Wolf-Hirschhorn Syndrome (4p16.3 Deletion)

Distal 4p monosomy: a contiguous gene syndrome whose critical region includes NSD2 (WHSC1), LETM1 and NELFA (WHSC2).

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Wolf-Hirschhorn syndrome is the clinical expression of loss of a terminal portion of chromosome 4’s short arm. Unlike many recurrent microdeletion syndromes, WHS does not arise through recombination between low-copy repeats with fixed breakpoints. Deletion sizes range from below 2 Mb to above 30 Mb, and a substantial proportion arise from unbalanced translocations. This structural heterogeneity explains much phenotypic variation and makes complete cytogenomic characterisation an integral part of diagnosis rather than merely a technical detail [1, 7, 9].

The syndrome’s history parallels cytogenetic advances. After cri du chat syndrome (5p deletion) was delineated, patients were observed with a short-arm deletion of a group B chromosome but without its characteristic cry or other features. Autoradiographic labelling showed that the deficient chromosome was 4 rather than 5 [16]. In 1961, Kurt Hirschhorn and Cooper mentioned a child with a visible chromosome 4–5 deletion in the Human Chromosome Newsletter. In 1965, Hirschhorn, Cooper and Firschein published the case as “deletion of the short arms of chromosome 4-5 in a child with midline fusion defects”. Ulrich Wolf and colleagues described a B-chromosome deletion without cri du chat syndrome in the same journal and in The Lancet, assigning it to chromosome 4 [21–24].

Subsequent decades brought high-resolution banding, fluorescence in situ hybridisation (FISH) probes targeting 4p16.3 and, this century, chromosomal microarray. Each revealed smaller deletions, cryptic rearrangements and revised critical-region boundaries, initially 165 kb (WHSCR), then a more distal segment (WHSCR-2) [12, 24, 25]. In parallel, Battaglia, Carey and colleagues’ natural history studies, beginning with 15 patients in 1999 and expanding to 87 in 2008, corrected the uniformly bleak prognosis conveyed to families and proposed the first health supervision guidance [13, 26, 27].

Exome sequencing added a further nosological layer: intragenic loss-of-function NSD2 variants cause a distinct, milder phenotype termed Rauch-Steindl syndrome, which shares some features with WHS but does not reproduce it [24, 28]. The WHS GeneReviews chapter, last updated in 2015, was retired in April 2019 following an editorial decision concerning non-recurrent deletions; it remains available as a historical reference and is used here with that caveat, compared with series published between 2016 and 2026 [1]. No WHS-specific international professional society guideline was identified; supervision recommendations derive from natural history cohorts, expert reviews and, for the perioperative period, the OrphanAnesthesia recommendation revised in December 2025 [13, 29, 30]. The only WHS-specific national guideline identified is the French PNDS (French National Diagnosis and Care Protocol), published by the Haute Autorité de Santé in December 2022 and drafted by a multidisciplinary group from the Île-de-France developmental anomalies reference centre, with review by geneticists from the other regional centres, a general practitioner, a patient association and a family; it is based on a literature review and expert consensus, without evidence grades assigned to the recommendations [20].

2. Molecular Genetics and Pathophysiology

2.1. Architecture of 4p16.3 and definition of critical regions

Band 4p16.3 is a gene-rich subtelomeric region. Chromosome ends comprise telomeric repeats (TTAGGG), followed by subtelomeric sequences and gene-dense segments; small terminal losses can therefore have severe clinical consequences. After telomere loss, the end may be stabilised through “telomere healing”, retention of the original telomere with an interstitial deletion, or capture of another chromosome’s telomere through rearrangement, producing a derivative chromosome with associated partial trisomy [31].

The first critical region (WHSCR) was refined to 165 kb between D4S166 and D4S3327 using patients with terminal and interstitial deletions [25]. In 2003, Zollino and colleagues described eight patients with terminal deletions of 1.9–3.5 Mb. One with a 1.9 Mb deletion preserved WHSCR despite a typical phenotype, prompting definition of WHSCR-2 within a more distal 300–600 kb interval between D4S3327 and D4S98–D4S168 [12]. The Brazilian reference textbook presents these two regions as determining classification as WHS [17]. Current ClinGen curation assigns the terminal 4p16.3 region (ISCA-37429) haploinsufficiency score 3, sufficient evidence, and triplosensitivity score 2, emerging evidence. It contains LETM1, NSD2 and NELFA and spans approximately 1.7 Mb [5]. The prevailing interpretation is that WHS is a true contiguous gene syndrome, with contributions from several genes in an approximately 1.5–1.9 Mb interval and more proximal genes in large deletions [1, 7, 16].

2.2. Candidate genes and proposed mechanisms

Andersen and colleagues studied three patients with de novo interstitial deletions below 400 kb involving WHSC1 and LETM1. They had growth deficiency, feeding difficulties and motor and speech delay, but no seizures or typical face, leading to the conclusion that loss of these genes is necessary but insufficient for the complete phenotype [6]. Ho and colleagues’ high-resolution microarray study of 48 individuals associated interstitial deletions sparing the 4p terminus with absence of seizures (p = 3.59 × 10⁻⁶). Four of five patients with a distal breakpoint at least 751 kb proximal to the telomere never had seizures; the fifth had one febrile seizure. Including published data, seizure susceptibility was refined to a 197 kb region beginning 368 kb from the telomere [35]. In the 140-patient Spanish and Latin American cohort, more refractory epilepsy was associated with 8–11 Mb deletions. The authors propose three levels: an epileptogenic core at 0–2 Mb, modifier region at 2–8 Mb and resistance threshold above ~8–11 Mb, with DRD5 a proximal candidate. This hypothesis lacks functional validation [15].

A terminological discrepancy merits attention. Nimura and colleagues’ 2009 study described the protein as an H3K36 trimethyltransferase [32]; current GeneGuidance curation, based on OMIM, describes NSD2 as an H3K36-specific dimethyltransferase that does not trimethylate this residue in nucleosomes. Patient-variant functional studies measure H3K36me2 loss [4, 28]. Clinically, isolated or deletion-associated NSD2 loss of function produces a recognisable peripheral-blood DNA methylation signature [36].

2.3. Rearrangement types and implications

In Battaglia and colleagues’ series of 87 patients, 65 had an apparently pure de novo terminal deletion; 1 Mb array-CGH, performed in 34 patients, revealed an unbalanced translocation in 15 (44%) [13]. South and colleagues, using array-CGH in 33 patients, found unbalanced translocations in 15 (45%), seven of which were cryptic and undetected by karyotype combined with targeted FISH; three involved the short arm of an acrocentric chromosome and escaped both array-CGH and subtelomeric FISH [9]. In the cohort of 140 patients from Spain and Latin America, studied mainly with SNP arrays, terminal deletions predominated (87.1%), approximately 46% had complex or additional rearrangements and 39.5% had terminal duplications suggestive of derivative chromosomes; mean deletion size was 9.12 ± 6.78 Mb [37]. Zollino and colleagues observed that, with the exception of t(4p;8p), WHS-associated rearrangements are neither mediated by segmental duplications nor associated with a parental inversion polymorphism at 4p16.3 [7]. The French PNDS summarises the distribution as approximately 55% “pure” deletions, terminal or interstitial and almost always de novo, 40–45% derivative chromosomes from translocations (with distal 4p monosomy and partial trisomy of the other segment) and a minority of complex rearrangements: ring chromosome 4, with simultaneous loss of 4pter and 4qter, and 4p inversion-duplication-deletion (inv dup del 4p), in which the terminal deletion is accompanied by an inverted duplication of the adjacent segment; annex 4 of the protocol illustrates a terminal 4p16.3–p16.1 deletion of approximately 10 Mb and a ring chromosome 4 characterised by CMA [20].

