Pallister–Killian Syndrome (Mosaic Tetrasomy 12p)

Literature and regulatory information updated: 6 October 2026.

Pallister–Killian syndrome (Pallister mosaic syndrome, Killian/Teschler-Nicola syndrome, mosaic tetrasomy 12p, isochromosome 12p mosaicism)

0. Initial Reference Table

1. Introduction

Pallister–Killian syndrome is a rare chromosomal abnormality defined by the mosaic presence, restricted to certain tissues, of a supernumerary isochromosome consisting of two copies of the short arm of chromosome 12, increasing the number of 12p copies to four in cells carrying it [1, 2]. It combines variable developmental and intellectual disability, epilepsy, skin pigmentation abnormalities and a characteristic facial appearance, accompanied in variable proportions by pulmonary, cardiac, renal, gastrointestinal, genitourinary, ophthalmological and auditory malformations [2]. It is a prototype of tissue-distributed mosaic aneuploidy, and this biological property, more than rarity, determines diagnostic difficulty: the isochromosome is found in skin fibroblasts and slowly renewing tissues, but rarely in peripheral blood, the usual postnatal cytogenetic sample [1, 15].

The entity's history involves several partial phenotypes converging on the same cytogenetic diagnosis. In 1977, Philip Pallister and colleagues described adults with intellectual disability, unusual facies and marker chromosome mosaicism in the Birth Defects Original Article Series, under the designation “Pallister mosaic syndrome” [1, 25]. In 1981, Teschler-Nicola and Killian described a 3-year-old girl with intellectual disability, unusual facial appearance and abnormal hair, and in 1983 Schroer and Stevenson reported a second case; only subsequently was it recognised that Pallister's adults and Killian's children shared the same condition [1]. According to OMIM, tetrasomy 12p was not recognised in the initial descriptions because fibroblasts were not studied; according to a personal communication from Pallister (2003) cited there, fibroblast chromosomes had in fact been analysed by his colleague Lorraine Meisner, but the unidentified chromosome was misinterpreted [3]. OMIM also highlights the relative frequency of diaphragmatic defects and supernumerary nipples in the founding descriptions [3]. In 1985, Hunter and colleagues concluded that a patient they had published as “tetrasomy 21” actually had tetrasomy 12p and emphasised that the abnormal line was virtually confined to fibroblasts [26]. That same year, Gilgenkrantz and colleagues published the first prenatal diagnosis, confirmed by enzyme assays, and summarised cases published under different names [27]. In 1986, Raffel and colleagues described the first patient with isochromosome mosaicism also in lymphocytes [28]. In 1987, Peltomäki and colleagues confirmed molecularly that the marker consisted of two identical short arms of chromosome 12, consistent with an isochromosome, and Warburton and colleagues confirmed the 12p origin of the supernumerary chromosome in one original Pallister mosaic syndrome case [3]; that year, Reynolds and colleagues assembled 11 patients, ranging from a 22-week fetus to a 45-year-old man, and proposed that the abnormality pattern permitted clinical diagnosis [29, 30].

Since then, phenotypic delineation has relied on series assembled at family meetings and national cohorts. The series of 59 individuals assessed at family meetings of the US foundation dedicated to the syndrome in 2006, 2008, 2009 and 2010, compared with 152 literature cases, expanded the clinical spectrum and reaffirmed a mild developmental variant [14]. The British study of 22 patients, the first with population-based data, estimated birth incidence and showed that high birth weight and profound intellectual disability, described as classical, are not universal [12]. More recently, Italian groups prospectively characterised sleep, cognitive and sensory profiles and structural brain abnormalities [31–33]. The syndrome has no GeneReviews chapter or specific clinical guideline identified in consulted sources; the Orphanet record, reviewed by experts from the European ERN ITHACA network and updated in March 2025, constitutes the European reference synthesis [2].

2. Molecular Genetics and Pathophysiology

2.1 Isochromosome 12p and tetrasomy

Isochromosome i(12)(p10) is a supernumerary metacentric chromosome whose two arms are mirror copies of 12p, joined at the centromeric region (band p10); because each carrier cell retains both normal chromosomes 12, the result is tetrasomy 12p and disomy 12q [2, 23]. Generally, the marker contains virtually the entire short arm: microarray studies describe gains of approximately 34 Mb from 12p13.33 to 12p11.1, with over 200 OMIM-annotated genes [8, 34]. In mosaics, the microarray signal ratio reflects a mixture of cells with two and four copies, so reports frequently express copy number as “×2~4” or “×3” rather than “×4” [8, 9]. Published coordinates mostly refer to reference genome GRCh37/hg19 and are reproduced here as published, without conversion to GRCh38. As this is a chromosomal alteration, there is no sequence variant to normalise using HGVS nomenclature; the relevant nomenclature is ISCN, for example mos 47,XX,+i(12)(p10)[1]/46,XX[99] for a karyotype in which one of 100 metaphases contains the isochromosome [34].

Structural variants with the same phenotype are described. Mosaic hexasomy 12p results from two isochromosomes in the same cell; in one published case it was present in 20% of fibroblasts in a girl with mild delay, dilated hypertrophic cardiomyopathy, polydactyly and hypopigmented patches, and in another in a girl followed for 10 years with severe global delay, epilepsy and cardiomyopathy [4, 35]. In Vogel and colleagues' 5-year-old girl, hexasomy was found in 18% of fibroblasts by FISH and comparative genomic hybridisation, and at 5 years delay was mild, with an intelligence quotient of 81; the first live case, described by Choo and colleagues, had 35% tetrasomy and 15% hexasomy, cleft palate, rhizomelic shortening and CDH [3]. These cases did not confirm the hypothesis that more copies would imply a more severe phenotype, and Vogel and colleagues attributed phenotypic variation mainly to the tissue types containing the mosaic line [3, 4]. In the British series, two of 22 patients (9.1%) had hexasomy 12p [3, 23]. Analphoid markers with inverted duplication of 12pter-12p12.3 or 12pter-12p13.31 have also been described, maintaining centromeric function without usual alpha satellite sequences and contributing to narrowing the critical region [5, 36]. In Lyon, a child with a classical phenotype had a derivative from an exchange between the two chromosome 12 homologues, with distal tetrasomy 12p13.33p12.1 and trisomy 12p12.1q12 [7]. In one girl, tetrasomy resulted from a supernumerary ring chromosome with two copies of 12p13-cen, present in 38% of buccal mucosal cells and 41% of fibroblasts and absent from blood; the authors attributed better-than-usual developmental progress up to 2 years to the smaller tetrasomic segment or a different tissue distribution, possibly postzygotic in origin [3]. Finally, trisomy 12p due to interstitial duplication or unbalanced translocation produces an overlapping presentation, requiring distinction between these potentially inherited forms and the sporadic isochromosome [1, 2, 6].

