanced or precocious puberty, described in some patients, may require suppressive treatment prescribed by an endocrinologist [1, 33]. The sources consulted specify no KBG-specific drug, dose or duration; one child treated with growth hormone also received a GnRH agonist [73]. Puberty should be monitored at each appointment during childhood and adolescence (section 11). The French PNDS defines precocious puberty as breast development before 8 years or increased testicular volume before 9 years and recommends referral to paediatric endocrinology also for moderately advanced puberty or advanced bone age, because both worsen the height prognosis [18].

7.8. Teeth and face

Dental anomalies are treated according to usual dental and orthodontic practice [1]. The 2026 orofacial review recommends participation of a maxillofacial surgeon and orthodontist in the team [66]. Dental and orthodontic assessment should form part of follow-up from tooth eruption [1, 10]. The French PNDS recommends dental consultation from eruption of the first teeth and at the ages of the preventive dental examinations of the French health insurance scheme then in force (3, 6, 9, 12, 15, 18, 21 and 24 years), fluoride varnish for enamel hypoplasia, orthodontics for crowding and prostheses for oligodontia; persistent oral feeding disorder may hinder care, and prior speech and language therapy improves orthodontic treatment [18]. This three-yearly schedule has been replaced: since 1 April 2025, the French oral prevention programme “M'T dents tous les ans” offers an annual dental examination to everyone aged 3 to 24 years, bringing the French interval closer to the annual or more frequent follow-up recommended in the other sources [1, 113].

7.9. Ear, hearing and upper airway

Chronic otitis media may require ventilation tubes, tonsillectomy or adenoidectomy, and hearing loss may benefit from hearing aids, with school hearing support services [1]. The French PNDS warns that tonsillectomy or adenoidectomy performed without prior screening for velar insufficiency may markedly worsen the speech disorder; it recommends looking for velar insufficiency at every ENT examination (nasal regurgitation, difficulty articulating some consonants or drinking through a straw), starting speech and language therapy targeting airflow and missing sounds, and proposing pharyngoplasty or veloplasty only after at least 6 months of well-conducted therapy; it treats otitis media with effusion with ventilation tubes and, in conductive hearing loss, recommends looking for an ossicular malformation [18]. The French series recommends complete audiological and radiological assessment and ENT follow-up for all, given the frequency of ossicular chain anomalies and stapes fixation [67]. Whether intensive antibiotic treatment of otitis prevents hearing loss is unknown [20]. Sleep apnoea may persist after adenotonsillectomy, as in one British patient [19].

7.10. Spine, spinal cord and orthopaedics

Scoliosis and kyphosis are treated according to usual orthopaedic practice [1]. Van der Leij and colleagues, within ERN-ITHACA, recommend anteroposterior and lateral chest and whole-spine radiographs after diagnosis or at least before age 10 because of the frequency of kyphosis and lordosis, with attention to structural vertebral and rib defects; hand radiography should follow local short-stature protocols; scoliosis present before the pubertal growth spurt should be followed because of the risk of worsening; and further radiographs should be requested if clinically suspected, given variable age at onset [22]. Cervical ribs and variations in rib number are generally asymptomatic but may cause errors in vertebral level counting on imaging [22]. Signs of tethered cord require neurosurgical referral because the condition is surgically treatable [92]. The French PNDS, which predates these recommendations, considers systematic radiography without clinical signs unnecessary and bases surveillance on clinical examination of spinal posture throughout growth, especially at puberty, with paediatric orthopaedic referral for a rib hump and annual or six-monthly follow-up during rapid growth when there is scoliosis, kyphosis or vertebral malformation; the prominent sacrum rarely requires surgery and may benefit from an ergonomic cushion at school, and clino-camptodactyly is only rarely operated on [18].

7.11. Heart

Heart disease is treated according to usual cardiological practice [1]. A detailed echocardiogram at diagnosis identifies left outflow tract lesions, left-sided valve disease and AVSD [68]. Ascending aortic dilatation in two adults suggests that cardiovascular assessment should not end in childhood [82]. By expert consensus, the French PNDS proposes echocardiography at diagnosis, repeated at 10 and 18 years in children without heart disease, and in adults at diagnosis and then every 10 years, to screen for secondary valvulopathy [18].