The Brazilian textbook summarises 50–60% de novo deletions (designated interstitial or proximal in its table) and 45% translocations, of which 85% are de novo and 15% inherited from balanced familial rearrangements [17]. Smith gives 87% de novo deletions and 13% with a balanced-translocation carrier parent [16]. Proportions differ because series used different resolutions: translocation frequency increased as arrays replaced karyotyping and FISH.

2.4. Genotype–phenotype correlations

Correlation is partial. Meloni and colleagues described classic phenotypes with submicroscopic deletions and mild impairment with large deletions. Unbalanced translocations add partial trisomy effects and may make the presentation more or less severe than predicted [1]. Zollino and colleagues’ prognostic factors were deletion extent, complex chromosomal rearrangements and seizure severity [7, 16]. In the 140-patient cohort, global functional assessment score (GFAP) correlated with deletion size, additional rearrangements, sex (higher scores in boys) and epilepsy severity. Associated terminal duplication was linked to higher birth weight and less intrauterine growth restriction than isolated deletion [37].

2.5. Allelic disorders and related conditions

WHS frequency does not apply to Rauch-Steindl syndrome. Its defining series included 28 patients (18 new, 10 published), insufficient to estimate prevalence [4, 28]. ClinGen classifies the NSD2–syndromic intellectual disability relationship as definitive (2021) and assigns haploinsufficiency score 3 (2023) [41].

3. Clinical Spectrum and Manifestations by System

3.1. Overall frequencies

Source: [1]. The French PNDS (French National Diagnosis and Care Protocol) stresses that there are no formal clinical criteria or published clinical score and reproduces the same frequency strata, placing immune dysfunction in the 50–75% group and hepatic (adenoma), diaphragmatic and digestive anomalies below 25%. The protocol’s summary gives brain anomalies in 33% and urinary malformations in 25%, whereas the main text reports structural central nervous system anomalies in approximately 80% and urinary malformations in more than 30%; the protocol does not explain the discrepancy, which is consistent with source series that differed in whether imaging was systematic [20]. The cohort of 140 patients from Spain and Latin America, published in 2025, recorded psychomotor delay in 98.9%, epilepsy in 98.9%, characteristic face in 97.8%, intrauterine growth restriction in 94.2%, hypotonia in 89%, renal and urological anomalies in 53%, congenital heart disease in 44.5% and behavioural or autism spectrum disorders in 22–62.8%, depending on the source [15].

3.2. Face and skull

Facial appearance in infants and children is the principal recognition feature. It includes the “Greek warrior helmet” configuration, formed by a broad nasal bridge continuing into the forehead without depression; microcephaly; high anterior hairline with prominent glabella; hypertelorism; epicanthic folds; highly arched eyebrows, sometimes with medial-half defects; short philtrum; downturned mouth corners (“fish mouth”); micrognathia; and simple or malformed ears with preauricular pits or tags [1, 16]. The Oxford Desk Reference also highlights drooping, everted lower lids, a short nose and very short philtrum [31]. Posterior midline scalp defects and cranial asymmetry are described [16]. The appearance is recognisable from birth through childhood and becomes less evident at puberty; smaller deletions produce subtler facial features [1, 13].

3.3. Growth and feeding

Growth restriction begins in utero and persists after birth, with short stature and slow weight gain despite adequate energy and protein intake; microcephaly (head circumference below the 2nd centile) is present in almost all patients, except some with cryptic unbalanced translocations [1, 13]. Specific growth charts exist: Antonius and colleagues (101 children aged 0–4 years), Shimojima and Yamamoto (34 individuals aged 15 months to 24 years) and, in 2025, Calhoun and colleagues (65 patients, length/height and weight from birth to 18 years and head circumference up to 2 years). The latter series showed an almost absent pubertal growth spurt and more individuals within the typical range than expected [42, 43]. Feeding difficulties result from hypotonia, orofacial clefts, poorly coordinated swallowing with aspiration and gastro-oesophageal reflux, which, unlike in the healthy infant, tends to persist and contributes to poor weight gain and respiratory disease [1]. Smith’s emphasises that severe feeding difficulties, often requiring gastrostomy, are a major problem in the first year [16]. The French PNDS reproduces the Antonius 0–4-year charts in an annex and adds that cleft palate worsens sucking and swallowing difficulties [20, 42].

3.4. Neurodevelopment, behaviour and language

Intellectual disability is present in all patients, but its range is broader than classically described. In Battaglia and colleagues’ 2008 series, disability was mild in 10%, moderate in 25% and severe/profound in 65%; expressive language was mostly limited to guttural or disyllabic sounds, but 6% constructed simple sentences [1, 13]. Approximately 45% walk between the ages of 2 and 12 years (25% independently, 20% with support); approximately 10% achieve daytime continence, usually between 8 and 14 years; approximately 30% achieve some independence in feeding (10% feed themselves), dressing and undressing (20%) and simple household tasks [1, 16]. All patients followed up showed slow but steady progress [13, 26]. Fisch and colleagues assessed 12 children aged 4–17 years with some expressive language: mean IQ 44.1, mean adaptive behaviour quotient 37.3, relative strengths in verbal and quantitative reasoning and in socialisation, and attention-deficit/hyperactivity disorder in 7 of 12 [44]. In the cohort of 140 patients, the ability to form sentences was associated preferentially with small deletions (18 of 19 patients with this ability were in the smaller-deletion group) [37]. Stereotypies (hand-washing or hand-flapping, rocking) occur in 25–50% according to GeneReviews and in approximately half of patients according to the French PNDS, which does not recognise in WHS a behavioural profile distinct from that of other forms of intellectual disability or profound multiple disability, but describes relational difficulties and recommends assessing at each visit the onset of behavioural changes and their cause (pain, reflux, otitis, sleep disturbance) [1, 20]. Comprehension is often limited to simple commands; hypotonia and cleft palate add rhinolalia to the expressive language disorder. Communicative intent is present in most patients and progresses with augmentative and alternative communication systems, and patients with greater expressive skills also have better socialisation [20].