2.2 Origin of the isochromosome

The formation mechanism is incompletely understood and proposals are not mutually exclusive. Polymorphic marker analysis favours maternal meiosis II nondisjunction followed by abnormal centromeric division in most patients: a chromosome 12 trisomic zygote would be non-viable unless secondary isochromosome formation eliminates acentric long arms [10, 37]. In a 1999 review, all determined-origin cases except one were maternal, and the authors considered a premeiotic mitotic error [11]. In the Turkish series of 15 patients, origin was maternal in six of seven cases studied and paternal in one, without phenotypic differences between groups, making an imprinting effect unlikely [10]. Cases with maternal prezygotic origin, with three distinct fibroblast alleles, and a fetus with a paternal isochromosome and 47,+12 and 47,+i(12p) lines, interpreted as postzygotic formation, exist [38, 39]. Occurrence is associated with advanced parental age: the population-based British study showed a statistically significant risk increase with parental age without distinguishing maternal from paternal contribution, and in the US series mean maternal age was 31.7 years and paternal age 34.9 years [9, 23].

2.3 Tissue-distributed mosaicism

The defining feature of the syndrome is uneven isochromosome distribution between tissues and over time. The isochromosome is detected in amniocytes, chorionic villi, skin fibroblasts and bone marrow, but rarely peripheral blood lymphocytes; in a review cited in several series, detection rates were 0–2% in lymphocytes, 50–100% in fibroblasts and villi and 100% in amniocytes and bone marrow [1, 8, 13, 15]. In a French collaborative study of 19 fetuses and children, mosaicism ranged from 1–3% in lymphocytes to 6–100% in amniocytes, chorionic cells and fibroblasts [40]. Orphanet indicates isochromosome presence in 30–100% of fibroblast metaphases [2]. In a newborn, direct bone marrow preparations had the isochromosome in 100% of metaphases, phytohaemagglutinin (PHA)-stimulated marrow in 23%, the first blood culture in 10% and, at 2 months, none; the isochromosome was present in all lung and testicular metaphases [41].

Several phenomena explain this distribution. In rapidly renewing tissues such as blood and marrow, the abnormal line tends to be replaced by the normal line; in slowly renewing tissues such as skin and buccal mucosa, it persists longer [23, 42]. Isochromosome-carrying lymphocytes divide poorly following PHA stimulation, so the proportion of positive interphase nuclei exceeds that of metaphases, and loss is not primarily due to anaphase lag [43]. In cultures, the isochromosome is more stable in fibroblasts than blood, amniocytes or marrow, is more frequent in young cultures and young donors, particularly fetal donors, and the proportion of abnormal mitoses falls during prolonged fibroblast culture and amniocyte subculture [29, 44, 45]. In a newborn described by Schubert and colleagues, the isochromosome was in 4% of cultured lymphocytes and 93% of fibroblasts, falling to 40% and 28% in the fourth and fifth subcultures; in a fetus in the same study, absent from fetal blood at 21 weeks, it was present in 100% of metaphases from prolonged umbilical cord culture [3]. Wenger and colleagues concluded that tissue mosaicism is best explained by in vivo, and perhaps also in vitro, isochromosome loss from 47,+i(12p) cells [3]. In a single nucleotide polymorphism (SNP) microarray study, blood isochromosome frequency decreased with age but remained stable in fibroblasts [37]. Among 3124 small supernumerary marker chromosome cases, 52% were mosaics, but all Pallister–Killian syndrome patients are, distinguishing it from entities such as Emanuel or cat-eye syndrome [46].

The abnormal cell proportion measured in one tissue does not predict severity. Unique and several series emphasise that severely affected children may have low proportions and mildly affected children high proportions because counts in accessible tissues do not reflect the brain or other organs during development [9, 10, 23]. In the Turkish series, severity was independent of karyotypic mosaicism level, and the British study found no genotype–phenotype correlation in any studied tissue [10, 12]. In an Egyptian report, the patient with profound impairment had 40% tetrasomic fibroblasts and the patient with moderate impairment 25%, an observation of two cases that cannot be generalised [47].

2.4 Critical region and dosage consequences

Comparison of patients with partial 12p duplications and a Pallister–Killian phenotype defined a minimum critical region at 12p13.31 [1, 6]. The region includes approximately 26 candidate genes, including ING4 and CHD4, involved in transcriptional regulation, chromatin remodelling and the cell cycle, although no evidence attributes a specific phenotypic component to any one of them [8, 9]. De novo variants in CHD4 in this region cause a distinct monogenic entity, Sifrim–Hitz–Weiss syndrome, with overlapping facial phenotype and milder intellectual disability [8].

Functional studies show that isochromosome effects extend beyond 12p genes. In fibroblasts from 17 patients, 354 genes showed altered expression (180 increased and 174 decreased), with enrichment in developmental genes such as homeobox genes, decreased ZFPM2, GATA6 and SOX9, and IGFBP2 overexpression, and further evidence for the 12p13.31 critical region [48]. In single-cell clones from one patient, 13% of 12p genes were overexpressed, including ATN1, COPS7A and NECAP1 in 12p13.31, but the median increase was 1.3-fold, below that expected for tetrasomy, indicating partial dosage compensation; 89% of dysregulated genes lay outside 12p, and isochromosome-containing cells showed hypomethylation of gene-poor 12p regions [49]. The 12p microRNAs are overexpressed in fibroblasts, with reduced targets such as MEIS2 and UQCRB, suggesting an additional mechanism of pleiotropic effects [50]. Approximately 60% of fibroblast lines secreted more IGFBP2 than controls and serum IGFBP2 was elevated in 40% of patients, who had the most severe postnatal growth retardation, offering a hypothesis for neonatal macrosomia followed by growth deceleration [51]. For the neurological phenotype, 63 nervous-system-enriched 12p genes and minimal regions associated with atrophy (12p13.33–12p13.2) and corpus callosum abnormalities (12p13.33–12p12.3) were identified [52].

3. Clinical Spectrum and Manifestations by Organ System

3.1 Data sources and ascertainment biases

Available frequencies derive from different populations and are not directly comparable. The US Children's Hospital of Philadelphia (CHOP) cohort was recruited at family meetings and underpinned epilepsy, cardiac and gene expression series; system-specific frequencies summarised by Stone and colleagues from this cohort and the Izumi and Krantz review are most frequently cited [13, 14, 53]. The British study sought all patients in Great Britain and applied structured assessment to 22 participants aged 4 months to 31 years [12]. Italian series are prospective but focused on paediatric neurology [31–33], and prenatal diagnostic series overrepresent diaphragmatic hernia because it prompts targeted investigation [54]. No patient in a French postnatal series had CDH, which the authors attributed to fetal death or pregnancy termination associated with this malformation, and Unique notes that families of patients with more severe heart disease may not participate in studies; postnatal cohorts thus tend to underrepresent the most severe cases [7, 23].

3.2 Growth

The characteristic pattern is normal or increased birth weight, length and head circumference, followed by postnatal length and head circumference deceleration, with a frequent tendency towards obesity [1]. Prenatal overgrowth is described as weight, length and head circumference above the 50th percentile [13]. In the British series, however, all birth weights were within 2.67 standard deviations of the mean, and macrosomia should not be required for diagnosis [12]. The anterior fontanelle closes late and puberty occurs at the normal age in girls and is delayed in boys [8]. Elevated serum IGFBP2 in 40% of patients, associated with more marked postnatal growth retardation, and low IGF-1 described in a Romanian patient support an endocrine mechanism hypothesis, not yet translated into therapeutic guidance [8, 51].

