Schinzel-Giedion Syndrome and SETBP1 Haploinsufficiency Disorder

SETBP1-related diseases: classic and atypical Schinzel-Giedion syndrome (gain of function), SETBP1 haploinsufficiency disorder (loss of function, including 18q12.3 deletions), SETBP1-related disorders due to missense variants outside the degron and, for the differential diagnosis, somatic SETBP1 variants in myeloid neoplasms

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and clinical delineation

In 1978, Albert Schinzel and Andreas Giedion described two siblings, a boy and a girl, with severe midface retraction, multiple skull anomalies (short sclerotic base, numerous wormian bones, wide sutures and fontanelles), clubfoot, congenital heart disease, hydronephrosis and hypertrichosis; the long tubular bones had increased density, and the children lived 24 hours and 16 months [1, 19]. Victor McKusick assigned the eponym in the OMIM (Online Mendelian Inheritance in Man) catalogue, noting the possibility of confusion with another syndrome bearing Schinzel's name and with Langer-Giedion syndrome, a form of trichorhinophalangeal syndrome [1]. There followed the observations of Donnai and Harris in 1979, who added facial telangiectasias, and of Kelley, Zackai and Charney in 1982, who summarised the picture in the triad of congenital hydronephrosis, skeletal dysplasia and severe developmental delay [1, 20, 21].

The phenotype was delineated through isolated cases and small series. Al-Gazali and colleagues reviewed ten patients in 1990, noted that consanguinity had not in fact been documented and, given two siblings of different sex, admitted a dominant disease with gonadal mosaicism in a parent [1, 22]. Robin and colleagues described in 1993 a malignant sacrococcygeal teratoma soon after birth and proposed that embryonal neoplasms were a recurrent complication; Rodriguez and colleagues, in 1994, recorded a lumbosacral primitive neuroectodermal tumour and counted three embryonal tumours among 19 published patients [1, 23, 24]. Shah and colleagues documented in 1999, by serial magnetic resonance imaging, a progressive neurodegenerative process of grey and white matter, and Minn and colleagues, in 2002, added megacalycosis, alacrima with corneal hypoaesthesia and a tuning-fork malformation of the stapes [1, 25, 26]. In 2008, Lehman and colleagues described the 46th published patient, with splenopancreatic fusion at autopsy, and proposed the clinical diagnostic criteria that still serve as a reference today [27].

1.2. Gene identification and recognition of an allelic spectrum

In 2010, Hoischen and colleagues sequenced the exome of four unrelated patients and found heterozygous de novo SETBP1 variants in all of them; by Sanger sequencing they found variants of the same gene in eight of nine additional patients, all concentrated in an 11-base-pair interval encoding conserved amino acids, which suggested a dominant-negative or gain-of-function effect [10, 28]. The 13 patients met Lehman's criteria and were of European ancestry, from Europe (7), New Zealand (3), Australia (2) and the United States (1) [1].

The following year, Filges and colleagues showed that deletions that reduce SETBP1 expression cause developmental and expressive language delay, with a phenotype distinct from SGS, and Marseglia and colleagues described a 372 kb 18q12.3 microdeletion with mild intellectual disability and expressive speech impairment [6, 29, 30]. In 2014, Coe and colleagues built a morbidity map of copy-number variations (CNV) in 29,085 children with developmental delay and 19,584 controls, resequenced 26 candidate genes in 4716 cases and 2193 controls and identified SETBP1 among ten genes enriched for loss-of-function variants, associated with intellectual disability and loss of expressive language; OMIM then created entry 616078 (MRD29) [6, 13].

In 2017, Acuna-Hidalgo and colleagues brought together 47 patients with SGS (26 new) and four individuals with a milder phenotype and de novo variants adjacent to the hot spot, p.(Glu862Lys), p.(Ser867Arg) and p.(Thr873Ile), showed that hot spot variants disrupt a degron and lead to protein accumulation, and established the relationship with the recurrent somatic variants in myeloid leukaemias [4, 9]. In 2021, two series with 34 and 31 individuals delineated SETBP1 haploinsufficiency disorder (SETBP1-HD) and showed that speech and language disorder is its central feature [17, 31]. In 2025, Wong and colleagues studied 18 individuals with missense variants or an in-frame deletion outside the degron and characterised SETBP1-related disorders as a third group, with its own mechanism [9].

1.3. Current nomenclature and classifications

The two GeneReviews chapters divide the spectrum into four designations: classic SGS (gain-of-function variants in the 12-base-pair hot spot of exon 4, with a severe phenotype meeting Lehman's criteria); atypical SGS (gain-of-function variants adjacent to, but not within, the hot spot, with a partially overlapping and milder phenotype); SETBP1-HD (truncating variants and deletions specific to SETBP1); and SETBP1-related disorders (missense variants of unknown functional effect, not adjacent to the hot spot), a designation that has also been used for the whole spectrum [5, 8]. OMIM keeps two phenotypes, 269150 and 616078, both with autosomal dominant inheritance and mapping key 3 [10]. Orphanet uses ORPHA:798 for SGS and ORPHA:436151, with the name «intellectual disability-expressive aphasia-facial dysmorphism syndrome», for SETBP1-HD [2, 7].

The 2025 international Delphi panel attempted to define new diagnostic criteria for classic («type I») and atypical SGS, but the experts did not accept definitive criteria; they agreed, for care purposes, to use a single term, «SGS», for the whole SETBP1 gain-of-function spectrum (90% agreement), and to apply the same recommendations to anyone with a suggestive phenotype and a de novo variant of uncertain significance near the degron (100%) [3]. Classification by mechanism (gain versus loss of function) is what guides management, because only gain of function is associated with visceral malformations and tumour risk [5, 8].

1.4. Definition of the entities in scope

Classic SGS is defined clinically by Lehman's criteria (section 5) or molecularly by a pathogenic or likely pathogenic gain-of-function variant in residues 868–871 of SETBP1 in a patient with suggestive findings [5]. Atypical SGS requires a pathogenic variant adjacent to the hot spot and suggestive findings; a p.(Asp874Val) variant, adjacent to the degron, caused a complete classic picture, which shows that the boundary between the two forms is molecularly imprecise [5, 32]. SETBP1-HD is a molecular diagnosis: there are no consensus clinical criteria, and the disease is established by identification of a heterozygous loss-of-function variant or a deletion including SETBP1 [8]. SETBP1-related disorders group missense or in-frame variants whose pathogenicity and mechanism are established with clinical, segregation and functional data [9].

1.5. Related entities

Somatic SETBP1 variants in myeloid neoplasms are not inherited and do not constitute germline predisposition; they appear in section 2 because of their mechanistic relationship with SGS and in section 6 as a differential diagnosis, alongside hereditary predisposition to myeloid neoplasms [5, 33]. SET-related intellectual developmental disorder involves the binding partner of the SETBP1 protein, but is a different gene; Ritscher-Schinzel or 3C syndrome shares an eponym and is a distinct entity [1].

2. Molecular Genetics and Pathophysiology

2.1. The SETBP1 gene and the SEB protein

The SETBP1 gene lies at 18q12.3 (GRCh38, chromosome 18: 44 680 073–45 068 510); it was initially mapped to 18q21.1 by fluorescence in situ hybridisation and repositioned by alignment with the reference genome [10]. The MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript is NM_015559.3, which encodes isoform A, NP_056374.2, of 1596 amino acids; the original description by Minakuchi and colleagues indicated a protein of 1542 amino acids and 170 kD [9–11]. The protein, called SEB (SET-binding protein), has a central region of homology with SKI, a C-terminal SET-binding domain (amino acids 1238–1434 of SETBP1 bind to amino acids 182–223 of SET), three PPLPPPPP repeats, three bipartite nuclear localisation signals and six PEST sequences; the main 5.8 kb transcript is ubiquitous and the protein is mainly nuclear [10].

