2q37 Deletion Syndrome (Brachydactyly–Intellectual Disability) and HDAC4-Related Disorders

Class of alterations of the 2q37 band and the HDAC4 gene: terminal or interstitial 2q37 deletion or microdeletion syndrome (brachydactyly–intellectual disability syndrome, Albright hereditary osteodystrophy-like syndrome), isolated HDAC4 haploinsufficiency due to small deletions or loss-of-function variants, neurodevelopmental disorder with central hypotonia and dysmorphic facies due to HDAC4 missense variants at the 14-3-3 protein binding site, and 2q37.1 rearrangements with overexpression of C-type natriuretic peptide.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

Deletion of the terminal portion of the long arm of chromosome 2 was first described by Gorski and colleagues in 1989, in a hypotonic male infant with mild dysmorphism whose karyotype was 46,XY,del(2)(q37) [10, 22]. In the following years reports accumulated of deletions visible on the karyotype and, with the introduction of subtelomeric fluorescence in situ hybridisation (FISH) probes and, later, of chromosomal microarray, of submicroscopic deletions, until the condition became one of the most frequently recognised subtelomeric deletion syndromes [9, 10]. Leroy and colleagues counted more than 115 patients published between 1983 and 2012, of whom 74 had a pure 2q37 deletion (71 distal and 3 interstitial) and 41 had associated rearrangements (37 reciprocal translocations and 4 deletions with inverted duplication); in only 27 of these 115 patients had the deletion been precisely mapped [9]. A 2026 report mentions about 150 cases described worldwide [14].

The next conceptual milestone was the link between the deletion and the phenotype of Albright hereditary osteodystrophy (AHO). In 1995, Wilson and colleagues described five patients with brachymetaphalangia and ID similar to those of AHO; four had visible de novo 2q37 deletions, and the fifth, with a normal karyotype and normal bioactivity of the alpha subunit of the stimulatory G protein (Gsα), had a 2q37 microdeletion demonstrated by polymorphic markers and FISH [23]. The common region included the most telomeric marker of the long arm, D2S125, and the authors proposed screening for 2q37 deletions in all patients with brachymetaphalangia and ID and considering the region a candidate for brachydactyly type E [23]. In the same year, Phelan and colleagues described four unrelated patients, all normocalcaemic and with an AHO phenotype compatible with pseudopseudohypoparathyroidism (PPHP), carrying small terminal del(2)(q37) deletions, the first consistent karyotypic anomaly associated with AHO [24]. Hence the names “AHO-like syndrome” and “Albright hereditary osteodystrophy type 3”, which coexist with brachydactyly–intellectual disability syndrome (BDMR), adopted by OMIM [1–3].

The search for the gene responsible for the brachydactyly advanced by successive narrowing of the critical region: Giardino and colleagues restricted it to 2q37-qter from a cryptic unbalanced translocation t(2;6)(q37.3;q26); Shrimpton and colleagues reduced it to about 3 Mb and proposed GPR35, GPC1 and STK25; Aldred and colleagues defined, in 20 patients with 2q37.3 monosomy, minimal deletion intervals for the main phenotypes [25]; and Chaabouni and colleagues delimited a region of about 2 Mb at 2q37.3 containing HDAC4, GPC1 and STK25 [2, 3, 26]. In 2010, Williams and colleagues analysed six individuals with overlapping deletions at 2q37.3, reduced the candidates from more than 20 genes to one, HDAC4, and identified intragenic de novo HDAC4 variants in patients with the same phenotype and no deletion; they concluded that HDAC4 haploinsufficiency causes BDMR and showed that loss of HDAC4 reduces the expression of RAI1, the Smith-Magenis syndrome gene [27]. This conclusion was later qualified by families with small deletions including HDAC4 and normal cognition or no brachydactyly (Villavicencio-Lorini 2013, Wheeler 2014, Jean-Marçais 2015), which led OMIM to reclassify the two original intragenic variants as variants of uncertain significance and to keep the relationship between HDAC4 deletion and the phenotype as an “association pending confirmation” [7, 11, 28, 29].

In 2021, Wakeling and colleagues described a distinct allelic entity: seven patients with de novo HDAC4 missense variants clustered at the 14-3-3 protein binding site, with a severe neurological phenotype that the authors explicitly separated from BDMR; OMIM catalogued it as NEDCHF (#619797) [4, 5]. In 2023, Takeyari and colleagues reported the first family with BDMR and an HDAC4 missense variant outside that site, interpreted as loss of function [30].

1.1 Nomenclature and reclassifications

OMIM uses the title “Chromosome 2q37 deletion syndrome” with the alternative titles “Albright hereditary osteodystrophy-like syndrome” and “brachydactyly-mental retardation syndrome; BDMR”, and marks the entry with the contiguous gene syndrome symbol [2]. Orphanet classifies the condition as “2q37 microdeletion syndrome” (ORPHA:1001), with the synonyms “Albright hereditary osteodystrophy type 3”, “brachydactyly-intellectual disability syndrome”, “Del(2)(q37)”, “Deletion 2q37” and “Monosomy 2q37qter”, and codes it in ICD-10 as Q93.5 [1]. The bone dysplasia atlas by Spranger and colleagues includes “mental retardation/brachydactyly syndrome” and “AHO-like syndrome” in the brachydactyly type E section and recommends reserving the term brachydactyly E for the autosomal dominant form in which shortening of the metacarpals and metatarsals is the dominant sign [15]. The designation “intellectual disability” replaces the historical expression “mental retardation” in the English name. GeneGuidance associates the 2q37 microdeletion with OMIM number 619797, which is a mapping error: the number of the deletion syndrome is 600430, and 619797 corresponds to NEDCHF [2, 4, 12].

1.2 Entities of the class

2. Molecular Genetics and Pathophysiology

2.1 Architecture of the region and types of rearrangement

The 2q37 band is the last band of the long arm of chromosome 2 and is divided into the sub-bands 2q37.1, 2q37.2 and 2q37.3; in the hg19 reference it contains at least 197 genes between 230.7 and 243.2 Mb [6]. The most distal sub-band includes a small subtelomeric region, 2qtel, with polymorphic deletions and duplications without clinical effect, present in about 5% of the population; in three of eight families studied by Leroy and colleagues, one of the parents carried this polymorphism, which must not be confused with the pathogenic deletion [9]. The ClinGen database classifies the “2q telomere” region (chr2:241,988,449–242,157,305) and an adjacent population region with a score of 40, “dosage sensitivity unlikely” [35].

Subtelomeric regions are gene-dense, so small imbalances can have a marked clinical effect [38]. A terminal deletion can be stabilised by three mechanisms: regeneration of the telomere (“telomere healing”), retention of the original telomere with formation of an interstitial deletion, or capture of another telomeric sequence by rearrangement, with formation of a derivative chromosome; terminal deletions can also result from unbalanced segregation of a reciprocal translocation, in which case they coexist with duplication of a segment of the partner chromosome [38]. At 2q37 all these types are observed: isolated terminal deletions, interstitial deletions, inversions, ring chromosomes and translocation derivatives, the latter with an associated partial trisomy that modifies the phenotype [3, 6, 9].

Most terminal deletions are between 2 and 9 Mb; GeneReviews gives a largest telomeric deletion of about 10 Mb and a smallest frequently of 3 to 4 Mb, with the smallest terminal deletion then known being 2.7 Mb and a paternal terminal deletion of 1.6 Mb in a patient with delay and dysmorphism [3, 6]. About 80% of deletions are visible on the karyotype and 20% are cryptic [10]. There are no recurrent breakpoints [6].

2.2 The HDAC4 gene

HDAC4 (2q37.3; GRCh38 2:239,048,168–239,401,649) encodes histone deacetylase 4, a class IIa deacetylase homologous to yeast Hda1 [7]. The MANE Select transcript is NM_001378414.1 (protein NP_001365343.1); the older literature uses NM_006037.3/.4 (27 exons; protein of 1,084 amino acids, NP_006028.2) [3, 8]. The protein of about 1,085 amino acids has the catalytic domain from residue 802, with histidines 802 and 803 required for activity; it does not bind DNA directly, but is recruited by the transcription factors MEF2C and MEF2D, whose activity it represses, and bridges to the NCOR2–HDAC3 corepressor complex [7]. It has a calmodulin-binding domain overlapping the MEF2-binding domain, so calcium releases MEF2 from repression [7]. The cellular localisation of HDAC4 is regulated by phosphorylation: binding to 14-3-3 proteins retains it in the cytoplasm and dephosphorylation allows entry into the nucleus [4, 12].

In the skeleton, HDAC4 is expressed in prehypertrophic chondrocytes and inhibits the transcription factor RUNX2, required for chondrocyte hypertrophy; Hdac4 knockout mice have premature ossification due to ectopic and early chondrocyte hypertrophy, and Hdac4 overexpression inhibits hypertrophy and differentiation [7]. The kinase SIK3 forms a complex with Hdac4 in hypertrophic chondrocytes and anchors it in the cytoplasm; without SIK3, Hdac4 accumulates in the nucleus, represses Mef2c and blocks hypertrophy [7]. HDAC4 is also a target of the cartilage-specific microRNA miR-140 [7]. This mechanism explains brachydactyly type E: loss of one copy of HDAC4 releases chondrocyte hypertrophy and leads to premature closure of the growth plates of the metacarpals and metatarsals, especially of the fourth and fifth rays [7, 15]. PTH and PTHrP signalling through the PTH1R receptor, Gsα and cAMP controls the same chondrocyte differentiation, and its inactivating disorders (iPPSD) also shorten the metacarpals through premature epiphyseal closure, which explains the similarity between the 2q37 deletion and AHO [15, 39].

In the nervous system, HDAC4 participates in neuronal survival (retina) and in sleep regulation: mice heterozygous for a splicing variant with marked reduction of Hdac4 are healthy and fertile but have more non-REM sleep, and SIK3 promotes sleep by phosphorylating Hdac4 at serine 245 [7]. These data help to interpret the frequency of sleep disturbances, although they do not demonstrate causality in humans.

2.3 HDAC4 haploinsufficiency: evidence and limits

In favour of the central role of HDAC4 are the 200 kb minimal overlap defined by Williams and colleagues, the patient with a 2.68 Mb terminal deletion distal to HDAC4 who had delay, obesity, autistic behaviour and seizures but no brachydactyly, and the two intragenic de novo variants (a 1 bp insertion in exon 19, in historical nomenclature 2399insC, with a frameshift without nonsense-mediated decay; and a 65 bp deletion in intron 5 with probable alteration of the splicing of exons 5 and 6) [2, 7, 27]. Morris and colleagues described a mother with a cryptic balanced translocation t(2;10) and mild symptoms (HDAC4 expression 67% of normal) and her son with 2q37.1 monosomy and 10q26.1 trisomy and a more severe phenotype (expression 23%), suggesting a dosage effect [3, 40]. Le and colleagues, in a review of 101 published cases plus 2 new patients, concluded that HDAC4 is the main genetic contributor, with incomplete penetrance [16].

Against the sufficiency of HDAC4 are three families: Villavicencio-Lorini and colleagues (three generations, interstitial deletion of about 800 kb with HDAC4, FLJ43879 and TWIST2, very mild delay and dysmorphism, none with brachydactyly), Wheeler and colleagues (mother and two children with an 887 kb deletion including the entire coding sequence of HDAC4, normal intelligence and BDE in the mother and the elder child) and Jean-Marçais and colleagues (father and three children with a deletion of 491 to 813 kb including HDAC4 and TWIST2, BDE and short stature without ID) [2, 11, 28, 29]. In Leroy's series, two patients with HDAC4 deletion had no brachydactyly, and in Gavril's a patient without loss of HDAC4 had BDE [6, 9]. Consequently, OMIM reclassified the Williams variants as of uncertain significance and ClinGen assigns HDAC4 a haploinsufficiency score of 1 (“little evidence for dosage pathogenicity”), with no evidence of triplosensitivity [7, 35]. The current reading is that of a gene necessary for brachydactyly in most cases and contributing to the neurobehavioural phenotype, with incomplete penetrance and variable expressivity, against a background in which other genes of the region and the genetic background modulate the outcome [9, 16].