3.3 Craniofacial phenotype and its evolution

In infants, the most characteristic findings are sparse frontal and particularly temporal hair, sparse eyebrows and eyelashes, prominent forehead, ocular hypertelorism, epicanthal folds, broad flat nasal root, short nose with anteverted nares, full cheeks and a long philtrum with a thin upper lip and marked Cupid's bow [1]. At birth, temporofrontal baldness combined with abundant vertex hair creates a pattern Schinzel compared to a “Mohawk” hairstyle, which later disappears [3]. In the British series, all babies lacked frontotemporal hair, which gradually improved, but most retained alopecic areas or other hair and eyebrow abnormalities [3]. Extension of philtral skin into the upper lip vermilion is termed “Pallister lip” and was recorded in all Philadelphia cohort probands [2, 13]. Other findings include a high palate or cleft palate or uvula, micrognathia, large low-set posteriorly rotated ears with thick lobules, ear pits and a short neck, sometimes with redundant skin folds [1, 55]. Oxford describes a forehead appearing broad because of a high hairline and temporal sparsity, a large mouth and full philtrum, with usually normal head circumference [15, 55].

Facial appearance changes with age. Initially sparse anterior hair grows between 2 and 5 years; the tongue, normal-sized in newborns, becomes macroglossic; micrognathia evolves into prognathism; and the adolescent and adult face is coarse, with thick lips, an everted lower lip, broad nasal root and high forehead [1]. In older children and young adults, initial hypotonia may be replaced by muscular hypertonia with contractures [56]. Recognition of this adult phenotype enabled targeted cytogenetic investigation in a 36-year-old man with profound impairment and epilepsy [57]. During 16 years of Romanian follow-up, the skull became brachycephalic, frontotemporal alopecia lessened without disappearing, zygomatic regions flattened and the nose changed from flat and broad to tapered [8]. Transient excess forehead and ear hair and iris stromal atrophy with a pinpoint pupil were also described in an infant [8].

3.4 Skin, appendages and connective tissue

Hypopigmented and hyperpigmented streaks or patches along Blaschko's lines are the cutaneous expression of mosaicism and were found in 45% of Philadelphia cohort probands [1, 13]. They may be invisible at birth, become evident only after sun exposure or detectable only with a Wood's lamp, and in a series of 11 patients most had generalised pigmentary dysplasia sometimes visible only with this lamp [13, 23, 30]. In a mildly affected 15-year-old boy, hyperpigmented streaks specifically prompted fibroblast analysis [58]. In the British series, pigmentary lesions were present in 67%, supernumerary nipples in 43%, short broad hands in 57% and limb shortening in 24% [3]. Pericardial agenesis and focal axillary cutaneous aplasia have been described [3]. Other descriptions include loose or redundant skin, lymphoedema, supernumerary nipples, hypohidrosis or anhidrosis and slow-growing nails and hair [1, 8, 12, 23].

3.5 Central nervous system

Development and cognition. Smith describes profound intellectual disability with minimal language, repetitive hand and body movements, self-injurious behaviour, seizures and hypotonia, while recording increasing identification of mildly affected patients through molecular techniques [1]. In a study of 16 patients aged 16 months to 19 years, 11 of the 13 over 24 months had developmental levels below 8 months and were non-ambulant and non-verbal; two could walk and speak, and one fulfilled autism criteria [59]. In the British study, intellectual disability was mild or moderate in 27.6%; almost three-quarters of individuals over 18 months did not speak, and approximately 38% acquired walking, versus 17% in the US series and 30% in a 1997 French estimate [12, 23]. In a prospective Italian study of 22 patients aged 9 months to 28 years, all aged 42 months or less had psychomotor delay and, among those older than 42 months, 15 had a low quotient and one was in the normal range; stereotypies were frequent and more intense with lower Vineland-II adaptive scores, and the sensory profile predominantly showed low registration, sensory seeking and tactile and auditory hypersensitivity [32]. Patients with high or near-normal cognitive functioning have been published, including an adolescent who attended mainstream school until 14 years and a child with almost normal development after Burkitt lymphoma treatment [58, 60, 61]. Distinguishing tetrasomy 12p from classical Pallister–Killian syndrome matters: some i(12p) carriers have mild learning difficulties and isolated pigmentary changes [62, 63].

Epilepsy. In a structured survey of 51 patients with confirmed tetrasomy 12p (median age 4 years 9 months), 27 (53%) had epilepsy, beginning before 3.5 years in 85% and with mean onset age 2 years 4 months; the most frequent types were myoclonic seizures (56%), generalised convulsions (48%) and clusters of tonic spasms resembling infantile spasms (30%), and 48% had more than one seizure type [64]. In that series, 96% had received antiseizure medication, 70% continued having seizures and 63% remained on medication [64]. In an Italian multicentre series of 13 children, all had epilepsy, with mean onset at 19 months; epileptic spasms, late-onset or in the first year, were most common, and a significant proportion achieved good control [65]. Epilepsy frequency in previous series ranged from 39% to 59% [65]. Early-onset myoclonic epilepsy with low-frequency photosensitivity (1–6 Hz) and electrographic neonatal seizures have been described, contradicting the notion that newborn seizures are rare [8, 66, 67]. Non-epileptic paroxysmal events are frequent and video-electroencephalographic monitoring (video-EEG) was decisive in distinguishing them; EEG shows slow background activity and generalised and focal paroxysms [68]. Seizures may first occur in adolescence or adulthood, and in three French patients began between 4 and 7 years [7, 23].

Neuroimaging. In a review of 93 patients with intracranial investigation, 77.4% had structural abnormalities, mainly ventricular (45.8%), corpus callosum (25.0%) and cerebral atrophy (29.2%), with macrocephaly in 12.5% and polymicrogyria in 4.2% [52]. The first systematic magnetic resonance study, with blinded review of 31 Italian children, found abnormalities in all but one: cerebral hypoplasia/atrophy in 74%, ventriculomegaly in 65% (with communicating hydrocephalus in two), corpus callosum abnormalities in 67% (mainly splenial hypoplasia), enlarged cisterna magna in 50% and polymicrogyria in 48%, always perisylvian and bilateral in 10 of 14 [33]. The pineal gland appeared cystic in 64% of the 28 evaluated patients, and one developed a cystic tumour; imaging findings did not correlate with delay, epilepsy, vision or sleep [33]. In the same authors' literature review, which separated examination types, structural abnormalities were recorded in 34% and polymicrogyria in 4%, far below frequencies in the series with blinded image review [33]. Vermian dysplasia, cortical developmental malformations, white matter abnormalities, atlas assimilation and tethered cord operated on at 5 months are also described [69, 70].

Sleep. In 14 children studied by questionnaire and video-polysomnography for at least 24 hours, 92% had abnormal Sleep Disturbance Scale for Children scores, particularly sleep initiation and maintenance and breathing disorder subscales; polysomnography showed increased arousal index and N3 sleep percentage, reduced sleep efficiency and, in the 10 patients assessable, a higher apnoea–hypopnoea index than controls [31]. Unique describes persistence of the newborn sleep pattern and prolonged sleep requirements in some infants [23].