Sialorrhoea (drooling) is very common. It results from ineffective swallowing associated with sensory and motor disturbances of the oral region, with continuous salivary secretion that increases with contact of the oral mucosa (food-related or not) and with irritation of the distal oesophagus by reflux. Consequences include perioral skin irritation, oral dehydration, digestive and transit problems, constantly wet clothing and social rejection; when saliva is aspirated, there is a risk of aspiration pneumonia [20]. Recent reports, including a Brazilian girl assessed in childhood and adolescence and two North American children with full neuropsychological assessment, documented diagnoses of autism spectrum disorder and argue for formal diagnostic assessment, rather than isolated screening, adjusted to cognitive level [45, 46].

3.5. Epilepsy and EEG

Sources: [14, 15]. Distinctive electroencephalographic abnormalities include diffuse spike/wave complexes or ill-defined sharp elements at 2–3.5 Hz, in long bursts activated by sleep, and high-amplitude spike-polyspike/wave complexes at 4–6 Hz over the posterior third, frequently triggered by eye closure; they often persist beyond the seizures [1, 14]. The French PNDS (French National Diagnosis and Care Protocol) adds useful semiological details: seizures may be prolonged (more than 15 minutes) and occur in clusters; approximately half of children have clusters or status epilepticus in the first three years; tonic spasms, myoclonic seizures and focal impaired-awareness seizures are less frequent; postictal hemiplegia may occur; and the myoclonias of atypical absences are sometimes interpreted as tics, which delays appropriate treatment. The distinctive EEG abnormalities, present in 90%, are not necessarily accompanied by clinical seizures [20]. In the 2025 cohort, status epilepticus correlated with larger deletion, more medicines, poorer control, poorer motor and cognitive development and more comorbidities; afebrile seizures emerged as a marker of severity [15].

3.6. Other system-specific manifestations

3.7. Neoplasia and haematology

WHS is not an established cancer predisposition syndrome, but there are signals to consider. Sharathkumar and colleagues described two girls with myelodysplastic syndrome (refractory cytopenia with ring sideroblasts at 6 years, progressing to excess blasts within less than a year; refractory cytopenia with dysplasia at 5.5 years, progressing to acute lymphoblastic leukaemia within a month) [56]. Prunotto and colleagues reported hepatic adenomas in adolescence in two patients; Battaglia and colleagues gathered, in 2018, seven cases of hepatocellular neoplasia (three previous and four new), one progressing to hepatocellular carcinoma, and propose that hepatocellular neoplasia may be part of the natural history [1, 57, 58]. These figures are cumulative cases and do not allow absolute risk to be calculated. The French PNDS (French National Diagnosis and Care Protocol), although citing the 2018 review, counts only three patients with hepatic adenoma (one with hepatocellular carcinoma) and two children with haematopoietic dysfunction; it does not propose systematic hepatic or haematological surveillance and refers adenoma to hepatology and oncology, with surgical treatment or chemotherapy depending on the number and size of the lesions [20, 58].

3.8. Prenatal phenotype

A review of 118 cases with ultrasound abnormalities (4 original, 114 published) found multiple malformations in 59.3%. The most frequent findings were fetal growth restriction (76.3%), facial abnormalities (28.8%), central nervous system abnormalities (27.1%) and minor ultrasound markers (23.7%), followed by heart and genitourinary abnormalities (19.5% each), increased nuchal translucency (12.7%), skeletal abnormalities (11.9%) and single umbilical artery (10.2%) [59]. A Chinese series of ten fetuses (2020–2026) identified growth restriction as the most frequent indication and one case flagged by non-invasive prenatal testing (NIPT) with a 4p15.31p16.3 deletion [60]. Three-dimensional ultrasound may show the Greek helmet profile in growth-restricted fetuses [1]. Renal histology in a fetus with a 17.92 Mb deletion showed oligomeganephronia, proposed as the substrate for renal hypoplasia in larger deletions [54].

4. Clinical Recognition and Warning Signs

Recognition rests on prenatal-onset growth restriction, microcephaly, hypotonia, global delay and characteristic facial appearance. Prolonged or clustered febrile seizures in the first year strengthen suspicion. Zollino and colleagues’ proposed minimum diagnostic criteria define the core phenotype: typical face, intellectual disability, growth delay, congenital hypotonia and seizures or EEG abnormalities [7, 12]. The Oxford Desk Reference includes WHS in approaches to microcephaly (58% of deletions visible on G-banded karyotype), nasal abnormalities (high nasal root) and coloboma, reflecting common routes to consultation [31].

In moderate forms, without marked growth restriction, significant feeding disorder or malformations, suspicion arises mainly from the combination of neurodevelopmental disorder and facial morphology; in the prenatal period, ultrasound signs are generally non-specific and the diagnosis usually results from a chromosome study performed for another indication [20]. A frequent pitfall is diagnosis by conventional karyotype: since only 50–60% of deletions are visible, a normal karyotype does not exclude the syndrome [1, 16]. Another is the overlap with Rauch-Steindl syndrome, in which the face, growth and delay evoke WHS, but without seizures in most cases and with no deletion on CMA [28, 38].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Confirmatory criterion

Diagnosis is established by demonstrating a heterozygous deletion including the 4p16.3 critical region, approximately 1.4–1.9 Mb from the telomere [1]. The core phenotype without a detectable deletion does not confirm WHS; alternative causes, including intragenic NSD2 variants, require reconsideration [28, 38]. Very distal deletions sparing the critical region may be benign or associated with mild delay, growth deficiency and seizures without diagnostic WHS features. Proximal interstitial deletions (4p12–p16) excluding the critical region constitute a distinct syndrome [1, 35].

5.2. Available tests and limitations

CMA is recommended first-line for unexplained childhood developmental delay or intellectual disability, ASD or multiple congenital anomalies, including after a normal karyotype [1, 31]. Sensitivity here concerns the proportion of critical-region deletions detected in patients with WHS rather than clinical phenotype sensitivity. A suggestive face with normal CMA may indicate Rauch-Steindl, another syndrome or low-level mosaicism; detection depends on platform. SNP arrays are more sensitive to mosaicism than array CGH but do not quantify its percentage well [31].

5.3. Reporting and nomenclature

CMA reports should give the reference genome (GRCh38 recommended), minimum and maximum deletion coordinates, size, included genes (at least NSD2, LETM1, NELFA and relevant recessive genes such as IDUA), any duplicated segment, ACMG/ClinGen copy-number classification and method limitations [5, 63]. ISCN describes deletion through genome version, band, measured breakpoint coordinates and copy number (x1). Older GRCh37 coordinates (for example, chr4:419,224–2,010,962 in GeneReviews) must not be mixed with GRCh38 without validated conversion [1, 5]. Regional point variants require versioned MANE transcripts: NSD2 NM_001042424.3, LETM1 NM_012318.3, NELFA NM_005663.5 [8]. The NSD2 variant NM_001042424.3:c.2137G>C (p.Gly713Arg), reported in 2026 in a child with Rauch-Steindl syndrome, lies at exon 11’s last base and caused exon exclusion in 53% of transcripts with a frameshift (p.Leu672Glyfs*20). It illustrates a missense-designated variant acting through splicing, requiring RNA evidence [39]. Phenotypic similarity alone does not make a VUS pathogenic; episignatures and RNA studies support reclassification [36, 39].

