Trisomy 8 is a rare chromosomal disorder characterized by the presence of an extra copy of chromosome 8 in some or all cells of the body, most commonly in mosaic form where only a subset of cells are affected.[1] Complete (non-mosaic) trisomy 8 is typically lethal and results in miscarriage during the first trimester of pregnancy, whereas the mosaic variant, also known as Warkany syndrome 2, is compatible with life and accounts for nearly all diagnosed cases.[1][2] The condition has an estimated prevalence of 2–4 per 100,000 live births for the mosaic form, with males affected approximately three to four times more often than females.[3][1]The etiology of trisomy 8 involves nondisjunction, or improper separation of chromosomes during cell division, which can occur during meiosis in gamete formation or postzygotically in early embryonic mitosis, leading to mosaicism.[2][1] In rare cases, it may stem from spontaneous correction of an initial full trisomy or low-level parental mosaicism, but the vast majority of instances are sporadic and not inherited.[1] The severity and distribution of symptoms depend on the proportion of trisomic cells and the tissues involved, with higher mosaicism levels generally correlating with more pronounced effects.[1][3]Clinical manifestations of mosaic trisomy 8 are highly variable but often include mild facial dysmorphism, such as a prominent or high forehead, hypertelorism (widely spaced eyes), deep-set eyes, a broad nose, thick lower lip, and high-arched palate.[1][2] Skeletal anomalies affect about 65% of individuals and may feature camptodactyly (permanently bent fingers), scoliosis, absent or hypoplastic patellae, joint contractures, and characteristic deep creases on the palms and soles.[1][3] Other common issues encompass urinary tract malformations (in 40% of cases), congenital heart defects (in 25%), and mild to moderate intellectual disability (with IQ typically 50–75) accompanied by delayed speech and behavioral challenges like hyperactivity or aggression.[1] Individuals with mosaic trisomy 8 also face an elevated risk of hematologic malignancies, including acute myeloid leukemia and myelodysplastic syndrome.[3]Diagnosis is established through cytogenetic analysis, such as karyotyping of blood, skin, or amniotic fluid cells, often following prenatal ultrasound findings like hydronephrosis or intrauterine growth restriction.[1][2] Additional techniques like chromosomal microarray or whole exome sequencing may support confirmation.[1] There is no cure, and management involves a multidisciplinary team addressing specific symptoms, such as surgical interventions for heart or skeletal defects, speech therapy, educational support, and regular monitoring for cancer risk.[1] With appropriate care, many affected individuals achieve a normal lifespan, though outcomes vary based on the extent of mosaicism and complications.[2]
Genetics and classification
Definition and nomenclature
Trisomy 8 is a rare chromosomal aneuploidy disorder characterized by the presence of three copies of chromosome 8 in affected cells, rather than the normal two copies found in a typical humankaryotype of 46 chromosomes. In viable individuals, the condition most commonly manifests as mosaicism, wherein only a subset of cells carries the extra chromosome 8, while others maintain the euploid state. Full, non-mosaic trisomy 8 is generally incompatible with life and results in early miscarriage.[4]The disorder is alternatively known as Warkany syndrome 2, a eponymous designation honoring the pediatrician Josef Warkany, who first delineated its clinical features in the mid-20th century. This nomenclature specifically distinguishes it from Warkany syndrome 1, an obsolete term for a distinct X-linked recessive condition involving microcephaly and intellectual disability. The name "trisomy 8" reflects the underlying genetic anomaly: "trisomy" denotes the triplication of a chromosome, while "8" identifies the specific chromosome involved, as human autosomes are numbered from 1 to 22 in descending order of size, with chromosome 8 being the eighth largest pair. This standard numbering system, established through karyotyping techniques, facilitates precise identification of chromosomal abnormalities.[5][6]
Genetic mechanism