SET is a nuclear oncogene that inhibits the phosphatase PP2A (protein phosphatase 2A) and participates in DNA replication; SEB has been associated with cell proliferation, neuronal migration and neurogenesis, and regulates transcription by binding to promoter regions, with high expression in the developing brain [5, 8]. Wong and colleagues confirmed that SEB activates transcription near promoters even without direct DNA binding, in the manner of a chromatin remodeller, and identified FOXP2, a gene whose variants cause childhood apraxia of speech, as a direct transcriptional target [9]. Antonyan and colleagues described SETBP1 nuclear bodies in contact with the nuclear lamina and proposed a role in higher-order chromatin organisation [34]. In the gnomAD database (v2.1.1), SETBP1 is constrained for loss of function (observed/expected ratio 0.02; interval 0.01–0.11), but not for missense (0.9; Z-score 1.1) [9].

2.2. Two opposite mechanisms: excess and deficit of protein

Classic SGS results from heterozygous gain-of-function variants in a 12-base-pair hot spot of exon 4, which encodes residues 868–871 in the SKI domain. These four residues form part of a canonical degron, recognised by E3 ubiquitin ligases that tag the protein for degradation; with the variant, the degradation machinery binds inefficiently, degradation decreases and SEB accumulates [4, 5]. In atypical chronic myeloid leukaemia (aCML), the G870S variant abolishes a ubiquitination site and the cells expressing it have more SETBP1 and SET, lower PP2A activity and greater proliferation [10, 35].

SETBP1-HD results from the opposite: nonsense and frameshift variants, presumed to be eliminated by nonsense-mediated decay, and deletions of the locus halve the dose of SEB [8, 9]. The ClinGen dosage curation assigns SETBP1 haploinsufficiency a score of 3, sufficient evidence (assessment of 23 May 2018), with no evidence of triplosensitivity [36]. In forebrain progenitor cells derived from patients with SGS and with SETBP1-HD, compared with first-degree relatives of the same sex, the extremes of SETBP1 dose alter signalling molecules such as AKT in opposite directions, which indicates that the protein functions within a narrow dose window [34]. The two diseases differ in mechanism and are not grades of a single severity continuum [8, 34].

Missense variants outside the degron have a third mechanism. In patient fibroblasts and transfected HEK293T/17 cells, several lead to SETBP1 accumulation and increased proliferation without altering the SET/PP2A axis, but ubiquitination is not reduced for most of them; the common effect is loss of DNA binding and transcriptional activation, including of FOXP2, with complete loss in the case of p.(Thr962del), and a variable capacity for neuronal differentiation [9]. The authors concluded that these variants act through loss of function independent of protein abundance, which explains the partial overlap with SGS and with SETBP1-HD [9].

2.3. Variant spectrum and nomenclature

The hot spot variants of classic SGS, normalised in VariantValidator on the MANE transcript and the GRCh38 genome, are listed in the following table; the historical numbering of the 2010 papers (for example, D868N, I871T, G870S) corresponds to the same protein position, with no need for conversion [5, 10, 11].

The atypical SGS variants described include p.(Glu862Lys), p.(Ser867Arg) and p.(Thr873Ile) [4, 9]. In SETBP1-HD, the variants are nonsense, frameshift and deletions; 88% of pathogenic variants are detected by sequencing and 12% by targeted deletion/duplication analysis, and there is no genotype–phenotype correlation [8]. The variants published by Coe and colleagues include p.(Arg143ValfsTer64), p.(Trp532Ter), p.(Arg625Ter), p.(Arg626Ter), p.(Ile822TyrfsTer13) and p.(Ser1011Ter), described in the notation of the original paper [10]. Structural rearrangements that disrupt the gene, balanced at microarray resolution, are a recurrent mechanism of SETBP1-HD that microarray and exome may fail to detect [12, 38].

2.4. Genotype–phenotype correlations

Within SGS, substitutions of residue D868 increase the protein most, confer greater cell proliferation in vitro and have been associated with a higher incidence of cancer than the other germline variants; those of residue I871 increase the protein little and are more frequent in SGS than in leukaemias [4]. The AACR (American Association for Cancer Research) group considered, in 2025, that these data do not yet allow the genotype–phenotype correlation to be used to guide tumour surveillance [39]. The p.(Ile871Met) variant, with a predicted effect similar to that of other substitutions of the same residue, was associated with prolonged survival and absence of several classic features [37].

For variants outside the degron, severity follows the distance from the degron: five individuals with variants in residues 862–874 (excluding 868–871) had severe or profound intellectual disability, four did not speak and none walked without support, but they did not meet Lehman's criteria; seven with variants in residues 854–858 had mild or moderate intellectual disability and all walked from four years of age; four outside the SKI domain had a variable phenotype [9]. The p.(Asp874Val) variant, adjacent to the degron, caused canonical SGS, which shows that proximity to the degron does not by itself predict severity [32].

2.5. Penetrance, expressivity and mosaicism

The penetrance of gain-of-function variants is complete in the patients described, but expressivity varies, even within classic SGS [5]. In atypical SGS, a missense variant was transmitted by an unaffected parent, without mosaicism being excluded; the same p.(Glu858Lys) was described in another family as inherited from an asymptomatic mother in whom the variant was de novo [5, 9, 14]. In SETBP1-HD, maternal transmission of p.(Gln809Ter) by a mother with intellectual disability shows that adults with the disease can reproduce [15]. A child with juvenile myelomonocytic leukaemia with a PTPN11 variant and mosaicism for SETBP1 has been described, and the Delphi panel recommends studying excised tissue and, if negative, a skin biopsy when mosaicism is suspected [3, 40].

2.6. Somatic variants in myeloid neoplasms

Piazza and colleagues found somatic SETBP1 variants in 17 of 70 aCML (24.3%; 95% confidence interval 16–35%); 92% were located between codons 858 and 871 and were identical to those of SGS, and patients with the variant had higher leucocytosis (p=0.008) and a worse prognosis (p=0.01) [10, 35]. Makishima and colleagues detected variants at asp868, ser869, gly870, ile871 and asp880 in 17% of secondary acute myeloid leukaemias and in 15% of chronic myelomonocytic leukaemias (CMML), associated with advanced age, monosomy 7 or 7q deletion and poor prognosis, acquired during leukaemic evolution [10, 33]. In juvenile myelomonocytic leukaemia (JMML), SETBP1 and JAK3 are frequent targets of secondary mutations associated with worse outcome [41]. The NUP98::SETBP1 fusion, by t(11;18)(p15;q12), has been described in a paediatric T-cell acute lymphoblastic leukaemia [42].

Somatic variants are more disruptive of the degron than germline ones, and the functional threshold for myeloid transformation appears higher than that needed to alter prenatal development; this explains why JMML has been described in a single patient with SGS [4, 5]. Somatic variants are confined to neoplastic cells and do not confer hereditary predisposition, and the germline loss-of-function variants of SETBP1-HD do not increase tumorigenesis [8]. The MYST family acetyltransferases interact with SETBP1 and have been proposed, in preclinical models of 2026, as a therapeutic target in leukaemias with mutated SETBP1 [43].

2.7. Pathophysiology by organ and experimental models

Expression of SETBP1 in the human fetal urinary tract, at 10 and 12 weeks, in the urothelium of the ureter and renal pelvis, in periureteral and renal hilar nerve trunks and in a subset of cortical tubules, is compatible with a role in the functional differentiation of the ureter, and anomalies of the pelviureteric junction, the vesicoureteric junction and megaureter are the dominant urological expression of SGS [37]. In mice with the atypical Setbp1 S858R variant (published designation, in murine protein numbering), there are cell type-specific changes in gene expression and alternative splicing in the cerebral cortex and kidney (33 and 62 genes with altered junction usage, respectively) [44, 45]. Mice producing human degron-mutant SETBP1 develop hydrocephalus in more than half of cases and are short-lived [46]. The Setbp1+/- mouse has hyperactivity, reduced social interest, increased olfactory exploration and hypoexcitability of layer 5 projection neurons of the medial prefrontal cortex, a parallel with the ADHD and autism spectrum disorder (ASD) of SETBP1-HD [47]. Induced pluripotent stem cell models of SETBP1-HD show changes in neurogenesis and in fate choice of neural progenitors [48, 49].

