Mosaic Autosomal Trisomies and Pigmentary Mosaicism (Hypomelanosis of Ito)

A class of conditions in which a cell line trisomic for an autosome coexists with a euploid line in the same individual, in the placenta, or in both, with a phenotype that depends on the chromosome involved, the origin of the error, the tissue distribution, and any uniparental disomy; it includes pigmentary mosaicism along the lines of Blaschko (formerly hypomelanosis of Ito), a cutaneous sign of postzygotic chromosomal or genic mosaicism.

Literature and regulatory information updated: 27 October 2026.

0. Reference Summary Table

0.1. General parameters of the two entities in this article

0.2. Class of mosaic autosomal trisomies compatible with live birth

The column "risk of abnormal outcome" refers to true mosaicism in amniocytes and comes from the North American series of 151 cases by Hsu and colleagues (1997) or, for chromosomes 13, 18, 20, and 21, from the series of 305 cases by Wallerstein and colleagues (2000); Orphanet case counts refer to published cases, not to prevalence.

0.3. Genic causes of pigmentary mosaicism

1. Introduction

1.1. Definitions

Mosaicism is the presence in an individual of two or more cell populations derived from the same zygote that have subsequently acquired a genetic difference; the mechanisms that give rise to it are mitotic nondisjunction, trisomic rescue, and new somatic mutation [29]. It is distinct from chimerism, in which the different cell lines derive from separate zygotes and are each normal, a situation described in some patients with segmental dyspigmentation [6, 76]. In mosaic autosomal trisomy, a 47-chromosome line carrying an extra copy of an autosome coexists with a euploid line; when postzygotic nondisjunction involves an autosome, the reciprocal monosomic line is lost and only the trisomic and normal lines persist, unlike the situation with the X chromosome, in which the 45,X line can persist [29].

Prenatal diagnosis adds categories of its own. Pseudomosaicism is an abnormal line that arises in laboratory culture and is absent from the conceptus [77]. Confined placental mosaicism (CPM) is the presence of the abnormal line only in placental tissue, with a chromosomally normal fetus, and is subdivided into type I (cytotrophoblast), type II (mesenchyme, villous core), and type III (both layers); true fetal mosaicism (TFM) is the presence of the abnormal line in the fetus, and the Grati classification describes six types combining trophoblast, mesenchyme, and amniocytes [2, 3, 77]. The term rare autosomal trisomy (RAT) designates any trisomy other than those of chromosomes 13, 18, 21, X, or Y, and entered clinical vocabulary with genome-wide prenatal cell-free DNA screening [2, 78].

Pigmentary mosaicism is the cutaneous expression of mosaicism: areas of skin with hypo- or hyperpigmented streaks or whorls that follow the lines of Blaschko, most pronounced on the trunk [14, 29]. The historical designation "hypomelanosis of Ito" described the hypopigmented form; because it can be difficult to decide whether the abnormal skin is the lighter or the darker, recent reviews prefer "pigmentary mosaicism", qualified as hypo- or hyperpigmentation [5, 6].

1.2. Historical milestones

In 1901 Alfred Blaschko published an atlas of 83 patients with naevoid anomalies and 63 with acquired linear dermatoses, in which he drew the lines that now bear his name: V-shaped on the back, S-shaped or whorled on the lateral trunk, and linear on the limbs, corresponding to no nerves, vessels, or lymphatics and interpreted as tracing embryonic cell migration [6]. In 1952 Ito described incontinentia pigmenti achromians, initially without extracutaneous findings; the condition was later recognised as neurocutaneous because of the frequency of brain involvement and epilepsy [5, 79]. The association with chromosomal mosaicism was documented in reports such as that of Ritter and colleagues (1990), who described a mosaic with a ring chromosome 22 and proposed HI as a clinical marker of chromosomal mosaicism of any type in individuals whose skin is dark enough to make it visible [80]. In 1996 Hatchwell put forward the unifying hypothesis of mosaic functional disomy in females with an X;autosome translocation and HI [74], and in 1999 Küster and König summed up the consensus in the title "Hypomelanosis of Ito: no entity, but a cutaneous sign of mosaicism" [81].

In the field of trisomies, Haslam and colleagues reported the first case of mosaic trisomy 9, with multiple congenital anomalies, in 1973, and Feingold and Atkins described the first complete trisomy 9 in lymphocytes the same year [31, 50, 82]. In 1983 Kalousek and Dill, studying placental and fetal tissues from 46 pregnancies, identified two in which mosaicism was confined to the chorion, establishing the concept of CPM [83]. The Canadian collaborative study by Worton and Stern (1984), with more than 12,000 amniocenteses, established the classification of mosaicism in culture into levels I to III, and Hsu's group in New York published guidelines in 1992 for distinguishing pseudomosaicism from true mosaicism in amniocytes, revised in 1999 [84–86]. The series of Hsu (1997) and Wallerstein (2000) provided the first chromosome-by-chromosome correlations between amniocyte karyotype and outcome [39, 57].