7.12. Gastrointestinal tract, eyes, urinary tract and neurosurgery

GORD and constipation are treated conventionally, and feeding may require feeding therapy, a dietitian and, if persistent, gastrostomy [1]. Strabismus and refractive errors are treated in ophthalmology [1, 93]. Cryptorchidism is treated in urology [1]. The French PNDS adds that an NGT or gastrostomy is sometimes needed temporarily, that GORD is treated with lifestyle and dietary measures and H2 antagonists or proton pump inhibitors (PPIs) according to usual paediatric recommendations, that encopresis should be screened for and treated, that men with untreated cryptorchidism may have fertility problems and that female fertility is, in principle, normal [18]. As a dosing reference, the US label for omeprazole (Prilosec®, delayed-release granules for oral suspension) indicates, for symptomatic GORD from 1 to 16 years, 5 mg (5 to <10 kg), 10 mg (10 to <20 kg) or 20 mg (≥20 kg) once daily for up to 4 weeks; for erosive oesophagitis, the same doses for 4 to 8 weeks and, between 1 month and 1 year, 2.5 mg (3 to <5 kg), 5 mg (5 to <10 kg) or 10 mg (≥10 kg) once daily for up to 6 weeks; these doses apply to paediatric GORD in general and have not been studied in KBG [114]. For the eyes, the PNDS also recommends the examinations of the French national vision screening programme (first week, 9 months, 2.5 years and 6 years), prompt examination for strabismus, nystagmus or an abnormal pupillary reflex, and cycloplegic refraction, because refractive errors may go unnoticed without it [18]. A young adult with KBG and an enlarging posterior fossa arachnoid cyst underwent cystoperitoneal shunting; at 18 months cyst volume decreased from 34 to 10 mL, left superior temporal sulcus perfusion normalised and there were gains in IQ, verbal index, executive functions, emotional regulation and verbal memory, maintained at age 22, but causality was not demonstrated and this is an isolated case [96].

7.13. Regulatory status

The search of FDA and EMA orphan designations and the European clinical trials registry was not exhaustive, so absence of results does not prove absence of applications [115]. National access in Portugal and Brazil was not included in the sources consulted.

7.14. Trials and intervention studies

Secondary outcomes of NCT06465641 include the SDQ emotional subscale, reactivity on the Emotion Dysregulation Inventory, Goal Attainment Scaling, a personal questionnaire, the adverse-effect checklist, the Family Assessment Device and baseline Autism Diagnostic Observation Schedule (ADOS-2) [17]. Available somatropin data come from uncontrolled series, without randomisation or a comparison group, so they do not allow estimation of an effect with a confidence interval or comparisons between series; SDS change is a relative measure that must be interpreted alongside starting height and bone age [16]. No published negative trials or trials of cause-directed therapies such as gene therapy or antisense oligonucleotides were found [115]. Other registries found are observational (Sanford rare disease registry, Simons Searchlight, palliative care in rare diseases and a study of ANKRD11 in T lymphocytes in hepatitis B that does not concern KBG) [115, 116].

7.15. Developments in the last 12 months

Between October 2025 and October 2026 no formal guideline or regulatory authorisation emerged [1, 115]. New evidence is as follows, by level. Published clinical tools: the KBG-specific growth chart (January 2026), Radboudumc skeletal recommendations (February 2026), PhenoScore for missense variants (March 2026) and three-dimensional facial analysis (September 2026) [8, 22, 72, 99]. Clinical cohorts: epilepsy reviews with 163 and 233 patients, the prenatal series of 19 fetuses, the comparison between 65 Chinese and 519 non-Chinese patients, the Turkish series of 36 patients, the review of 68 microdeletions, the Saudi series and the orofacial review of 614 patients [9, 12, 47, 52, 53, 61, 66, 85]. Isolated therapeutic reports: long-acting somatropin and arachnoid cyst shunting [96, 111]. Preclinical studies: ANKRD11 condensates restricting hypertranscribed genes (July 2026) and the role in T lymphocytes, the latter outside KBG [43, 44]. Ongoing trial: N-of-1 methylphenidate, without results [17]. The KBG Foundation announced a natural history study and patient registry, whose protocol was not published in the sources consulted [117].