Autonomic function and behaviour. The British series described new findings of anhidrosis or hypohidrosis (40%) and hyperventilation episodes (23%), suggesting autonomic involvement, and autistic features in 27% [3, 12]. Fever without a focus and infections without fever have also been reported, interpreted as possible hypothalamic dysfunction [8].

3.6 Sensory organs

In the Philadelphia cohort, 77% had hearing loss, usually bilateral, sensorineural in 38%, conductive in 29% and mixed in 33%; 87% had ocular involvement, 75% visual impairment due to strabismus, nystagmus or myopia and 19% legal blindness [1, 13]. In the British series, 17 of 22 had hearing impairment and 17 of 22 visual impairment [23]. Cortical visual impairment, optic nerve atrophy or hypoplasia, ptosis, cataracts, fundal hypopigmentation and retinal pigment epithelium abnormalities are also described, the latter interpreted as retinal pigmentary mosaicism [1, 23, 71]. Cleft palate, high palate and external auditory canal stenosis favour serous otitis and conductive hearing loss, and some patients' hearing improves with age [1, 23].

3.7 Visceral malformations

Heart. Among 81 probands with at least one cardiac assessment, 37% had structural heart disease, most frequently atrial or ventricular septal defects (n = 12), with occasional bicuspid aortic valve, aortic dilatation and hypertrophy or cardiomyopathy; the authors proposed cardiac assessment at diagnosis and longitudinal follow-up [72]. Aortic dilatation was first described in an infant in a three-patient series [73]. In the Brazilian series, two patients had an atrial septal aneurysm [71].

Diaphragm and lung. Congenital diaphragmatic hernia (CDH) was found in 11% of Philadelphia cohort probands but in 11–29% of published cases, depending on ascertainment [13, 71]. In the international Congenital Diaphragmatic Hernia Study Group registry, with 12,553 patients born between 1996 and 2020, Pallister–Killian syndrome accounted for 5.5% of CDH-associated syndromes, with survival to discharge of 39.1% [74]. CDH is the abnormality most strongly determining neonatal survival [1, 23]. Neonatal apnoea, tracheomalacia, supraglottic cyst, severe obstructive apnoea and progressive subglottic stenosis have also been described [23, 52, 75].

Digestive and genitourinary systems and abdominal wall. Gastrointestinal involvement was recorded in 52% of Philadelphia probands, with intestinal malrotation in 12%, umbilical hernias, anteriorly placed anus, dysphagia, gastro-oesophageal reflux and constipation [13]. Imperforate anus, persistent urogenital sinus or cloaca, omphalocele, inguinal hernias, renal abnormalities, hypospadias, cryptorchidism and small genitalia are described [1, 13]. In a surgical report, one newborn required anorectoplasty for imperforate anus with a fistula and another emergency laparotomy for malrotation with volvulus [76].

3.8 Skeleton, limbs and oral cavity

Rhizomelic or proportionate limb shortening, broad hands with short fingers, postaxial polydactyly, fifth-finger clinodactyly, sacrococcygeal appendage, congenital hip dislocation, hyperlaxity, kyphoscoliosis and joint contractures, the latter appearing between 5 and 10 years, form part of the presentation [1, 2]. In three infants, Jamuar and colleagues described a mild but recognisable radiological pattern, with delayed vertebral body and pubic ossification, broad anterior ribs and broad long-bone metaphyses, particularly femoral, and proposed it as a diagnostic sign [73]. In orodental assessment of 21 European probands, 57% had an atypical dental pattern with multiple missing teeth, particularly permanent first molars, and 10% double teeth; gingivitis and caries increased with age, gingival hyperplasia was frequent and the occlusal pattern combined a high palate, mandibular prognathism, anterior open bite and crossbites [77]. Tooth eruption is delayed [1].

3.9 Tumours

There is no established association between tetrasomy 12p and cancer. OMIM records a 15-year-old girl with a pineal tumour and recalls that i(12p) is a frequent cytogenetic marker in testicular and ovarian germ cell tumours and has been observed in pineal germ cell tumours, a somatic context distinct from the syndrome [3]. A child with Burkitt lymphoma, whose authors discuss the location of AICDA, overexpression of which has been implicated in the tumour's t(8;14) translocation, and a 27-month-old girl with pineocytoma have been published [61, 78]. The frequency of pineal cysts in the Italian MRI series, with one cystic tumour, keeps the question open, without data justifying a cancer surveillance protocol [33].

3.10 Natural history

A significant proportion of affected individuals are stillborn or die neonatally; seizures usually begin in childhood and many survivors remain bedridden and without language [1]. Nevertheless, patients have been identified between 40 and 50 years and the oldest published patient was 45 years old [1, 8, 30]. Eight individuals died in the British study, aged between one hour (a birth at 21 weeks) and 38 years; recorded causes were prematurity, aspiration, epilepsy and respiratory infections [23]. In the Brazilian series, one patient died at 5 days from respiratory problems and another at 14 years from pneumonia [71].

4. Clinical Recognition and Red Flags

Clinical recognition is decisive because the most frequently requested test, stimulated lymphocyte karyotyping, is usually normal; Oxford emphasises that without clinical suspicion communicated to the laboratory, mosaicism may not be sought on array or in other tissues [1, 15]. The table summarises signs prompting targeted investigation at each life stage.

In the approach to postnatal mosaicism, Oxford lists sparse temporal hair as suggestive of Pallister–Killian syndrome, alongside body asymmetry, streaky pigmentation and supernumerary nipples, signs shared with other mosaic aneuploidies [15]. In coarse facies assessment, it includes asking about pigmentation along Blaschko's lines and proposes skin biopsy to investigate this syndrome too [55]. In overgrowth assessment, tetrasomy 12p is among chromosomal abnormalities associated with excessive growth [82]. For polyhydramnios, the syndrome is cited in relation to CDH and among fetal overgrowth syndromes [83].

Prenatally, fetuses have a growth profile described as typical, with biparietal diameter and head circumference above the 90th percentile and femoral growth retardation below the 10th percentile, and fetal movements may be reduced [8, 34]. No ultrasound finding is individually specific or constant, and all may be absent: second-trimester ultrasound was normal in two of five pregnancies in a Chinese series [9, 17]. In a French fetal pathology series, facial dysmorphism was most frequent (five of six cases) and only one fetus had CDH, suggesting hernia-recruited series overestimate its frequency [54]. Automated facial phenotypic software analysis completely separated photographs of syndrome patients from unaffected individuals and distinguished them from Emanuel syndrome, and is proposed as an adjunct where molecular cytogenetic access is limited [84].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

No validated formal clinical criteria exist. Diagnosis relies on clinical suspicion, based on facial pattern, streaky pigmentation, hypotonia and associated malformations, and laboratory demonstration of mosaic 12p gain, usually as an isochromosome [2, 30]. Orphanet emphasises that clinical recognition is decisive because the additional chromosome is usually absent in routine lymphocyte testing, and that cytogenetic distinction between mosaic i(12p) and 12p duplication due to unbalanced translocation is essential for counselling [2].

5.2 Postnatal tests and their limitations

Tissue selection is as important as method selection. Peripheral blood is most accessible but has the lowest isochromosome frequency and loses it with age; buccal mucosa and skin retain mosaicism; and cell culture, required for karyotyping, selects against the abnormal line [37, 43, 44]. The table assembles reported performance of each approach, with the caveat that proportions derive from small series of already diagnosed patients, rather than diagnostic accuracy studies in unselected populations.