2.8. Allelic disorders and differences in inheritance between sources

All sources consulted classify SGS and SETBP1-HD as autosomal dominant [2, 5, 7, 10]. The Oxford Desk Reference lists SGS as autosomal recessive in the hypertrichosis chapter, but as dominant, due to de novo SETBP1 variants, in the chapter on increased bone density; the recessive indication corresponds to the historical hypothesis of consanguinity, which was not confirmed [1, 50, 51]. Orphanet adds to dominant inheritance the mention «not applicable», which reflects sporadic occurrence [2].

3. Clinical Spectrum and Manifestations by System

3.1. Nature and limits of the data

The clinical data on SGS come from case reports, from a series of 47 patients with molecular confirmation assembled in 2017, from reviews that cross-reference the literature before and after 2010 and, since 2025, from a series of 16 children assessed with standardised instruments [4, 5, 52]. The GeneReviews frequencies are given as ranges (for example, 75–100%) and those of Orphanet, from 2014, as point percentages from earlier series; both describe mainly patients receiving intensive supportive care and do not constitute untreated natural history [2, 5]. The data on SETBP1-HD come from 47 individuals published up to 2024, from 31 participants assessed for speech and language and from 22 participants in the Simons Searchlight registry, with ascertainment bias towards children referred for speech or behavioural delay [8, 17, 53].

3.2. Classic Schinzel-Giedion syndrome

3.2.1. Frequency of manifestations

Source of the GeneReviews columns: Hoischen and colleagues (2010) and Acuna-Hidalgo and colleagues (2017), brought together by Duis and van Bon [5]. The differences between the tumour risk values (about 10% to about 25%) reflect different denominators, periods and inclusion criteria, and no study has measured a cumulative incidence by age [2, 5, 39].

3.2.2. Facies and growth

The facial phenotype is recognisable at birth: high prominent forehead, midface retrusion that, in marked cases, draws a «widened figure of eight», bitemporal narrowing, short nose with low root and anteverted nares, shallow orbits with apparent proptosis, deep infraorbital groove, hypertelorism, adherent helix with protruding lobules and low-set ears; the anterior fontanelle and sutures are wide, with the metopic suture open down to the nasal root, and the neck is short with redundant skin [2, 5, 16]. In atypical SGS, the facies is similar but less coarse [5]. Birth weight and length are usually normal; growth deficiency is postnatal, and head circumference, almost always below the 50th centile and often near the 10th centile at birth, decelerates and results in microcephaly in about 80% [5, 16].

3.2.3. Nervous system

All patients have developmental delay and moderate to profound intellectual disability, and most never speak or walk independently [5]. In the series of 16 children assessed with the Vineland-3 scale (median age 5 years and 7 months; range 6 months to 12.5 years), receptive and expressive language corresponded on average to 0–1 month, gross motor skills to about 2 months and fine motor skills to about 4 months; 13 (81%) attended to a voice, 15 (94%) produced pleasure vocalisations and one (6%) followed simple instructions, with individual relative strengths [52].

Epilepsy begins in the neonatal period or later, with tonic, tonic-clonic, myoclonic or focal motor seizures and infantile epileptic spasms syndrome in about 25%; the electroencephalogram (EEG) shows multifocal spikes or hypsarrhythmia, and most epilepsies are refractory to antiseizure medications, adrenocorticotrophic hormone (ACTH), corticosteroids and ketogenic diet [5]. Hypotonia predominates at birth and spasticity appears later and progresses, with secondary scoliosis [5]. The most frequent structural changes are partial or complete agenesis of the corpus callosum, progressive cortical atrophy, ventriculomegaly and hydrocephalus, cortical anomalies, delayed myelination and choroid plexus cysts [5]. Serial MRI documented a progressive neurodegenerative process of grey and white matter, with normal metabolic studies, and an autopsy showed a small brain with less white matter, without storage material [1, 25]. A Portuguese girl with a posterior fossa malformation, arachnoid cysts and stretching of the pituitary stalk had central hypothyroidism and central diabetes insipidus [1, 54].

Cerebral visual impairment, defined as bilateral visual impairment of cerebral origin with normal pupillary reflexes, occurs in 70–80%; there are also small optic discs, optic disc pit, strabismus and alacrima with corneal hypoaesthesia, the latter a useful sign for diagnosis [1, 5, 26]. Hearing impairment affects about 90%, mainly bilateral sensorineural, mild to profound and sometimes asymmetrical; mixed or conductive deafness may be due to a tuning-fork stapes or a flattened cochlear turn [5, 26, 55]. Severe sleep disturbance, prolonged crying and irritability require a search for a treatable cause, such as urinary tract infection, hydrocephalus or sacrococcygeal teratoma [5].

3.2.4. Kidney and urinary tract

Unilateral or bilateral hydronephrosis, from mild pyelectasis to severe hydronephrosis, is the most constant visceral finding; it may be seen on prenatal ultrasound or appear only in infancy [5]. In one review, 31 of 35 patients had hydronephrosis due to proximal or distal ureteric stenosis or vesicoureteral reflux [37]. The mechanisms include pelviureteric junction stenosis, vesicoureteric junction dysplasia, ureteric stenosis, hydroureter, megaureter, vesicoureteral reflux and megacalyces (megacalycosis, non-obstructive dilatation of the calyces due to underdevelopment of the medullary pyramids) [1, 5, 16]. Bladder atony favours persistent urinary tract infections, recurrent pyelonephritis leaves renal scars, and renal cysts, multicystic dysplastic kidney with malignant degeneration and bilateral staghorn calculi of calcium oxalate and phosphate have been described [5, 55, 56]. In atypical SGS, two patients had medullary cystic kidneys, pyelectasis and chronic urinary tract infections [5].

3.2.5. Genitalia, perineum and skeleton

Boys have micropenis (which on prenatal ultrasound may look like ambiguous genitalia), hypospadias, hypoplastic scrotum and cryptorchidism; girls have a bifid or hypoplastic uterus, hypoplastic labia minora or majora, a deep interlabial sulcus and hymenal atresia; in both the perineum is short with an anteriorly placed anus [5, 16, 27].

Radiographs show a short, steep and sclerotic skull base, a wide occipital synchondrosis (before 12 months, a gap between the two parts of the occipital bone), a poorly mineralised calvaria, wormian bones, dense petrous pyramids, hypoplastic first ribs, broad ribs, long or irregular clavicles, hypoplastic or absent pubis with a wide symphysis, hypoplastic distal phalanges, short thumb metacarpals, thick cortex and increased density of the long bones, distal widening of the femur and tibial bowing [2, 5, 16]. In the limbs there is mesomelic brachymelia, talipes equinovarus or valgus, rocker-bottom foot, severe flat foot, hyperconvex nails, hypoplastic dermal ridges, single palmar crease, clenched hand and, in 5–10%, postaxial polydactyly, mainly of the hands; syndactyly, camptodactyly and radioulnar synostosis have also been described [1, 5, 16].