The identification of postzygotic monogenic causes of pigmentary mosaicism began with Mirzaa and colleagues (2016), who found the mosaic MTOR variant p.(Thr1977Ile) in children with megalencephaly, polymicrogyria, and blaschkoid pigmentation [87]. RHOA (Vabres 2019), TFE3 (Villegas 2019; Lehalle 2020), the French series of MTOR-related HI (Carmignac 2021), GNA13 (El Masri 2025), and ACTB (Castillon 2026) followed [5, 9–12, 88]. The nationwide introduction of genome-wide prenatal cfDNA screening in the Netherlands (TRIDENT-2 study, 2017–2019) and in Belgium yielded the first population series of RAT detected at screening [27, 89].

1.3. Nomenclature and reclassification

Orphanet has flagged the entry ORPHA:435 ("Ito hypomelanosis") as obsolete and no longer treats it as an entity [24]. The term remains useful descriptively for the cutaneous sign, and Happle advised against the terms incontinentia pigmenti achromians, naevus depigmentosus/achromicus, and segmental pigmentation disorder as designations for the same heterogeneous condition [6]. The hyperpigmented form has its own Orphanet entry as linear and whorled naevoid hypermelanosis (LWNH, linear and whorled nevoid hypermelanosis; ORPHA:79150) [18], and the coexistence of hyper- and hypopigmentation is termed cutis tricolor [6]. The recently described genic entities have their own names: RHOA-related mosaic ectodermal dysplasia, with the OMIM designation "ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic" (EDFAOB) [9, 20], and TFE3-related neurodevelopmental disorder [21, 26].

Two statements in the reference textbooks are outdated. The 8th edition of Smith's (2022) states that a monogenic basis for HI probably does not exist, and the Oxford Desk Reference (2017) that the point mutations and small copy-number changes responsible for pigmentary mosaicism without a chromosomal cause had not yet been described [4, 13]. Both have been superseded by the MTOR, RHOA, TFE3, GNA13, and ACTB series mentioned above; in the French cohort, mosaic MTOR explained more than one third of patients with HI and seizures [5].

In cytogenetic nomenclature, the ISCN (International System for Human Cytogenomic Nomenclature) describes mosaicism with the metaphase count of each line in square brackets, for example mos 47,XY,+9[4]/46,XY[50], and uniparental disomy as upd(15)mat [47, 90].

1.4. Scope and related entities

This article treats as a class all mosaic autosomal trisomies compatible with live birth, with in-depth coverage of trisomies 9, 14, 20 and 22 and of trisomies 7 and 15 because of their uniparental disomy implications, placental mosaicism and its interpretation at prenatal screening and diagnosis, and chromosomal and genic pigmentary mosaicism with diagnosis in non-haematological tissues. Mosaic trisomies with a distinct clinical picture of their own are not developed here (trisomy 21, sex chromosome mosaicism and Turner syndrome and X polysomies, trisomy 18, trisomy 13, mosaic trisomy 16 and chromosome 16 CPM, mosaic trisomy 8, Pallister-Killian syndrome and diploid/triploid mixoploidy), nor are incontinentia pigmenti and the PIK3CA-related overgrowth spectrum.

2. Molecular Genetics and Pathophysiology

2.1. Origin of the trisomic line: mitotic error and trisomic rescue

As a rule, a rare autosomal trisomy is viable only in mosaic form, and by the end of the first trimester the vast majority of fetal RATs are already mosaic [2]. Two mechanisms give rise to the trisomic line. In the first, a euploid zygote undergoes postzygotic mitotic nondisjunction – failure of sister chromatids to separate at mitosis – in an embryonic or placental cell; the reciprocal monosomic line for an autosome is lost and the trisomic line persists against a background of euploid cells [2, 29, 91]. In the second, a meiotic error produces a trisomic zygote and, in a fraction of cells, mitotic loss of the extra chromosome ("trisomic rescue", complete or partial) restores euploidy [2]. The distinction has practical consequences: meiotic origin is associated with a higher proportion of affected blastomeres, a greater likelihood of fetal involvement, a risk of uniparental disomy (UPD) in the rescued line, and a correlation with FGR, whereas mitotic origin leaves a background of many euploid cells, lower fetal risk, and virtually no added risk of UPD [2]. Advanced maternal age, a risk factor for meiotic trisomies, is therefore also a risk factor for mosaicism through rescue [29, 92].

The predominant origin differs by chromosome. Trisomies 14, 15, 22 (acrocentrics), and 16 are predominantly maternal meiotic; trisomies 2, 3, 7, and 8 are mostly mitotic; trisomies 12 and 20 have a variable origin, and for trisomy 9 the data are insufficient [2]. In trisomy 14, 93% of cases with determined origin are meiotic (73% maternal and 20% paternal); in trisomy 22, 98%; in trisomy 15, the trisomic line is of meiotic origin in 85% (maternal) and, in the European EUCROMIC study (1986–1992), in about 50% of trisomy 15 CPM cases [2, 92, 93].