General consensus documents contextualise these results. The 2010 consensus establishing chromosomal microarray as first-line testing for developmental delay, autism spectrum disorder and multiple congenital abnormalities acknowledges that low-level mosaicism is generally undetectable by arrays [92]. The 2021 American College of Medical Genetics and Genomics (ACMG) guideline recommends considering exome or genome sequencing as first- or second-line testing in these children [93]. In both cases, normal blood results do not exclude the syndrome with a suggestive phenotype because the limitation lies in tissue, not merely method resolution [15, 86].

Published recommendations differ regarding the first step. Alqahtani and colleagues propose early blood microarray before skin biopsy [7]; Karaman and colleagues, interphase buccal FISH with blood karyotype first-line [10]; Costa and colleagues, buccal MLPA before biopsy [71]; Arghir and colleagues, blood and buccal MLPA or buccal DNA microarray for less evident presentations [8]; and Hodge and colleagues maintain that skin tissue remains the reference standard because blood microarray does not detect all cases [86]. Di Donato and colleagues also emphasise that, with suggestive clinical findings, a single positive blood metaphase should not be dismissed and warrants additional tests [34]. Oxford recommends, where suspicion persists with normal blood array and karyotype, karyotype and array in another tissue, such as fibroblasts or skin or saliva DNA, and indicates buccal smear FISH as useful when a recognised mosaic phenotype is suspected [15].

5.3 Postnatal algorithm proposed from the sources

The following scheme is not a published guideline; it systematises recommendations from the above sources and should be adapted to local laboratory availability.

The report should identify the tissue analysed, method, cell number or signal ratio, estimated mosaicism percentage, genomic interval with reference genome version and structural form (isochromosome, analphoid marker, derivative), and record detection limitations [7, 8, 34]. Mosaicism percentage should be interpreted as descriptive of the tissue and collection time, rather than prognostic [10, 23].

5.4 Prenatal diagnosis

Mosaicism is diagnosed in 0.3% of amniocenteses and just over 2% of chorionic villus samples (confined placental mosaicism in 1.9% and true fetal mosaicism in 0.19%), and abnormal cell percentage does not reliably indicate fetal involvement or severity [79]. In Pallister–Killian syndrome, the isochromosome is detectable in amniocytes and fibroblasts but only rarely in fetal blood [79]. False-negative fetal blood, villus and amniotic fluid results have been described, including normal villus karyotype in a fetus subsequently found to have the syndrome [17, 90]. Doray and colleagues proposed, when ultrasound indicators exist, starting with villus or placental sampling and performing amniocentesis if normal, avoiding fetal blood because of low isochromosome frequency in lymphocytes, and using FISH, particularly interphase FISH on uncultured cells [16, 17]. In a Polish series, the aneuploid cell percentage was higher in amniotic fluid than cord blood, and the authors prefer amniocentesis, emphasising laboratory communication to modify routine procedures [18]. In a fetal phenotype review summarised by OMIM, prenatal diagnosis occurred between 13 and 32 weeks, usually incidentally because of maternal age, increased nuchal translucency or fetal abnormality, and the most frequent distinguishing findings were rhizomelic shortening, CDH, thickened nuchal fold, increased prenasal thickness, postaxial polydactyly and polyhydramnios; the authors recommend amniotic fluid sampling because villi may mislead, with uncultured amniocyte microarray and karyotype [3]. In a Czech series, a pregnancy with normal villus karyotype and microarray had amniocentesis at 18 weeks showing 80% mosaicism [94].

Culture-free techniques reduce in vitro selection. The isochromosome decreases rapidly during amniocyte subculture, and in a Chinese series one fetus had a normal first amniocentesis karyotype but 12p microarray gain, subsequently confirmed in amniotic fluid, cord blood, placenta and skin; metaphase FISH was normal and interphase FISH showed lines with two, three and four 12p copies [9, 45]. In four fetuses diagnosed by third-trimester cordocentesis, the isochromosome was in 2–5% of cultured lymphocytes with extended 100-cell counting, and SNP-array on uncultured DNA showed gain of the entire short arm [80]. Conversely, in an Italian case microarray alone did not demonstrate mosaicism, reinforcing the combination of karyotype, FISH and array [95].

Genome-wide non-invasive prenatal cell-free DNA (cfDNA) screening may reveal the syndrome incidentally. In a series of 29,007 pregnancies screened between 2016 and 2017, three had gain of the entire chromosome 12 short arm, confirmed as mosaic tetrasomy 12p in fetal tissue or amniotic fluid [19]. In another case, increased first-trimester 12p signal prompted amniocentesis with non-mosaic 47,XY,+i(12p) and four-copy 12p microarray; following termination, fetal skin and the fetal placental side showed 12p gain and the maternal placental side was normal [96]. The 2023 ACMG guideline recommends cfDNA screening for trisomies 21, 18 and 13 and sex chromosome aneuploidies, and considers identification of other abnormalities an emerging area [97]. A screening 12p signal therefore requires invasive diagnostic confirmation and counselling regarding phenotypic variability.

6. Differential Diagnosis

Pallister–Killian syndrome is distinguished principally by infant temporal alopecia, Pallister lip, pigmentary streaks and malformations such as CDH and supernumerary nipples, with profound hypotonia [1, 2]. Given overlap between Fryns syndrome, Pallister–Killian syndrome, trisomy 12p and Sifrim–Hitz–Weiss syndrome, Arghir and colleagues proposed a severity spectrum hypothesis, which remains speculative [8].

7. Treatment and Risk Management Strategies

7.1 Principles

There is no therapy targeting tetrasomy 12p or medicine authorised for the syndrome in the United States or European Union; Orphanet lists no specific orphan designations for ORPHA:884 and ClinicalTrials.gov had no registered studies for the condition at the search date [2, 20, 99]. Management is symptomatic, multidisciplinary and problem-based: Orphanet summarises early CDH surgery where repairable, standard seizure treatment and motor, psychomotor and language rehabilitation as early as possible [2]. No specific clinical guideline was identified; the following recommendations derive from applicable organ-specific guidelines (CDH, anorectal malformations) and published cohort surveillance proposals, and are identified accordingly.

7.2 Perinatal period and congenital diaphragmatic hernia

Isolated CDH treated in a tertiary centre has survival above 50%, whereas CDH with an abnormal karyotype or other major abnormalities has a poorer prognosis, and parents should be referred early for paediatric surgical consultation [16]. In the international Congenital Diaphragmatic Hernia Study Group registry, survival to discharge was 34% in syndromic CDH and 76.7% in non-syndromic CDH, with a non-repair rate of 53% in the syndromic group and survival of 73% among operated patients; Pallister–Killian syndrome had survival of 39.1% [74]. The authors conclude that care-goal decisions influence outcomes and early genetic diagnosis may guide that decision [74]. These figures describe patients registered over 25 years with heterogeneous repair decisions and should not be used as individual probabilities.