2.4 Other genes of the region and correlations by phenotype

Deletion size correlates poorly with severity: Fisch and colleagues observed the highest intelligence and developmental quotients in the largest deletions (10.1 and 9.5 Mb) and the lowest in the smallest (7.9 and 6.6 Mb), with no association with the breakpoint; deletions of 9.5 to 10 Mb with a mild phenotype and of 828 kb with a severe phenotype have been described [6, 41]. The proposed correlations result from overlapping deletions in small series and should be read as hypotheses. The French PNDS summarises the same evidence in three operational points: of the genes of the band, eleven have a potential role in the phenotype without demonstrated involvement; HDAC4 and PER2, at 2q37.3, are almost always included in the critical region, and HDAC4 haploinsufficiency mainly explains the brachydactyly, facial features, growth and weight changes and neurobehavioural disorders; and anomalies of the urinary tract and brain appear to cluster in proximal deletions, starting at 2q37.1, the same ones that, being the largest, are most often associated with overweight [9, 13].

Ogura and colleagues compared two Japanese boys: one with a 3.2 Mb deletion that included HDAC4 and a typical BDMR phenotype, the other with a 2.3 Mb deletion without HDAC4, normal intelligence and late acquisition of complex motor skills; both had a profile of visuospatial dyspraxia, which points to other neurodevelopmental genes telomeric to HDAC4 [33]. Iwata-Otsubo and colleagues described the smallest 2q37.3 deletion distal to HDAC4 (827.1 kb, 16 OMIM genes) in a 4-year-old boy with language delay, altered behaviour, mild dysmorphism and brachyclinodactyly of the fifth finger, inherited from a mother with learning difficulties [32]. A Brazilian family from Brasília with a deletion downstream of HDAC4 had ID, dysmorphism, microcephaly and congenital heart disease, without BDE [6, 34].

2.5 Recessive genes in the region and unmasking

A hemizygous deletion can unmask a recessive pathogenic variant on the remaining allele; the Oxford Desk Reference mentions this mechanism among the explanations for phenotypic discordance between a parent and child carrying the same CNV [43]. At 2q37 lie genes for autosomal recessive diseases of practical relevance: UGT1A1 (2q37.1), whose variants cause Gilbert syndrome and Crigler-Najjar syndrome types 1 and 2 — the Gilbert promoter insertion, A(TA)7TAA, is heterozygous in about 50% and homozygous in 9% of European and North American populations [44]; D2HGDH (2q37.3), the cause of D-2-hydroxyglutaric aciduria type I when biallelic [45]; DIS3L2 (2q37.1), the cause of Perlman syndrome [3]; COL6A3 (Bethlem myopathy 1), TWIST2 (Barber-Say syndrome), PER2 (advanced sleep phase syndrome) and CAPN10 (susceptibility to type 2 diabetes), listed among the genes deleted in published cases [46, 47]. ClinGen assigns D2HGDH and TWIST2 a score of 30, “gene associated with autosomal recessive phenotype” [35]. The sources consulted do not quantify the frequency of unmasked recessive disease in the 2q37 deletion; prolonged jaundice or an organic aciduria in a carrier justifies sequencing of the remaining allele (inference from the described mechanism).

2.6 NEDCHF: the regulatory gain-of-function allele

The seven variants of the series by Wakeling and colleagues affect a single regulatory segment, the 14-3-3 protein binding site [4, 5]. Normalised in VariantValidator, the variants are, on the MANE transcript NM_001378414.1 (numbering identical to that of NM_006037.4 in this region): c.743C>T p.(Pro248Leu) (NC_000002.12:g.239144705G>A), present in four patients; c.742C>G p.(Pro248Ala) (g.239144706G>C); c.740A>G p.(Glu247Gly) (g.239144708T>C); and c.731C>A p.(Thr244Lys) (g.239156654G>T), all de novo and absent from gnomAD [7, 8]. Co-immunoprecipitation showed reduced binding to 14-3-3β for p.(Thr244Lys) and p.(Glu247Gly), with reduced cytoplasmic sequestration and a greater amount of nuclear HDAC4 [7]. The mechanism is not haploinsufficiency: it is a gain of inappropriate nuclear activity, which a deletion or a truncating variant does not reproduce [12]. In mice, expression of constitutively nuclear Hdac4 reduces non-REM sleep, which shows that nuclear excess has consequences opposite to those of loss [7].

2.7 Other HDAC4 variants described

Takeyari and colleagues identified, in a Japanese family with four affected individuals, the variant NM_001378414.1:c.2204G>A p.(Arg735Gln) (NC_000002.12:g.239102805C>T), absent in the unaffected mother and located outside the 14-3-3 site, interpreted as loss of function and responsible for BDMR [8, 30]. Ianniello and colleagues reported in 2025 a de novo frameshift variant, NM_006037.4:c.3136_3137del p.(Gln1046AspfsTer29), which on the MANE transcript corresponds to NM_001378414.1:c.3151_3152del p.(Gln1051AspfsTer29) (NC_000002.12:g.239053538_239053539del), in a girl with global psychomotor delay, hypotonia, epilepsy evolving into Lennox-Gastaut syndrome and a cortical malformation of the polymicrogyria type [8, 48]. The two intragenic variants of Williams (2010) were published in nomenclature predating current standards and were not normalised to the MANE transcript in the sources consulted; OMIM classifies them as of uncertain significance [7]. Reports should state the MANE transcript, because numbering diverges between NM_006037.4 and NM_001378414.1 in the 3' region of the gene.

2.8 2q37.1 rearrangements and C-type natriuretic peptide

NPPC, at 2q37.1, encodes C-type natriuretic peptide (CNP), which acts on the NPR2 receptor and regulates endochondral ossification; activation of the pathway increases cGMP, inhibits the MAPK pathway of FGFR3 signalling and stimulates growth of the cartilaginous plates [36]. Balanced translocations with breakpoints clustered at 2q37.1, near the 5' end of DIS3L2, separate NPPC from a distant negative cis regulatory element and cause CNP overexpression, with postnatal overgrowth, marfanoid habitus, arachnodactyly and a long hallux (overgrowth syndrome due to CNP overexpression, MIM 615923) [36, 37]. Tassano and colleagues described two 2q37 deletions with opposite effects: a 1.9 Mb interstitial 2q37.1 deletion that included NPPC and exons 1 to 14 of DIS3L2, with pathological short stature and normal plasma CNP and expression; and a 4.5 Mb 2q37.1q37.3 deletion, which disrupted DIS3L2 at exon 6, with marfanoid habitus, arachnodactyly, mild syndactyly, severe scoliosis, plasma CNP-22 more than four times that of controls and NPPC overexpression [37]. The position of the proximal breakpoint at 2q37.1 can thus alter growth in opposite directions.

2.9 Inheritance, penetrance and modifiers

The deletion behaves as an autosomal dominant trait. The great majority are de novo; about 5% of published deletions resulted from a balanced translocation or inversion in a parent, some cryptic [3, 10]. The French PNDS gives a rather different proportion, 75% de novo deletions and 25% found in one of the parents, without citing the source series; the figure is incompatible with the absence of inherited deletions in the French series of 14 patients and with the approximately 5% of the compilations, and only approaches them if parental balanced rearrangements are added to the small interstitial deletions transmitted by mildly affected parents, described in several families from 2013 onwards [9, 11, 13, 28]. In either scenario, the practical consequence is the same: parental testing is mandatory. In Leroy's series no patient inherited the deletion, the parental origin was paternal in five and maternal in four, with no effect on the phenotype, and no imprinting effect was demonstrated [3, 9]. The 2013 GeneReviews described complete penetrance with variability, but later data from families with small deletions and the review of 103 patients show incomplete penetrance of core components such as BDE and ID [3, 16, 28]. Factors that modify the phenotype: additional CNVs (partial trisomies in translocation derivatives; 1p36, 20p12.3, 6p25, 3q29, 9q34 or 11p15 duplications in published series), variants on the remaining allele and the genetic background [6, 9, 49]. Somatic mosaicism has been described (46,XX,1qh+/46,XX,1qh+,del(2q37.3) in 8 of 30 metaphases) with a typical phenotype [6].

2.10 Complex rearrangements and interaction with PTH signalling

The coexistence of a 2q37 deletion and other alterations explains atypical phenotypes: a complex rearrangement with 2p25 duplication and 2q37.2q37.3 deletion was associated with severe growth hormone deficiency with pituitary hypoplasia [50]; an 8.2 Mb 2q37.1 deletion with two duplications was associated with a testicular sex cord-stromal tumour at 3 months [49]. Elli and colleagues described the first two patients with a simultaneous GNAS imprinting defect (PHP1B/iPPSD3) and 2q37 deletion, and a fraction of patients with 2q37 deletion have mild PTH resistance, which suggests interaction of the products of these genes with the Gsα–cAMP pathway [51, 52]. A study of nuclear architecture in mesenchymal cells from a family with partial HDAC4 deletion found altered positions and interchromosomal interactions between chromosomes 2, 12 and 17, a research finding without clinical application [53].

3. Clinical Spectrum and Manifestations by System

3.1 Frequency of manifestations in the main series

Published frequencies vary with the mode of ascertainment, the size of the series, the inclusion of associated rearrangements and the age of the patients, and most come from compiled case reports, not from population cohorts. The table brings together the sources with a known denominator.

Sources for the table: [3, 6, 9, 10, 16, 41]. The difference between the 77% BDE of Leroy's compilation and Le's 48% reflects different inclusion criteria; Leroy attributes the discrepancy in weight to the lack of body mass index (BMI)-for-age curves in older reports and to the semantic heterogeneity between “overweight” and “obesity” [9]. The proportion of females is higher than that of males (44 boys and 65 girls in the compilation of 112) [3, 9].

3.2 Facies and growth

The facies is the most constant sign and persists into adulthood (39-year-old patient in the French series) [9]. Smith's book describes sparse hair, sparse arched eyebrows, frontal bossing, a round face with full cheeks, midface hypoplasia, deep-set eyes, epicanthus, upslanting palpebral fissures, a depressed nasal bridge, a short nose with hypoplastic or notched nares, a prominent, low columella, a short philtrum, a thin upper lip with a hypoplastic Cupid's bow, a high palate and microtia [10]. In Leroy's series the predominant features were a small nose with a V-shaped tip (11/13), a small mouth with thin lips (12/13), a smooth philtrum (11/13), thin eyelids (10/13), narrow palpebral fissures (8/13), low-set ears (8/13), a large chin (7/13), unruly hair with a low hairline (6/13), frontal bossing (5/13) and prominent malar bones (5/13) [9]. In the review of 103 patients the frequencies were: low hairline 46%, frontal bossing 41%, thin upper lip 39%, broad face 35%, arched eyebrows 32%, short palpebral fissures 27%, depressed nasal bridge 25%, deep-set eyes 19%, prominent columella 18% and hypoplastic alae nasi 15% [6]. The facial phenotype can be subtle and has been distinguished by stereophotogrammetry [3]. The Romanian series added thick eyebrows (5/9), a high hairline (2/9), microcephaly (6/9) and one craniosynostosis [6].