5.4. Diagnostic algorithm

5.5. Initial assessment following diagnosis

5.6. Initial assessment according to the French PNDS

The PNDS (French National Diagnosis and Care Protocol) organises the initial assessment by organ, adapted to age at diagnosis and to investigations already performed. The content overlaps with that of GeneReviews, with differences in several systematic investigations.

Source: [1, 20].

6. Differential Diagnosis

The French PNDS (French National Diagnosis and Care Protocol) limits the main differential to proximal 4p deletion, the Seckel and primary microcephaly spectrum, Smith-Lemli-Opitz syndrome and Angelman syndrome, and considers that the absence of a terminal 4p deletion excludes WHS [20]. Rauch-Steindl syndrome and cri du chat syndrome are part of the differential diagnosis. The Brazilian reference book highlights CHARGE syndrome and Opitz G/BBB syndrome as the main clinical differentials, distinguished by inheritance pattern, genetic testing and facial gestalt [17]. In current practice, most of these entities are separated by CMA, but clinical distinction retains value when the result is normal or when the deletion does not explain the whole picture [40].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no cause-directed treatment and no medicine specifically authorised for WHS. Management is symptomatic, multidisciplinary and focused on quality of life, with early rehabilitation and surveillance for predictable complications [1, 17]. The antiseizure medicines mentioned are authorised for seizure types or epilepsy syndromes, not for WHS; their use follows seizure semiology, and the choice is based on observational series and surveys, without controlled trials in the syndrome [1, 15, 67]. The French PNDS (French National Diagnosis and Care Protocol) adds three general rules: medicines are used within the indications and conditions of the marketing authorisation; renal function should be checked before introducing potentially nephrotoxic medicines, because some patients progress to renal failure; and surgery follows the protocols for the general paediatric population, but the indication should be discussed by a multidisciplinary team, weighing benefit and risk, with advance planning of postoperative care in patients with multiorgan involvement or profound multiple disability [20].

7.2. Epilepsy: strategy and evidence

The 2015 GeneReviews chapter recommended starting valproate after the first seizure because almost 95% have multiple, often febrile seizures and approximately one third develop valproate-responsive atypical absences. Atypical absences were controlled by valproate alone or with ethosuximide; clonic, tonic-clonic, absence or myoclonic status responded to intravenous benzodiazepines. Carbamazepine was to be avoided because it may worsen atypical absences [1]. In the 87-patient series, epilepsy was controlled in 81%, mainly with valproate and phenobarbital [14]. GeneReviews proposed antiseizure medication withdrawal after five seizure-free years because EEG abnormalities may persist without seizures [1].

Later data changed prescribing patterns. In a US caregiver survey (141 responses, ages 4 months–61 years), clobazam, levetiracetam and lamotrigine performed best. Carbamazepine, phenytoin and oxcarbazepine had little effect or worsened seizures and, together with phenobarbital and topiramate, were least tolerated; levetiracetam, clobazam and clonazepam showed better tolerability [67]. In the Spanish/Latin American cohort, 85.9% of patients with epilepsy received medication, 47.4% monotherapy, 42.2% had used at least three drugs and 17.2% had received at least three simultaneously. Valproate (62.2%) and levetiracetam (36.3%) predominated, followed by clobazam/clonazepam (21.5%), lamotrigine (11.1%), oxcarbazepine/carbamazepine (9.6%), topiramate (5.2%) and ethosuximide (2.2%). Diazepam was used intermittently during fever (5.9%); phenobarbital persisted mainly in Latin American infants. Lacosamide was described as ineffective or harmful. Fever sensitivity did not predict resistance to any specific drug [15]. In Japan, sodium bromide was effective in four of four patients and associated with an earlier last status episode (1 year and 8 months versus 3 years and 4 months without bromide); a 2016 report described cessation of migrating focal seizures with phenobarbital and potassium bromide [49, 50]. Bromides are absent from the consulted US/EU antiseizure labels; use is local, and no dose is presented.

The French PNDS, published after the North American survey, considers valproate, levetiracetam, lamotrigine and clobazam first-line medicines, on the basis of reported efficacy and tolerability. Ethosuximide may be added for the treatment of absences, but not as monotherapy, because of the risk of concomitant generalised seizures. Status epilepticus generally responds to intravenous benzodiazepines (diazepam). Carbamazepine, oxcarbazepine and phenobarbital (grouped in the text as “carboxamides”, a term that does not apply to phenobarbital) are described as less effective, potentially aggravating and, when effective, associated with more adverse effects than valproate or levetiracetam. The protocol recommends starting treatment shortly after the first seizure, because almost 95% of patients have multiple seizures and approximately one third develop atypical absences, and proposes attempting withdrawal after five seizure-free years, without making the decision conditional on the EEG [20]. This guidance agrees with GeneReviews on early initiation and on withdrawal, but differs in the choice of medicine: GeneReviews favoured valproate alone and the 2009 series controlled epilepsy mainly with valproate and phenobarbital, whereas the PNDS advises against phenobarbital and includes lamotrigine and clobazam in the first line [1, 14, 20].

These sources cannot rank drugs by efficacy: designs are observational, outcomes caregiver-reported or extracted from records, and era and access differences confound comparison. Similarity to Dravet syndrome (prolonged febrile seizures, early status, worsening with sodium channel blockers) prompted proposals to extrapolate cannabidiol, fenfluramine and stiripentol. This is clinical analogy rather than WHS trial evidence; their WHS use is outside authorised indications [15, 66].

7.3. Medicines, labelled doses and regulatory status

The following doses are those of the labels for the authorised seizure types and are not WHS-specific doses; neither GeneReviews nor the French PNDS gives doses, so the label is the available reference. In the USA, the valproate label carries a boxed warning: children under two years of age are at considerably increased risk of fatal hepatotoxicity, especially on polytherapy, with congenital metabolic disorders, severe epilepsy with intellectual disability or organic brain disease; in this group it should be used with extreme caution and as monotherapy [68]. This warning describes precisely the profile of many infants with WHS and should be weighed against the historical recommendation to start valproate after the first seizure [1, 68]. The OrphanAnesthesia recommendation also notes that valproate may alter platelet function and coagulation factors, which requires assessment before surgery [30].

Regulatory table sources: [68–70, 74–83]. Authorisation does not guarantee national reimbursement or availability; INFARMED and ANVISA databases were not consulted for these products.

7.4. Feeding, growth and sleep

Feeding management includes oral motor therapy, techniques and devices for hypotonic infants or clefts before surgical repair, tube feeding for poorly coordinated swallowing, and conventional reflux treatment. In one series, almost 44% underwent gastrostomy and occasionally fundoplication [1]. Syndrome-specific charts prevent interpreting syndrome-related growth as malnutrition while retaining nutritional assessment [42, 43]. A 2026 report described a boy with WHS and stimulation-test-confirmed partial growth hormone deficiency, treated for 11 years with recombinant growth hormone. Height improved from approximately −4.2 to −1.3 standard deviations without major adverse effects [84]. This single proven-deficiency case does not support routine treatment but supports endocrine assessment for disproportionately low growth velocity. Sleep problems without a medical cause and reinforced by parental attention respond to withdrawal of parental attention, a behavioural intervention [1].