7.16. Agents to avoid, pregnancy, perioperative care and transition

Ototoxic drugs should be avoided because of the risk of hearing loss [1]. In a woman with KBG, there are no universal pregnancy problems, and care is adapted to the manifestations: cardiology and maternal-fetal medicine for congenital heart disease, neurology for epilepsy [1]. Women with epilepsy have higher mortality during pregnancy, ASMs reduce that risk, and although ASM exposure may increase fetal risk (depending on drug, dose and gestational stage), this risk is generally lower than that of untreated seizures; treatment should be discussed before conception, with possible transition to a lower-risk drug [1, 118]. The sources consulted contain no KBG-specific perioperative recommendations; before anaesthesia, assessment focuses on known comorbidities such as heart disease, sleep apnoea, palatal anomalies and swallowing difficulties [1, 19]. Transition to adult care should be planned in adolescence, and coordination passes to the general practitioner [1, 19]. Adult data show persistent needs in mental health, epilepsy, vision, hearing and cardiovascular health [82, 95]. The French PNDS adds that, in a woman with KBG receiving medication (antiepileptic, cardiac or thyroid drug), the specialist should review treatment as soon as a pregnancy is planned, that valproic acid should be replaced by a drug with lower teratogenic risk before contraception is stopped, and that the pregnancy of an affected person should be followed at a multidisciplinary prenatal diagnosis centre (CPDPN), with ultrasound targeted at cardiac, urological and palatal malformations and at IUGR [18]. It also recommends an organised transition with adult services at the end of adolescence, a genetics clinic appointment at that stage and therapeutic education programmes that encourage patient and family participation in managing comorbidities and in the transition [18].

7.17. Source recommendations and differences

The sources agree on echocardiography, audiological, ophthalmological and dental assessment at diagnosis, assessment for palatal anomalies and early intervention [1, 19, 20, 68]. They differ on three points. The first is EEG: GeneReviews reserves it for suspected seizures, whereas Guo and colleagues and a family association propose baseline EEG for all, although Guo acknowledges that the justification remains to be investigated [1, 20, 119]. The second is skeletal imaging: GeneReviews proposes skeletal radiographs at initial assessment, and van der Leij specifies whole-spine and chest radiographs in two views by age 10, whereas Low 2016 reserved radiographs and bone age for selected patients [1, 19, 22]. The third is growth hormone: GeneReviews recommends considering it, Aukema advocates treating patients with short stature irrespective of GHD within prospective studies, and the 2026 chart records continuing debate because of missing adult-height data [1, 8, 16]. For hearing, GeneReviews indicates annual assessment or as indicated, the Dutch series regular testing for all and the French series complete radiological assessment and ENT follow-up for all [1, 32, 67].