2.2. Embryonic lineages and tissue distribution

Prenatal diagnosis assumes that the fetus, placenta, and membranes derive from the same conceptus with the same constitution; mosaicism breaks this rule [94]. The Gardner and Sutherland scheme reproduced in the Oxford Desk Reference distinguishes six situations in the fetoplacental unit: complete concordance, confined placental mosaicism, fetoplacental mosaicism, complete fetoplacental discordance, fetal mosaicism with a nonmosaic placenta, and fetal mosaicism with a normal placenta; the needle path determines whether an abnormal line present in the placenta is detected or missed at CVS [94]. The fertilised egg gives rise to the trophoblast precursor and the inner cell mass, which forms the hypoblast and the epiblast; the latter gives rise to the embryonic ectoderm and the primitive streak (mesoderm and endoderm) [77]. Direct or short-term culture preparations of chorionic villi reflect the cytotrophoblast; long-term culture reflects the extraembryonic mesoderm, which is closer to the fetus; amniocytes are a mixture of cells from the amnion and from the fetal skin, gastrointestinal tract, and respiratory and urogenital tracts, and best reflect the fetus [3, 77, 94]. "Fetal" cell-free DNA comes from apoptotic cells of the outer cytotrophoblast, so cfDNA screening reproduces the karyotype of the trophoblast rather than that of the fetus [2, 32].

The Grati classification (2017), summarised by Döttelmayer and Fauth (2026), describes six types of mosaicism detected at CVS, with the observed frequencies: CPM I (abnormal trophoblast, normal mesenchyme and amniocytes) 35.73%; CPM II (mesenchyme only) 40.45%; CPM III (both layers, normal amniocytes) 10.36%; TFM IV (trophoblast and amniocytes) 1.55%; TFM V (mesenchyme and amniocytes) 5.36%; TFM VI (all tissues) 6.55% [3]. Types I and II are more likely mitotic and type III more likely meiotic [2]. The probability of true fetal mosaicism is 36.6% when both placental layers are affected, 3.9% when only the trophoblast is affected, and 12.1% when only the mesenchymal core is affected, and it exceeds 80% when the trophoblast is mosaic and the core is homogeneously affected [3]; the Lannoo review cites similar values (35%, 4%, and 12%) [2].

After birth, the distribution of the trisomic line also differs between tissues, and blood is often the least informative tissue. In trisomy 22, negative selection of trisomic cells in blood delays diagnosis, and mosaicism is easier to detect in fibroblasts than in lymphocytes [29, 69]. In trisomy 20, trisomic cells are almost never confirmed in newborn blood and are found in urine, kidney, or skin [66, 95]. In mosaic trisomy 16, trisomic cells never exceeded 1% of cultured lymphocytes in the Hsu and Benn series [96]. Cell culture introduces a bias of its own, because aneuploid cells proliferate less and the normal clone is favoured [2, 6]; for postzygotic genic variants, the allele fraction is higher in fresh skin than in cultured fibroblasts [9].

2.3. Frequency of trisomies across development

The frequency of each trisomy declines between the preimplantation embryo and prenatal screening, and this decline is an indirect indicator of viability. The following table reproduces the per-100,000 data compiled by Lannoo and colleagues (embryoblast on day 3, trophectoderm on day 5, early miscarriages, CVS, and cfDNA screening) [2].

Aneuploidy was detected in 31.7% (673/2119) of day-3 embryos, 11.1% (3920/35,171) of day-5 trophectoderm biopsies, 0.4% (237/57,539) of CVS samples, and 0.3% (867/282,027) of cfDNA screens; RATs accounted for 22% (564/2564) of the early miscarriages analysed [2]. Trisomies 1 and 19 are seen in preimplantation embryos but are exceptional thereafter, which classifies them as nonviable; for most of the others, the frequency at cfDNA screening does not exceed 5% of that observed in the trophectoderm, with the exception of chromosome 7 (49%), consistent with a postzygotic origin restricted to the trophoblast [2]. Mosaic aneuploidy is detected in 19% of trophectoderm biopsies, and in a prospective nonselection trial the developmental potential of blastocysts with low- to medium-level mosaicism was comparable to that of euploid blastocysts [2, 97].

2.4. Uniparental disomy

UPD is the inheritance of both copies of a chromosome (or of a segment) from a single parent; it requires at least two errors, and the main mechanism is trisomic rescue, in which loss of the paternally derived chromosome leaves two maternal copies, or vice versa [2, 47]. Mosaic trisomy of postzygotic origin is not associated with UPD [2]. Mitotic recombination, which is rare, is another mechanism: it produces mosaic paternal UPD in some cases of Beckwith-Wiedemann syndrome, as well as loss of heterozygosity, an important step in tumorigenesis [98]. If the meiotic error occurred in meiosis I, the resulting UPD is heterodisomic; in meiosis II, isodisomic; crossing-over produces segmental combinations of iso- and heterodisomy, as in the case described in section 10 [47, 99].