When active treatment is chosen, the CDH EURO Consortium European consensus (2015 update) applies, with key recommendations of planned delivery after 39 weeks in a high-volume centre, avoiding neuromuscular blockers in the delivery room, preductal saturation targets between 80% and 95% and postductal above 70%, PaCO2 between 50 and 70 mmHg, conventional mechanical ventilation as the initial strategy and consideration of intravenous sildenafil for severe pulmonary hypertension [100]. The dosing part of the consensus was not consulted, and the label does not cover this situation: in the EU, injectable sildenafil (Revatio® 0.8 mg/mL) is authorised only in adults with pulmonary arterial hypertension who are temporarily unable to take the oral form, at 10 mg three times daily as an intravenous bolus, and is not recommended below 18 years; the oral form is authorised from 1 to 17 years (10 mg three times daily up to 20 kg and 20 mg three times daily above 20 kg); the European SmPC adds that, outside the authorised indications, sildenafil should not be used in newborns with persistent pulmonary hypertension, because the risks outweigh the benefits, based on a randomised trial of intravenous sildenafil added to inhaled nitric oxide in 59 newborns, with no significant difference in treatment failure (27.6% versus 20.0% with placebo) [101]. The US label likewise indicates 10 mg three times daily intravenously only in adults [102]. Neonatal use in CDH is therefore outside the label conditions, and the dose follows the neonatal intensive care unit protocol. A report of CDH repair at two weeks in an infant with Pallister–Killian syndrome and left ventricular hypoplasia describes conventional ventilation, inhaled nitric oxide, intraoperative hypotension requiring transfusion and tracheostomy on postoperative day 55 [103].

7.3 Airway, breathing and anaesthesia

Hypotonia, macroglossia, micrognathia or prognathism and palatal abnormalities predispose to upper airway obstruction; neonatal apnoea requiring oxygen and home monitors, tracheostomy in some infants, severe obstructive apnoea treated with nocturnal non-invasive ventilation and progressive subglottic stenosis, potentially fatal through obstruction and difficult intubation, have been described [23, 31, 52, 75]. Anaesthetic reports recommend preanaesthetic assessment targeting associated malformations, particularly cardiac, and difficult airway preparation; in a 5-year-old Brazilian child, MRI under general anaesthesia with sevoflurane by face mask and an oropharyngeal airway was uncomplicated as an outpatient [104]. The sleep series authors recommend otorhinolaryngological assessment and respiratory and anaesthetic follow-up to decide whether non-invasive ventilation during sleep is required [31].

7.4 Epilepsy

There is no specific antiseizure regimen. In the 51-patient series, the most used drugs were levetiracetam (37%), valproic acid (37%) and topiramate (33%), and levetiracetam was considered “most helpful” by parents in 22%; assessment was by parental questionnaire and does not permit efficacy comparison [64]. In three infants with myoclonic epilepsy and photosensitivity, levetiracetam was effective and well tolerated in the two treated [66]. In the Italian series of 13 children, treatment response varied but a significant proportion achieved good control [65]. Video-EEG is recommended to distinguish seizures from non-epileptic paroxysmal events before escalating therapy [68]. Unique reports medically supervised ketogenic diet success in some children with drug-resistant epilepsy, association-derived information without a published series [23].

Levetiracetam dosage follows the product label and seizure type rather than the syndrome. The US Keppra® label specifies, for partial-onset seizures, 7 mg/kg twice daily from 1 to 6 months, increasing by 7 mg/kg twice daily every two weeks to 21 mg/kg twice daily; 10 mg/kg twice daily from 6 months to 4 years, up to 25 mg/kg twice daily; and 10 mg/kg twice daily from 4 to 16 years, up to 30 mg/kg twice daily; in adults, 500 mg twice daily, up to 1500 mg twice daily (recommended maximum 3000 mg/day), using the oral solution below 20 kg [105]. The European SmPC agrees below 6 months (7 mg/kg twice daily, up to 21 mg/kg twice daily) and in adults and adolescents weighing 50 kg or more (500 mg twice daily, up to 1500 mg twice daily), but, from 6 months up to 50 kg, it starts at 10 mg/kg twice daily and allows increases of 10 mg/kg twice daily every two weeks up to 30 mg/kg twice daily, without the 25 mg/kg twice-daily ceiling that the US label sets from 6 months to 4 years; below 25 kg it recommends the 100 mg/mL oral solution [106]. In Portugal and the EU, the reference dose is that of the European SmPC. The same label warns of behavioural changes and psychotic symptoms (non-psychotic behavioural symptoms in 38% of treated children aged 4 to 16 years versus 19% with placebo), suicidal ideation, somnolence, severe skin reactions and drug reaction with eosinophilia and systemic symptoms (DRESS), and of the need for gradual withdrawal [105]. Use in myoclonic seizures in children under 12 years and outside juvenile myoclonic epilepsy is not included in US or EU indications and constitutes off-label use [105, 106].

7.5 Sleep

Sleep disturbance is almost universal in the Italian series, which recommends screening with the Sleep Disturbance Scale for Children, polysomnography when respiratory disturbance is suspected and active treatment; as a first approach it proposes parental education and behavioural interventions and, as the first-line pharmacological option, melatonin [31]. In the European Union, prolonged-release melatonin Slenyto® was authorised on 20 September 2018 for insomnia in children and adolescents aged 2 to 18 years with autism spectrum disorder and/or Smith–Magenis syndrome; the Commission decision of 26 August 2024 extended the indication to neurogenetic disorders with aberrant diurnal melatonin secretion and/or nocturnal awakenings, and that of 17 March 2025 added insomnia at 6 to 17 years with ADHD, whenever sleep hygiene measures are insufficient. In autism spectrum disorder and neurogenetic disorders, the starting dose is 2 mg, increased to 5 mg if the response is insufficient, up to a maximum of 10 mg, once daily 0.5 to 1 hour before bedtime, with reassessment at 3 months and monitoring at least six-monthly [107]. Pallister–Killian syndrome is not named in the label, and its inclusion within the category of neurogenetic disorders with nocturnal awakenings is a clinical decision. The Italian series mentions melatonin doses up to 15 mg, above the Slenyto® maximum, and first-generation antihistamines or clonazepam if melatonin is ineffective; these options are off-label in this population [31, 107].

7.6 Feeding, digestive system and anorectal malformations

Hypotonia, suck–swallow–breathing incoordination and palatal abnormalities cause feeding difficulties; some children require nasogastric feeding or gastrostomy, cleft palate teats or caloric supplementation, and reflux is controlled with medication, thickeners and positioning or, if insufficient, fundoplication [23]. Intestinal malrotation may present with volvulus and requires surgical suspicion [76]. For imperforate anus and other anorectal malformations, Orphanet refers to the 2025 ERN eUROGEN European guidelines, recommending multidisciplinary treatment and lifelong follow-up [2, 108].

7.7 Hearing, vision, oral cavity and skeleton

Hearing loss should be characterised and treated with hearing aids or, in serous otitis, ventilation tubes; the P1 cortical auditory evoked potential has been used to assess central auditory pathway maturation in children with hearing loss and multiple disabilities, including one patient with the syndrome [23, 109]. Visual impairment, frequently cortical, requires ophthalmological assessment and visual stimulation [13, 23]. Frequent missing teeth, gingivitis, caries and malocclusion justify early orodental surveillance and multidisciplinary preventive measures, and dental treatment may require sedation [77, 110]. Scoliosis and kyphosis may require adapted seating, orthoses or surgery, hip dysplasia or dislocation should be monitored, and tethered cord has been treated by sectioning the filum terminale [23, 70].