Trisomy 8, particularly in its mosaic form, primarily arises from post-zygotic nondisjunction events during mitosis in early embryonic development, resulting in an extra chromosome 8 in a subset of somatic cells while others retain the normal diploid complement. This mitotic error leads to the formation of two daughter cells: one with three copies of chromosome 8 (trisomic) and one with a single copy (monosomic), with the monosomic lineage typically not surviving, thereby establishing mosaicism. Such de novo post-fertilization occurrences predominate, accounting for the majority of cases in liveborn individuals, as evidenced by molecular analyses showing reduction to homozygosity or dosage imbalances consistent with mitotic duplication rather than meiotic segregation errors.[7][8]Additional mechanisms contributing to mosaicism include anaphase lag, where a chromosome fails to properly attach to the spindle apparatus and is excluded from the nucleus, or broader chromosome missegregation during cell division, both of which can generate aneuploid cell lines post-zygotically. While rare instances of parental origin through meiotic nondisjunction have been documented—such as maternal meiosis I errors in some confined placental mosaicism cases or spontaneous abortions—these are exceptional and often incompatible with full-term viability, underscoring the predominance of somatic, non-inherited events in constitutional trisomy 8. Phenotypic variability in mosaic trisomy 8 may also be influenced by genetic modifiers, such as additional pathogenic variants identified through exome sequencing.[9][7][10]The genetic implications of this extra chromosome involve altered gene dosage across the duplicated regions of chromosome 8, leading to potential overexpression of resident genes in affected cells. For instance, the GSR gene on 8p21.1, encoding glutathione reductase, has demonstrated increased enzymatic activity in trisomic cells from patients with constitutional trisomy 8 mosaicism, contributing to oxidative stress imbalances. More broadly, microarray studies indicate that approximately 65% of protein-coding genes on chromosome 8 exhibit elevated expression in trisomic fibroblasts compared to euploid cells, with downstream effects potentially influencing cellular pathways related to development and homeostasis, though not all genes show dosage sensitivity. The variable proportion of trisomic cells (mosaicism levels) can modulate phenotypic severity, with higher percentages generally correlating with more pronounced effects.[11][7]
Types of trisomy 8
Trisomy 8 is classified into several types based on the extent and distribution of the extra chromosome 8 material across cells, which significantly influences viability and clinical outcomes. Complete, or non-mosaic, trisomy 8 involves the presence of an extra full copy of chromosome 8 in all cells of the body. This form arises typically from meiotic nondisjunction and is almost always lethal during embryonic or fetal development due to profound disruptions in cellular function and organogenesis, accounting for approximately 0.8% of first-trimester miscarriages. Survival to birth is exceedingly rare, with no well-documented cases of long-term viability.[12][13][14]In contrast, mosaic trisomy 8 occurs when only a subset of cells contains the extra chromosome 8, while others have the normal two copies, resulting from postzygotic mitotic errors. This mosaicism allows for greater viability, as the proportion of affected cells can range widely, often from low levels (e.g., 5-20%) to higher ones (up to 95% in some tissues), enabling most diagnosed individuals to survive to birth and beyond. Mosaic trisomy 8 represents the vast majority of liveborn cases, with an estimated prevalence of 1 in 25,000 to 50,000 births.[15][16][17]The phenotypic variability in mosaic trisomy 8 is heavily influenced by tissue-specific distribution of the aneuploid cells, where the extra chromosome may be more prevalent in certain tissues like skin fibroblasts compared to others such as peripheral blood lymphocytes. For instance, mosaicism levels can differ significantly between embryonic, extra-embryonic, and somatic tissues, affecting the severity of manifestations based on which cell lineages are impacted. This uneven distribution complicates diagnosis and prognosis, as standard blood karyotyping may underestimate the mosaicism if it is confined to non-hematopoietic tissues.[15][17][9]Partial trisomy 8 refers to duplications of specific segments of chromosome 8, such as interstitial or terminal regions (e.g., 8q21 to 8qter or 8p segments), rather than a full extra chromosome, often resulting from unbalanced translocations or other structural rearrangements. This type is rare and distinct from complete trisomy, though nomenclature can overlap when partial duplications mimic full trisomy effects in mosaic forms; it is generally viable but presents with features dependent on the duplicated segment's size and location. Unlike full or mosaic forms involving the entire chromosome, partial trisomy 8 does not typically lead to embryonic lethality but requires precise cytogenetic analysis for differentiation.[18][19][16]
Clinical presentation
Craniofacial features