UPD has two clinical consequences. On chromosomes with imprinted genes, it alters the dosage of monoallelically expressed genes: phenotypes are documented for maternal UPD of chromosomes 7, 11, 14, 15, and 20 and paternal UPD of chromosomes 6, 11, 14, 15, and 20, and the effect is debatable for chromosomes 2 and 16 [47]. On any chromosome, isodisomy can unmask homozygosity for a recessive variant inherited from the carrier parent; the absolute risk is very low, and no guideline recommends looking for regions of homozygosity for this reason [2, 47].

The risk of UPD depends on the chromosome. After mosaic trisomy 15 confined to the placenta at CVS, the empirical risk of UPD is 11–25% according to the American College of Medical Genetics and Genomics (ACMG) document, and the Lannoo review found maternal UPD15 in 38% (8/21) after RAT 15 at screening, with no paternal UPD15 reported [2, 47]. For chromosome 7, maternal UPD7 is exceptional (~1%, 1/109) [2]. No UPD was observed in 14 cases of RAT 14 or in 5 of RAT 20, nor UPD6 in 8 cases of RAT 6 (0.85% of RATs at screening), nor UPD11 in 9 of RAT 11 (0.96%) [2]. Nonmosaic maternal UPD11 has never been observed and may be lethal [2]. The position statement of the International Society for Prenatal Diagnosis (ISPD) estimates the overall risk of UPD in a pregnancy with CPM of an imprinted chromosome at 2.1% [32].

2.5. Basis of pigmentary mosaicism

Melanocytes, cells of neural crest origin located among the basal cells of the epidermis, produce eumelanin and pheomelanin in melanosomes that they transfer to keratinocytes; depigmentation corresponds to absent or nonfunctional melanocytes, and hypopigmentation to reduced or partially functional melanocytes [101]. The lines of Blaschko trace the migration of ectodermal cells, keratinocytes, and melanocytes; lymphocytes and fibroblasts are mesodermal, which explains why an abnormal line visible in the skin may be absent from the cells usually cultured [75]. Taibjee and colleagues proposed that the chromosomal abnormalities of pigmentary mosaicism act through specific disruption of the expression or function of pigmentation genes [102].

Happle described seven archetypal patterns of cutaneous mosaicism: type 1a, narrow Blaschko bands (for example, HI); type 1b, broad bands (for example, McCune-Albright syndrome); type 2, checkerboard or "flag" pattern with sharp midline demarcation; type 3, phylloid pattern, with leaf-like or oblong macules; type 4, patchy pattern without midline separation (for example, giant melanocytic naevus); type 5, lateralisation (for example, CHILD syndrome); and type 6, sash-like pattern [6].

The chromosomal causes are heterogeneous. In the review of 651 patients, the abnormal karyotype involved chromosomes 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 16, 18, 20, and 22 and the sex chromosomes, mosaics with translocations between chromosomes 1, 6, 12, 13, 14, and 21, and six X;autosome translocations [6]. In females with a balanced X;autosome translocation with a pericentromeric X breakpoint, the phenotype may result not from disruption of an X-linked gene but from mosaic functional disomy of the X sequences above the breakpoint; spreading of X inactivation into the translocated autosome may contribute, as in the boy with t(X;15)(p21.1;q11.2) described by Sakazume, with hypermethylation of SNRPN and OCA2, a Prader-Willi–like phenotype, and hypopigmentation [74, 103, 104]. OMIM entry 300337, which linked HI to Xp11, is historical [17].

2.6. Genes of pigmentary mosaicism

MTOR. The MTOR gene (1p36.22; OMIM 601231) encodes a serine/threonine kinase that regulates growth, proliferation, metabolism, and autophagy; the known pathogenic variants are activating (gain of function) and mainly hyperactivate the mTORC1 complex [19]. In the constitutional state they cause Smith-Kingsmore syndrome (SKS), and in mosaic form they cause a spectrum ranging from focal cortical dysplasia type II confined to the brain to HI with megalencephaly [5, 19, 87]. In the French cohort of Carmignac (2021), mosaic variants included p.(Lys1452Asn), p.(Cys1483Tyr), p.(Ala1519Val), p.(Ala1519Thr), p.(Glu1799Lys), p.(Thr1977Ile), p.(Ile2017Thr), p.(Ser2413Ile), p.(Glu2419Lys), p.(Leu2427Pro), and p.(Ile2501Phe), with p.(Glu1799Lys), p.(Glu2419Lys), and p.(Ala1519Thr/Val) recurring in two patients each and p.(Thr1977Ile) in three [5]. In fibroblasts with p.(Glu2419Lys), phosphorylation of AKT Ser473 and p70S6K Thr389 increased after amino acid deprivation, with no constitutive activity in rich medium [5]. Hypopigmented skin had fewer melanocytes (mean 5.2 per field vs. 15.8 in controls), fewer mature melanosomes, and fewer melanosomes transferred to keratinocytes, and the authors attribute the hypopigmentation to partial suppression of melanogenesis by mTORC1 activation, a mechanism shared with the hypomelanotic macules of tuberous sclerosis complex (TSC) [5]. In the Mirzaa study, the variants activated mTORC1 and caused neuronal hypertrophy that was reversed by everolimus in cultured neurons, and the variant allele fraction (VAF) showed a gradient centred on the most epileptogenic area [87].