The 2020 French PNDS adds or changes the following points. For criteria, it adopts Low 2016, which identifies fewer patients than the 2023 proposal (70% versus 88.7% in the Spanish cohort) [18, 21]. For EEG, it aligns with GeneReviews and reserves it for suspected seizures [1, 18]. For skeletal imaging, it dispenses with radiography without clinical signs, unlike GeneReviews and van der Leij [1, 18, 22]. For renal ultrasound, it makes it systematic at diagnosis, whereas the British series reserved it for selected cases [18, 19]. For the heart, it is the only source that defines echocardiographic reassessment without heart disease (at 10 and 18 years; in adults, every 10 years) [18]. For intervals, it proposes annual ENT review even with a normal examination and six-monthly review if there is otitis or hearing loss, ophthalmology at the ages of the French national screening programme instead of the annual assessment in GeneReviews, and dental consultation at the preventive ages of the health insurance scheme (three-yearly in 2020, annual from 3 to 24 years since 2025) and annually in adults, instead of at least six-monthly [1, 18]. For growth hormone, it limits the indication to persistent short stature after IUGR and to GHD, with stimulation tests and prior MRI, whereas Aukema advocates studies with inclusion irrespective of GHD [16, 18]. For growth, it states that no specific chart exists, a situation superseded by the 2026 chart [8, 18]. For recurrence risk after a de novo case, it quantifies it at 1–3% because of gonadal mosaicism, where GeneReviews states only that it is slightly above population risk, and below 1% for deletions [1, 18]. The PNDS itself has an internal inconsistency: the text indicates six-monthly follow-up at the reference centre in the first three years of life and the summary table in the first two [18].

8. Reproductive Options and Family Counselling

8.1. Inheritance and proportion of de novo cases

KBG is inherited in an autosomal dominant manner and typically arises de novo [1]. Among intragenic variants, approximately 85% are de novo and 15% inherited from an affected parent [1, 34, 49]. In recent molecular series, 36 of 39 patients with known origin (92.3%) had a de novo variant and three had inherited it from an affected mother [21]; in Guo's series, 12 were de novo, three inherited (two maternal and one paternal) and one from a parent with low-level mosaicism [20]; in the Dutch skeletal cohort, 33 of 38 (87%) were de novo [22]; and all 12 fetuses in the Chinese series had de novo alterations [70]. For 16q24.3 deletions, 70–90% are de novo and 10–30% have a mildly affected parent or a parent with a mosaic deletion [1, 120]. The abstract of the 2017 review, reporting de novo variants in “approximately one third” of cases, is contradicted by later data with explicit denominators [21, 26].

8.2. Parental assessment and recurrence risks

In a simplex case, the parents should be tested for the identified alteration; de novo origin is confirmed only with negative parental testing and confirmed biological parentage [1]. If the variant is not found in parental leucocytes, the explanation is a de novo alteration or gonadal or somatic-gonadal mosaicism; leucocyte testing may not detect somatic mosaicism and does not detect gonadal mosaicism [1]. A mosaic parent may be mildly or minimally affected [1, 20, 50]. For deletions, parental assessment includes a genomic test detecting the deletion and a karyotype to exclude a balanced translocation or other predisposing rearrangement [1].

Source: [1, 57]. The French PNDS estimates the recurrence risk for siblings at 1–3% when the alteration is not found in either healthy parent, because of gonadal mosaicism [18]. Severity in offspring is unpredictable, because expressivity varies within families and a parent's phenotype does not predict the child's [1, 19]. A mildly affected mother may be diagnosed only after her child [1, 10].

8.3. Cascade testing and at-risk relatives

Testing of at-risk relatives follows identification of the alteration in the proband. A positive family history forms part of the suggestive findings, and parents with a mild phenotype (macrodontia, short stature, learning difficulties) should be examined and tested [1, 19]. Missense variants inherited from apparently unaffected parents require reassessment of classification, with episignature and careful parental phenotyping, before incomplete penetrance is presumed [15, 34].

8.4. Prenatal diagnosis and preimplantation genetic testing

Once the familial alteration is identified, prenatal diagnosis and PGT are possible [1]. Perspectives on using prenatal diagnosis vary among professionals and families, and the decision is personal [1]. In pregnancies without a family history, prenatal diagnosis results from ultrasound findings followed by CMA and exome; in a Chinese series of 19 fetuses, 15 pregnancies were terminated and four resulted in live births, and in another series four of 12 pregnancies reached term, with a classic phenotype at 12 months [12, 70]. These numbers reflect decisions in Chinese hospitals and are not generalisable. Because the postnatal phenotype ranges from mild ID with independent living to more severe presentations, prenatal counselling should present the full spectrum, including adult data [1, 82, 95].