Individuals with mosaic trisomy 8 often exhibit mild to moderate craniofacial dysmorphisms that contribute to a characteristic facial appearance. A prominent forehead is a common feature, frequently accompanied by a high anterior hairline and a low posterior hairline, giving the head a distinctive elongated or scaphocephalic shape.[1][4]Ocular and nasal abnormalities are also prevalent, including hypertelorism, deep-set eyes (observed in approximately 50% of cases), and a prominent nasal bridge with a bulbous or upturned nose tip. The eyes may appear widely spaced due to hypertelorism, while the nasal features contribute to a broad midface. Ears are typically low-set and dysplastic, often with prominent antihelices and large lobules. Micrognathia, or a small jaw, is frequently noted, sometimes associated with everted lower lips and a short philtrum.[1][4][20]Additional intraoral and facial traits include a high-arched palate, with cleft palate occurring in about 8% of affected individuals, and occasional facial asymmetry. These features can vary significantly based on the percentage of trisomic cells in the mosaicism; lower mosaic levels tend to result in milder dysmorphisms, while higher levels may accentuate the prominence of these traits.[1]
Skeletal and joint abnormalities
Skeletal and joint abnormalities are prominent features in individuals with mosaic trisomy 8 syndrome, often manifesting as a combination of dysplastic bone development and progressive joint limitations. Common findings include camptodactyly, characterized by flexion contractures of the second through fifth fingers and toes, affecting up to 70% of cases, and clinodactyly, involving curved fingers due to shortened metacarpals and metatarsals. Deep plantar and palmar furrows are also frequent, occurring in approximately 75% of affected individuals, contributing to distinctive foot creases and potential mobility issues.[1][21]Spinal anomalies are prevalent, with vertebral malformations reported in 65% of cases, encompassing scoliosis, kyphoscoliosis, hemivertebrae, and vertebral fusions that may lead to structural deformities such as a short neck or elongated trunk. Additional skeletal dysplasias include absent or hypoplastic patellae, broad dorsal ribs, and pectus carinatum or excavatum, alongside abnormalities in diaphyses and epiphyses of bones like the radius, femur, and humerus. These features often overlap subtly with craniofacial dysmorphism but primarily affect the axial and appendicular skeleton.[1][21][20]Joint involvement typically presents with reduced mobility and contractures, including arthrogryposis that progresses with age, leading to limitations in multiple joints such as elbows, hips, and knees. Hip dysplasia, manifested as coxa valga, and short stature are recurrent, with radiographic evaluations revealing delayed bone age and occasional abnormal clavicles. Monitoring is essential, as some contractures and spinal curvatures, like scoliosis, may worsen over time, necessitating orthopedic interventions to maintain function.[1][21][22]
Developmental and neurological aspects
Individuals with mosaic trisomy 8 typically exhibit mild to moderate intellectual disability, with intelligence quotient (IQ) scores generally ranging from 50 to 70.[23][24] This range allows many affected individuals to attend school and achieve employment in adulthood, though supportive education is often required.[23] In some cases, intelligence may be within the normal range.[1]Developmental delays are a hallmark feature, prominently affecting speech acquisition, gross and fine motor skills, and the attainment of key milestones.[25][26] For instance, children often experience delayed walking and other locomotor achievements, alongside slower progress in personal-social and adaptive functions.[27] Speech development is particularly impacted, with expressive and receptive language skills lagging behind peers, sometimes remaining at a preschool level into later childhood.[28][29]Behavioral characteristics can include hyperactivity and attention deficits, resembling attention-deficit/hyperactivity disorder (ADHD) in some cases.[30] Aggression and mood swings occur occasionally, with rare instances of self-injurious or violent tendencies.[31] Autism-like features, such as social interaction challenges, have been reported in select cases, particularly those involving pericentromeric regions of chromosome 8.[32]Neurological manifestations often involve hypotonia during infancy, contributing to early motor challenges.[33][34] Seizures occur in a subset of individuals, with epilepsy noted as a common associated symptom.[1][35]The severity of intellectual disability and developmental delays does not correlate directly with the percentage of trisomic cells observed in peripheral blood analyses.[1] However, variability in mosaicism across tissues, including the brain, influences the neurocognitive profile, with higher trisomic involvement in neural cells potentially linked to more pronounced delays.[3]
Visceral and other manifestations