RHOA. The RHOA gene (3p21.31; OMIM 165390) encodes a Rho-family GTPase. The postzygotic variants of mosaic ectodermal dysplasia are inactivating, with a dominant-negative effect (reduced stress fibres and reduced phosphorylation of MYPT1 Thr696 and MLC2 Thr19) [9]. The gene is intolerant of missense variants (z = 3.70), with no loss-of-function alleles in the population, and was considered lethal in the germline state, surviving only in mosaic form [9]. In 2025 Nakato and colleagues described the first nonmosaic germline variant, p.(Arg68Ser), in a girl with EDFAOB features without blaschkoid lesions [71]. In tumours, somatic RHOA variants are gain-of-function (diffuse gastric cancer in 25.3%; p.Gly17Val in 68% of angioimmunoblastic T-cell lymphomas) and have no germline implication [20].

GNA13. The recurrent postzygotic variant GNA13 c.599G>A p.(Arg200Lys) causes gain of function of Gα13, with hyperactivation of the RHOA/ROCK pathway and of YAP, rounding of melanocytes, and defective melanosome transfer; it defines a mosaic hypopigmentation syndrome with intestinal atresia [10].

ACTB. Postzygotic ACTB variants were described in 2026 in three French patients with HI; the variant c.1004G>A p.(Arg335His) had previously been described in the constitutional state in a fetus with cystic hygroma, omphalocele, and cystic kidneys [11]. The phenotype is distinct from Becker naevus (somatic ACTB p.Arg147Ser/Cys variants) and from Baraitser-Winter syndrome (germline variants) [11].

TFE3. The TFE3 gene (Xp11.23; OMIM 314310) encodes a transcription factor retained in the cytoplasm by the Rag GTPases, Ragulator, and folliculin and phosphorylated in an mTOR-dependent manner [21]. Pathogenic variants lie in the domain required for cytoplasmic inactivation and render TFE3 constitutively nuclear, which blocks exit from pluripotency and links the mTOR/lysosome pathway to pigmentary mosaicism [21, 88]. In Lehalle's series of 17 individuals, the variants were de novo and missense except for one splice variant, 11 of 13 were in exon 4, and three were recurrent; at least two boys were mosaic [12]. Somatic TFE3 fusions (Xp11 renal cell carcinoma, alveolar soft part sarcoma) do not imply germline predisposition [21].

PHF6 and DDX3X. In females, de novo PHF6 and DDX3X variants produce mosaic-type pigmentary changes, explained by random X inactivation; Zweier and colleagues described seven females with PHF6 variants and a phenotype distinct from male Börjeson-Forssman-Lehmann syndrome, with linear cutaneous hyperpigmentation [13, 72, 73].

KITLG, GNAQ, and GNA11. A mosaic KITLG variant has been described in LWNH (indirect attribution, cited by Carmignac) [5]. Mosaic activating variants of GNAQ and GNA11, at very low levels in affected tissues and undetectable in blood, cause extensive dermal melanocytosis and phakomatosis pigmentovascularis and belong, together with McCune-Albright and Sturge-Weber syndromes, to the group of mosaic heterotrimeric G-protein disorders [105].

2.7. Normalised variants

The following variants were normalised in VariantValidator (GRCh38, MANE Select transcript) [106]. The remaining MTOR variants in the Carmignac series have only protein notation in the sources reviewed, except for c.4556C>T p.(Ala1519Val), and were not converted [5].

Vabres and colleagues used transcript NM_001664.3; the c. position is unchanged in MANE version .4 [106]. The third ACTB variant is a deletion-insertion, c.1044delinsCTTCCACCTTCCACCTTCCATC p.(Ser348_Leu349insPheHisLeuProProSerIle) [11].

2.8. Genotype–phenotype correlations and allelic disorders

In mosaic trisomies, the severity of malformations and impairment broadly correlates with the percentage of trisomic cells in the various tissues, but the percentage measured in lymphocytes or amniocytes has weak predictive value: in trisomy 9, the Li cohort (16 patients) found no correlation between the lymphocyte level and severity, and the percentage of abnormal cells at CVS or amniocentesis does not reliably predict the likelihood of fetal mosaicism or its severity [31, 50, 94]. There are partial exceptions: for chromosomes 12, 15, 16, and 20 there is some evidence of a correlation between outcome and the percentage at amniocentesis, and in trisomy 20 the outcome was abnormal in 4.5% with fewer than 50% trisomic cells and in 20% above 50% [2, 57].