The French PNDS (French National Diagnosis and Care Protocol) details the feeding sequence. A nasogastric tube is the first option when swallowing is ineffective; gastrostomy, needed in approximately 45%, is decided jointly (gastroenterology, cardiology, paediatric neurology) according to the severity of the difficulties, tube dependence and aspiration risk, and is not specific to WHS. Speech and language therapy targeting oral feeding skills should begin early when there is impaired suck-swallow coordination or a cleft. Gastro-oesophageal reflux is treated as in the general population, with thickened feeds, positioning during and after meals and H2 antagonists or proton pump inhibitors; when reflux and impaired oral feeding coexist, Nissen fundoplication may be discussed during the same operation as the gastrostomy [20]. The protocol does not specify a medicine or dose. For comparison, the US label for omeprazole (Prilosec®) provides, for erosive reflux oesophagitis, 2.5 mg (3 to <5 kg), 5 mg (5 to <10 kg) or 10 mg (≥10 kg) once daily from 1 to 12 months, for up to 6 weeks, and, from 1 to 16 years, 5 mg (5 to <10 kg), 10 mg (10 to <20 kg) or 20 mg (≥20 kg) once daily for 4–8 weeks [85]; the famotidine oral suspension label provides, for reflux, 0.5 mg/kg once daily up to 3 months and 0.5 mg/kg twice daily from 3 to 12 months (up to 1 mg/kg per dose; maximum 40 mg/day) and, from 1 to 17 years, 0.5 mg/kg twice daily for reflux disease with oesophagitis (maximum 40 mg twice daily) [86].

Regarding growth hormone, the PNDS records that few patients have been treated, with an immediate increase in growth velocity but limited gain in final height, that the place of this treatment is not established and that it should only be considered after assessment by paediatric endocrinology [20]. Austin and colleagues described two New Zealand girls with WHS, severe short stature and a normal growth hormone response on stimulation tests (peaks of 35 and 15 µg/L): height went from −4.6 to −1.64 standard deviations over 5.5 years in the first case, with marked deceleration after discontinuation, and from −3.4 to −2.1 standard deviations in the second, without complications or increased seizures [87]. These two cases, like the 2026 report with proven partial deficiency, do not establish efficacy in WHS [84]. There is no defined dose for the syndrome; if treatment is considered, the closest labelled condition is the child born small for gestational age without catch-up growth, for which the US label of somatropin (Genotropin®) indicates up to 0.48 mg/kg/week subcutaneously, starting at 0.24 mg/kg/week in younger children with less severe height deficit; this is an extrapolation from another indication [88].

7.5. Other systems

Skeletal abnormalities (clubfoot, scoliosis, kyphosis) should receive early physiotherapy and surgery when indicated [1]. Heart defects are generally simple and correctable [1]. Hearing loss warrants a hearing-aid trial [1]. Eye abnormalities receive conventional treatment; in a 2026 Japanese series, three children with congenital nasolacrimal obstruction achieved resolution of epiphora without recurrence after dacryoendoscopy-guided endoluminal recanalisation [1, 89]. Vesicoureteric reflux warrants antibiotic prophylaxis; antibody deficiency may require intravenous immunoglobulin or continuous antibiotics [1, 53]. Hepatic adenomas are treated according to number and size with surgery or chemotherapy [1]. Dental care is feasible; WHS contraindicates no dental procedure, with decisions mainly determined by epilepsy control and cooperation [52].

The French PNDS (French National Diagnosis and Care Protocol) adds details by organ system. For heart defects, surgical or medical treatment follows the usual protocols, and a child without malformation on the echocardiogram at diagnosis does not need systematic cardiology follow-up if no symptoms arise. Renal function and proteinuria should be monitored regularly, with referral to nephrology if there is impaired function, hypoplasia, agenesis, a renal cyst or a malformation that is bilateral or capable of reducing glomerular filtration. Hypospadias and cryptorchidism follow the usual treatment, with paediatric surgery or urology and endocrinology; vesicoureteral reflux may justify antibiotic prophylaxis. Clubfoot should be corrected by an orthopaedic surgeon experienced with children who walk late, and spinal alignment should be examined at each visit. Otitis and ophthalmological abnormalities are sought through systematic examinations; glaucoma is more difficult to treat than in the non-syndromic form. Toothbrushing begins with the eruption of the first tooth, which may be delayed, with a suitable toothbrush recommended by paediatric dentistry; when cooperation or anxiety requires it, treatment is carried out under conscious sedation with an equimolar mixture of oxygen and nitrous oxide, in a practice belonging to the French Handident network or in hospital. The remaining malformations (diaphragmatic, digestive) are treated in the usual way [20].

In antibody deficiency, the PNDS accepts intravenous immunoglobulin or continuous antibiotic therapy and recommends the usual vaccination schedule, or that defined by immunology, with verification of the serological response and adjustment of the number of doses [20]. The protocol does not specify a dose; the European SmPC of an intravenous immunoglobulin (Privigen®) provides, in primary immunodeficiencies with antibody deficiency, a starting dose of 0.4–0.8 g/kg followed by at least 0.2 g/kg every 3–4 weeks, adjusted to obtain a trough IgG of at least 6 g/L (usually 0.2–0.8 g/kg per month), and, in secondary immunodeficiencies with severe or recurrent infections, 0.2–0.4 g/kg every 3–4 weeks [90]. Isolated IgA deficiency, also described in WHS, is not in itself an indication for immunoglobulin.

Pain is difficult to recognise in patients with severe intellectual disability and limited communication. The PNDS recommends using the observer-rated scales developed for children with intellectual disability and refers the detection, assessment and treatment of pain in the non-verbal patient to the French PNDS on profound multiple disability [20].

7.6. Sialorrhoea

The French PNDS proposes a stepwise approach. Speech and language therapy is the mainstay when sialorrhoea results from oral hypotonia and impaired swallowing. Neck flexion may increase visible drooling, but reduces the risk of saliva aspiration and aspiration pneumonia. Medicines are reserved mainly for patients with saliva aspiration: the transdermal hyoscine (scopolamine) patch, applied behind the ear, begins to act 6 to 12 hours later and lasts 72 hours, with drowsiness, thickened bronchial secretions, constipation and urinary retention as the main adverse effects; botulinum toxin injections into the parotid and submandibular glands, bilateral, ultrasound-guided and with analgesia, last 3 to 6 months. Salivary gland diversion surgery is major and rarely considered [20]. The protocol does not specify doses; labelled doses and regulatory status are as follows.