Renal anomalies are common in individuals with mosaic trisomy 8, affecting approximately 40% of cases and including hydronephrosis, horseshoe kidney, and vesicoureteral reflux.[36][1] These abnormalities often arise due to disrupted embryonic development of the urinary tract and may require monitoring for potential complications such as recurrent infections or impaired kidney function.[37]Cardiac defects occur in approximately 25% of affected individuals, with ventricular septal defects (VSD) and patent ductus arteriosus (PDA) among the most frequently reported.[1][38] These congenital heart anomalies can range from minor septal communications to more complex great vessel malformations, though many resolve spontaneously or with intervention.Genitourinary issues are prevalent, particularly in males, where cryptorchidism (undescended testes) and hypospadias are observed.[39] In females, uterine anomalies have been reported, contributing to potential reproductive challenges later in life.[37]Gastrointestinal malformations, such as imperforate anus, occur occasionally and are associated with the broader spectrum of anorectal malformations in mosaic trisomy 8.[40][41] These defects may necessitate surgical correction in infancy to ensure proper bowel function.Hearing loss, either conductive due to recurrent ear infections or sensorineural, affects a subset of individuals.Mosaic trisomy 8 is linked to an increased risk of hematological disorders, including myelodysplastic syndromes and acute myeloid leukemia, likely due to the extra chromosome's impact on cellular proliferation in bone marrow cells.[42][24]
Diagnosis
Prenatal diagnosis
Prenatal diagnosis of trisomy 8 primarily involves a combination of screening and confirmatory techniques to detect full or mosaic forms during pregnancy. Initial screening often begins with ultrasound evaluation, which may reveal nonspecific findings such as intrauterine growth restriction (IUGR), oligohydramnios, nuchal thickening, hydronephrosis, or other structural anomalies that prompt further genetic testing. These ultrasound markers are not diagnostic on their own but increase suspicion, particularly in cases of suspected mosaicism where phenotypic variability is common.[1]Non-invasive prenatal testing (NIPT) using cell-free fetal DNA (cffDNA) from maternal blood offers a screening option for chromosome 8 aneuploidy, including trisomy 8. NIPT analyzes fetal DNA fractions to identify copy number variations, with reported cases of successful initial detection of mosaic trisomy 8 at levels such as approximately 10% in uncultured neonatal cord blood.[43] However, sensitivity for mosaicism remains limited due to the preferential placental origin of cffDNA and potential underrepresentation of low-level fetal mosaicism, leading to false negatives or positives from confined placental mosaicism (CPM).[43] Positive NIPT results for trisomy 8 require confirmatory invasive testing, as the test's positive predictive value varies and cannot reliably distinguish fetal from placental involvement.[44]Invasive diagnostic procedures, such as chorionic villus sampling (CVS) at 10-13 weeks or amniocentesis at 15-20 weeks, provide definitive analysis through karyotyping of fetal or placental cells. Karyotyping detects the extra chromosome 8 in metaphases, while rapid methods like fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA) confirm aneuploidy or mosaicism within days. CVS is more likely to identify trisomy 8 mosaicism due to its sampling of placental tissue, where CPM is frequent; in one series of 17 cases, 14 were initially detected by CVS, but only 2 were confirmed in follow-up amniocentesis, highlighting the need for dual sampling to assess fetal involvement.[45]Amniocentesis, sampling true fetal cells, is preferred for confirmation to minimize overestimation of fetal risk from placental findings.[46]Genetic counseling is essential following a prenatal diagnosis of trisomy 8, particularly for mosaic cases, due to highly variable outcomes influenced by the degree of mosaicism and tissue distribution. In apparent CPM, where trisomy 8 is confined to the placenta, pregnancy outcomes are generally favorable, with studies reporting live births without major anomalies in the majority of cases and only a 22% risk of adverse events like IUGR across autosomal trisomies.[47] For confirmed fetal mosaicism, counseling should emphasize potential normal development in low-level cases (e.g., <20% affected cells) versus risks of developmental delays or structural issues in higher levels, with serial ultrasounds recommended for monitoring. Parents are advised that 20-50% of mosaic detections may resolve to normal fetal karyotypes, but long-term neurodevelopmental follow-up is warranted regardless.[44]Recent advances in next-generation sequencing (NGS)-based methods have enhanced prenatal detection of mosaic trisomy 8 by improving resolution for low-level aneuploidies in both NIPT and invasive samples. NGS alongside traditional karyotyping has demonstrated higher accuracy in identifying mosaic copy number variations in amniotic fluid, facilitating earlier and more precise risk stratification.[48] These innovations, including genome-wide cfDNA analysis, are particularly valuable for trisomy 8, where mosaicism complicates interpretation, though validation in large cohorts continues.[48]