For MTOR, variants in the kinase domain are associated with more hearing problems and dysmorphism, those in the FAT domain with more autistic behaviour, and p.(Glu1799Lys) with a more uniform neurodevelopmental course [19]. In MTOR-related HI, severity did not correlate with the proportion of mutated brain cells, and one patient had a paradoxical VAF (25% in normal skin and 10% in hypopigmented skin), interpreted as possible death of the mutated cells through autophagy [5]. The allelic disorders of MTOR include apparently isolated focal cortical dysplasia type II (OMIM 607341), with brain-confined variants in 12/77 (15.6%) of a focal cortical dysplasia type II cohort studied by deep sequencing of paired brain and blood DNA, hemimegalencephaly, and sporadic tumours with somatic variants [19, 109, 110].

2.9. Mosaic variegated aneuploidy

MVA is an autosomal recessive disorder of chromosome segregation in which the karyotype shows a heterogeneous mixture of trisomies and monosomies of many chromosomes, characteristically in about 25% or more of cells, sometimes with gain or loss of two or three autosomes in the same cell and premature chromatid separation [14, 15]. The genes are BUB1B (MVA type 1; 15q15.1; OMIM 257300), which encodes a mitotic spindle checkpoint protein, CEP57 (type 2; OMIM 614114), and TRIP13 (type 3; 5p15.33; OMIM 617598), all with biallelic variants [15, 111–115]. The GeneGuidance database assigns "autosomal dominant" inheritance to ORPHA:1052 in the field imported from Orphanet; the Oxford Desk Reference and OMIM describe autosomal recessive inheritance, and the founding series identified biallelic variants, so the dominant classification is a mapping error [14, 15, 111].

3. Clinical Spectrum and Manifestations by System

3.1. Principles common to the class

The phenotype of a mosaic trisomy results from the chromosome involved, the origin of the error, the proportion and distribution of trisomic cells, and any UPD in the euploid line [2, 99]. Some manifestations recur across almost the entire class: FGR of prenatal onset and postnatal growth delay, congenital heart disease (mainly ventricular septal defect [VSD] and atrial septal defect [ASD]), mild dysmorphism, body asymmetry with hemihypotrophy, pigmentary changes along Blaschko lines, and ID of variable degree, sometimes absent [29, 48, 58, 68]. Hemihypertrophy is more common in children with normal development or who are constitutionally large, whereas hemihypoplasia points more towards a mosaic chromosomal disorder, often accompanied by developmental and growth delay and dysmorphism [116]. Seizures are common in mosaic karyotypes that affect the brain [29]. Natural history data come from reports and small series subject to ascertainment bias, except for the follow-up of prenatal diagnoses, which shows a high proportion of normal outcomes for some chromosomes (20, 3, 11, and 17 without fetal involvement) [2, 64, 66].

3.2. Mosaic trisomy 9

Smith's summarises the syndrome as "joint contractures, congenital heart defects, and low-set malformed ears", with growth deficiency of prenatal onset and severe ID [50]. The face has a sloping forehead with a narrow bifrontal diameter, short upslanting palpebral fissures, deep-set eyes, a prominent nasal bridge with a short root and a small, fleshy tip, a prominent upper lip overlapping a retruded lower lip, micrognathia, and low-set, posteriorly rotated, malformed ears [50]. The skeleton shows abnormal position or function of the hips, knees, feet, elbows, and digits, kyphoscoliosis, a narrow chest, and hypoplasia of the sacrum, iliac wings, pubic arch, and toe phalanges; about two thirds of patients have congenital heart disease [50]. Occasional anomalies include Dandy-Walker malformation, hydrocephalus, microphthalmia, Peters anomaly, cleft lip or palate, triphalangeal thumbs, stippled cartilage mineralisation, diaphragmatic hernia, multiple pilomatricomas, and genitourinary anomalies (hypoplastic genitalia, XX sex reversal, cryptorchidism, cystic dilatation of the renal tubules, hydronephrosis) [50]. Orphanet adds the frequency of cutaneous lesions of pigmentary mosaicism along Blaschko lines [1]. The figures in Smith's show a 22-week fetus with a sloping forehead, broad nasal bridge, prominent upper lip, and micrognathia, and a growth-restricted term stillborn infant with extended elbows, flexed hips and knees, extended wrists with clenched hands, and hypoplastic nails (description from the captions) [117].

The cohort of Li and colleagues (2021; Children's Hospital of Philadelphia and Cincinnati; 16 patients, 13 female, aged 7 days to 14 years) provides the most complete contemporary description [31]. There were prenatal complications in 13/16, and FGR or a small fetus in 9; seven were born preterm (29+2 to 41+1 weeks), ten had a birth weight below the 10th percentile, and twelve had a prolonged neonatal hospital stay because of prematurity or respiratory or feeding problems [31]. At follow-up, weight and length were below the 10th percentile in ten patients each; frequent findings were craniofacial dysmorphism, heart disease, feeding and respiratory difficulties, cryptorchidism, hip dysplasia, seizures, and developmental delay; less common were craniosynostosis (2/16), hearing loss (6/16), ptosis (5/16), iris coloboma (2/16), aortic dilatation (1/16), intestinal malrotation (2/16), and tethered cord (3/16), and the authors added astigmatism (4/16), hyperopia (3/16), amblyopia (2/16), and diaphragmatic eventration (1/16) [31]. Magnetic resonance imaging (MRI) in 14 patients showed ventriculomegaly in six [31]. Global delay was universal, especially of speech, without regression; at least three patients were essentially nonverbal, walking emerged between 18 and 25 months in the five with recorded milestones, and a 14-year-old girl functioned at a fifth-grade level with moderate ID [31]. The level of mosaicism in lymphocytes ranged from 4% to 80% (median 20%) [31].