In the French pathway, a request for prenatal or preimplantation diagnosis is submitted to a CPDPN after a process involving several consultations (geneticist, gynaecologist, organ specialists) and interviews with a psychologist; the familial alteration is sought in chorionic villi at 12 weeks of gestation or in amniotic fluid from 16 weeks, by FISH of the 16q24.3 region or Sanger sequencing of ANKRD11, and the procedural risk (approximately 1 in 200) is weighed against the recurrence risk [18]. Preimplantation diagnosis is offered when one member of the couple is affected, in five authorised centres (Montpellier, Paris, Nantes, Grenoble and Strasbourg), and is not considered justified when the parents are healthy and the alteration is de novo [18]. In a new pregnancy of a couple with an affected child, it recommends specialist ultrasound surveillance at a CPDPN, and molecular diagnosis prompted by an ultrasound sign should also consider other causes, because prenatal signs are non-specific [18].

8.5. Counselling content and minors

Counselling should take place before pregnancy, and discussion of risk and reproductive options should be offered to affected or at-risk young adults [1]. Central points are dominant inheritance with a 50% offspring risk, variable expressivity, possible parental mosaicism, the adult severity spectrum and availability of prenatal diagnosis and PGT [1]. The sources consulted do not specifically address predictive testing in asymptomatic minors. Counselling should be renewed throughout follow-up, for example when adolescents reach family-planning age [1]. The French PNDS recommends disclosing the diagnosis in a dedicated consultation, jointly by the prescriber and a geneticist when the prescriber belongs to another specialty, with a psychologist present, and repeating the consultation a few weeks later to revisit the information and introduce the team; it also recommends a genetics clinic appointment in adolescence on the 50% transmission risk, several consultations and psychological support before a parental project, and an urgent consultation if another pregnancy is under way; in prenatal disclosure, the information includes the possibility of termination of pregnancy for medical reasons, discussed at the CPDPN, particularly if there is a severe malformation [18].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

Population prevalence of KBG is unknown [1]. Available numbers measure different things. The Orphanet prevalence category (<1/1 000,000) and count of 164 cases are based on published cases and do not reflect true frequency [7]. GeneReviews counts more than 375 individuals with an ANKRD11 variant described in the literature and approximately 200 adults [1]; a 2026 systematic review brought together 614 patients [66], and the 2026 ethnic comparison included 519 non-Chinese patients [53]. The growth-chart publication estimates approximately 800 known individuals worldwide based on published cases and association registries, and describes KBG as one of the most common monogenic neurodevelopmental disorders [8]. In the DDD study, 14 additional individuals with an ANKRD11 variant were identified among the first 4,294 trios analysed, placing the gene among frequent Mendelian causes of developmental delay [19]. These values measure frequency among patients tested for developmental delay or the number of known cases, and cannot be converted into population prevalence [1, 7]. In 2020, the French PNDS counted slightly more than 200 published cases and described penetrance as almost complete and expressivity as variable [18].

9.2. Geography, ancestry and founder effect

Data come mainly from Western Europe and North America, with growing series from Asia and Latin America. In Europe, there are cohorts from Italy (Brancati 2004; Digilio 2022; Auconi 2023; Alfieri 2021), the United Kingdom and New Zealand (Low 2016, with DDD), the Netherlands (Ockeloen 2015; Buijsse 2023; van der Leij 2026), France (Goldenberg 2016; Rhamati 2023), Spain (Martinez-Cayuelas 2023), Poland (Kutkowska-Kaźmierczak 2021) and a European collaboration involving Italy, Finland, Belgium, the Netherlands, the Czech Republic, Spain, Cyprus, Georgia, Estonia and Switzerland (Loberti 2022) [19, 21, 22, 28, 32, 33, 49, 62, 67, 68, 74, 77, 84]. In the USA, data come mainly from surveys and videoconferences with families recruited through associations, with possible recruitment bias [20, 69, 93]. Outside these regions, there are series from China, Turkey, India, Colombia, Saudi Arabia, Korea and Australia [47, 52, 53, 60, 63, 71, 76, 100].