7.8 Development, communication and behaviour

Rehabilitation should begin early [2]. Unique describes benefits from tactile sign language, augmentative and alternative communication, physiotherapy and occupational therapy, as well as hydrotherapy and hippotherapy [23]. Identification of sensory profiles of low registration and sensory seeking prompted Italian authors to propose sensory integration and self-regulation interventions, extrapolated from other neurodevelopmental disorders [32]. One of the two better-functioning patients in a 16-patient series fulfilled autism criteria, leading the authors to question an increased risk, as yet unestablished [59].

7.9 Regulatory status

Marketing authorisation does not guarantee availability or reimbursement in each country; availability and reimbursement in Portugal (INFARMED) and Brazil (ANVISA/CONITEC) depend on each medicine and each formulation and are not stated in the sources consulted.

7.10 Trials, therapeutic studies and recent developments

None of these studies is a controlled trial: therapeutic data are limited to observational series with parental or retrospective collection, without a comparison group, and cannot rank antiseizure drugs or estimate response rates. The hypothesis of pharmacologically eliminating aneuploid cells, tested with AICAR in fibroblasts, relies on increased baseline energy and proteotoxic stress in isochromosome cells, but has not been tested in an animal model or humans in consulted sources [21]. The October 2026 search identified no registered trials, authorisation applications, Committee for Medicinal Products for Human Use (CHMP) opinions or regulatory decisions for the syndrome in the preceding 12 months [20, 99]; publications identified from that period were clinical reports, including the Italian neonatal case in section 10 and a series of 198 prenatally diagnosed CDH cases in which the syndrome was among karyotypically detected abnormalities [34, 113]. This negative search does not prove the absence of ongoing unregistered studies.

8. Reproductive Options and Family Counselling

8.1 Recurrence risk

The syndrome is sporadic in all published cases described by Orphanet, and Unique knows no family with a second affected child [2, 23]. A 1997 French collaborative study nevertheless mentions one preliminary recurrence report, without data allowing evaluation [40]. The theoretical risk arises from isochromosome germline mosaicism in a parent, which is why prenatal diagnosis may be offered in a subsequent pregnancy [2, 23]. Oxford contextualises this within mosaicism generally: risk is negligible when mosaicism results from mitotic nondisjunction, exists when it results from trisomy rescue because of possible parental germline mosaicism, and is usually low, with prenatal diagnosis offered for reassurance [15]. The advanced parental age association should be mentioned without converting it into an individual numerical risk, which sources do not provide [9, 10].

8.2 12p duplications and parental karyotype

When the phenotype results from 12p duplication rather than a free isochromosome, a parental balanced translocation should be excluded because recurrence risk is then rearrangement-specific [2, 8]. In trisomy 12p, frequently resulting from parental balanced translocations, both parental karyotypes are indicated [8]. In the four couples in a Chinese prenatal diagnostic series, no chromosome 12 rearrangements, such as pericentric inversions, that might favour isochromosome formation were found [80].

8.3 Prenatal counselling

Counselling following prenatal diagnosis is difficult for three reasons: abnormal cell percentage in amniotic fluid or villi does not predict severity; ultrasound may identify malformations but not cognitive outcome; and tetrasomy 12p is not synonymous with classical Pallister–Killian syndrome, so the full spectrum, including mild forms, should be discussed [23, 62, 79]. The 1997 French series, finding severe intellectual disability in survivors, recommended prenatal cytogenetic investigation whenever ultrasound suspicion was high [40]. In several prenatal series, couples chose pregnancy termination after diagnosis, a decision belonging to the couple following balanced information [19, 94]. Discordant dizygotic twins have been described, with one affected twin and the other typically developing [114].

8.4 Affected individuals and families

Individuals with mosaic tetrasomy 12p considering having children should be referred for genetic consultation [23]. No data on fertility or offspring of affected individuals were found in consulted sources. Counselling should include referral to patient associations, Unique in the United Kingdom and PKS Kids, PKS UK and PKS Italia, and information about ERN ITHACA as the European reference network [22–24].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

The only population-based estimate identified is British, with birth incidence 5.1 per million live births, obtained from a study seeking all known patients in Great Britain [12]. Orphanet cites an estimated birth prevalence of approximately 1/20,000, classifies formal prevalence as unknown and considers frequency underestimated because of difficulties identifying tissue-restricted mosaicism, particularly in blood [2]. A Turkish report cites estimated incidence approximately 1/25,000 without identifying the source population [110]. The US series of 59 patients states that no formal prevalence estimate has been made [14]. The nearly order-of-magnitude difference between 5.1 per million and 1/20,000 reflects different methods, clinical ascertainment of diagnosed cases in the former and estimation without an explicit population denominator in the latter, and both should be interpreted as limits of a poorly known frequency. Published cases exceeded 200 in 2016, and Unique then had 71 members with the syndrome in several countries [23]. In a genome-wide cfDNA screening programme, 3 of 29,007 pregnancies had 12p gain confirmed as mosaic tetrasomy, a proportion of positive prenatal screening results rather than birth prevalence [19]. In CDH, the syndrome represented 5.5% of associated syndromes in an international registry [74].

Several reviews mention a moderate female predominance, but recent series are heterogeneous: 39 boys and 12 girls in the US epilepsy series, 14 boys and 17 girls in the Italian MRI series and 11 of each sex in the Italian cognitive study, reflecting recruitment rather than the birth sex ratio [8, 32–34, 64].

9.2 Populations studied

The syndrome has been described on every continent and in families of all origins, with no known environmental factors or founder effect described in consulted sources [23]. The largest cohorts are North American (Philadelphia, Utah) and European (Great Britain, Italy, France) [7, 12, 14, 33, 40, 64]. Gene expression and oral health series reported Caucasian participants, limiting generalisability of molecular findings [48, 77]. Series and cases also exist from Turkey, Romania, China, Poland, the Czech Republic, Egypt, Oman, with the first published case in the Arab world, and Australia, with a proband of Māori ancestry [8–10, 18, 47, 52, 80, 94, 115].

In Brazil, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo reviewed 10 patients followed between 1990 and 2015, diagnosed between the prenatal period and 3 years; all had normal blood karyotypes (nine studied), the isochromosome was present in 50–100% of fibroblasts and 75–100% of amniocytes, and buccal MLPA confirmed diagnosis in three patients [71]. Compared with literature, epilepsy, auditory and ophthalmological impairment and gastrointestinal malformations were less frequent, no patient had CDH, pigmentary changes were present in six of ten and two had atrial septal aneurysms [71]. Maternal age at conception ranged from 16 to 39 years [71]. An anaesthesia report in a 5-year-old was also published in Brazil [104]. No Portuguese data were found in consulted sources, which does not demonstrate their absence.

9.3 Special populations

Adult information is scarce and derives mainly from case reports and family surveys: Unique describes variable personal care dependence, epilepsy potentially beginning or worsening in adolescence, sleep apnoea and osteoporosis in one woman, and improved environmental interaction with age; only individuals with forms so mild they lack the classical presentation achieve independent living [23]. Puberty may be normal or slightly delayed and seizure frequency increased during puberty in one girl [8, 23]. No data on pregnancy in affected women were found in consulted sources.