The classic natural history is death in the early postnatal period in most patients; among survivors, growth delay and severe motor and intellectual disability are the rule, but several children walk unaided, have social skills and minimal speech, and manage part of their daily care [50]. Bruns described long-term survivors, and three adults aged 19, 24, and 24 years have been published [31, 118]. In Brazil, Zen and colleagues (Porto Alegre, 2011) reported two patients with prolonged survival: a boy aged 6 years 5 months with an asymmetric triangular face, right microtia, micropenis, and the karyotype mos 47,XY,+9[4]/46,XY[50] in lymphocytes, and a 2-year-old girl with triphalangeal thumbs, heart disease, hearing loss, hypotonia, and dysphagia, with mos 47,XX,+9[3]/46,XX[69] [90].

3.3. Mosaic trisomy 14

The review by Fujimoto and colleagues (1992; 13 published cases and 2 new ones) found in more than 90% growth delay (15/15), psychomotor delay (10/10), a broad nose (13/14), dysplastic or low-set ears (15/15), micrognathia (15/15), a short neck (11/12), congenital heart disease (14/15), and micropenis with cryptorchidism (6/6); also frequent were a prominent forehead (12/14), hypertelorism (8/13), a large mouth (10/14), cleft or high-arched palate (10/14), body asymmetry (8/12), and abnormal skin pigmentation (6/10) [59]. Four children died before 4 months of age and one at 3 years after cardiac surgery; the oldest patient, aged 29 years, had functional language and basic independence [59]. Shinawi and colleagues (2008) described five patients with low-level mosaicism detected by array comparative genomic hybridisation (aCGH) or karyotype, with variable delay, congenital anomalies, pigmentary lesions, and dysmorphism, and suggested that the condition is more common than previously thought [119].

The combination of mosaic trisomy 14 with maternal UPD14 (Temple syndrome) in the euploid line had been reported in only eight live births by 2018, and Yakoreva and colleagues recommend testing for mosaic trisomy 14 in every patient with atypical Temple syndrome [120]. The Balbeur case, presented in section 10, illustrates this overlap [99]. In 2026, two cases were published: a fetus with craniofacial, cardiac, and limb malformations and FGR at 15 weeks, with trisomy levels varying among tissues at autopsy and no correlation with severity, and a 10-year-old girl with severe short stature, delay, and a patent ductus arteriosus, with 6% trisomic metaphases on karyotype and about 50% gain of chromosome 14 on SNP microarray [121, 122].

3.4. Mosaic trisomy 20

Trisomy 20 is among the most frequent mosaic trisomies at amniocentesis and has the best prognosis in the class. In Hsu's review (1991) of 103 prenatal diagnoses, about 90% (90/101) of fetuses or children had a grossly normal phenotype; the trisomic cells were probably extraembryonic or confined to specific fetal organs (kidney, skin) [66]. In the Wallerstein series (2000), the outcome was abnormal in 6.5% (10/152), and the normal live-born infants had a mean of 27% trisomic cells [57]. Robinson and colleagues (2005), drawing on the literature, estimated only 4% abnormal outcomes when the percentage of trisomic cells was below 40%; levels were higher in male fetuses, with no difference in the frequency of abnormal outcome [95]. In 14 prenatal cases from New Zealand, all with 8–50% mosaicism, 12 children were physically and developmentally normal with follow-up of up to 10 years, and two had minor anomalies [92, 123].

The phenotype, when present, is subtle. Willis and colleagues (2008) described in three patients vertebral anomalies (spinal stenosis, vertebral fusion, kyphosis), hypotonia, lifelong constipation, sloping shoulders, and significant learning difficulties with normal intelligence, and proposed evaluating for these findings even when the examination at birth is normal [67]. Baty and colleagues (2001) reported two girls with normal intelligence and hypopigmented areas after mosaic trisomy 20 at amniocentesis, with trisomic cells in the urinary sediment (25% and 100%) and a normal cord blood karyotype [124]. LWNH with postnatally confirmed mosaic trisomy 20 has also been described [125]. Rare severe forms include psychomotor and speech delay, heart disease, and horseshoe kidney [65].