Growth follows varied patterns. Postnatal short stature may become evident only in adulthood; some patients have early overgrowth, premature epiphyseal closure and short final stature [10]. Feeding difficulties and gastro-oesophageal reflux can cause faltering growth in infancy [3, 10]. Growth hormone deficiency has been described in few patients: three reports up to 2017, with increased growth velocity after treatment, and a severe case with pituitary hypoplasia in a complex rearrangement [47, 50]. Macrosomia at birth and macrocephaly with normal magnetic resonance imaging were described in a Colombian child [46].

3.3 Hands, feet and skeleton

Brachydactyly type E is characterised by shortening of the metacarpals and metatarsals, most frequent in the fourth and fifth rays, sometimes only in the fourth, symmetrical and caused by premature closure of the growth plates; the distal phalanx of the thumb is often short [10, 15]. The manifestation appears in mid-childhood and may not be apparent in young children, although it has been described before 1 year of age; it has no functional implication [3, 15]. The review of 101 published cases and 2 new patients quantifies this age dependence: BDE was recorded in 48% of the total, but in 70% when only the 31 patients assessed at 10 years or older were counted, and the most affected ray was the fourth, in the metacarpal in 37% and in the metatarsal in 27%, followed by the fifth and the third [16]. A radiologically normal hand in a young child therefore does not rule out the diagnosis. In Leroy's series it was detected from 4 years of age; brachymetacarpia was present in 9/13, always most severe in the fourth ray (fifth ray in four, third and fourth in one), and brachymetatarsia in 6/11 [9]. Some patients with BDE and developmental delay also have syndactyly [54]. It is accompanied by small hands and feet, brachymetaphalangia, clinodactyly of the fifth finger, mild cutaneous syndactyly, persistent fetal fingertip pads, abnormal palmar creases, broad hallux (6/14) and limb asymmetry (2/14) [9, 10]. Joint hypermobility and laxity, joint dislocation, scoliosis, pectus carinatum or excavatum, genu valgum or recurvatum and flat feet are common [3, 10]. Osteopenia was found in several patients from 3 years of age, without defined clinical implications [3]. Exostoses and accidental fractures have been reported [51].

3.4 Neurodevelopment, cognition and behaviour

Most patients have developmental delay or mild to moderate ID, but the spectrum ranges from severe ID, with absent language at 9 and 11 years in two French patients, to average cognition (a university student with autism) and sheltered occupational roles (a library assistant) [3, 9]. Fisch and colleagues applied a cognitive-behavioural battery to nine children aged 3.9 to 17.75 years: IQ of 36 to 59 in the five assessed with the Stanford-Binet (4th edition), adaptive behaviour far below expected on the Vineland scale (developmental quotient from the scale minimum to 55) and a CARS score in the autism spectrum in five of eight (63%) [41]. Language and social skills may improve with age, which makes clinical diagnosis more difficult at later ages [46].

Behavioural changes are frequent and heterogeneous. In the review of 103 patients: ASD 30%, repetitive behaviour 24%, hyperactivity 15%, aggressiveness 12%, friendly disposition 12%, delayed social skills 10% and attention deficit 9% [6]. The patients with intragenic variants described by Williams had reduced pain sensitivity, onychotillomania, self-injury (head-banging, self-biting, skin picking with scarring), aggressive tantrums, stereotypies, food-seeking behaviour and sleep disturbances, a profile that prompted the initial suspicion of Smith-Magenis syndrome [2, 27]. In Leroy's series, 10/12 had abnormal behaviour, 7/12 ASD and 4/12 attention deficit or hyperactivity [9]. In the Romanian series only one patient had ASD, but four had stereotypies, excessive friendliness, laughing fits, aggressiveness or attention deficit hyperactivity disorder (ADHD) [6]. Visuospatial perception deficits and developmental dyspraxia have been described [33]. A girl with a de novo 2q37.1 deletion combined ID, dysmorphism, digestive anomalies and autistic traits, a combination the authors considered an identifiable syndrome [55]. One third of the adolescents and adults followed by Unique have a sleep disorder [21].

3.5 Epilepsy and central nervous system

Epileptic seizures occur in 16% to 35% of patients, depending on the source, and are generalised tonic-clonic, partial or myoclonic; febrile seizures are also observed [3, 6, 9]. In most children there is no underlying brain malformation and the seizures respond well to the usual antiseizure medications; among 12 adults in Unique, two had seizures in childhood, controlled, with resolution at 10 years in one of them [21]. Brain malformations (10% in the review of 103) include agenesis or hypoplasia of the corpus callosum, Dandy-Walker malformation, cerebral atrophy, holoprosencephaly, ventriculomegaly, hydrocephalus, subependymal cyst and cerebellar anomalies [3, 6, 10]. Hypotonia is frequent in infancy (27% in the review of 103) [6]. Microcephaly occurs in about 10% according to Smith and was more frequent in recent series [6, 10].

3.6 Heart and vessels

Congenital heart disease occurs in 16% to 30% of patients, mainly ventricular and atrial septal defects and patent ductus arteriosus; coarctation and hypoplasia of the aortic arch, tetralogy of Fallot, subvalvular aortic stenosis and bicuspid aortic valve have also been described [2, 3, 6, 10, 14, 31]. An 8-month-old Japanese child with atrial and ventricular septal defects, patent ductus arteriosus and right ventricular outflow tract stenosis developed postoperative junctional ectopic tachycardia that required prolonged venoarterial extracorporeal membrane oxygenation, prolonged renal replacement therapy and delayed chest closure [56]. Dilated cardiomyopathy has been described as an occasional finding [10, 47]. The literature review specifies the severity of the whole: of the 16% of cardiac anomalies recorded, most were mild, with ventricular or atrial septal defects and non-specific murmurs, coarctation and aortic arch anomalies were described in a small number of patients, and valvular anomalies or major malformations occurred in 3 of the 101 cases reviewed [16]. Cardiac screening at diagnosis is therefore justified by the possibility of a correctable lesion and not by a high risk of severe heart disease.

3.7 Digestive system, nutrition and weight

Feeding difficulties and gastro-oesophageal reflux, sometimes severe and requiring surgery, are common in infancy [3, 10]. Digestive malformations include intestinal malrotation, duodenal atresia or stenosis, pyloric stenosis, hiatus hernia, oesophageal atresia, anal atresia or anterior anus and anorectal malformation; umbilical and inguinal hernias are frequent [3, 6, 9, 10]. Splenic volvulus has been reported [57]. Excess weight increases with age and accelerates at puberty, with gynoid distribution in girls; half of the adolescents and adults in Unique had no weight problem, and diet and exercise sufficed in most [3, 21]. In the French series, overweight (BMI above +1 SD for age, 2007 World Health Organization curves) was present in five patients over 4 years of age and obesity (above +2 SD) in three over 7 years, mainly in deletions larger than 4.8 Mb [9]. In the Romanian series four of nine patients were underweight, two of them with associated CNVs or digestive malformations, and five had fat accumulation in the upper chest [6]. A Japanese child with habitual vomiting had dental erosion, multiple caries, a high palate, a narrow maxillary arch and severe anterior crowding [14].

3.8 Kidney, genitourinary tract and tumours

Renal and urinary anomalies (horseshoe kidney, ectopic kidney, megaureter, vesicoureteric reflux), cystic kidneys as a late finding, cryptorchidism, hypospadias, hypoplastic gonads and bicornuate uterus have been described [3, 9, 10, 31]. A mother and daughter with a 4 Mb 2q37 deletion had Mayer-Rokitansky-Küster-Hauser syndrome [58]. Focal xanthogranulomatous pyelonephritis has been described in a child [59].

Wilms tumour was reported in three children with an isolated 2q37 deletion (Conrad 1995, Olson 1995, Viot-Szoboszlai 1998), all diagnosed before 2 years of age, and in two patients with rearrangements (der(2)t(2;15)(q37;q22) and add(2)(q35)), diagnosed between 2 and 3 years [3]. In all cases with an isolated deletion, the centromeric breakpoint was proximal at 2q37.1, and not at the more frequent level of 2q37.3 [60]. The risk estimate varies: about 1% for 2q deletions (Jones 2011, cited by GeneReviews), less than 3% for 2q37 deletions as a whole (Oxford Desk Reference) and less than 5% for those that spare 2q37.1 [3, 10, 60]. These estimates rest on case reports without a population denominator, and screening of a large series of terminal 2q deletions found no other cases [3]. A testicular sex cord-stromal tumour was described at 3 months in a boy with an 8.2 Mb 2q37.1 deletion and additional CNVs [49].

3.9 Endocrinology and bone metabolism

Patients with 2q37 deletion do not, as a rule, have hormone resistance or subcutaneous ossifications, unlike AHO due to GNAS defects, and Gsα bioactivity is normal [3, 23, 61]. There are exceptions: Elli and colleagues found 2q37 deletions in 4 of 73 patients (5.5%) with a previous clinical diagnosis of pseudohypoparathyroidism type 1A or PPHP without a known molecular defect; all four had brachydactyly and cognitive impairment, three had mild PTH resistance (PTH 135, 130 and 83 pg/mL; calcium 8.82, 7.97 and 7.9 mg/dL) and all had hyperphosphataemia, with normal 25-hydroxyvitamin D and TSH and no ectopic ossifications [51]. A Chinese man with hypocalcaemia, raised PTH, short stature, obesity, a round face and a short fourth metacarpal, without GNAS or STX16 alteration on MS-MLPA, had a 2q37 deletion of about 4.18 Mb identified by exome sequencing; the authors counted six previous reports of this association [52]. In the family with the HDAC4 p.(Arg735Gln) variant, two of four affected individuals had hypothyroidism [30]. Puberty generally occurs at the usual age, but precocious or delayed puberty and premature adrenarche have been described; seven of eight girls and women in Unique had disruptive premenstrual symptoms [21]. Menarche followed by secondary amenorrhoea has been reported [3].

3.10 Other systems

Ophthalmological findings include strabismus, refractive errors, iris coloboma and ptosis; auditory findings include congenital or sensorineural hearing loss and atresia of the external auditory canal [2, 3, 10, 47]. Skin findings include moderate to severe eczema, translucent skin with telangiectasias, cutaneous laxity, hypertrichosis and alopecia [3, 6, 10]. Widely spaced, inverted, low-set or supernumerary nipples, asthma, recurrent respiratory infections with antibody deficiency, tracheomalacia, diaphragmatic hernia and cleft palate have been described [9, 10, 31, 46]. The French PNDS estimates at about 30% the proportion of patients with malformations of more than one system (brain, cardiac usually minor, urogenital and digestive) and adds to the list microphthalmia, tracheolaryngomalacia, retrognathia with cleft soft palate or Pierre Robin sequence, obstructive sleep apnoea–hypopnoea syndrome, recurrent otitis, anomalies of tooth number and position and hip anomalies; it considers refractive errors frequent and brain magnetic resonance imaging abnormal in more than half of patients, almost always with non-specific findings [13]. The same protocol recommends that the attending physician look, from adulthood, for signs of systemic lupus erythematosus and inflammatory bowel disease; the recommendation rests on genome-wide association studies that place a lupus susceptibility locus at 2q37 and on isolated reports of immune alterations in carriers, and not on a frequency measured in this syndrome [9, 13].

3.11 Adolescence and adulthood

Data on adults are scarce: about 23 adults had been described in the literature when Unique compiled 39 adolescents and adults [21]. Most live with their family or in residential settings; one adult lived alone with support for weekly shopping [21]. Mood changes, obsessive-compulsive behaviour and aggressiveness are reported, sometimes requiring psychiatric follow-up [21]. A 21-year-old woman with moderate ID had a brief psychotic episode, with agitation, pressured speech, nihilistic delusions and disturbed sleep and eating, preceded by family stressors and a respiratory infection, which improved with a low-dose antipsychotic and joint follow-up by general psychiatry and intellectual disability psychiatry [62]. Reproduction is possible: affected women have had children, familial transmissions of small deletions are documented and there are no reports of men with a visible deletion who have had offspring [3, 10, 11, 58].