The glaucoma described in WHS contraindicates glycopyrronium and calls for caution with hyoscine; thickening of bronchial secretions weighs against anticholinergics in patients with recurrent aspiration, who are precisely the candidates for treatment [1, 91, 93].

7.7. Rehabilitation, communication, schooling and transition

For screening and early intervention, the French PNDS follows the HAS recommendations on neurodevelopmental disorders and refers the most severely affected patients to the PNDS on profound multiple disability. Hypotonia and postural delay justify physiotherapy and/or psychomotor therapy from the first months: active work improves postural control and gross and fine motor skills, and passive work limits contractures and deformities (contractures, scoliosis). Occupational therapy assesses the environment and proposes adaptations and equipment (moulded seat, adapted pushchair, wheelchair, walker, bath chair, adjustable bed), and physical and rehabilitation medicine directs the motor plan. In the first months, the child should be referred to an early intervention service that coordinates rehabilitation (in France, a CAMSP, up to 6 years, with subsequent follow-up by a SESSAD, CMP, CMPP or equivalent service); if the wait is long, rehabilitation should begin with independent practitioners [20].

Oral language is affected in almost all patients. Speech and language therapy should begin early, after an ENT assessment that excludes aggravating factors, and augmentative and alternative communication systems (Picture Exchange Communication System, PECS; Makaton) should be introduced without hesitation, because they allow needs to be expressed and do not prevent speech from emerging; parents may need training [20].

For most children, the degree of intellectual disability does not allow mainstream schooling, and the PNDS often considers placement, from 4–6 years, in a medical-educational institute more appropriate. When school inclusion is possible, it generally requires a support assistant for the pupil with a disability and preparation with the educational team 6 to 9 months before the start of the school year. At around 5 years, a full neuropsychological assessment informs the choice between mainstream schooling with support, an inclusive education unit or a medical-educational institute, with regular reassessments [20].

In adulthood, autonomy is generally insufficient for independent living, and the protocol recommends referral to residential services (homes with medical support, day centres or equivalent). The transition from paediatric to adult services should be planned in advance on both the medical and socio-educational levels, including a legal protection measure on reaching the age of majority (in France, family authorisation, curatorship or guardianship) [20].

Therapeutic education begins when the diagnosis is disclosed and is aimed at the parents and, when possible, the patient. The objectives are to understand the disease and its treatments, with their adverse effects and precautions; to know how to act in the event of epileptic seizures, discomfort or pain; to prevent complications; and to master the technical procedures (tube or gastrostomy feeding, seizure management, oral hygiene). It may be delivered in individual or group sessions [20].

7.8. Emergencies and emergency card

The PNDS includes a national emergency card, personalised and completed by the referring physician, which the patient should carry. It contains the contact details of relatives, the attending physician, the specialist and the follow-up centre; priority information for the emergency setting (difficult intubation, epilepsy, heart defect, immune deficiency, possibility of parenteral nutrition or gastrostomy); a checklist (hypotonia, reflux, gastrostomy, heart defect, immune deficiency, diaphragmatic hernia, epilepsy and its control, dental and mandibular abnormalities, synostoses, arthrodeses, osteoporosis); the level of comprehension and expression and the means of communication (oral, sign language, pictograms, tablet); sensory impairments; allergies and current treatments. The card should be updated when the information changes significantly [20].

7.9. Anaesthesia and perioperative care

Source: [30]. The French PNDS (French National Diagnosis and Care Protocol) considers that there is no proven anaesthetic risk, but notes difficulties with venous access, intubation and weaning from ventilatory support; regarding malignant hyperthermia, it mentions a single suspected case in the 1980s, never confirmed by another, whereas the OrphanAnesthesia recommendation counts two old reports; both sources consider it unproven [20, 30]. A 2026 report of acute airway obstruction due to grade 4 adenotonsillar hypertrophy, with submucous cleft and laryngomalacia, required emergency tracheostomy with inhalational induction and ketamine to preserve spontaneous ventilation [55].

7.10. Trials, registries and recent research

A ClinicalTrials.gov search on 6 October 2026 identified no WHS-directed therapeutic trials. The only actively recruiting study including WHS is the observational CoRDS rare disease registry (Sanford; NCT01793168), also used for caregiver-reported adult outcomes [94, 95]. NSD2 inhibitor trials (for example, t(4;14) multiple myeloma) target somatic enzyme hyperactivity and do not apply to WHS, whose mechanism is dosage loss [4, 94]. During the past 12 months, research produced induced pluripotent stem cell lines from four patients with p15.1–p16.3 deletions involving approximately 100 genes, with underexpressed neural crest development genes (preclinical research); a clinical global functional assessment score (GFAP) validated in 140 patients and proposed as a future outcome measure; and growth charts to age 18 [37, 43, 96]. No trials found in the search does not establish absence of unregistered or planned studies.

7.11. Divergences between the French PNDS and the other sources

Common source for the PNDS column: [20].

8. Reproductive Options and Family Counselling

The risk to the family depends on the mechanism. The parents of a proband are clinically unaffected; approximately 55% of patients have a simple de novo deletion and 40–45% an unbalanced translocation, which may be de novo or inherited from a parent with a balanced rearrangement; parental testing for a balanced rearrangement involving 4p16.3 is therefore always recommended [1]. The Brazilian book recommends G-banded karyotyping of peripheral blood in both parents and considers the recurrence risk negligible when the parental karyotype is normal [17]. The French PNDS (French National Diagnosis and Care Protocol) recommends karyotype and FISH in both parents and, if one of them carries a balanced rearrangement, a family study extended to adults at risk of being carriers; it gives a minimum recurrence risk of 1% for de novo deletions, due to germline mosaicism, and a higher risk when there is a balanced parental rearrangement [20]. GeneReviews adds 4p subtelomeric FISH in both parents, because cryptic translocations may escape the karyotype [1]. There are no specific empirical risks for translocations between 4p and each other chromosome [1].

Two reports changed parental testing approaches. Faravelli and colleagues described a healthy mother with partial facial phenotype, borderline developmental delay and childhood seizures carrying a 1.5 Mb 4p deletion; her son had a 2.8 Mb deletion and typical WHS [97]. South and colleagues described a subtelomeric deletion in a phenotypically and cytogenetically normal mother that expanded almost tenfold in her affected daughter, which conventional karyotype and FISH would have classified as de novo or benign [64]. Expansion risk in an unaffected parent is unquantified [1].

The French PNDS sets prenatal diagnosis from 11 weeks of gestation by chorionic villus sampling or from 16 weeks by amniocentesis; it allows non-invasive prenatal screening (NIPT) to be discussed when the familial deletion is larger than 5 Mb and reserves preimplantation genetic testing for couples in which one parent carries a balanced rearrangement. When WHS is diagnosed during pregnancy, the couple should be seen in a genetics clinic and follow-up is coordinated by a multidisciplinary prenatal diagnosis centre; given the severity and incurability of the disease, the protocol considers a request for termination of pregnancy for medical reasons admissible within the French legal framework [20]. In pregnancies without a known risk, WHS may be detected by ultrasound (growth restriction, with or without malformations) or by NIPT with CNV analysis, whose findings must be confirmed by invasive testing [59, 60]. Counselling should include up-to-date natural history data, notably the improvement of seizures with age, survival into adulthood in most patients and the spectrum of autonomy, avoiding the uniformly negative prognosis conveyed in the early decades [10, 13, 98]. In adolescence, girls with WHS treated with valproate are covered, in the EU, by the pregnancy prevention programme [83].