Differences between populations concern frequencies of facial traits and some comorbidities. The comparison of 65 Chinese with 519 non-Chinese patients found differences in ears, triangular face, nares, synophrys, philtrum, hairline, spinal anomalies and recurrent otitis media, and interethnic differences even among the 51 c.1903_1907del carriers [53]. In Turkey, height below −2 SD occurred in 30.4%, ID in 82.6% and behavioural abnormalities in 52.2% of 23 individuals, and in another Turkish series the proportion of deletions was 19.4% and all missense variants were in the C-terminal degron [47, 63]. In India, ID and skeletal anomalies occurred in 14 of 15 and short stature in 13 of 15 [100]. In Colombia, all ten patients had delay or ID [71]. No founder variants have been described, and deletions are non-recurrent [1]. The growth chart recommends adjusting interpretation to the population of origin because, for example, a Dutch child with KBG is taller than a British child [8].

9.3. Portugal and Brazil

The sources consulted include no Portuguese or Brazilian estimates. Researchers from Coimbra (Louro P, Ramos L) participated in the 2015 Dutch-Swedish-Portuguese series, and researchers from Coimbra and Lisbon (Louro P, Sousa SB, Dias P, Neves MT) in the epigenetic signature description, indicating Portuguese patients in those cohorts without the abstracts specifying their number [15, 32]. The only Brazilian datum found is patient 1 in the 2025 Italian series, born in Brazil and adopted in Italy [11]. Lack of data in the sources consulted does not demonstrate absence of publications in those countries.

9.4. Special populations

Females tend to have a milder phenotype, contributing to underdiagnosis of carrier mothers [10, 26]. Adults are underrepresented because many have never had access to genomic testing [1]. People with ID and ASD may have difficulty communicating pain, and four patients in Guo's series had a high or absent pain threshold, which may delay recognition of intercurrent illness [20]. Adolescent lifestyle interventions should be adapted to learning difficulties and sensory needs [8].

9.5. Reference networks and patient associations

The relevant European reference network is ERN-ITHACA, dedicated to rare congenital malformations and rare ID; several authors of the growth hormone recommendations and skeletal study belong to this network [16, 22, 23]. Patient associations and resources include the KBG Foundation, a US volunteer organisation maintaining a patient registry, a guide for newly diagnosed families and a natural history study [117]; the KBG Syndrome Association, with a health considerations page based on family reports, which does not replace clinical recommendations [1, 119]; Radboudumc's Human Disease Genes portal, allowing families and clinicians to share data [105]; and Simons Searchlight, a registry including ANKRD11 [116]. GeneReviews also lists the Children's Craniofacial Association, World Craniofacial Foundation, MedlinePlus and the LOVD, ClinVar, HGMD and Iranian ANKRD11 variation databases [1].

In France, diagnosis and follow-up are coordinated by the reference and competence centres for developmental anomalies and malformation syndromes (CLAD) of the AnDDI-Rares network, in liaison with the centres of the DéfiScience network (rare diseases of brain development and ID) and with the reference centres for language and learning disorders (CRTLA) [18]. KBG is not on the list of long-term conditions, and the PNDS serves as the reference for applying for copayment exemption as an off-list condition (ALD at 100%), alongside the MDPH application; in 2020, the French patient association was being set up [18].

10. Illustrative Clinical Case

In 2025, Serra and colleagues described three unrelated Italian patients diagnosed at 18 years, 13 months and 3 months, showing how age at diagnosis changes the available signs [11]. The images referred to were consulted through their published captions in PubMed Central.