3.2.6. Heart, airways, gastrointestinal tract, skin and teeth

The most frequent heart defects are atrial septal defect, patent foramen ovale and patent ductus arteriosus; occasionally there is ventricular hypoplasia, valvular dysplasia or cardiac hypertrophy [2, 5]. Choanal stenosis, micrognathia, tracheobronchomalacia, pulmonary hypoplasia, progressive gingival hypertrophy and excessive mucus production hinder breathing and swallowing and increase the risk of aspiration and pneumonia; a very short epiglottis and vocal cord paralysis have been described [5, 10]. Constipation, gastro-oesophageal reflux and aspiration are common, and chronic vomiting and gastroparesis may occur; there are cases of hypoplasia of the pancreatic tail, annular pancreas, splenopancreatic fusion and hepatosplenomegaly [5, 27]. At the autopsy of a four-day-old newborn, the pancreatic ducts and the laryngeal and bronchial glands were dilated and filled with mucus, with an appearance similar to cystic fibrosis but normal CFTR studies [5].

Generalised hypertrichosis, present at birth, may regress; there are facial haemangiomas in 25%, dry erythematous skin, cutis marmorata and hypoplastic nipples [5]. The teeth show hypodontia, delayed eruption and gingival thickening from birth, unrelated to antiseizure medications; in one infant, gingival hyperplasia began at seven months, two weeks before any antiseizure medication, and required gingivectomies at four and six years [5, 57].

3.2.7. Neoplasms

About 25% of patients with classic SGS develop a neoplasm, mainly of neuroepithelial origin, present at birth, in the first year or later; no neoplasms have been described in atypical SGS [5]. The most frequent tumour is sacrococcygeal teratoma (benign or malignant); followed by lumbosacral primitive neuroectodermal tumour, lumbosacral teratoma, hepatoblastoma, Wilms tumour, extradural ependymomas (including an anaplastic ependymal tumour with myxopapillary and ependymoblastic differentiation) and a malignant retroperitoneal tumour in a multicystic dysplastic kidney [5, 39, 56]. Juvenile myelomonocytic leukaemia has been described in one patient [4]. Deaths from tumours occurred in a 24-month-old child, from organ failure due to sacrococcygeal teratoma, and in a five-year-old, from recurrence of an extradural ependymal tumour [5]. Pelvic tumours may cause urinary or intestinal obstruction, and intensification of chemotherapy seems barely feasible because of the risk of infection [5].

3.2.8. Pregnancy and the neonatal period

Pregnancy may be complicated by polyhydramnios, and ultrasound may show hydronephrosis (between weeks 18 and 37, in about 40% of cases), ambiguous genitalia, heart disease, overlapping fingers and the typical facial profile [2, 5]. In the newborn, hypotonia and respiratory failure predominate [2]. An Indian girl born at 33 weeks from a dizygotic twin pregnancy had progressive hydrocephalus, bilateral hydronephrosis with reflux, atrial septal defect, talipes equinovarus and bilateral sensorineural deafness, with a normal co-twin [58].

3.2.9. Survival

In the original series, the two children lived 24 hours and 16 months [1]. Among the 13 patients of 2010, the known ages at death were 3, 6 and 7 months, the third year of life (two patients) and 9.25 years, one patient survived to 4.5 years and four were alive between 1 and 3 years at the time of publication; the authors wrote that most die before ten years of age [10, 28]. Smith reports death usually before two years from respiratory failure or infection and an adolescent survivor as the longest; Beaman and colleagues cite up to half of deaths before two years, mainly from pneumonia or epilepsy, and one patient alive at 15 years [16, 37]. The causes of death described are pneumonia (including aspiration pneumonia), sepsis, pulmonary hypoplasia, intractable epilepsy, tumours and sudden cardiac arrest, and survival relates to the number and severity of manifestations [3, 5]. These values describe published patients, many before current complex care, and do not allow a median survival to be estimated [3].

3.3. Atypical Schinzel-Giedion syndrome and variants near the degron

Patients with atypical SGS have mild to severe developmental delay, less epilepsy, less coarse facies and, in some, renal anomalies (medullary cystic kidneys, pyelectasis), cerebral visual impairment and deafness [5]. In the 2025 series, the five individuals with variants in residues 862–874 had severe or profound intellectual disability, four did not speak, none walked without support, three had spasticity, two focal or tonic-clonic seizures and two renal anomalies [9]. The girl with p.(Ile871Met) was in good general health at 11 years, with growth above average, first words at two years, walking at 30 months and only a few words at 12 years (section 10) [37].

3.4. SETBP1 haploinsufficiency disorder

Source: Leonardi and colleagues (2020), Jansen and colleagues (2021) and Morgan and colleagues (2021), brought together in GeneReviews [8].

3.4.1. Motor function

In the speech series, 94% had a gross or fine motor disorder; gross motor function is better than fine motor function [8, 17]. Hypotonia is noticed in infancy and persists in childhood; the age at sitting without support ranges from 6 to 15 months, at crawling from 9 to 19 months and at walking from 13 to 36 months, and about 70% have fine motor delay, with difficulty in handwriting that aggravates literacy difficulties [8].

3.4.2. Speech and language

The communication disorder is the central feature. Half of children say their first words at 18 months, and 80% have severe childhood apraxia of speech (CAS), defined by inconsistent errors on consonants and vowels, lengthened coarticulatory transitions and inappropriate prosody; with therapy, the apraxia lessens and dysarthria becomes more evident, and the associated phonological disorder increases the risk of reading and writing difficulties [8, 17]. In the series of 31 participants (12 boys; 8 months to 23 years; 28 with loss-of-function variants and 3 with 18q12.3 deletions), 68% had intellectual disability, 32% were minimally verbal and used sign language, gestures or digital devices, comprehension was better than expression in only 29%, and oral language and literacy were lower than social, motor and adaptive skills, regardless of motor or intellectual ability [17]. The children are sociable and want to communicate, but social language is below that of their peers [8]. In a patient with an IQ of 76, first words appeared at 18 months, he hardly spoke until four years and, at 14, spoke with incorrect word order and word-finding difficulty [10].

3.4.3. Cognition and behaviour

Intellectual disability, present in about 80% according to GeneReviews, ranges from mild to severe; children with IQ between 80 and 90 were in general diagnosed because of severe speech or behavioural disorder [8]. Attention deficit, hyperactivity and impulsivity predominate, often with a diagnosis of ADHD; there is also anxiety, ASD or autistic traits, sleep disturbance, self-injury and aggression, restricted interests and sensory hypersensitivity [8]. In the Simons Searchlight registry (22 individuals with SETBP1-HD and 5 with SETBP1-RD), all had intellectual disability or developmental delay, ADHD, ASD or seizures, and speech delay; social motivation was a relative strength, and sleep, visual and gastrointestinal disorders, hypotonia and high pain tolerance were frequent [53].

3.4.4. Other organs

Refractive errors (mainly hypermetropia, also astigmatism and myopia) and strabismus affect about half [8]. Weak sucking and slow feeding may require a nasogastric tube in infancy, and at preschool age there is difficulty with solid or lumpy foods; drooling may irritate the skin; ankyloglossia (3–5% in the general population) may affect feeding and articulation, but does not cause the speech delay [8]. Digestive problems include diarrhoea, constipation, food allergies and reflux; cryptorchidism is the only urogenital anomaly described [8]. Seizures (about 20%) are mainly febrile seizures of infancy; there was generalised epilepsy in three individuals, two with onset in infancy and one at 22 years, and in one of them the antiseizure medication was successfully withdrawn at six years [8, 10]. Fourteen individuals had skeletal changes (bilateral hip dysplasia, vertebral anomalies, hyperkyphosis, hyperlordosis) and ten of these mild changes of the extremities (fifth finger clinodactyly, 2–3 syndactyly, brachydactyly, pes cavus) [8].

The dysmorphic features are subtle and do not form a recognisable gestalt: ptosis, blepharophimosis, broad nasal root, hypertelorism, full nasal tip and high palate, and, in Coe's series, long face, characteristic eyebrows and, in some, café-au-lait spots [6, 8, 31]. Growth is normal; brain MRI was normal in 19 of 22 individuals, with delayed myelination in two and a thin corpus callosum with rotated hippocampal tail in one [8]. Life expectancy does not appear to be reduced, several adults have been described, and data on behavioural and neurological evolution in adulthood are scarce [8].