The PNDS sets specific rules for disclosure of the diagnosis: a dedicated consultation, in an appropriate setting and preferably with both parents or guardians, conducted by the physician who requested the test or by a WHS expert, with another team member when useful (psychologist, genetic counsellor, nurse). The information covers the disease and its complications, the need for multidisciplinary follow-up, the test results, the mode of transmission and genetic counselling, which may be explored further at a second consultation. Involvement of a psychologist during or shortly after disclosure, a subsequent consultation with the physician and provision of patient association contacts are recommended; in France, applications for exemption from patient co-payments as an unlisted long-term condition and for recognition of disability should be started at the same time [20].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency: what each figure measures

WHS is a chromosomal disorder without a founder effect: rearrangements arise mainly de novo, without recurrent variants transmitted in isolated populations. Literature has long quoted “1/50 000” or “1/20 000–1/50 000” births, with female predominance of 2:1 [1, 13, 17]. These are not recent population-based figures and require interpretation using each source’s denominator.

Female predominance is consistent: 2.11:1 in the 140-patient cohort, 2:1 in the Spanish study, and 26 women among 35 adults in the Italian/US series [15, 98, 99]. Boys in the 2025 cohort had poorer functional scores and larger deletions, interpreted cautiously by the authors, also considering healthcare access and reporting differences [37].

9.2. Regional cohorts

The largest clinical datasets come from the USA and Italy (87 patients in 2008 and 87 in the 2009 epilepsy study; 141 US support-group survey responses in 2018), the United Kingdom (registry used for mortality and adult seizure studies), and Spain/Latin America (51 patients in 2017; 140 in 2025, including 75 from Spain, two of Moroccan origin, and 65 from Latin America: 39 Argentina, 9 Mexico, 6 Venezuela, 5 Chile, 3 Ecuador, 2 Colombia and 1 Peru) [10, 13–15, 47, 51, 67]. Latin American patients were assessed at annual family meetings in Buenos Aires and had a greater overall epilepsy burden than Spanish patients, with more infant phenobarbital use [15]. Series also come from Egypt (ten patients, a branchial fistula described as novel), Japan (epilepsy and cell lines) and China (prenatal phenotype) [49, 59–61, 96].

In Brazil, the Fortaleza reference textbook chapter by Brazilian geneticists summarises WHS for national clinical practice and cites a Pará case report [17]. A 2025 report by Brazilian authors described a female patient assessed in childhood and adolescence, with ASD signs and severe language and behavioural impairment despite continued intervention [45]. Brazilian researchers also analysed WHS epileptogenic gene networks using 94 CMA-characterised patients [34]. No Portuguese population data were found in the sources consulted. The Brazilian textbook cites a University of Coimbra master’s dissertation on genotype–phenotype correlation, which was not consulted [17]. Absence from consulted sources does not demonstrate absence of published data.

9.3. Special populations and equity

Absence of a founder effect does not eliminate indirect population effects. When a deletion includes a recessive gene, pathogenic variant frequency in the population of origin determines the probability of an unmasked second disease. The 2026 mucopolysaccharidosis type I case involved IDUA p.Pro533Arg, frequent in North African populations, particularly Moroccan ancestry [40, 100]. Family quality of life was assessed in 34 Spanish parents representing 50% of registered families: emotional well-being was most affected, and only 27% reported overall satisfaction [101]. In the 2025 cohort, epilepsy severity was associated with a relative leaving employment to provide care [15].

9.4. Reference networks and organisations

ERN ITHACA (congenital anomalies, dysmorphic syndromes and intellectual disability) is the relevant European network; the Spanish centre coordinating the 2025 cohorts belongs to it [15, 18]. ERN EpiCARE covers rare and complex epilepsies [19]. Patient organisations include the US 4p- Support Group, the United Kingdom and Ireland Wolf-Hirschhorn Syndrome Trust, Associazione Italiana Sindrome di Wolf-Hirschhorn (AISiWH), and Asociación Española de Síndrome de Wolf-Hirschhorn (AESWH), a partner in Spanish and Latin American studies [1, 15, 102–104]. Sanford’s US CoRDS registry collects natural history data [94].

In France, the PNDS was coordinated by the Île-de-France reference centre for developmental anomalies and malformation syndromes (Robert Debré Hospital, Paris), with project management support from ERN ITHACA. Follow-up relies on the reference and competence centres of the AnDDI-Rares network, organised into six regional centres (Île-de-France; South-West-Occitania-Réunion; North-West inter-region; West; East; South-East), with competence centres that include the overseas departments (Guadeloupe, Martinique, Réunion), on the intellectual disability reference centres of the DéfiScience network and, for language, on the reference centres for language and learning disorders. The family doctor or paediatrician refers to the centre, provides routine follow-up (growth, head circumference, development, vaccination), screens for complications (seizures, sleep, behaviour, infections, digestive), initiates rehabilitation and coordinates care with the centre. The social framework includes exemption from patient co-payments as an unlisted long-term condition, the application to the departmental centre for persons with disabilities (MDPH), the education allowance for a child with a disability (AEEH) and the disability compensation benefit (PCH) [20].

There is no French WHS-specific association; many families join the Valentin APAC association, which brings together patients with chromosomal rearrangements and took part in the PNDS working group. The protocol also lists Unique (Rare Chromosome Disorder Support Group, United Kingdom), the Wolf-Hirschhorn Syndrome Trust and the 4p- Support Group (USA) [20, 102, 103].

10. Illustrative Clinical Case

10.1. WHS and mucopolysaccharidosis type I: deletion unmasking a recessive disorder (Cifuentes-Uribe and colleagues, 2026)

The third child of unrelated North African parents without a genetic disease family history presented early with extensive congenital dermal melanocytosis, axial hypotonia, soft palate cleft, feeding difficulties and conductive hearing loss. Echocardiography showed a small patent foramen ovale and small ductus arteriosus. Developmental delay became evident in the first months, with progressive thoracolumbar kyphosis and febrile seizures, followed by recurrent respiratory infections and obstructive sleep apnoea. Initial facial features were compatible with WHS (hypertelorism, broad flat nasal bridge, short nose, micrognathia, prominent glabella), but during the second year they became progressively coarser, with thicker eyebrows, prominent lips and a depressed nasal bridge [40].