Patient 3, diagnosed at 3 months. The second child of non-consanguineous Slovenian parents had first-trimester combined screening showing increased trisomy 21 risk; amniocentesis, with single-nucleotide polymorphism microarray (SNP-array) and a 46,XY karyotype, was normal. Polyhydramnios, fetal growth restriction and suspected lower-limb rhizomelia followed, and he was born by emergency caesarean section at 38 weeks and 6 days, with Apgar score 9/10, weight 2324 g (1st centile, −2.51 SD), length 47.7 cm (9th centile) and HC 33.8 cm (25th centile) [11]. In the NICU, a triangular face, large anterior fontanelle with wide metopic suture, prominent ears, bifid tongue, brachydactyly and 5th-finger clinodactyly and shawl scrotum were observed; whole-body radiography and ultrasound scans were normal, there was a small restrictive membranous VSD and otoacoustic emissions were normal [11]. Tooth eruption at 3 months prompted Sanger sequencing of ANKRD11, identifying NM_013275.6:c.1903_1907del, p.(Lys635GlnfsTer26), the most frequent recurrent variant; the parents declined segregation testing [6, 11]. Recurrent otitis led to brainstem auditory evoked potentials at 3 years and 6 months, with a bilateral threshold of 45 dB HL and mild conductive hearing loss. At 4 years and 2 months, growth was normal (weight 15 kg, 15th centile; height 101.7 cm, 32nd centile; HC 51.5 cm, 29th centile), with upper incisor macrodontia and mild neuromotor delay, without seizures [11]. Figure 3 shows, at 3 years and 6 months, a high forehead, square face, thick eyebrows with slight synophrys, broad nasal bridge with a bulbous tip and anteverted nares, long philtrum, thin upper lip, prominent ears with a hypoplastic antihelix and retrognathia [11]. This patient's course, with normal growth at age 4, is consistent with the lower frequency of short stature and neurodevelopmental impairment described for c.1903_1907del, although an isolated case does not demonstrate it [21].

Patient 2, diagnosed at 13 months. The fourth daughter of healthy non-consanguineous parents was born at 38 weeks by caesarean section, with Apgar 8/9, weight 2490 g (7th centile), length 46.2 cm (10th centile) and HC 35 cm (87th centile) [11]. At 2 months and 12 days she had growth delay (weight at the 1st centile, −2.44 SD), axial hypotonia and tongue protrusion; at 5 months, a high forehead with large anterior fontanelle, prominent ears, broad nasal bridge, bulbous tip, thin upper lip, brachydactyly and 5th-finger clinodactyly (Figure 2a) [11]. At 13 months, fine motor impairment and delayed fontanelle closure prompted array-CGH, showing a de novo 634 kb 16q24.3 deletion (GRCh37, 88,873,958–89,507,835) involving CDT1, APRT, GALNS, TRAPPC2L, ACSF3, CDH15 and ANKRD11 [11]. She followed a psychomotor stimulation programme. At age 3 she weighed 10.5 kg (2nd centile), with length 90 cm (12th centile) and HC 49 cm (66th centile), moderate hyperactivity, bruxism and nail biting, normal developmental assessment, a patent foramen ovale and, without seizures, a moderately abnormal EEG with bilateral posterior slow activity (Figure 2b) [11]. The deletion includes CDH15, one of the flanking genes associated with greater severity [4].

Patient 1, diagnosed at 18 years. A girl born in Brazil, adopted and living in Italy from 1 year and 6 months, with a fragmentary family history (paternal uncle with epilepsy) [11]. She walked at 20 months; after age 2 she manifested a language disorder, ID and externalising behaviour, and seizures began at age 12 [11]. At age 18 she weighed 74 kg (95th centile), measured 154 cm (6th centile, −1.58 SD) and had HC 56 cm (63rd centile); Figure 1 shows a square face, curly hair, thick eyebrows with synophrys, hypertelorism, mild epicanthus, broad nasal bridge with a bulbous tip, short philtrum, upper central incisor macrodontia with crowding, thick lower lip, large prominent ears and brachydactyly of the 1st, 2nd and 5th fingers with 5th-finger clinodactyly [11]. Echocardiography showed mild mitral and tricuspid regurgitation and brain MRI was normal. Array-CGH was normal and the panel identified an ANKRD11 deletion described as “c.1902_1907del” with consequence p.Lys635fs, and a heterozygous EHMT1 variant, c.103G>A p.(Asp35Asn), of unestablished significance [11]. The published ANKRD11 variant designation is internally inconsistent because a six-nucleotide deletion does not shift the reading frame, whereas the stated protein consequence coincides with that of the recurrent c.1903_1907del variant [6, 11]. The patient was taking levetiracetam 1000 mg daily in two divided doses and aripiprazole 10 mg daily; she had moderate ID, completed vocational school with a support teacher, was independent in activities of daily living, performed simple calculations and used a computer at a basic level, with physical aggression towards peers and a short attention span [11]. Figure 4 maps the three alterations.