Postnatal diagnosis
Postnatal diagnosis of trisomy 8, typically mosaic in form, is often prompted by the identification of dysmorphic facial features, such as a prominent forehead or deep-set eyes, or by developmental delays in infancy and early childhood.[4] These clinical indicators lead to targeted genetic evaluation in affected individuals.[1]The standard confirmatory test involves conventional karyotyping using G-banding on cultured peripheral blood lymphocytes, which directly visualizes the extra chromosome 8 and quantifies the mosaicism percentage by analyzing at least 20 metaphase spreads.[49] This technique identifies the karyotype as mos 47,XX/XY,+8[variable]/46,XX/XY[normal], confirming the diagnosis in most cases where mosaicism is present in hematopoietic cells.[49]For suspected partial trisomies or when standard karyotyping is inconclusive, advanced methods such as array comparative genomic hybridization (array CGH) or single nucleotide polymorphism (SNP) microarray are employed to detect copy number variations and low-level mosaicism with higher resolution.[50] Array CGH has been particularly useful in delineating segmental duplications of chromosome 8 in mosaic ring chromosome cases, providing precise breakpoints not visible by karyotyping alone.[51] If blood analysis yields normal results but clinical suspicion persists, a skin biopsy for fibroblast culture and karyotyping is recommended to assess tissue-specific mosaicism, as the trisomic cell line may be confined to dermal layers.[17]Diagnostic challenges arise with low-level mosaicism below 10%, which may evade detection in single-tissue sampling and necessitate analysis of multiple tissues, such as blood, skin, and urine, to avoid false negatives.[52]Blood-only testing can miss confined mosaicism, as demonstrated in cases where skin fibroblasts revealed trisomy 8 despite normal peripheral blood karyotypes.[17]According to the American College of Medical Genetics and Genomics (ACMG) guidelines, chromosomal microarray analysis is a first-tier test for postnatal evaluation of developmental delays or congenital anomalies suggestive of aneuploidy, with follow-up karyotyping or FISH recommended for mosaicism confirmation; in suspected trisomy 8 cases, extended tissue analysis is advised if initial results are normal.[50]
Differential diagnosis
Trisomy 8 mosaicism, also known as Warkany syndrome 2, presents with variable features including craniofacial dysmorphism, deep palmar and plantar furrows, skeletal anomalies, and mild to moderate intellectual disability, which can overlap with several other genetic and environmental conditions. Differential diagnosis requires careful clinical evaluation and is confirmed by cytogenetic testing such as karyotyping to identify the mosaic extra chromosome 8 in affected cells.[37]Beckwith-Wiedemann syndrome (BWS) may be considered in the differential due to shared overgrowth features and occasional facial similarities like ear creases, but BWS is distinguished by macroglossia, omphalocele, hemihypertrophy, neonatal hypoglycemia, and increased tumor risk, arising from imprinting defects or mutations at 11p15.5 rather than chromosomal trisomy.[53] Cornelia de Lange syndrome (CdLS) shares elements of facial dysmorphism (e.g., low anterior hairline) and limb anomalies, but CdLS typically involves more profound intrauterine and postnatal growth restriction, upper limb reduction defects, hirsutism, and severe intellectual disability due to mutations in cohesin pathway genes such as NIPBL.[54]Other aneuploidies, including trisomy 18 (Edwards syndrome), can mimic the multiple congenital anomalies of trisomy 8, but trisomy 18 is far more severe, featuring rocker-bottom feet, overlapping flexed fingers, microcephaly, and profound hypotonia with high perinatal lethality, verified by karyotype revealing an extra chromosome 18.[55] Partial 8p deletions present contrasting effects to trisomy 8, with prominent congenital heart defects, behavioral issues, and milder skeletal involvement but without the characteristic deep creases; these deletions involve loss of genetic material on the short arm of chromosome 8, leading to neurodevelopmental challenges opposite to the duplications in trisomy.[56]Non-genetic conditions like fetal alcohol spectrum disorder (FASD), particularly fetal alcohol syndrome, overlap in craniofacial traits such as a prominent forehead, hypertelorism, and developmental delays, but FASD lacks chromosomal aberrations and is linked to prenatal alcohol exposure, often with additional features like thin upper lip and smooth philtrum.