3.12 NEDCHF

The seven patients of Wakeling and colleagues, aged 2 to 20 years, all had ID and central hypotonia; three did not speak, three used single words and one had fluent speech after therapy; only one walked independently [4]. Three of six had epileptic seizures and two of three a movement disorder; magnetic resonance imaging was abnormal in five of seven (cerebellar atrophy in two and ventriculomegaly in two) [4]. The dysmorphism included hypertelorism (4/5), a full lower lip (5/6), widely spaced teeth (4/6), an upswept frontal hairline whorl (4/7), long palpebral fissures (5/6) and large ears (3/5); there was drooling in all those assessed (6/6), sleep disturbance in three, kyphosis or scoliosis in four, congenital hip dislocation in two and late closure of the anterior fontanelle in two [4]. This picture differs from BDMR in its motor and language severity and the absence of brachydactyly [5, 30].

3.13 Variability and unexpected phenotypes

Variability is the rule. Patients with the same deletion, including siblings, have different phenotypes, and large deletions may have mild expression [6, 41]. Some patients with pure deletions lack the most recognisable signs or have a more severe picture, such as Felty syndrome (rheumatoid arthritis, splenomegaly and neutropenia) in a patient with a PDCD1 deletion [9]. Unexpected phenotypes should prompt a search for additional CNVs and for variants on the remaining allele [9, 49].

4. Clinical Recognition and Warning Signs

In the newborn and infant, suspicion arises in the presence of hypotonia with feeding difficulties, reflux and faltering growth, associated with mild facial dysmorphism (thin arched eyebrows, deep-set eyes, prominent columella with hypoplastic alae nasi, thin upper lip), septal heart disease, hernias, abnormal nipples or digestive malformations [3, 10, 31]. At this age brachydactyly is absent or subtle, so its absence does not rule out the diagnosis [3, 9].

At preschool and school age, the typical picture combines developmental and language delay, autism spectrum behaviour or hyperactivity, sleep disturbance, progressive weight gain and shortening of the fourth and fifth metacarpals or metatarsals [3, 9]. A simple manoeuvre on examination is to ask the child to make a fist and observe the profile of the knuckles: depression of the fourth and fifth knuckles suggests short metacarpals and justifies a hand radiograph [63]. In the approach to obesity with delay, AHO has severe obesity from 6 months of age, whereas Prader-Willi syndrome has it from 18 to 24 months [63].

The French PNDS describes three other contexts of discovery. In adolescents and adults seen in a genetics clinic for ID, the combination of short stature, overweight, BDE and a suggestive facies, in particular the shape of the nose (V-shaped tip, hypoplastic alae, smooth philtrum and thin upper lip), leads to clinical suspicion [13]. The widespread use of CMA also allows diagnoses without prior suspicion in people with apparently isolated ID or behavioural disorder, more often adults in whom the morphological signs had not been recognised [13]. Prenatal diagnosis outside a family history was exceptional in 2019, but tends to increase with the use of CMA in the presence of ultrasound anomalies [13].

The AHO-like phenotype (ID, brachymetaphalangia of rays 3 to 5, short stature and obesity) is the classical presentation of distal deletions; the Oxford Desk Reference notes that some patients with an AHO-like phenotype, BDE and developmental delay have a 2q37 deletion that includes HDAC4 [3, 10, 64]. In any patient with clinical suspicion of AHO, PPHP or pseudohypoparathyroidism without a GNAS defect, especially if they have ID, behavioural changes and hyperphosphataemia or raised PTH, the 2q37 deletion should be sought [39, 51, 52]. It should also be considered in patients referred with suspected Smith-Magenis, Kabuki or CHARGE syndrome (choanal atresia in carriers of an unbalanced t(2;21) translocation) with negative specific tests [2, 3].

Clinical warning signs are: an abdominal mass, haematuria or hypertension in a young child with a deletion that includes 2q37.1 (Wilms tumour) [3, 60]; new epileptic seizures; persistent vomiting or acute abdominal pain (malrotation, volvulus) [10, 57]; signs of heart failure (congenital heart disease or cardiomyopathy) [47]; symptomatic hypocalcaemia [51]; growth deceleration with low IGF-1 (growth hormone deficiency) [47]; behavioural regression, agitation or psychotic symptoms in adolescents and adults [62]. There is no newborn screening for this condition. In the prenatal period the deletion may escape conventional karyotyping: in a fetus investigated for increased nuchal translucency, the karyotype was normal and only postnatal array revealed the 2p25/2q37 rearrangement [50].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

There are no validated formal clinical criteria for 2q37 deletion syndrome; the diagnosis is cytogenomic and is defined by demonstration of a deletion that includes part or all of the 2q37 band, interpreted as pathogenic according to ACMG/ClinGen standards [3, 65]. GeneReviews lists the elements that prompt suspicion: developmental delay or ID, brachymetaphalangia of rays 3 to 5 (often only of the fourth), short stature, obesity, hypotonia, characteristic facies, autism or ASD, joint hypermobility or dislocation and scoliosis; the combination of the first four constitutes the AHO-like phenotype [3]. For the differential diagnosis with the inactivating PTH/PTHrP signalling disorders (iPPSD), the 2018 international consensus defines AHO by two major criteria, BDE with premature epiphyseal fusion and short adult stature relative to the unaffected parent, and three additional ones (stocky build, round face and obesity, ectopic ossifications); PTH resistance is defined by the combination of hypocalcaemia, hyperphosphataemia and raised PTH without vitamin D deficiency and with normal magnesium and renal function [39]. BDE is shared by many conditions and, for the diagnosis of iPPSD, must be combined with another major criterion or two minor ones [51]. In the 2q37 deletion, Gsα bioactivity, cAMP after stimulation and serum calcium are normal in most patients [61].

5.2 Tests in order and their limitations

A normal CMA does not exclude NEDCHF or an intragenic HDAC4 variant, and normal HDAC4 sequencing does not exclude the 2q37 deletion [12]. The French PNDS accepts as means of confirmation karyotype with 2q37 locus-specific FISH, CMA, qPCR, MLPA and CNV analysis of sequencing data, and reserves karyotype and FISH for the study of chromosomal mechanics (pure deletion or associated with another rearrangement) and CMA for the definition of the breakpoints; in the presence of a suggestive picture with a negative deletion search, it recommends clinical reassessment and sequencing of HDAC4 as first intention [13]. The proportion of deletions visible on the karyotype (80–85%) is not the clinical sensitivity of the test for the syndrome, because it depends on the mode of ascertainment of the historical series, enriched for large deletions [3].

5.3 Interpretation and report content

The report should state the ISCN nomenclature with coordinates and genome version (for example, arr[GRCh37] 2q37.2q37.3(236869919_242782258)x1, a heterozygous loss of 5.912 Mb classified as pathogenic), the type of alteration (terminal or interstitial), whether or not HDAC4 and 2q37.1 are included, the clinically relevant genes involved (including recessive disease genes such as UGT1A1 and D2HGDH) and the presence of other CNVs [43, 46, 65]. Classification of a small deletion limited to HDAC4 requires care: ClinGen assigns HDAC4 a haploinsufficiency score of 1, and there are families with deletions that include the gene and a minimal phenotype [11, 28, 35]. For sequence variants, the report should state the MANE transcript (NM_001378414.1), the HGVS nomenclature, the zygosity, the origin (de novo or inherited) and the ACMG/AMP class, distinguishing variants at the 14-3-3 binding site (NEDCHF) from loss-of-function variants (BDMR) [5, 8, 30]. Variants of uncertain significance benefit from segregation studies and phenotypic comparison; the two original Williams variants remain classified by OMIM as of uncertain significance [7].

5.4 Parental testing

Parental testing is mandatory in subtelomeric deletions, to exclude a cryptic balanced translocation or inversion with implications for future pregnancies and for other relatives; as the array may be normal in a balanced carrier, karyotype, FISH or genome sequencing is used [3, 10, 18]. The finding of a 2qtel polymorphism in a parent does not have the same significance as the patient's deletion [9]. In small interstitial deletions, a mildly affected parent may carry the same deletion [11, 32].

5.5 Targeted complementary investigation

In the presence of an AHO phenotype, the investigation includes calcium, phosphate, PTH, 25-hydroxyvitamin D, TSH and free T4, and a hand radiograph [39, 63]. If iPPSD is suspected, exclusion of GNAS defects (sequencing and MS-MLPA) precedes or accompanies the CMA; Elli and colleagues recommend testing for the 2q37 deletion in iPPSDx patients with brachydactyly, ID or behavioural changes and raised PTH [51, 52]. In patients with faltering growth and low IGF-1, growth hormone secretion is assessed [47]. The French PNDS rules out diagnoses of the GNAS locus (AHO, pseudohypoparathyroidism, PPHP) by normal calcium, phosphate and PTH and by study of GNAS by sequencing, MLPA and methylation analysis, and Prader-Willi syndrome, evoked by the combination of delay, overweight and axial hypotonia, by 15q11 methylation analysis [13].

5.6 Prenatal and preimplantation diagnosis

In families with a balanced rearrangement or known deletion, prenatal diagnosis is performed on chorionic villi (10 to 12 weeks) or amniocytes (15 to 18 weeks), by CMA or karyotype with FISH confirmation, because terminal deletions are difficult to visualise in fetal cells; preimplantation genetic diagnosis is possible once the familial alteration has been identified [3]. With incidental prenatal detection, the individual prognosis is uncertain, given the variability [3, 16]. In France, prenatal care is coordinated with the multidisciplinary prenatal diagnosis centres (CPDPN), which bring together obstetricians, midwives, geneticists, genetic counsellors, paediatricians, surgeons and psychologists; if, after a prenatal diagnosis, the couple request a termination of pregnancy for medical reasons, the decision is discussed at the CPDPN to which the request is addressed [13].

5.7 Evaluation after diagnosis

5.8 Diagnostic algorithm

1. Child with DD/ID, ASD or malformations, with or without an AHO-like phenotype → CMA [3, 17].
2. CMA with 2q37 deletion → define size, inclusion of HDAC4 and 2q37.1, recessive genes and associated CNVs; parental testing by karyotype/FISH (and CMA if the deletion is small and interstitial) [3, 18].
3. Translocation derivative or ring suggested → karyotype of the patient [3].
4. Normal CMA with AHO-like phenotype → calcium, phosphate, PTH and TSH; if compatible with iPPSD, study of GNAS; if negative, sequencing of HDAC4 or exome [3, 39, 51].
5. Severe central hypotonia, profound ID and drooling without brachydactyly, with normal CMA → exome, with attention to HDAC4 missense variants at the 14-3-3 site [4, 12].

6. Differential Diagnosis

Albright hereditary osteodystrophy is the main differential. The hands may be indistinguishable, but the 2q37 deletion does not present with subcutaneous ossifications and only exceptionally with hormone resistance, Gsα is normal, and ID and behavioural changes are more frequent [3, 51, 69]. In AHO due to GNAS, the distal phalanx of the thumb is the most frequently shortened bone, followed by the fourth, fifth and third metacarpals, and there are cone-shaped epiphyses and periarticular calcifications in about half of patients [69]. Final stature in AHO ranges between 137 and 152 cm and mean IQ is around 60 [67]. The Spranger atlas insists that chromosomal study is necessary to distinguish the two conditions [69]; Table 13.12.1 of the same atlas summarises the laboratory profile: in del 2q37.3, calcium, cAMP after stimulation and erythrocyte Gsα are normal [61].