3.5. SETBP1-related disorders

Individuals with variants in residues 854–858 have mild to moderate intellectual disability, milder motor delay, independent walking from four years, normal growth and, with p.(Glu858Lys), two of four were minimally verbal; outside the SKI domain, the picture is variable, from mild impairment to a severe phenotype with p.(Thr962del) (no walking, tonic-clonic seizures, bilateral ptosis) [9]. In the seven individuals with a speech assessment, babbling was limited and language low in all subdomains [9]. Compared with SETBP1-HD, individuals with SETBP1-RD in the Simons Searchlight registry reported more cardiac, orthopaedic and somatic problems and more difficulty with bowel control [53].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

The combination of polyhydramnios, hydronephrosis, ambiguous genitalia or micropenis, heart disease, overlapping fingers and a profile with prominent forehead and midface retrusion should lead to consideration of SGS; hydronephrosis is visible in only about 40% of cases, between weeks 18 and 37, and may appear only after birth [2, 5]. The Delphi panel recommends amniocentesis with genetic testing when there are prenatal anomalies suggestive of a neurodevelopmental disease and fetal echocardiography when there are structural anomalies [3]. In SETBP1-HD, a fetus with cortical anomalies and a subependymal cystic area at 25 weeks was diagnosed by targeted testing in a family with maternal transmission [15].

4.2. Newborn and infant

In the newborn, SGS is suggested by the facies, wide fontanelle, hypertrichosis, genital anomalies, talipes equinovarus, hydronephrosis and hypotonia with respiratory or feeding difficulty [2, 5]. Lehman's criteria accept hypotonia as the equivalent of developmental delay in the neonatal period [5]. The clinical approach chapters of the Oxford Desk Reference place SGS in the differential diagnosis of hypertrichosis with genital anomalies and of increased bone density with wide fontanelle, choanal stenosis and hydronephrosis, and SETBP1 among the rare genes of early myoclonic encephalopathy [50, 51, 59]. The Delphi panel recommends including SETBP1 in the molecular work-up of infants up to three years with severe delay or epilepsy of unknown cause (100% agreement) and of older children with severe intellectual disability (93%) or epilepsy (77%) [3].

4.3. Child with speech delay

SETBP1-HD should be considered in a child with mild motor delay and hypotonia who speaks late, has inconsistent speech errors compatible with apraxia, language disorder and ADHD-like behaviour, especially if there are refractive errors or strabismus, drooling, ankyloglossia or cryptorchidism; intellect may be normal or borderline [8]. Loss-of-function SETBP1 variants have been identified in independent cohorts selected for childhood apraxia of speech, which justifies genetic testing of these children [17].

4.4. Warning and emergency signs

In SGS, severe irritability, inconsolable crying or sudden sleep disturbance require a search for urinary tract infection, hydrocephalus or sacrococcygeal teratoma; an increase in head circumference and a change in alertness, mood or tone justify brain or spinal imaging [3, 5]. A rapidly growing mass, persistent pain or unexplained symptoms should prompt immediate assessment, and the appearance of bleeding or bruising justifies a full blood count [5, 39]. Fever with urosepsis, respiratory difficulty due to secretions or aspiration and prolonged seizures are the main emergencies [3, 5].

4.5. Newborn screening

None of the entities is the subject of biochemical newborn screening; diagnosis depends on clinical recognition and sequencing [5, 8].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria for classic SGS

Source: GeneReviews, adapted from Lehman and colleagues [5, 27]. The 13 patients of the 2010 study met these criteria [1]. The 2025 Delphi panel did not propose alternative criteria, but defined the core features that, with a gain-of-function variant, allow the patient to be managed as SGS: developmental delay (93%), prominent forehead (82%), midface retraction (82%), large fontanelles (80%), hydronephrosis (79%) and hypertrichosis (77%), to which a short upturned nose and hypertelorism are added (75%); for the atypical form, a confirmed pathogenic variant (90%), a milder phenotype with craniofacial findings (80%) and developmental delay (70%) [3]. There are no clinical criteria for SETBP1-HD [8].

5.2. Molecular tests

When SGS is suspected, the Delphi panel recommends always seeking a molecular diagnosis (89%), with rapid genome sequencing (93%) or exome or SETBP1 sequencing (77%); exome and genome have the advantage of identifying another cause if SGS is not confirmed [3]. GeneReviews prefers a multigene panel that includes SETBP1 and reserves single-gene testing for limited resources or for patients meeting Lehman's criteria [5]. Sequencing detects all pathogenic SGS variants described, and intragenic deletions or duplications are not expected [5].

In SETBP1-HD, in a child with developmental delay, one may start with a chromosomal microarray, which detects 18q12.3 deletions, and proceed to an intellectual disability panel or exome; some panels do not include SETBP1, and single-gene testing is rarely useful [8]. About 88% of pathogenic variants are detected by sequencing and 12% by deletion/duplication analysis [8].

5.3. Limitations of the tests

Exome sequencing and microarray may fail to detect balanced rearrangements that disrupt the gene; two of three patients with structural rearrangements in SETBP1 had a normal microarray, and characterisation required optical genome mapping and genome sequencing [12]. Analysis of parental leucocytes does not detect all somatic mosaicism or exclusively germline mosaicism [5]. A negative result does not exclude the disease, and a clinical diagnosis of SGS without an identified variant is possible: not all patients with a compatible clinical picture have a detected SETBP1 variant [37]. The proportion of variants detectable by each method is not equivalent to the clinical sensitivity of the test [8].

5.4. Interpretation and report content

The report should state the gene, the MANE transcript and version (NM_015559.3), the HGVS c. and p. description, the zygosity, the origin (de novo, inherited or undetermined) and the classification according to the ACMG/AMP (American College of Medical Genetics and Genomics / Association for Molecular Pathology) criteria, in which pathogenic and likely pathogenic are equivalent for clinical decision-making [5, 11]. The location of the variant defines the entity: within residues 868–871 (classic SGS), adjacent (atypical SGS), truncating or deletion (SETBP1-HD) or distant missense (SETBP1-RD) [5, 8]. A variant of uncertain significance neither establishes nor excludes the diagnosis; the Delphi panel recommends managing as SGS a patient with a suggestive phenotype and a de novo variant of uncertain significance near the degron [3, 5]. For variants outside the degron, segregation, the PhenoScore tool (which combines automated facial analysis and Human Phenotype Ontology terms) and functional assays help with classification [9].

In patients with myeloid neoplasms, the SETBP1 variants described on blood or bone marrow panels are somatic, confined to the neoplastic cells and acquired during the course of the disease, and do not indicate hereditary predisposition [8, 33].

5.5. Non-molecular investigations

The skeletal survey documents sclerosis of the skull base, wide synchondroses, cortical density and broad ribs; renal and bladder ultrasound documents hydronephrosis; EEG and brain and spinal MRI complete the neurological assessment, and liver ultrasound and alpha-fetoprotein (AFP) are part of the initial tumour assessment [5]. There is no diagnostic biochemical biomarker [5, 8].

5.6. Prenatal and preimplantation diagnosis

Once the variant has been identified in a family member, prenatal diagnosis and preimplantation genetic testing are possible [5, 8]. In the presence of suggestive fetal anomalies, amniocentesis with exome or genome is the route recommended by the Delphi panel [3].

6. Differential Diagnosis

AR, autosomal recessive; AD, autosomal dominant.