At 17 months, CMA identified a 5.8 Mb 4p16.3–p16.2 deletion, confirming WHS. Some unexplained findings did not immediately prompt metabolic investigation. At 18 months, a “blast” analyser flag led to manual blood film review, showing lymphocytes with metachromatic cytoplasmic inclusions (Gasser cells) rather than blasts. Urinary glycosaminoglycans were elevated, including dermatan and heparan sulphate, and leucocyte α-L-iduronidase activity was deficient. Molecular testing showed a biallelic mechanism: complete deletion of one IDUA allele within the 4p deletion and pathogenic NM_000203.5(IDUA):c.1598C>G (p.Pro533Arg) on the other allele, inherited from the father. An expert panel classifies the variant as pathogenic in ClinVar (VCV000011910). The article once reverses the designation to “p.Arg533Pro”, but p.Pro533Arg is correct [40, 100]. The deletion diagram and clinical, radiological and cytological findings appear in Figure 2 of the original article, and the diagnostic timeline in Figure 1 [40].

The child met severe MPS I (Hurler syndrome) criteria. The team considered early haematopoietic cell transplantation, the standard treatment, unsuitable because of severe pre-existing neurodevelopmental impairment attributable to WHS and MPS I. Weekly laronidase enzyme replacement (Aldurazyme®) began at 19 months and was well tolerated. During follow-up, upper respiratory infections decreased and non-invasive ventilation was gradually withdrawn. Cardiac disease remained stable (mild aortic valve thickening with grade 1 regurgitation), as did kyphosis and corneal clouding. Hypotonia persisted, but motor development progressed (developmental age approximately 9 months at chronological age 2 years and 9 months), epilepsy was controlled with levetiracetam, and urinary glycosaminoglycans fell to the upper age-specific reference limit [40].

The case illustrates three lessons. First, 4p deletions may unmask recessive disorders in included genes, which CMA reports should identify. Second, findings inconsistent with expected natural history (extensive melanocytosis, progressive kyphosis with anterior vertebral beaking, coarse features, progressive respiratory involvement) require a second diagnosis rather than expanding WHS phenotype. Third, transplantation versus enzyme therapy reflected this child’s neurological context and must not be generalised: laronidase is EU-authorised for non-neurological MPS I manifestations, while transplantation follows that disease’s own guidance [40, 105].

11. Prognosis and Long-Term Follow-up

11.1. Mortality and survival

In the 2001 British study of 146 patients with known vital status, 96 were alive, 37 had died and 13 were detected prenatally. Crude infant mortality was 17% (23/132), and mortality during the first two years 21% (28/132). Large de novo deletions (proximal to and including p15.2) were associated with increased age-adjusted mortality (odds ratio 5.7; 95% CI 1.7–19.9). Deletion and translocation survival curves did not differ significantly (p = 0.11), with median survival above 34 years for de novo deletions and above 18 for translocations [10, 31]. The Spanish study did not corroborate concentration of deaths in the first two years. In the 140-patient cohort, recorded mortality was 10.5% (6/57) with deletions ≥9.5 Mb and 2.4% (2/87) otherwise, a borderline difference (p = 0.062) [15, 99]. OrphanAnesthesia cites approximately 30% mortality in the first two years, mainly from aspiration pneumonia, seizures or heart failure. This exceeds British cohort measurements and is not used here as an estimate [10, 30]. SGRT emphasises poorer prognosis and greater early mortality with larger deletions, with survival determined by complications [17].

11.2. Neurological and functional trajectory

Epilepsy tends to improve with age. In the 87-patient series, seizures ceased at a median of 4 years and 6 months and 55% were seizure-free. In a British survey of 27 adults (mean age 24.8), 66% had been seizure-free for at least 3 years, with the last seizure occurring at a mean age of 11.3. Pure-deletion patients were more likely to be seizure-free than translocation patients (odds ratio 6.5; 95% CI 1.1–38.6) [14, 51]. The 2025 cohort confirmed age-associated medication withdrawal but not age-associated seizure absence, and found that more status episodes predicted poorer motor and language development [15]. GFAP correctly classified 89.0% using age-adjusted developmental delay and 93.4% after adding deletion size, making it a candidate stratification instrument [37].

In adulthood, the phenotype retains growth restriction, microcephaly and intellectual disability, with a face similar to that of childhood; severe internal anomalies are less frequent among the adults described, which also reflects selective survival [106]. Among 35 adults (19 to 55 years) followed in Italy and the USA, 66% needed almost total care, 31% were partially independent and 3% fully independent; 66% had good overall health [98]. The French PNDS (French National Diagnosis and Care Protocol) adds, for adults, neurological surveillance for spasticity and progressive rigidity [20]. In the caregiver-reported outcomes study of 30 adults from the CoRDS registry, most were described as healthy; of the 12 with data on daily activities, 2 were partially independent and 10 needed total care [95].

11.3. Surveillance

GeneReviews and the Battaglia series do not set intervals and recommend systematic follow-up, readjusted as skills and needs change [1, 13]. The French PNDS (French National Diagnosis and Care Protocol) is the only source with a schedule by specialty; the protocol’s summary and table differ on the frequency of reference-centre visits [20]. The transition to adulthood requires planning, because most adults will continue to need high levels of support, albeit often with good overall health [95, 98].

12. Summary and Final Considerations

Wolf-Hirschhorn syndrome results from terminal 4p loss including the 4p16.3 critical region. It is a contiguous gene syndrome: NSD2, LETM1 and NELFA hemizygosity contributes to growth, facial appearance and development; more distal genes influence seizures and proximal genes worsen extensive-deletion phenotypes. Variable size, frequent unbalanced translocations and potential unmasking of recessive disease explain why one diagnosis includes children walking independently with simple language and children requiring total care.

Diagnosis uses CMA, detecting more than 95% of deletions, complemented by karyotype or FISH to define rearrangements and mandatory parental studies. Normal karyotyping does not exclude WHS; normal CMA with a suggestive phenotype should prompt NSD2 variant investigation. Rauch-Steindl syndrome is milder and should not receive the WHS prognosis.

Epilepsy is the principal early medical problem: it affects more than 90%, almost always before age 3, is frequently fever-triggered and produces status epilepticus in approximately half. It usually improves with age, but more status episodes are associated with poorer development. Valproate and levetiracetam are most used, sodium channel blockers perform worse in available series, and all choices rely on observational evidence. Valproate’s under-two hepatotoxicity warning and the European pregnancy-prevention programme must inform decisions.

The most recent frequency estimates, from the English registry for 2015–2020, place live-birth prevalence at 1.16/100 000, below the 1/50 000 figure repeated in the literature. Early mortality, approximately 21% in the first two years in the British series, is lower than previously described, and many patients reach adulthood in good overall health, although with high support needs. The 2022 French PNDS (French National Diagnosis and Care Protocol) is the only specific national guideline and adds a follow-up schedule by specialty, lamotrigine and clobazam to the first-line antiseizure options, a stepwise approach to sialorrhoea and an emergency card. Current priorities are complete genomic characterisation, early and active seizure control, nutritional and respiratory support, haematological, renal and hepatic surveillance, mechanism-informed reproductive counselling and support for families, coordinated with ERN ITHACA and patient associations.

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