The authors conclude that suspicion may arise in infancy from a large fontanelle, early dentition and prenatal findings [11]. The drug treatments in the case are individual management decisions rather than recommendations for the syndrome; epilepsy and behaviour treatment follows the principles in section 7.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Life expectancy appears normal, with an adult alive at 76 years among the reported cases [1, 82]. Most adults have mild or borderline ID, and KBG is compatible with independent living, employment and parenthood in some patients [1, 33, 82]. Epilepsy is the main marker of poorer outcome: it is associated with moderate to severe ID (relative risk 4.6) and lower adaptive functioning, and no adult with active seizures lived independently [62, 81, 95]. Epilepsy remits in approximately 70% after approximately 10 years [85]. Behavioural problems diminish in many patients in adulthood, but psychiatric comorbidities persist in more than two thirds of reported adults [25, 82]. Adult height tends to be lower relative to childhood height because of postpubertal deceleration [8]. Extended microdeletions have, on average, a more guarded neurological prognosis [4]. Adult cognitive decline and ascending aortic dilatation have been described in few cases, without an estimable frequency [82]. Prognostic data derive from treated-disease series with access to rehabilitation and specialist care, rather than natural history without intervention.

11.2. Surveillance

Cancer surveillance is not indicated [1]. The French PNDS intervals result from expert consensus rather than surveillance studies; no source defines validated intervals for the aorta in adults or for EEG in patients without seizures [1, 18, 82]. In patients treated with somatropin, Aukema and colleagues recommend monitoring bone age, scoliosis, apnoea, blood glucose and IGF-1, without specifying intervals [16].

12. Summary and Final Considerations

KBG syndrome results from loss of function of one ANKRD11 allele, a chromatin regulator required for brain, craniofacial, skeletal and cardiac development. Approximately 80% of patients have a sequence variant, mainly truncating in the large coding exon, and approximately 20% a 16q24.3 deletion, including deletions removing only the promoter region and non-coding exons; larger deletions, involving flanking genes such as ZFPM1, CDH15 and ZNF778, constitute 16q24.3 microdeletion syndrome, with more heart disease, thrombocytopenia, astigmatism and neurological severity. Most cases are de novo, and inherited carriers are often mildly affected mothers.

The presentation combines developmental delay, particularly language delay, generally mild ID, ADHD and ASD, macrodontia of the permanent upper central incisors, a facial gestalt with a triangular face, thick eyebrows and bulbous nose, postnatal short stature, spinal and rib anomalies, conductive hearing loss with otitis, epilepsy in approximately one quarter and congenital heart disease. No sign is mandatory, and the facial features and macrodontia become evident only with age, which is why KBG is underdiagnosed and is now identified mainly through exome testing. Genetic testing must include copy-number analysis of the 5′ region, and the episignature and facial phenotyping tools help classify variants of uncertain significance.

Treatment is supportive and multidisciplinary: early intervention, echocardiography, hearing, ophthalmological, dental and palatal assessments, spinal radiography, seizure control and growth monitoring using specific charts. Somatropin improves height in a subgroup of patients, but without GHD its use is off-label and adult-height data are insufficient; methylphenidate is being evaluated in an N-of-1 trial. The prognosis generally allows adult life with partial or complete independence, conditioned mainly by epilepsy and psychiatric comorbidities. The 2020 French PNDS is the only national care protocol; current priorities are an international consensus guideline, prospective growth hormone studies and adult natural history data.

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