In patients with complete classic SGS, the combination of the facies, hydronephrosis and radiological changes is usually enough for clinical recognition; the differential diagnosis matters mainly in moderate or atypical forms, without hydronephrosis, and in infants with coarse facies, in whom lysosomal and peroxisomal diseases should be excluded [3, 5]. Osteodystrophy with coarse facies was singled out by the experts as a particularly relevant differential diagnosis [3]. In SETBP1-HD, the phenotype has no distinguishing features, and the differential diagnosis encompasses all forms of intellectual disability with severe speech disorder, resolvable only by genetic testing [8]. The SETBP1 variants described in patients with myeloid neoplasms and without a syndromic phenotype are somatic and not inherited [5, 8].

7. Treatments and Risk Management Strategies

7.1. Sources of recommendations and general principles

There is no mechanism-directed treatment for any of the SETBP1-related diseases, and management is supportive [5, 8]. For SGS, the references are the 2024 GeneReviews chapter, which reflects the authors' experience, the 2025 international Delphi consensus, with 81 recommendations approved out of 94 proposed by a panel of 20 experts from the United States (15), the United Kingdom (4) and the Netherlands (1), with a consensus threshold above 70%, and the 2025 AACR update on tumour surveillance [3, 5, 39]. For SETBP1-HD, the reference is the 2021 GeneReviews, revised in 2024, with the care recommendations proposed in the 2021 series [8, 31]. None of these sources derives from clinical trials; the Delphi consensus had a targeted, non-systematic literature review and convenience sampling through the patient foundation, and several recommendations rest on few responses (n between 4 and 18) [3].

The Delphi panel defined as principles shared decision-making with parents or carers, who should be involved and informed as much as possible (100%), early and continued involvement of a multidisciplinary team and early education, from diagnosis, about what palliative care can offer in daily life (100%) [3]. The recommendations apply to any patient with confirmed SGS or with a suggestive phenotype and a gain-of-function variant, including variants of uncertain significance near the degron, and their frequency should be adapted to the clinical situation, local guidance and the family's goals of care [3].

7.2. Schinzel-Giedion syndrome: initial assessment

GeneReviews allows a whole-body MRI at diagnosis to study the brain, lung, spinal cord, pancreas, liver, spleen and urinary tract; in atypical SGS, the benefit of examinations requiring anaesthesia should be weighed against a tumour risk that has not been described [5].

7.3. Schinzel-Giedion syndrome: treatment by system

7.3.1. Epilepsy and emergency plan

Epilepsy is treated with antiseizure medications, ACTH or corticosteroids according to the usual protocols, by an experienced neurologist; no drug has shown specific efficacy in SGS, and seizures are often refractory, including to the ketogenic diet [5]. The Delphi panel recommends a written emergency plan, with training of carers in the administration of rescue benzodiazepines: buccal or nasal midazolam as first choice and rectal diazepam as second (100% agreement, n=7) [3]. The panel did not set doses; the reference doses are those on the medicine labels, and the choice of formulation depends on age and availability in each country [3, 60, 61].

The 2025 Delphi consensus mentions nasal diazepam from 6 years and nasal midazolam from 12 in the United States, and buccal clonazepam as off-label use; the nasal diazepam label has since been extended to 2 years [3, 62]. Benzodiazepines require attention to respiratory depression, especially in patients with hypotonia, aspiration or apnoea; the labels recommend considering a first administration under supervision in patients at increased risk [60, 61]. The experts also recommended considering standardised hormonal treatments for cycle-related seizures, mood changes and menstrual irregularity (82%) [3].

7.3.2. Feeding, reflux and motility

Most children need tube feeding; the Delphi panel recommends using a tube in aspiration, poor weight gain and digestive intolerance (100%) and replacing the nasogastric tube with a gastrostomy or jejunostomy as soon as possible (73%) [3, 5]. Gastro-oesophageal reflux and gastroparesis are treated with the usual drugs, positioning and slow continuous pump feeding (91–100%); Nissen fundoplication may be considered in severe reflux with aspiration (91%), jejunal feeding when aspiration or reflux persists despite gastrostomy (87–91%), venting gastrostomy for bloating and gastric distension (100%) and surgery, such as colostomy, in severe dysmotility (90%) [3]. Constipation is treated with laxatives, colonic irrigation and glycerin or warm water enemas (91%), to which GeneReviews adds stool softeners, prokinetics and osmotic laxatives, daily or as needed [3, 5]. If the patient can feed orally, feeding therapy and thickening or cooling of foods improve safety [5].

7.3.3. Kidney and urinary tract

Hydronephrosis, megacalycosis, nephrolithiasis and multicystic dysplastic kidney should be actively treated (71–100%) [3]. Clean intermittent catheterisation is indicated in bladder atony (71%) and in recurrent infections due to neurogenic bladder (86%); antibiotic prophylaxis may prevent recurrent infections (71%), vesicostomy may be considered in urinary malformations and neurogenic bladder (71%), endoscopic injection (Deflux) treats vesicoureteral reflux (90%), and nephrostomy and bladder catheterisation treat recurrence of hydronephrosis (90–91%) [3, 5]. Renal function should be closely monitored, because recurrent pyelonephritis and structural anomalies cause renal scarring and chronic kidney disease [5].

7.3.4. Airways, lung and sleep

Accumulated secretions are treated with intensive pulmonary hygiene, including nebulisation (100%), oropharyngeal suction with a catheter or Yankauer tip (88%) and airway clearance vests (88%); frequent infections, with chest physiotherapy (100%); recurrent pneumonia due to reflux, with proton pump inhibitors (75%); and aspiration of saliva, with anticholinergics (100%) [3]. Central sleep apnoea is treated with positive pressure (100%) or supplemental oxygen (75%) [3]. Severe respiratory infections are treated as in the general population (71%), although these patients frequently need a higher level of respiratory care; GeneReviews allows antibiotic prophylaxis in recurrent infections [3, 5].

7.3.5. Drooling

Drooling can be treated with anticholinergics (100%), botulinum toxin injections into the salivary glands (100%) or, if clinically indicated, excision of salivary glands (75%) [3]. Oral glycopyrronium is the anticholinergic with an approved indication in severe chronic drooling in children with neurological disease, and its use in SGS and SETBP1-HD falls within that indication; the SETBP1-HD GeneReviews refers to the NICE (National Institute for Health and Care Excellence) evaluation of oral glycopyrronium bromide [8, 64, 65].

Anticholinergic adverse effects (constipation, urinary retention, thickening of secretions) weigh more heavily in this population, which has constipation, bladder atony and frequent respiratory infections, and renal function determines the glycopyrronium dose in the European label [5, 64].

7.3.6. Tone, orthopaedics, skin and teeth

Physiotherapy prevents contractures, scoliosis and hip dislocation, and changes in tone may be an unrecognised source of pain and irritability [5]. Contractures are treated with botulinum toxin (100%); scoliosis and hip dislocation with positioning devices, casts or splints and surgery (75–100%); clubfoot with orthoses (100%) or surgery (75%) [3]. Pressure ulcers justify referral to a wound clinic (100%) [3]. Dental care should address gingival hypertrophy, crowding, hypodontia and delayed eruption, with advice on oral hygiene (100%); severe gingival hyperplasia may require gingivectomy [3, 5, 57].

7.3.7. Vision, hearing and multisensory impairment

Ophthalmological treatment includes correction of refractive errors and strabismus and ocular lubrication in alacrima; cerebral visual impairment has no specific treatment, but vision therapy (100%) and referral to a cerebral visual impairment specialist for educational support, when the eye is structurally normal or when the impairment persists after correction (100%), are recommended [3, 5]. Hearing aids may help, and multisensory (vision and hearing) impairment specialists should be part of the team (100%) [3, 5].