Smith-Magenis syndrome shares self-injury, onychotillomania, sleep disturbance, food seeking and obesity; several patients with BDMR were referred with this suspicion, and Williams and colleagues demonstrated that loss of HDAC4 reduces the expression of RAI1, which gives a molecular basis to the overlap [2, 16, 27]. CMA distinguishes the two in most cases.

Isolated brachydactylies type E (HOXD13, PTHLH) have no ID or relevant dysmorphism, and the PDE3A form is associated with severe arterial hypertension in childhood [68]. Other conditions with short metacarpals include naevoid basal cell carcinoma syndrome, Biemond syndrome, 5p syndrome, multiple exostoses and acquired causes due to premature epiphyseal closure, such as sickle cell disease and juvenile idiopathic arthritis [15].

7. Treatments and Risk Management Strategies

7.1 Principles

There is no targeted treatment for the 2q37 deletion, HDAC4 haploinsufficiency or NEDCHF; there is no international scientific society guideline, randomised trial or authorised medicine for these conditions [12, 72]. The only specific national protocol is the 2019 French PNDS, prepared under the responsibility of the HAS by the reference centres for developmental anomalies of Caen and Reims, with the AnDDI-Rares network, general practitioners, other specialties, non-medical professionals and patient associations; it is based on a literature review and expert consensus and confirms that there is no curative treatment [13]. The histone deacetylase inhibitors used in oncology have no role and would act, in NEDCHF, in the direction opposite to the mechanism of altered regulation [12]. Management is multidisciplinary, coordinated by a clinical geneticist or another physician experienced with patients with complex needs, and involves genetics, speech therapy, occupational therapy, physiotherapy, developmental paediatrics, neurology, cardiology, gastroenterology, nutrition, ophthalmology and audiology, according to age and the problems present [3]. The available recommendations come from the GeneReviews chapter retired in 2013, the PNDS, reviews and case series and, for Wilms tumour, the working groups of the American Association for Cancer Research (AACR), and have the level of evidence of expert opinion [3, 13, 19, 71]. The PNDS assigns coordination to a physician at the reference or competence centre, working with the general practitioner or paediatrician, who is responsible for coordinating local care, checking that genetic counselling has been given, looking for complications with the reference team, managing intercurrent problems (infections, behavioural changes, medication adjustments), prevention (vaccinations up to date, screening) and psychological and medico-social support for the family [13].

7.2 Development, communication and education

Infants benefit from early intervention and school-age children from an individual education plan, with integrated occupational therapy, physiotherapy and speech therapy [3]. Periodic assessment of neurodevelopment and behaviour guides support, and language and social skills may improve over childhood [3, 46]. In patients with a visuospatial dyspraxia profile, detailed neuropsychological assessment identifies specific deficits that global IQ does not capture [33]. The PNDS sets out the pathway by age. From birth to preschool age, psychomotor delay is assessed and physiotherapy is instituted for hypotonia or delayed milestones, with psychomotor therapy and speech therapy, preferably in a multidisciplinary early intervention service (in France, the CAMSP) [13]. Between 5 and 11 years, neuropsychological and educational assessment guides schooling: mainstream education with or without a support assistant and therapeutic support, school inclusion units, adapted education or a medico-educational institution, according to level; placement is decided by the Maison Départementale des Personnes Handicapées (MDPH) with the parents and the teams [13]. Interventions follow the principles of the task-oriented approach: tasks meaningful to the child, active and voluntary engagement, a favourable environment, identified motivational factors and progression with repetition of motor situations; they include speech therapy, physiotherapy, psychomotor therapy, occupational therapy and sensory integration [13]. Acquisition of basic self-care skills (hygiene, dressing) and of adapted means of expression is encouraged, because it conditions the adult's well-being [13].

7.3 Behaviour, sleep and mental health

Behavioural changes (ASD, hyperactivity, aggressiveness, self-injury, stereotypies) are addressed with behavioural and educational interventions and, when necessary, with psychotropic drugs used for the same indications in the general population; there are no studies of these drugs in this syndrome, so the following doses come from the labels of the approved indications and represent extrapolation to the 2q37 deletion [73–75]. Sleep disturbance, present in one third of adolescents and adults, is addressed first with sleep hygiene measures [21, 75]. Prolonged-release melatonin (Slenyto®, centralised European Union authorisation, valid in Portugal) is indicated for insomnia in children and adolescents aged 2 to 18 years with ASD and/or neurogenetic disorders with aberrant daytime melatonin secretion or night-time awakenings, when sleep hygiene has been insufficient [75]. For irritability associated with autistic disorder, risperidone and aripiprazole have an indication approved by the United States Food and Drug Administration (FDA) [73, 74]. In the EU, risperidone is authorised from 5 years of age only for short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder, in children and adolescents with below-average intellectual functioning or intellectual disability. The starting dose is 0.25 mg/day below 50 kg (optimum 0.5 mg/day; maximum 0.75 mg/day) and 0.5 mg/day from 50 kg (optimum 1 mg/day; maximum 1.5 mg/day). Autism spectrum disorder is not a European indication [76]. Acute psychiatric episodes in adults have been treated with a low-dose antipsychotic and joint follow-up by general psychiatry and intellectual disability psychiatry [21, 62]. As some patients have reduced pain sensitivity, a painful cause should be sought in the presence of a recent change in behaviour or self-injury [2]. The PNDS considers behavioural therapy and psychotropic drugs frequently necessary, especially for attention deficit and anxiety disorders, after neuropsychological and, if needed, psychiatric assessment, and adds relaxation techniques; behaviour and the family's difficulties in managing it should be assessed early and regularly, with psychological support and a psychiatric opinion when medication is being considered [13]. Sleep disorders are actively sought and treated [13].

7.4 Epilepsy

Seizures are treated with conventional antiseizure medications chosen according to the type of seizure and epilepsy syndrome; most children with 2q37 deletion respond well and have no underlying brain malformation [12, 21]. There are no data favouring a specific antiseizure medication in this condition. In severe forms, such as the evolution to Lennox-Gastaut syndrome described with a truncating HDAC4 variant, the approach follows that of the epileptic encephalopathies [48].

7.5 Growth, feeding and weight

Infant feeding, gastro-oesophageal reflux and faltering growth are managed by nutrition and gastroenterology; reflux may require surgery [3]. Prevention of obesity is based on an active lifestyle and appropriate eating habits from childhood, with monitoring of BMI for age; weight gain often accelerates at puberty, and diet and exercise suffice in most cases, although some patients need controlled access to food [3, 9, 21]. The sources consulted do not describe pharmacological treatment of obesity in this syndrome. The PNDS recommends a balanced, high-fibre diet and regular adapted physical activity, combined with psychological support, with follow-up by a nutrition physician or dietitian when necessary, and accepts bariatric surgery for morbid obesity that meets the usual criteria and without contraindication; underweight is treated according to general rules [13]. The same protocol attributes a favourable effect on behaviour as well to physical activity and diet [13].

Gastro-oesophageal reflux and bowel habit changes (diarrhoea, constipation) are treated symptomatically in children and adults, after an organic cause (intestinal malrotation, food intolerance, inflammatory bowel disease) has been ruled out; constipation is treated for comfort and to prevent diverticulosis, and coeliac disease is sought in the presence of suggestive signs [13]. The PNDS calls for vitamin D supplementation according to the current paediatric recommendations, continued into adolescence, without a specific dose [13]. The 2022 French consensus of the French Society of Paediatrics, applicable by extrapolation, recommends 400 to 800 IU/day of colecalciferol from 0 to 18 years and 800 to 1600 IU/day from 2 to 18 years when vitamin D availability is lower, including obesity; if daily adherence fails, it accepts intermittent doses (50,000 IU every 3 months, or 80,000 to 100,000 IU twice in autumn and winter; in risk groups, 50,000 IU every 6 weeks or 80,000 to 100,000 IU every 3 months) and advises against single doses of 200,000 IU [77]. As obesity is frequent in the 2q37 deletion, the 800 to 1600 IU/day range is the one applicable to many adolescents.

Short stature justifies endocrine assessment. In patients with demonstrated growth hormone deficiency, somatropin has been used with increased growth velocity in four reports [47, 50]. The reference dose is that for paediatric growth hormone deficiency: 0.16 to 0.24 mg/kg/week subcutaneously in the FDA label for Genotropin® and 0.025 to 0.035 mg/kg/day (0.7 to 1.0 mg/m²/day) in the European summary of product characteristics (SmPC) for somatropin Omnitrope®, to be stopped when the epiphyses have fused [78, 79]. The patient of Cho and colleagues received 0.55 mg/kg/week, above the label range for this indication [47, 78]. Short stature without demonstrated growth hormone deficiency is not an approved indication in the 2q37 deletion, and somatropin has no indication in brachydactyly.

7.6 Heart, kidney and other malformations

Congenital heart defects follow the usual surgical indications; the report of a complicated postoperative course with junctional ectopic tachycardia and need for extracorporeal membrane oxygenation suggests careful perioperative planning in complex heart disease [56]. Dilated cardiomyopathy was treated with captopril, furosemide, spironolactone, carvedilol and digoxin, with improvement of ejection fraction from 26% to 53.6% [47]. Hernias, digestive malformations, cleft palate, clubfoot, cryptorchidism and scoliosis follow the usual surgical or orthopaedic treatment [3, 9]. Oral hygiene, treatment of caries and orthodontics deferred until there was sufficient cooperation allowed, in one patient, ten years without new caries [14]. According to the PNDS, most congenital heart defects require only monitoring and rarely surgical or percutaneous treatment, and renal and urinary malformations are treated without specificity related to the syndrome [13].

The PNDS details sensory and oral treatment. In ophthalmology, refractive errors are corrected with glasses and strabismus with occlusion of one eye, with or without surgery; the eyeball is measured to look for microphthalmia [13]. In ENT, otitis media with effusion is treated with transtympanic ventilation tubes, oral clefts with surgery, hearing loss with a hearing aid and obstructive sleep apnoea–hypopnoea with positive pressure ventilation [13]. In oral health, it recommends dental hygiene, regular follow-up and specialist opinion for anomalies of tooth number and malocclusion; dental examination, difficult in patients with ID and anxiety, can be done in facilities equipped for people with disabilities (in France, the Handident network), with conscious sedation using an equimolar mixture of oxygen and nitrous oxide (EMONO) in the absence of contraindication or, if needed, with anaesthesia [13]. The dosage and contraindications of EMONO are given in the dosage table [80].

Spinal and foot posture and joint hyperlaxity are assessed regularly, with their functional and postural impact; some foot changes require orthoses, and disabling hyperlaxity may benefit from predominantly proprioceptive physiotherapy and compression garments, without specificity related to the syndrome [13].

7.7 Calcium and phosphate metabolism

In the rare patients with PTH resistance, hypocalcaemia and hyperphosphataemia, treatment follows that of the iPPSD: acute correction of symptomatic hypocalcaemia with intravenous calcium gluconate and maintenance treatment with active vitamin D (calcitriol) or colecalciferol and oral calcium [39, 69]. The extrapolation from pseudohypoparathyroidism should be explicit, because the sources consulted do not describe the treated course in the 2q37 deletion; hypothyroidism, described in two members of a family with an HDAC4 variant, is treated according to general rules [30].

7.8 Wilms tumour surveillance

The most recent AACR position replaces that of 2017 for North America and keeps the decision individualised [19]. The available risk estimates (about 1% to less than 3%) derive from case series without a denominator, and the cases described occurred before 3 years of age [3, 60]. In practice, in deletions that include 2q37.1, surveillance by three-monthly renal ultrasound until 7 years is an option to discuss with the family; in deletions restricted to 2q37.2–2q37.3 there is no indication [3, 19].