[57] Rothmund-Thomson syndrome (RTS) shares skeletal abnormalities and potential skin findings, but is differentiated by early-onset poikiloderma, sparse hair, cataracts, and increased cancer risk due to biallelic RECQL4 mutations; mosaic trisomy 8 has been observed in some RTS patients, complicating distinction without genetic testing.[58]Key discriminators for trisomy 8 include the pathognomonic deep plantar furrow between the first and second toes, often bilateral and present from birth, alongside prominent antihelical crus and clinodactyly, which are not typical of the above mimics; ultimate confirmation relies on karyotype or fluorescence in situ hybridization demonstrating mosaicism for an extra chromosome 8.[59]
Management and prognosis
Treatment approaches
There is no curative therapy for mosaic trisomy 8, a condition caused by the presence of an extra chromosome 8 in some cells, and management focuses on symptomatic and supportive interventions to address associated manifestations such as cardiac defects, skeletal abnormalities, developmental delays, and other complications.[23][31]Treatment requires a multidisciplinary approach involving specialists in genetics, orthopedics, cardiology, developmental pediatrics, neurology, and other relevant fields to coordinate care tailored to the individual's symptoms and severity.[1][37] For instance, surgical correction may be indicated for cardiac anomalies, which occur in approximately 25% of cases, or renal defects such as vesicoureteral reflux, to prevent complications like infections or impaired function.[1][31]Physical and occupational therapy are key components for managing joint contractures, hypotonia, and motor delays, often incorporating exercises to improve coordination, posture, and daily functioning; innovative approaches like virtual reality-based neuromotor therapy have shown benefits in enhancing locomotion and cognitive skills in affected children.[23][12] Pharmacological options include recombinant human growth hormone for short stature when growth hormone deficiency is confirmed,[60]anticonvulsant medications such as phenytoin or phenobarbital for seizures,[13] and potentially other agents for behavioral issues like hyperactivity or aggression if they significantly impact quality of life.[31]Early intervention programs, including speech therapy, are essential to mitigate intellectual disability and support developmental milestones, with evidence indicating improvements in IQ scores and autonomy through consistent psychomotor and occupational interventions starting in infancy.[12] Supportive measures encompass hearing aids for auditory impairments, which affect a subset of individuals, and nutritional support such as feeding tubes or specialized diets to address feeding difficulties and promote adequate growth.[31][61]
Prognosis and long-term outcomes
The prognosis for individuals with mosaic trisomy 8 (T8M), also known as Warkany syndrome 2, varies significantly based on the level of mosaicism and the presence of associated complications, with outcomes generally favorable in cases of low-level mosaicism confined to non-critical tissues. In the absence of severe malformations or high mosaicism, life expectancy is typically normal, allowing many affected individuals to reach adulthood and beyond without early mortality.[1] However, higher levels of mosaicism or involvement of vital organs can lead to reduced survival, particularly if hematologic malignancies develop; constitutional T8M is associated with an increased risk of myeloid neoplasms, though the exact incidence is low.[1][62]Developmentally, most individuals with T8M exhibit mild to moderate intellectual disability, with average IQ scores ranging from 50 to 75, though some cases show normal cognition depending on the extent of mosaicism. Many achieve milestones such as independent living with appropriate support, including speech therapy for disproportionately delayed language skills, and a substantial proportion attend special education programs but go on to secure employment as adults.[23] Early multidisciplinary interventions, such as physical and occupational therapy, contribute to these trajectories by addressing motor delays and enhancing adaptive skills.[12]Long-term complications often include progressive skeletal issues, such as scoliosis, which may require bracing or surgical intervention in moderate to severe cases to prevent respiratory compromise or chronic pain. Infertility is common, particularly in males, due to associated genital anomalies like cryptorchidism or hypospadias, though some females have achieved pregnancy. Overall quality of life is improved with proactive management, as evidenced by reports from patient registries indicating that many adults live semi-independently or in supported settings while maintaining social and vocational engagement.