7.3.8. Development and communication

Early referral to a neurodisability specialist and to an early intervention programme from 0 to 3 years, followed by adapted preschool (100%), physiotherapy and occupational therapy (94%) and intensive speech therapy (93%) are recommended [3]. Augmentative and alternative communication (AAC), from picture exchange to speech-generating devices, does not hinder speech and should be assessed early; the 2025 series reinforces early feeding intervention and AAC and the need for instruments sensitive to small changes for future trials [5, 52].

7.3.9. Palliative care and family support

Assessment of the family's needs outside hospital, of palliative or hospice care, social services and home nursing should be routine (78–94%) [3]. Coordination of appointments, equipment and medication and respite for the carer are part of the plan [5].

7.4. Tumour surveillance in Schinzel-Giedion syndrome: divergent positions

The three sources agree on informing the family of the tumour risk and on performing a baseline assessment, but diverge on frequency: GeneReviews proposes a prolonged quarterly schedule, the AACR limits surveillance to the baseline assessment in severe forms and allows periodic surveillance in milder ones, and the Delphi consensus recommends routine surveillance without fixed intervals [3, 5, 39]. In practice, the decision should be shared with the family, taking into account life expectancy, the burden of examinations under anaesthesia and the goals of care; a rapidly growing mass, persistent pain or unexplained symptoms require immediate assessment under any schedule [3, 39]. When a tumour is found, the panel recommends a multidisciplinary meeting with the parents from diagnosis, for a personalised plan that considers comorbidities (100%); treatment follows the protocols for the tumour in question, with reservations about intensification of chemotherapy [3, 5]. SETBP1-HD does not require tumour surveillance, because loss of function does not increase tumorigenesis [8].

7.5. SETBP1 haploinsufficiency disorder

Therapy for apraxia of speech is based on a Cochrane review of interventions for this disorder, cited by the GeneReviews authors, and has not been tested specifically in SETBP1-HD [8, 66]. ADHD medications follow the indications and doses of the respective labels and general guidelines; the sources consulted do not describe a specific response in this disease [8].

7.6. Regulatory status

BUCCOLAM® and SIALANAR® are medicines centrally authorised by the European Commission, valid in Portugal; the sources consulted did not include the Infomed record or registration with ANVISA (Brazilian Health Regulatory Agency) [60, 64].

7.7. Clinical trials and developments

There are no clinical trials that allow the effect of any intervention to be estimated, nor any comparison between studies; the evidence on antisense oligonucleotides is preclinical, the authors have filed a patent and one of the co-authors belongs to an oligonucleotide company, which does not change the level of evidence [46]. In the 12 months before November 2026, the developments were the characterisation of variants outside the degron (2025), the standardised series on communication, feeding and motor function in SGS (2025), animal models of SGS and SETBP1-HD (2025–2026) and the preclinical work with oligonucleotides (2026); there were no specific announcements, marketing authorisation applications, opinions or regulatory decisions [9, 45–47, 52, 67].

7.8. Agents to avoid, anaesthesia, pregnancy and transition

Nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs and vancomycin, should be used with caution in SGS, because of the frequency of renal scarring from pyelonephritis and structural anomalies [5]. The glycopyrronium dose should be adjusted to renal function, and midazolam requires caution in chronic renal impairment [60, 64]. Examinations requiring anaesthesia (surveillance MRI) should be weighed against the anaesthetic risk, choanal stenosis, tracheomalacia, pulmonary hypoplasia and secretions, and the expected benefit [5, 39]. There are no data on pregnancy in patients with SGS, who are not known to reproduce; in SETBP1-HD, there is documented maternal transmission, and pregnancy should be accompanied by genetic counselling and prenatal diagnosis if desired [5, 15]. In the transition to adulthood, patients with SETBP1-HD need vocational and social support plans, and the rare adolescent survivors with SGS need coordinated transfer to adult complex care teams [8, 37].

8. Reproductive Options and Family Counselling

8.1. Mode of transmission and recurrence risk

All entities of the spectrum are autosomal dominant and almost always caused by a de novo variant [5, 8]. In classic SGS, there was recurrence in siblings with a clinical diagnosis in two families (the siblings of the original description and the siblings described by Antich and colleagues in 1995), attributed to parental germline mosaicism [5, 19, 68]. In atypical SGS, a missense variant was transmitted by an unaffected parent, without mosaicism being excluded, and in a family with SETBP1-HD recurrence in siblings was attributed to presumed parental mosaicism [5, 8, 14]. A dizygotic twin pregnancy with one affected and one normal twin illustrates the usual sporadic nature [58].

8.2. Parental testing and cascade testing

Once the variant has been identified in the proband, testing of the parents is recommended to establish the recurrence risk; testing in leucocytes does not detect all cases of somatic mosaicism or exclusively germline mosaicism [5, 8]. In SETBP1-HD, the variant may be present in a parent with intellectual disability or with mild manifestations, as in a family in which the mother with intellectual disability, a son and a fetus had NM_015559.3:c.2425C>T p.(Gln809Ter) [15]. Asymptomatic siblings of a patient with a de novo variant do not need testing for clinical purposes [37].

8.3. Prenatal and preimplantation diagnosis

Once the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible, and may be considered even when the variant is de novo, because of the residual risk of mosaicism [5, 8]. The best time to discuss the options is before a new pregnancy [5]. In the absence of a family history, suggestive ultrasound anomalies justify amniocentesis with exome or genome sequencing and fetal echocardiography [3]. In inherited SETBP1-HD, a prenatal diagnosis preceded by fetal cortical anomalies led to termination of pregnancy at 30 weeks [15]. Views on prenatal diagnosis vary among professionals and families, and the decision is a personal one [5].

8.4. Counselling in tumour predisposition syndromes

The 2026 ERN GENTURIS (European Reference Network on Genetic Tumour Risk Syndromes) guideline, with 16 recommendations based on 851 publications and consensus, recommends proactively offering reproductive counselling to all people with a tumour predisposition syndrome and to relevant relatives, with psychological support and multidisciplinary collaboration; Orphanet links this guideline to SGS [2, 69]. In SGS, counselling is directed mainly at the parents, because patients are not known to reproduce; young adults with mild SETBP1-HD should receive counselling on the 50% risk for offspring [5, 8].

8.5. Minors

When the proband's variant is de novo, the risk for other relatives is low, and siblings without signs of the disease were not tested in the case described in section 10; testing a child with clinical signs is part of the diagnostic assessment, and any request to test an asymptomatic minor should be discussed in a genetics clinic [5, 37].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

Orphanet classifies SGS and SETBP1-HD with a prevalence below 1 per 1 000 000; these categories do not derive from population studies [2, 7]. The birth prevalence of SGS is unknown; the published numbers are case counts: about 80 patients according to Smith (2022) and the Delphi consensus, about 90 according to Beaman and colleagues, more than 50 with molecular confirmation and more than 40 with a clinical diagnosis before 2010 according to GeneReviews, and five with atypical SGS [3, 5, 16, 37]. For SETBP1-HD, GeneReviews counted 47 published individuals with clinical data in 2024, with others recorded in databases without sufficient clinical information; the prevalence is unknown [8]. SETBP1 haploinsufficiency was identified in a large cohort of children with developmental delay, but that study does not measure population prevalence [13]. Counts of published cases do not convert into population rates [8].

9.2. Geographical distribution

The sources consulted describe no founder population or founder variant; the same hot spot variants recur in patients of different origins, always de novo [5, 10]. The 13 patients of the 2010 study were of European ancestry (Europe, New Zealand, Australia and the United States); there are published patients from Thailand, Japan, Korea, China, Turkey, Spain, France, Italy, the United Kingdom and India [1, 5, 32, 37, 58, 70, 71]. The Delphi panel brought together experts from the United States, the United Kingdom and the Netherlands [3].