10. Illustrative Clinical Case

10.1 Newborn girl diagnosed in peripheral blood (Italy, 2026)

Di Donato and colleagues described a newborn girl, the first child of healthy non-consanguineous parents, born in July 2020 by vaginal delivery at 41 weeks in a public maternity unit in Pescara; her mother was 43 years old, pregnancy involved maternal hypothyroidism treated with levothyroxine and prenatal ultrasound was normal [34]. Apgar scores were 8 and 9, weight 4030 g (95th percentile), length 54 cm (100th percentile) and head circumference 34.5 cm (59th percentile) [34]. Examination showed hypertelorism, an ogival palate, a white hair streak, ulnar finger deviation and anteriorly placed anus with a perineal fistula [34]. She developed severe respiratory distress with persistent pulmonary hypertension, required intubation and conventional and non-conventional ventilation and was treated with antibiotics for neonatal sepsis, with progressive improvement [34]. Brain ultrasound and MRI, fundus examination and otoacoustic emissions were normal; abdominal ultrasound and MRI showed a cystic lymphangioma and multiple bilateral ovarian cysts, and unilateral hydronephrosis was present [34].

Peripheral blood karyotyping showed the isochromosome in one of 100 metaphases, mos 47,XX,i(12)(p10)[1]/46,XX[99] (figure 1), and blood array CGH confirmed 12p13.33 to 12p11.1 gain (positions 0 to 34,597,280) (figure 2); from the logarithmic ratio of approximately +0.30 to +0.35, the authors estimated that 25–30% of cells carried the isochromosome [34]. The authors discuss that, under classical mosaicism exclusion tables, a single abnormal cell would not meet usual criteria, but, given the clinical presentation, it was diagnostic and justified the array [34]. The discussion describes the same proportion as “trisomy 12p-positive cells”, a terminological imprecision because array and karyotype correspond to mosaic tetrasomy. She was discharged at 30 days without evident neurological abnormalities, but from 3 months showed hypotonia and reduced motility and, at 6 months, marked hypotonia, severe neurological impairment and blindness, with normal auditory evoked potentials and no seizures [34].

The case illustrates three points discussed in this article: normal prenatal ultrasound does not exclude the syndrome; peripheral blood may be diagnostic neonatally, even with a single positive metaphase, if clinical suspicion prompts a culture-free method; and initial absence of neurological abnormalities does not predict progression [9, 34, 37]. Cystic lymphangioma and ovarian cysts are rarely reported findings with no established relationship to the syndrome [34].

10.2 2-year-old child diagnosed by skin biopsy (US, 2017)

Stone and colleagues described a 2-year-old boy, born at term after an uncomplicated pregnancy to a 32-year-old mother, with swallowing difficulty from birth and recurrent aspiration pneumonia [13]. He had suspected epileptic episodes, with normal brain MRI at 7 months and EEG at 8 months without epileptiform activity but mild bilateral cerebral dysfunction, and started levetiracetam; he had gross motor delay, hyperacusis, overstimulation in crowded settings, finger waving and snapping movements, plagiocephaly and intermittent alternating exotropia [13]. Family history included a maternal aunt and uncle with delay and epilepsy and a brother with learning difficulties; metabolic screens were non-diagnostic and blood microarray normal [13]. Dermatological examination showed Blaschkoid hypo- and hyperpigmented streaks on the trunk and limbs (figure 1), high forehead, widely spaced eyes, broad nasal root, low-set ears, extension of philtral skin into the upper lip vermilion and reduced hair density (figure 2) [13]. Two biopsies were performed, one of pigmented and one of clinically normal skin, and 55% of 20 cells or colonies analysed had isochromosome 12p [13].

This case shows the reverse pathway: normal blood microarray in a child beyond the neonatal period, an initial hypomelanosis of Ito hypothesis and diagnosis through integration of facial pattern with pigmentation and fibroblast analysis [13]. Family history of delay and epilepsy, interpretable as coincidental, does not alter counselling for a sporadic condition but would justify separate assessment of affected relatives.

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

Vital prognosis depends mainly on the perinatal period: a significant proportion of fetuses are stillborn or die neonatally, with CDH the main determinant, and survival to discharge of 39.1% in the international registry [1, 74]. Beyond this stage, with respiratory, digestive and epileptic complications controlled, long survival is possible, with patients published in their fifth decade [1, 23, 30]. Orphanet indicates that prognosis depends on mosaicism level, CDH and other abnormalities and epilepsy [2]; series studying the relationship between abnormal cell proportion and severity have not demonstrated it, so mosaicism measured in one tissue should not be used alone prognostically [10, 12]. Intellectual disability is severe to profound in most but mild to moderate in approximately one-quarter, walking is acquired by 17–38% and most do not develop spoken language [2, 12, 23]. Poulton and colleagues consider that presence or absence of polymicrogyria or other brain abnormalities may help predict neurodevelopment, but the Italian MRI series found no correlation between imaging findings and delay [33, 52].

11.2 Follow-up

No validated surveillance protocol or fixed intervals are defined in consulted sources. The table groups assessments recommended or justified by published series, with their sources, and intervals depend on clinical findings.

Transition to adult services should anticipate continued epilepsy, sleep, scoliosis and oral health follow-up, residential support needs and surveillance for complications such as aspiration, a cause of death recorded in the British study [23].

12. Summary and Concluding Remarks

Pallister–Killian syndrome results from a mosaic supernumerary isochromosome i(12)(p10), conferring tetrasomy 12p on carrier cells and unevenly distributed between tissues: frequent in fibroblasts, amniocytes and buccal mucosa, rare and progressively lost in peripheral blood [2, 37]. The isochromosome is maternally derived in most studied cases, associated with advanced parental age and almost always sporadic [9, 10]. The critical region lies at 12p13.31, and functional studies show partial dosage compensation and dysregulation of genes outside 12p [6, 48, 49].

The phenotype combines hypotonia, usually profound intellectual disability but mild to moderate in approximately one-quarter, epilepsy in approximately half, frequent deafness and visual impairment, structural brain abnormalities detectable in almost all by dedicated MRI, sleep disturbance, temporal alopecia, Pallister lip, pigmentary streaks and malformations, of which CDH most strongly determines survival [12, 13, 31, 33, 64, 74]. Birth frequency ranges from 5.1 per million in a British population-based estimate to approximately 1/20,000 in an Orphanet-cited estimate, and both are probably underestimated [2, 12].

Diagnosis depends on clinical suspicion and tissue and method selection: normal blood karyotype or microarray does not exclude the syndrome, and buccal mucosa and skin should be studied where suspicion persists [12, 15, 86]. Treatment is symptomatic and multidisciplinary, without targeted therapy, a registered clinical trial or ongoing regulatory process in consulted sources, with a preclinical hypothesis of selective aneuploid cell elimination [2, 20, 21]. Counselling should convey the low recurrence probability, the need to exclude parental translocation in 12p duplications and phenotypic unpredictability from mosaicism percentage [2, 10, 23].

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