7.9 Reference dosage of supportive drugs

7.10 Regulatory status

7.11 Clinical trials and developments

A ClinicalTrials.gov search on 1 November 2026 identified no therapeutic trials for the 2q37 deletion, BDMR or NEDCHF [72]. Registered are an online registry of people with genetic alterations and autistic traits that includes the 2q37 deletion (NCT01238250, Simons Searchlight, recruiting), a general rare disease registry (NCT01793168, recruiting) and an observational study from Taiwan on HDAC4 copy number variations and their expression in 35 patients with ASD (NCT03670381, completed in December 2017, with no results published in the sources consulted) [72]. In the 12 months before the update date, the literature added isolated reports: a de novo truncating HDAC4 variant with Lennox-Gastaut syndrome and polymicrogyria (2025) and the long-term dental management of a patient (2026), both at the level of a case report [14, 48]. No press releases, regulatory applications or authorisations were identified. The absence of results in a search does not demonstrate that there are no unregistered ongoing studies.

7.12 Anaesthesia, pregnancy and transition

The sources consulted do not describe specific anaesthetic complications; preoperative assessment should take into account heart disease, tracheomalacia, hypotonia, upper airway malformations (cleft palate, choanal atresia) and scoliosis [3, 10, 56]. There are no data on pregnancy in women with 2q37 deletion beyond reports of maternal transmission; the pregnancy of an affected woman justifies genetic counselling and obstetric follow-up attentive to uterine malformations [3, 10, 58]. Transition to adult care should include weight control, mental health, sleep, epilepsy, cardiac function in patients with heart disease and support for independent or residential living [21]. The PNDS describes the passage from adolescence to adulthood as a delicate period in medical, paramedical, educational and socio-occupational terms, and adds to the list pubertal monitoring, contraception and genetic counselling about offspring after puberty, vaccinations up to date, psychological assessment because of the risk of late psychiatric disorders, screening for autoimmune diseases and assessment of family carer exhaustion [13]. Socio-occupational integration is assessed with a social worker: skills assessment, guidance towards adapted or sheltered employment and procedures for recognition of disability [13]. From 18 years of age, the need for a legal protection measure for the vulnerable adult (curatorship, guardianship or family authorisation, under French law) is discussed with the family [13]. The only procedure with sedation that the PNDS addresses is dental treatment under EMONO or anaesthesia; pregnancy in female carriers is not dealt with in the protocol [13].

7.13 Pain assessment

The PNDS devotes an appendix to pain assessment, because ID and communication difficulties conceal it and pain sensitivity may be altered; there is no specific scale for the 2q37 deletion [2, 13]. Pain is assessed with a scale validated for age, cognitive capacity and context; self-assessment is preferred when possible and observer assessment is used below 4 years and in people with multiple disabilities or without verbal communication; the scale used for the first rating becomes the reference for subsequent ones [13]. Between 4 and 6 years, and in older children or adults with ID, two self-assessment scales are used together to test the capacity for self-assessment [13]. Any change in usual behaviour should suggest pain: in addition to the classical signs, apathy or psychomotor regression, self- or other-directed aggression, paradoxical laughter and an increase in abnormal movements or spasticity [13].

Source of the table: appendix 3 of the PNDS, adapted by the protocol from the recommendations of the French Society for the Study and Treatment of Pain and the National Resource Centre against Pain [13]. In case of doubt, assessment in a specialist pain clinic is useful [13].

7.14 Divergences between the PNDS and other sources

8. Reproductive Options and Family Counselling

Most 2q37 deletions are de novo and the parents have a normal karyotype [3, 9]. In about 5% of published cases, the deletion resulted from a balanced reciprocal translocation or an inversion in a parent, some cryptic, which makes parental testing by karyotype or FISH, and not by array alone, mandatory [3, 10, 18]. The recurrence risk for siblings depends on this testing. With normal parental karyotypes, GeneReviews considers it negligible; the Oxford Desk Reference estimates about 1% for apparently isolated de novo CNVs, due to low-level germline or gonosomal mosaicism, which has not been documented in the 2q37 deletion but cannot be excluded [3, 18]. With a parental balanced rearrangement, the risk is higher and depends on the rearrangement; the carrier's relatives should be tested [3]. If a parent has the same deletion or an HDAC4 variant, the risk for each child is 50% [3, 18, 51]. The PNDS considers a genetics clinic appointment indispensable after diagnosis, estimates the recurrence risk at about 1% when the deletion is de novo, attributed to germline mosaicism, and treats counselling as urgent when there is an ongoing pregnancy in the family, with chromosomal study of the parents' blood to exclude a rearrangement involving 2q37 [13]. The proportion of deletions found in a parent given by the same protocol (25%) differs from that of the compilations (about 5%), without changing the indication for parental testing [3, 10, 13].

According to the PNDS, the diagnosis is communicated in a dedicated and sufficiently long consultation, ideally multidisciplinary, with at least the physician who requested the test and a geneticist, possibly with a psychologist, and preferably with both parents when the patient is a child; it should explain the deletion and its limits (breakpoints) with the expected consequences, the need for adapted medical and paramedical care, the search for possible complications and the existence of patient associations [13].

The offspring of an affected person have a 50% risk of inheriting the deletion [3, 51]. Affected women have had children, and transmission of small interstitial deletions by parents with a mild phenotype or without ID is documented over several generations [10, 11, 28, 29]. Variable expressivity and incomplete penetrance prevent prediction of severity in a child from the parent's phenotype: in Morris's family, the mother with a balanced translocation and HDAC4 expression of 67% had mild symptoms and the son with an unbalanced deletion was more severely affected [40]. A mother and daughter with a 4 Mb deletion and Mayer-Rokitansky-Küster-Hauser syndrome had offspring through gestational surrogacy, and the authors emphasise that identification of the genetic cause allows preimplantation genetic diagnosis [58].

Prenatal diagnosis (chorionic villi or amniocentesis, by CMA, karyotype and FISH) and preimplantation genetic diagnosis are available once the alteration has been identified in the family [3]. The finding of a 2qtel polymorphism in a parent does not increase the recurrence risk of the pathogenic deletion [9]. Testing of at-risk children in families with a balanced rearrangement is justified by the possibility of Wilms surveillance when the deletion includes 2q37.1 [3]. NEDCHF results from de novo variants; the recurrence risk is low, limited to germline mosaicism [4, 18].

9. Special Considerations: Population Diversity and Epidemiology

There are no population incidence or prevalence studies of the 2q37 deletion. Orphanet assigns it the worldwide point prevalence class below 1/1,000,000, without a mean value, supported by a count of about 115 published cases [1, 12]; this figure measures cases described in the literature, not the frequency in the population. The count grew to about 150 cases in 2026 [14]. The 2019 French PNDS reports an incidence below 1/10,000 attributed to Orphanet, with more than 115 published cases; the value corresponds to a higher frequency class than the current one and does not derive from a population study, so both estimates indicate only a rare condition of unknown frequency [1, 13]. GeneReviews considers the prevalence unknown and the syndrome probably underdiagnosed, because of the difficulty of recognising small terminal deletions on the karyotype and of clinically recognising a facies that is sometimes subtle [3]. Subtelomeric deletions account for about 2.5% of learning difficulties, and in a telomere study of 11,688 individuals the pure 2qtel deletion was found in seven [9, 41]. In autism series, the deletion has been identified at low proportions (one patient in a series of more than 400 autistic individuals) [3]. In an Italian cohort of patients with a pseudohypoparathyroidism phenotype without a GNAS defect, the prevalence of 2q37 deletion was 5.5% (4/73) — a proportion in a selected population, not a population estimate [51].

The published series come from the United States (review of 103 patients; Wheeler's and Iwata-Otsubo's families; Fisch's neuropsychological series), France (14 patients from the network of French-speaking cytogeneticists), Romania (9 patients from Iasi), Italy (iPPSDx cohort; patients with NPPC deletion), Japan, Korea, China, Turkey, Israel, Colombia and Brazil [6, 9, 16, 28, 32–34, 37, 41, 46, 47, 51, 52, 58, 59]. No founder populations have been described, as expected in a condition that arises mostly de novo and without recurrent breakpoints [6, 9]. The compilation of 112 patients shows an excess of females (65 to 44), with no established explanation [9]. The patient with the smallest deletion distal to HDAC4 was African American [32]. In Brazil, a family from Brasília with a deletion downstream of HDAC4 has been described [34]; in Colombia, three patients [46]. The sources consulted contain no data from Portugal.

The relevant European reference network is ERN ITHACA, dedicated to rare congenital anomalies and rare intellectual disability [20]. The Unique association (Rare Chromosome Disorder Support Group), based in the United Kingdom, publishes family guides on the 2q37 deletion in children, adolescents and adults, reviewed by clinicians, as well as an easy-read version (2026) [21]. The Simons Searchlight registry collects data on people with 2q37 deletion and autistic traits [72]. GeneReviews identified no specific associations [3]. The PNDS also refers to the recommendations of Dyscerne, a European network of centres of expertise in dysmorphology [13].

In France, the organisation of care rests on the reference and competence centres for developmental anomalies and malformation syndromes, distributed by region (including the overseas territories), integrated into the AnDDI-Rares network, and on the DéfiScience network for intellectual disabilities of rare cause; the PNDS was coordinated by the Caen reference centre, with that of Reims [13]. Patients are referred by the general practitioner to a paediatric department or an adult specialist (neurologist, psychiatrist) and then to one of these centres for confirmation of the diagnosis [13]. Depending on the clinical picture, the syndrome justifies an application for registration as a long-term condition (ALD) and the submission of a file to the MDPH [13]. The social appendix of the PNDS lists the forms of support: before 20 years, the education allowance for a child with a disability (AEEH), the disability compensation benefit (PCH) and the daily parental presence allowance (AJPP); the inclusion mobility card, with priority and parking from a disability rate of 50% and invalidity endorsement from 80%; from 20 years, the age of transition to adulthood for the MDPH, the allowance for adults with disabilities (AAH), with a rate of 80% or of 50% to 79% with a substantial and lasting restriction of access to employment; and vocational guidance towards mainstream employment, adapted enterprises or work-support establishments (ESAT), or towards residential and medical facilities (foyer de vie, FAM, MAS), requested from 19 years [13]. The Caisse Nationale de Solidarité pour l'Autonomie has published a guide to support the MDPH in determining the disability rate in chromosomal anomalies [13]. There is no specific patient association in France or in French-speaking countries; families are directed to Valentin APAC, an association of carriers of chromosomal anomalies that took part in writing the protocol, and to the Alliance Maladies Rares [13].

10. Illustrative Clinical Case

Cho and colleagues, from Samsung Medical Center (Seoul), described a Korean girl, the first child of healthy non-consanguineous parents, born by caesarean section at 35 weeks weighing 2,400 g (25th–50th centile), with left microtia and a cup-shaped right pinna [47]. The conventional karyotype was 46,XX. At 2 years a right peripheral facial palsy was diagnosed, which persisted. Development was mildly delayed: first words at 12 months and walking with support at 15 months; she attended mainstream school with moderate learning difficulties [47].

At 7 years she was admitted with cough and vomiting; the radiograph showed cardiomegaly and the echocardiogram myocardial dysfunction with left ventricular dilatation, interpreted as myocarditis with dilated cardiomyopathy and heart failure, with recovery in three weeks. Four months later she was readmitted with fever, dizziness and chest pain; the estimated ejection fraction was 26% and the left ventricular end-diastolic diameter 5.9 cm (Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC5495980/figure/F1/), and cardiac magnetic resonance imaging showed dilated cardiomyopathy without fibrosis or congenital heart disease [47]. She was treated with captopril, furosemide, spironolactone, carvedilol and digoxin [47].