9.3. Portugal and Brazil

In Portugal, Santos, Cordeiro, Medeira, Mendonça, Lobo Antunes and Coelho Rosa published in 1994 the case of a girl with typical SGS (face, skeletal changes and hydronephrosis) with central hypothyroidism and central diabetes insipidus, secondary to a posterior fossa malformation with arachnoid cysts and stretching of the pituitary stalk; neonatal TSH was normal [1, 54]. In Brazil, Carvalho and colleagues described in 2015 two unrelated patients with SGS, one with a novel SETBP1 variant, and reviewed the literature, highlighting the facial gestalt associated with neurological involvement as the key to suspicion; the 2017 international series included patients followed at the Instituto Fernandes Figueira (Fiocruz, Rio de Janeiro) and in Ribeirão Preto (University of São Paulo) [4, 72]. The sources consulted provide no frequency data for either country.

9.4. Special populations

Patients with SGS are children with complex care needs, and survival into adolescence is rare; there are no data on adults with classic SGS [5, 37]. In SETBP1-HD, the adults described have normal life expectancy, and adult behavioural and neurological evolution is poorly documented [8]. Children with combined visual and hearing impairment need multisensory impairment specialists [3].

9.5. European network, registries and patient associations

The relevant European network is ERN ITHACA (European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability) [18]. The Schinzel-Giedion Syndrome Foundation maintains an international patient registry and promoted the Delphi consensus; the SETBP1 Society brings together families with SETBP1-HD and related disorders; the Simons Searchlight registry collects natural history data on rare neurodevelopmental diseases, including SETBP1, and Apraxia Kids supports families of children with apraxia of speech [5, 8, 67, 73, 74].

10. Illustrative Clinical Case

Beaman and colleagues described in 2025 a girl with SGS and prolonged survival, diagnosed on the basis of a urological anomaly [37]. The daughter of non-consanguineous parents of Irish origin, with two healthy siblings, she had a normal prenatal anomaly scan and was born at term weighing 3.88 kg (75th centile). At six months, recurrent febrile urinary tract infections prompted an ultrasound that showed 9.7 mm dilatation of the left distal ureter and left hydronephrosis; voiding cystourethrography was normal, without reflux, and the mercaptoacetyltriglycine renogram showed 47% function on the left. The diagnosis was primary non-refluxing megaureter, and antibiotic prophylaxis was started [37].

At four years she had another episode of urosepsis, with debris in the left renal pelvis and creatinine of 23 µmol/L; an abrupt narrowing of the distal ureter was dilated with a 5 French balloon and a stent was placed across the vesicoureteric junction, removed five months later. The hydronephrosis did not recur, and at 11 years the kidneys measured 10.9 and 11.1 cm, with normal parenchyma [37]. At 11 years she measured 152 cm (86th centile), weighed 53.4 kg (93rd centile) and had a head circumference of 53 cm (61st centile); she had a narrow head with reduced bitemporal diameter, prominent forehead, full cheeks, narrow palpebral fissures and curvature of the second and fourth fingers of the left hand and of the fourth toes. She said her first words at two years and walked at 30 months; at 12 years she communicated with few words and had a diagnosis of autism spectrum disorder; she had several febrile seizures, right divergent strabismus and reduced tear production, without deafness, feeding or bowel problems [37].

Exome sequencing identified NM_015559.3:c.2613T>G p.(Ile871Met), confirmed by Sanger and absent in both parents; there were no variants in 14 genes associated with lower urinary tract anomalies, and SETBP1 was not altered in eight other patients with megaureter [11, 37]. Immunohistochemistry of human fetal tissue showed SETBP1 in the urothelium of the ureter and pelvis, in periureteral and renal hilar nerve trunks and in a subset of tubules, which suggests a role in ureteric differentiation [37]. The authors attributed the survival and the absence of classic features (short nose, marked midface retraction, microcephaly, deafness and epilepsy) to the novel variant, without excluding that the variability reflects the historical bias of publishing only patients with the complete picture [37].

The case shows that SGS should be considered in the presence of a urinary tract anomaly with developmental delay and dysmorphic signs, even without the complete phenotype, and that variants of residue 871 may be associated with milder pictures, consistent with the weak effect of these substitutions on protein stability [4, 37]. The urological management described (dilatation and stent) is that of an individual case and not a general recommendation. The figures were consulted on the publisher's page: Figure 1, with pedigree, photograph at 12 years and electropherograms (https://www.frontiersin.org/files/Articles/1534192/xml-images/fped-13-1534192-g001.webp); Figure 2, with ultrasound images of the ureter and kidney, ureterogram with stent and resolution of the hydronephrosis (https://www.frontiersin.org/files/Articles/1534192/xml-images/fped-13-1534192-g002.webp); and Figure 3, with the fetal immunohistochemistry (https://www.frontiersin.org/files/Articles/1534192/xml-images/fped-13-1534192-g003.webp) [37].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

In classic SGS, life expectancy is reduced and relates to the number and severity of manifestations; the older series describe frequent death before two years and most before ten, from pneumonia, aspiration, sepsis, pulmonary hypoplasia, intractable epilepsy, tumours or sudden cardiac arrest, with rare adolescent survivors [5, 16, 28, 37]. Among the 13 patients of 2010, the known deaths occurred between 3 months and 9.25 years [10]. The Delphi consensus stresses that complex multidisciplinary care may improve quality and length of life, but there are no survival data under such care [3]. Individuals with atypical SGS or with variants of residue 871 may have a more favourable course, with survival into adolescence described [5, 37]. In SETBP1-HD, life expectancy does not appear to be reduced, and functional prognosis depends on the severity of the speech disorder, intellectual disability and behaviour [8].

11.2. Surveillance in Schinzel-Giedion syndrome

The GeneReviews tumour surveillance intervals derive from protocols for other childhood cancer predisposition syndromes, and the three sources diverge on frequency (section 7.4) [3, 5, 39].

11.3. Surveillance in SETBP1 haploinsufficiency disorder

SETBP1-HD requires neither tumour nor renal surveillance [8].

12. Summary and Final Considerations

SETBP1, at 18q12.3, encodes a nuclear protein that binds the SET oncogene and regulates transcription, and whose quantity is controlled by a degron in exon 4. Variants that inactivate this degron lead to protein accumulation and cause Schinzel-Giedion syndrome, a multisystem disease with characteristic facies, profound intellectual disability, refractory epilepsy, cerebral visual impairment and deafness, hydronephrosis and other urinary anomalies, genital and skeletal anomalies and a risk of neuroepithelial and embryonal tumours, especially sacrococcygeal teratoma; variants adjacent to the degron give milder atypical forms, although some produce the complete picture. Loss of one copy of the gene causes SETBP1 haploinsufficiency disorder, centred on apraxia of speech and language disorder, with mild motor delay, variable intellectual disability and ADHD-like behaviour, without visceral malformations or tumour risk. Missense variants outside the degron form a third group, with loss of function independent of protein abundance and severity that decreases with distance from the degron.

Diagnosis rests on exome or genome sequencing (rapid in the severely ill newborn) and, in haploinsufficiency, also on microarray and, when these are negative, on the search for structural rearrangements. The location of the variant determines the entity and, with it, management. In Schinzel-Giedion syndrome, the 2025 Delphi consensus organises care around shared decision-making, an early multidisciplinary and palliative team, the emergency seizure plan with buccal or nasal midazolam, gastrostomy feeding, active urological treatment, polysomnography and tumour surveillance, whose frequency differs between GeneReviews, the AACR and the consensus itself. In haploinsufficiency, intensive speech therapy, early augmentative communication and treatment of ADHD and anxiety are the main interventions. There is no approved targeted therapy and no clinical trials; antisense oligonucleotides that reduce SETBP1 prevented hydrocephalus in a murine model of Schinzel-Giedion syndrome, a result that is still preclinical. Genetic counselling is based on the usual de novo occurrence, a residual risk of germline mosaicism and the 50% risk for the offspring of adults with haploinsufficiency.

13. References

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