Epidemiology and history
Incidence and prevalence
Trisomy 8, primarily occurring in mosaic form, has an estimated birth prevalence of 1 in 25,000 to 50,000 live births worldwide.[1] This figure reflects the viable mosaic variant, where only some cells contain the extra chromosome 8, as complete non-mosaic trisomy 8 is typically lethal in utero and accounts for approximately 0.7% to 0.8% of spontaneous abortions but is exceedingly rare at birth, with fewer than 1 in 100,000 live births reported.[3][4]Prenatal detection rates exceed postnatal birth prevalence due to routine screening in high-risk pregnancies.[63] However, many cases remain undiagnosed postnatally, particularly low-level mosaicism, leading to underascertainment in population-based studies.[64]Demographically, trisomy 8 shows a male predominance with a sex ratio of approximately 4:1, though the condition arises sporadically from post-zygotic nondisjunction and is not inherited.[1] Unlike trisomies 21, 18, or 13, it lacks a strong association with advanced maternal age, with mean maternal age at diagnosis around 29 to 30 years.[64]Global variations in reporting are influenced by access to cytogenetic testing, with underdiagnosis prevalent in low-resource settings where prenatal screening and postnatal karyotyping are limited; data primarily derive from registries like Orphanet and the National Organization for Rare Disorders (NORD).[1][37]Incidence appears stable over time, as the condition stems from random mitotic errors without environmental or hereditary trends, though improved prenatal care and diagnostic technologies have enhanced early detection and potentially survival rates for mosaic cases.[1][64]
Historical background
Trisomy 8 was first described in 1962 by Josef Warkany and colleagues through cytogenetic studies of children exhibiting mental retardation, absence of patellae, and other malformations, initially identifying it as a chromosomal mosaicism without specifying the chromosome involved. In 1971, Jean de Grouchy and team confirmed the condition as mosaic trisomy 8 via fluorescence microscopy on a trisomy C mosaic case, leading to its designation as Warkany syndrome 2 in honor of Warkany's earlier clinical observations.[65]During the 1970s, case series further established the role of mosaicism in the variable phenotype, with reports by Fryns et al. (1974), Sanchez and Yunis (1975), Schinzel (1975), and a comprehensive international study by Riccardi (1977) compiling 70 patients to delineate characteristic features like dysmorphic facies, skeletal anomalies, and intellectual disability. Links to hematologic malignancies emerged in the 1980s, with early case reports documenting progression from aplastic anemia to leukemia in affected individuals, highlighting an increased risk of myeloid disorders.[66]The 1990s advanced understanding of mosaicism's tissue-specific distribution, as molecular studies like those by Robinson et al. (1998) analyzed nondisjunction origins and variability across tissues, explaining phenotypic heterogeneity beyond blood karyotypes. In the 2020s, next-generation sequencing (NGS) has improved prenatal detection of low-level mosaic trisomy 8, enabling earlier identification in cell-free DNA from maternal blood, as demonstrated in cases with favorable outcomes post-diagnosis.[67]Knowledge of trisomy 8 has evolved from viewing it primarily as a lethal full aneuploidy—often resulting in early miscarriage—to recognizing the mosaic form as a manageable condition with supportive care, aided by organizations like Unique that provide resources for families and promote natural history research.