At 10 years she was seen in paediatric endocrinology for short stature: 124.3 cm (−2.25 SD), 24.5 kg (−1.88 SD), BMI 15.9 kg/m² (−0.26 SD), mid-parental target height 163.5 cm, Tanner stage I [47]. She had a flat nasal bridge, deep-set eyes, arched eyebrows, a thin upper lip and anomalies of both pinnae; computed tomography showed bony atresia of the left external auditory canal, with normal hearing; she had congenital myogenic ptosis, operated on by levator muscle resection [47]. Radiographs showed bilateral shortening of the third, fourth and fifth metatarsals and metacarpals (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC5495980/figure/F3/). Full blood count, calcium, phosphate, creatinine, alkaline phosphatase, 25-hydroxyvitamin D, thyroid function, PTH and urine were normal; IGF-1 was 64.9 ng/mL (z −2.4) and bone age 10 years for a chronological age of 10 years and 3 months; renal ultrasound was normal [47].

High-resolution karyotype (550 bands) and a 2.7-million-probe array revealed a terminal deletion of about 8.3 Mb from 2q37.1 to 2qter, which included UGT1A4, UGT1A1, MLPH, COL6A3, PER2, TWIST2, HDAC4, NDUFA10, AGXT, KIF1A, PASK and D2HGDH; the parents had normal results (Figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC5495980/figure/F4/) [47]. Growth hormone stimulation tests showed peaks of 7.56 ng/mL (L-dopa) and 8.63 ng/mL (glucagon), interpreted as partial deficiency, and sellar magnetic resonance imaging showed a pars intermedia cyst [47]. She started somatropin at 10 years, at a dose of 0.55 mg/kg/week; eight months later she measured 133.1 cm (−0.9 SD), with a growth velocity of 8.8 cm and IGF-1 of 266.6 ng/mL (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC5495980/figure/F2/) [47]. At 10 years, on medication, she had no symptoms of heart failure and the ejection fraction was 53.6%, with an end-diastolic diameter of 46.8 mm [47].

The case brings together classical elements of the syndrome — facies, brachymetaphalangia of rays 3 to 5, mild delay, short stature and a normal conventional karyotype that concealed an 8.3 Mb deletion — with rare findings: dilated cardiomyopathy, peripheral facial palsy and partial growth hormone deficiency [47]. It also illustrates two points of management: the deletion includes 2q37.1 and UGT1A1, which has implications for Wilms surveillance in early childhood and for the interpretation of unconjugated hyperbilirubinaemia, and the somatropin dose used exceeds the label range for growth hormone deficiency and should not be taken as a reference [19, 44, 78]. The diagnosis of myocarditis with dilated cardiomyopathy does not allow the cardiomyopathy to be attributed to the deletion, and the authors consider the relationship uncertain [47].

11. Prognosis and Long-Term Follow-Up

Life prognosis depends mainly on the congenital malformations; the great majority of patients do not have a shortened life expectancy, although few adults have been described (about 23 in the literature and 39 adolescents and adults in the Unique compilation) [3, 21]. Functional prognosis is variable: most have mild to moderate ID and live with their family or in residential settings, some function almost independently and some carriers of small deletions that include HDAC4 have normal cognition [3, 11, 21, 28]. Deletion size does not predict cognitive performance [41]. Excess weight tends to increase with age, especially from puberty, and is the main preventable long-term medical problem [9, 21]. Epileptic seizures tend to be controllable [21]. Cystic kidneys and seizures appear as late findings [31]. Mental health in adolescents and adults (mood changes, obsessive-compulsive behaviour, aggressiveness, brief psychotic episodes) requires active surveillance [21, 62]. In NEDCHF, the motor and communication prognosis is more guarded, with independent walking in one of seven patients [4]. The French PNDS sets a schedule of visits at the reference or competence centre, which is denser in the first years and becomes more spaced out later: according to the follow-up appendix, monthly in the first year, three-monthly until 2 years and six-monthly until 5, annual until 15, every two years until 25 and every three years in adulthood, outside urgent situations; the text of the protocol gives, for the same initial phase, monthly visits until 9 months, three-monthly until 2 years and annual thereafter [13]. Wilms tumour surveillance and repeat renal ultrasound to look for cysts are not in the PNDS and follow the AACR and GeneReviews [3, 13, 19].

12. Summary and Final Considerations

2q37 deletion syndrome is one of the most recognisable subtelomeric deletions and results, in most cases, from a de novo terminal deletion of 2 to 10 Mb, and in a minority from a parental balanced rearrangement. The picture combines facial dysmorphism, developmental delay or ID that is usually mild to moderate, behavioural changes frequently in the autism spectrum, brachydactyly type E that becomes evident in mid-childhood, progressive weight gain and short stature, with cardiac, digestive, renal and nervous system malformations in some patients. Distal deletions reproduce the phenotype of Albright hereditary osteodystrophy without the subcutaneous ossifications and, as a rule, without hormone resistance, although a small fraction of patients with a pseudohypoparathyroidism phenotype without a GNAS defect have a 2q37 deletion and mild PTH resistance.

HDAC4, which represses chondrocyte hypertrophy and represses MEF2-dependent transcription, is the main gene, but it is not enough to explain the picture: small deletions that include it may give only brachydactyly and short stature, deletions that spare it may give delay and altered behaviour, and ClinGen curation still considers the evidence for haploinsufficiency limited. Missense variants at the 14-3-3 protein binding site cause a distinct and more severe entity, NEDCHF, through increased nuclear HDAC4. Rearrangements of 2q37.1 can alter NPPC expression and growth, and the deletion can unmask recessive diseases of genes in the region, such as UGT1A1 and D2HGDH.

Diagnosis rests on chromosomal microarray, complemented by chromosomal study of the parents to exclude balanced rearrangements, and on sequencing when the array is normal. Management is symptomatic and multidisciplinary, with emphasis on early intervention, educational support, treatment of behaviour and sleep, prevention of obesity, seizure control, correction of malformations and, in deletions that include 2q37.1, shared decision-making on ultrasound surveillance for Wilms tumour until 7 years of age. The recurrence risk is low when the deletion is de novo and 50% for the offspring of a carrier, with unpredictable expressivity.

13. References

1. Orphanet. 2q37 microdeletion syndrome (ORPHA:1001) [Internet]. Paris: INSERM; 2026 [accessed 1 Nov 2026]. https://www.orpha.net/en/disease/detail/1001
2. OMIM. #600430 Chromosome 2q37 deletion syndrome [Internet]. Baltimore: Johns Hopkins University; updated 25 Sep 2015. https://www.omim.org/entry/600430
3. Doherty ES, Lacbawan FL. 2q37 Microdeletion Syndrome [retired chapter, archived version]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2026. Published 3 May 2007; updated 31 Jan 2013. https://www.ncbi.nlm.nih.gov/books/NBK1158/
4. OMIM. #619797 Neurodevelopmental disorder with central hypotonia and dysmorphic facies; NEDCHF [Internet]. Baltimore: Johns Hopkins University; created 17 Mar 2022. https://www.omim.org/entry/619797
5. Wakeling E, McEntagart M, Bruccoleri M, Shaw-Smith C, Stals KL, Wakeling M, et al. Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome. HGG Adv. 2021;2(1):100015. doi:10.1016/j.xhgg.2020.100015.
6. Gavril EC, Nucă I, Pânzaru MC, Ivanov AV, Mihai CT, Antoci LM, et al. Genotype-Phenotype Correlations in 2q37-Deletion Syndrome: An Update of the Clinical Spectrum and Literature Review. Genes (Basel). 2023;14(2). doi:10.3390/genes14020465.
7. OMIM. *605314 Histone deacetylase 4; HDAC4 [Internet]. Baltimore: Johns Hopkins University; updated 22 May 2025. https://www.omim.org/entry/605314
8. VariantValidator [Internet]. Manchester: University of Manchester; 2026 [accessed 1 Nov 2026]. https://variantvalidator.org
9. Leroy C, Landais E, Briault S, David A, Tassy O, Gruchy N, et al. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients. Eur J Hum Genet. 2013;21(6):602-12. doi:10.1038/ejhg.2012.230.
10. Jones KL, Jones MC, del Campo M. 2q37 deletion syndrome (2qter subtelomeric microdeletion syndrome). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 84–85.
11. Jean-Marçais N, Decamp M, Gérard M, Ribault V, Andrieux J, Kottler ML, et al. The first familial case of inherited 2q37.3 interstitial deletion with isolated skeletal abnormalities including brachydactyly type E and short stature. Am J Med Genet A. 2015;167A(1):185-9. doi:10.1002/ajmg.a.36428.
12. GeneGuidance. HDAC4 — clinical curation of the gene and the condition 2q37 microdeletion syndrome. Accessed 26 Sep 2026.
13. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Microdélétion 2q37. Centre de Référence Anomalies du Développement et Syndromes Malformatifs de Caen et de Reims, filière AnDDI-Rares; texte d'août 2019. Saint-Denis La Plaine: HAS; 2019 Aug 21 [accessed 2026 Nov 6]. Available from: https://www.has-sante.fr/jcms/p_3097437
14. Homma H, Sakurai A, Ariizumi D, Nishii Y, Shintani S. Long-term Oral Management for 2q37 Deletion Syndrome Patient. Bull Tokyo Dent Coll. 2026;67(1):17-25. doi:10.2209/tdcpublication.2025-0022.
15. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Brachydactyly E (MIM 113300, 613380). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 462–463.
16. Le TN, Williams SR, Alaimo JT, Elsea SH. Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor. Am J Med Genet A. 2019;179(5):782-791. doi:10.1002/ajmg.a.61089.
17. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-64. doi:10.1016/j.ajhg.2010.04.006.
18. Firth HV, Hurst JA. Deletions and duplications (including microdeletions and microduplications). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 663–664.
19. Kalish JM, Becktell KD, Bougeard G, Brodeur GM, Diller LR, Doria AS, et al. Update on Surveillance for Wilms Tumor and Hepatoblastoma in Beckwith-Wiedemann Syndrome and Other Predisposition Syndromes. Clin Cancer Res. 2024;30(23):5260-5269. doi:10.1158/1078-0432.CCR-24-2100.
20. ERN ITHACA — European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability [Internet]. https://ern-ithaca.eu/
21. Unique — Rare Chromosome Disorder Support Group. 2q37 deletions in adults and adolescents. Version 1.1. Oxted: Unique; 2023. https://rarechromo.org/media/information/Chromosome%20%202/2q37%20deletions%20in%20adults%20and%20adolescents%20FTNW.pdf
22. Gorski JL, Cox BA, Kyine M, Uhlmann W, Glover TW. Terminal deletion of the long arm of chromosome 2 in a mildly dysmorphic hypotonic infant with karyotype 46,XY,del(2)(q37). Am J Med Genet. 1989;32(3):350-2. doi:10.1002/ajmg.1320320315.
23. Wilson LC, Leverton K, Oude Luttikhuis ME, Oley CA, Flint J, Wolstenholme J, et al. Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localized to 2q37. Am J Hum Genet. 1995;56(2):400-7.
24. Phelan MC, Rogers RC, Clarkson KB, Bowyer FP, Levine MA, Estabrooks LL, et al. Albright hereditary osteodystrophy and del(2) (q37.3) in four unrelated individuals. Am J Med Genet. 1995;58(1):1-7. doi:10.1002/ajmg.1320580102.
25. Aldred MA, Sanford RO, Thomas NS, Barrow MA, Wilson LC, Brueton LA, et al. Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes. J Med Genet. 2004;41(6):433-9. doi:10.1136/jmg.2003.017202.
26. Shrimpton AE, Braddock BR, Thomson LL, Stein CK, Hoo JJ. Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype. Clin Genet. 2004;66(6):537-44. doi:10.1111/j.1399-0004.2004.00363.x.
27. Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G, McLeod DR, et al. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am J Hum Genet. 2010;87(2):219-28. doi:10.1016/j.ajhg.2010.07.011.
28. Wheeler PG, Huang D, Dai Z. Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals. Am J Med Genet A. 2014;164A(7):1826-9. doi:10.1002/ajmg.a.36542.
29. Villavicencio-Lorini P, Klopocki E, Trimborn M, Koll R, Mundlos S, Horn D. Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4. Eur J Hum Genet. 2013;21(7):743-8. doi:10.1038/ejhg.2012.240.
30. Takeyari S, Yamamoto K, Fujiwara M, Ohata Y, Kitaoka T, Kubota T, et al. A family with brachydactyly mental retardation syndrome with a missense variant in HDAC4. Clin Pediatr Endocrinol. 2023;32(2):105-109. doi:10.1297/cpe.2022-0076.
31. Falk RE, Casas KA. Chromosome 2q37 deletion: clinical and molecular aspects. Am J Med Genet C Semin Med Genet. 2007;145C(4):357-71. doi:10.1002/ajmg.c.30153.
32. Iwata-Otsubo A, Darr KR, Torres-Martinez W, Hodge JC. Genotype-Phenotype Correlation of Distal 2q37 Deletions. Cytogenet Genome Res. 2022;162(5):237-243. doi:10.1159/000526660.
33. Ogura K, Takeshita K, Arakawa C, Shimojima K, Yamamoto T. Neuropsychological profiles of patients with 2q37.3 deletion associated with developmental dyspraxia. Am J Med Genet B Neuropsychiatr Genet. 2014;165B(8):684-90. doi:10.1002/ajmg.b.32274.
34. Moretti PN, Figueiredo ACV, Saliba A, Versiani BR, Oliveira SF, Pic-Taylor A, et al. Genotype and phenotype correlation in a family with a 2q37 deletion downstream of HDAC4. Am J Med Genet A. 2020;182(8):1861-1864. doi:10.1002/ajmg.a.61620.
35. ClinGen Dosage Sensitivity Curation. Gene curation list GRCh38 (HDAC4, DIS3L2, D2HGDH, TWIST2, KIF1A; 2q37.3 regions) [Internet]. ClinGen; 1 nov 2026. https://ftp.clinicalgenome.org/ClinGen_gene_curation_list_GRCh38.tsv
36. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. CNP-overexpression overgrowth syndrome (MIM 615923). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 826–827.
37. Tassano E, Buttgereit J, Bader M, Lerone M, Divizia MT, Bocciardi R, et al. Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations. PLoS One. 2013;8(6):e66048. doi:10.1371/journal.pone.0066048.
38. Firth HV, Hurst JA. Deletions and duplications (including microdeletions and microduplications). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 660–662.
39. Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018;14(8):476-500. doi:10.1038/s41574-018-0042-0.
40. Morris B, Etoubleau C, Bourthoumieu S, Reynaud-Perrine S, Laroche C, Lebbar A, et al. Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome. Am J Med Genet A. 2012;158A(8):2015-20. doi:10.1002/ajmg.a.35463.
41. Fisch GS, Falk RE, Carey JC, Imitola J, Sederberg M, Caravalho KS, et al. Deletion 2q37 syndrome: Cognitive-behavioral trajectories and autistic features related to breakpoint and deletion size. Am J Med Genet A. 2016;170(9):2282-91. doi:10.1002/ajmg.a.37782.
42. Imitola J, Khurana DS, Teplyuk NM, Zucker M, Jethva R, Legido A, et al. A novel 2q37 microdeletion containing human neural progenitors genes including STK25 results in severe developmental delay, epilepsy, and microcephaly. Am J Med Genet A. 2015;167A(11):2808-16. doi:10.1002/ajmg.a.37268.
43. Firth HV, Hurst JA. Deletions and duplications (including microdeletions and microduplications). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 665.
44. Firth HV, Hurst JA. Prolonged neonatal jaundice. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 288–291.
45. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 22, section 22.8 D-2-hydroxyglutaric aciduria types I and II.
46. Giraldo-Ocampo S, Pachajoa H. 2q37 deletion syndrome in a Colombian patient with macrocephaly: a case report. BMC Pediatr. 2022;22(1):569. doi:10.1186/s12887-022-03620-8.
47. Cho EK, Kim J, Yang A, Cho SY, Jin DK. 2q37 Deletion syndrome confirmed by high-resolution cytogenetic analysis. Ann Pediatr Endocrinol Metab. 2017;22(2):129-132. doi:10.6065/apem.2017.22.2.129.
48. Ianniello M, De Angelis V, Ottaiano A, Ruggiero R, Sirica R, Petrillo N, et al. Phenotypic Manifestations of a New Variant in HDAC4 Gene. Am J Med Genet B Neuropsychiatr Genet. 2025;198(6):32-37. doi:10.1002/ajmg.b.33029.
49. Sakai Y, Souzaki R, Yamamoto H, Matsushita Y, Nagata H, Ishizaki Y, et al. Testicular sex cord-stromal tumor in a boy with 2q37 deletion syndrome. BMC Med Genomics. 2014;7:19. doi:10.1186/1755-8794-7-19.
50. Vetro A, Pagani S, Silengo M, Severino M, Bozzola E, Meazza C, et al. Severe growth hormone deficiency and pituitary malformation in a patient with chromosome 2p25 duplication and 2q37 deletion. Mol Cytogenet. 2014;7:41. doi:10.1186/1755-8166-7-41.
51. Elli FM, de Sanctis L, Madeo B, Maffini MA, Bordogna P, Pirelli A, et al. 2q37 Deletions in Patients With an Albright Hereditary Osteodystrophy Phenotype and PTH Resistance. Front Endocrinol (Lausanne). 2019;10:604. doi:10.3389/fendo.2019.00604.
52. Yang Y, Jiang S, Nie M, Jiang Y, Li M, Xia W, et al. Novel 4.18 Mb deletion resulting in 2q37 microdeletion syndrome combined with PTH resistance found in one Chinese patient. Endocrine. 2024;85(1):331-340. doi:10.1007/s12020-024-03740-4.
53. Maass PG, Weise A, Rittscher K, Lichtenwald J, Barutcu AR, Liehr T, et al. Reorganization of inter-chromosomal interactions in the 2q37-deletion syndrome. EMBO J. 2018;37(15). doi:10.15252/embj.201696257.
54. Firth HV, Hurst JA. Syndactyly. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 328–329.
55. Galasso C, Lo-Castro A, Lalli C, Nardone AM, Gullotta F, Curatolo P. Deletion 2q37: an identifiable clinical syndrome with mental retardation and autism. J Child Neurol. 2008;23(7):802-6. doi:10.1177/0883073808314150.
56. Kowatari R, Sasaki H, Daitoku K, Miura F, Shimada J, Kitagawa Y, et al. From diagnosis to postoperative challenges: a comprehensive case report on 2q37 deletion syndrome with CHD. Cardiol Young. 2024;34(9):2042-2045. doi:10.1017/S1047951124026143.
57. Labiad C, Vaillant JC, Genser L. Splenic Volvulus and 2q37 Deletion Syndrome. J Gastrointest Surg. 2021;25(11):2999-3000. doi:10.1007/s11605-021-05013-1.
58. Daum H, Kremer E, Frumkin A, Meiner V, Diamant H, Harel I, et al. A Case Report of Familial Mayer-Rokitansky-Küster-Hauser Syndrome as Part of the Phenotypic Spectrum of the 2q37 Deletion. J Pediatr Adolesc Gynecol. 2024;37(1):95-97. doi:10.1016/j.jpag.2023.09.006.
59. Akyol Onder EN, Ozkol M, Nese N, Taneli C, Cankorur OO, Ozunan I. Focal Xanthogranulomatous Pyelonephritis in Brachydactyly Mental Retardation Syndrome (2q37 Deletion Syndrome). J Pediatr Genet. 2020;9(2):114-116. doi:10.1055/s-0039-1697624.
60. Firth HV, Hurst JA. Wilms tumour. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 620–622.
61. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Table 13.12.1, Differentiating criteria of pseudohypoparathyroidism and related disorders. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 477.
62. Lally K, Ibrahim N, Kelly M, Gulati G. Brief psychotic episode in a patient with chromosome 2q37 microdeletion syndrome. BMJ Case Rep. 2017;2017:bcr2017221012. doi:10.1136/bcr-2017-221012.
63. Firth HV, Hurst JA. Obesity with and without developmental delay. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 254–257.
64. Firth HV, Hurst JA. Brachydactyly. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 78–81.
65. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22(2):245-257. doi:10.1038/s41436-019-0686-8.
66. Lee S, Jang S, Kim JI, Chae JH, Kim KJ, Lim BC. Whole genomic approach in mutation discovery of infantile spasms patients. Front Neurol. 2022;13:944905. doi:10.3389/fneur.2022.944905.
67. Jones KL, Jones MC, del Campo M. Albright hereditary osteodystrophy. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 628–629.
68. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Table 13.7.1, Selection of conditions causing brachydactyly E as leading sign. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 463.
69. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Albright hereditary osteodystrophy (MIM 103580, 600430, 612462, 612463). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 475–478.
70. Firth HV, Hurst JA. Brachydactyly. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 80.
71. Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, et al. Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res. 2017;23(13):e115-e122. doi:10.1158/1078-0432.CCR-17-0710.
72. ClinicalTrials.gov [Internet]. Bethesda: National Library of Medicine; search “2q37”, “HDAC4”, “brachydactyly mental retardation” [accessed 1 Nov 2026]. https://clinicaltrials.gov
73. Risperidone tablets, prescribing information (ANDA 201003). Revised 25 Jun 2026. DailyMed, set id 03d3b52d-3a7d-4595-84c9-332da6ca9171.
74. Otsuka. ABILIFY (aripiprazole), prescribing information. NDA 021436. Revised 29 Jan 2025. DailyMed.
75. European Medicines Agency. Slenyto (melatonin) prolonged-release tablets: EPAR — product information (summary of product characteristics), sections 4.1 and 4.2. EMEA/H/C/004425; first authorisation 20 Sep 2018; extension to neurogenetic disorders (II/0025) 26 Aug 2024; ADHD indication (II/0028) 17 Mar 2025; product information updated 10 Jun 2026 [accessed 7 Nov 2026]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/slenyto
76. European Medicines Agency. Risperdal — Article 30 referral: Annex I–IV (harmonised summary of product characteristics, sections 4.1 and 4.2); CHMP opinion of 24 Jul 2008 and European Commission decision of 7 Oct 2008. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/risperdal
77. Bacchetta J, Edouard T, Laverny G, Bernardor J, Bertholet-Thomas A, Castanet M, et al. Vitamin D and calcium intakes in general pediatric populations: A French expert consensus paper. Arch Pediatr. 2022;29(4):312-325. doi:10.1016/j.arcped.2022.02.008.
78. Pfizer. GENOTROPIN (somatropin) for injection, prescribing information. BLA 020280. Revised 4 Aug 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=genotropin
79. European Medicines Agency. Omnitrope (somatropin): EPAR — product information (summary of product characteristics). https://www.ema.europa.eu/en/documents/product-information/omnitrope-epar-product-information_en.pdf
80. Air Liquide Santé International. KALINOX 50 %/50 %, gaz médicinal comprimé — résumé des caractéristiques du produit. Marketing authorisation of 15 Nov 2001. Base de Données Publique des Médicaments [accessed 6 Nov 2026]. https://base-donnees-publique.medicaments.gouv.fr/medicament/67577233/extrait