3.5. Mosaic trisomy 22

The systematic review by Trevisan and colleagues (Pavia and Rome, literature through December 2023) compiled about 25 postnatal and 18 prenatal cases [69]. In the postnatal cases (n = 25), there was congenital heart disease in 14 (ASD 7, VSD 6, pulmonary vein stenosis 4, patent ductus arteriosus 3, tetralogy of Fallot 2; complex defects in 5), neurodevelopmental impairment in 10 (ID assessed in 11: severe in 1, moderate in 3, mild in 5, and borderline-normal in 3), hypotonia in 8, hearing loss in 6, hypoplastic nails in 12, pigmentary changes in 8, body asymmetry in 11, fifth-finger clinodactyly in 11, webbed neck in 7, preauricular tags or pits in 15, genital anomalies in 11, anal malformation in 4, and dental anomalies in 6 [69]. In prenatal cases with data (n = 20), 17 had systemic findings (FGR in 17, increased nuchal fold in 5, oligohydramnios in 4), 10 facial findings, and 8 cardiac findings [69]. The Oxford Desk Reference highlights ear, cardiac, and renal anomalies and radial hypoplasia or aplasia, as well as the overlap with the Turner phenotype, already described by Wertelecki in 1986 [29, 126]. Crowe and colleagues (1997) reported a child with HI, hemiatrophy, growth delay, and ID, with an initially normal lymphocyte karyotype and trisomic cells mainly in fibroblasts, and maternal disomy in the disomic cells; Florez and Lacassie (2005) described a patient with normal intelligence [127, 128].

3.6. Mosaic trisomies 7, 15, and 2

Trisomy 7 is the most frequent RAT at cfDNA screening (30.5% of all RATs) and is almost always confined to the placenta [2]. Postnatal cases have Blaschko-linear pigmentary dysplasia, body asymmetry, enamel dysplasia, and developmental and growth delay, with some cases free of malformations [48]. In Portugal, Gouveia and colleagues (Centro Hospitalar e Universitário de Coimbra, 2016) described a 9-year-old boy with whorls and streaks of hypo- and hyperpigmentation over the whole body, hypertrichosis, and minor musculoskeletal and neurodevelopmental anomalies, without ID, with mosaic trisomy 7 in cultured fibroblasts and a previously normal fetal karyotype [129]. After fetal trisomy 7, intellectual development was normal and the incidence of (renal) malformations low in the Lannoo review; the risk of maternal UPD7 with a Silver-Russell phenotype is about 1% [2, 130].

Postnatal mosaic trisomy 15 combines FGR, heart disease, small dysplastic kidneys, cerebellar hypoplasia, digital and genital anomalies, and pigmentary changes; McPadden and colleagues (2015) reported a newborn with whorled hypopigmentation, abnormal cerebral vasculature, and dysplastic kidneys, and noted that very few live-born infants survive the first year [60, 131]. After fetal trisomy 15, the outcome was abnormal in 55% (12/22) [2].

Postnatal mosaic trisomy 2 combines FGR, microcephaly, micro- or anophthalmia, facial clefts, heart disease, neural tube defects, radioulnar hypoplasia, preaxial polydactyly, intestinal malrotation, Hirschsprung disease, and ventriculomegaly [38]. Sago and Chen found one case of true trisomy 2 in 58,000 amniocenteses, with oligohydramnios, FGR, hydronephrosis, and heart disease, normal chromosomes in blood, fibroblasts, and ascites, and 4/100 trisomic fibroblasts from a liver biopsy; among 10,500 CVS samples, the 11 fetuses with trisomy 2 in the villi were normal at birth [40]. After fetal trisomy 2, 86% (18/21) had an abnormal outcome and 46% (9/21) major malformations [2].

3.7. Other rare mosaic trisomies

3.8. Confined placental mosaicism and obstetric outcome

CPM has obstetric consequences of its own, even with a euploid fetus, because the aneuploid placenta may function poorly. Trisomy 16 is the model: in more than 80 pregnancies with trisomy 16 at CVS or screening and a normal amniocentesis, there was FGR in 53% (43/81), preterm birth in 40.2% (33/82), gestational hypertension or preeclampsia in 26.1% (23/88), fetal death in 6.1% (5/82), and structural malformations in 18.4% (16/87), mainly cardiac [2]. Probable CPM of trisomy 22 was associated with FGR in 44% of 16 cases, and in trisomy 2 there was an inverse correlation between the level of mosaicism and birth weight [2]. Among 101 small-for-gestational-age (SGA) newborns, placental aneuploidy was ten times more frequent than in controls (11.9% vs. 1.1%) [2].

For RATs other than 16, the studies diverge. In TRIDENT-2 (Netherlands, 2017–2019), 189 pregnancies with confirmed or presumed CPM, 94.7% due to RAT, had an adverse perinatal outcome in 52.9%, with relative risks (RR) compared with the general obstetric population of 18.5 for preeclampsia (8.5% vs. 0.5%; 95% CI 11.6–29.4), 5.5 for birth weight below the 2.3rd percentile (13.6% vs. 2.5%; 3.8–8.0), 2.2 for preterm birth, 2.1 for neonatal intensive care admission, and 1.6 for planned caesarean delivery; the associations persisted after excluding trisomy 16, with no increase in fetal structural anomalies in non-16 CPM [30]. By chromosome, CPM 7 was associated with birth weight below the 2.3rd percentile in 11.9% (RR 5.0), CPM 8 with induction of labour in 47.8% (RR 2.1), CPM 16 with preeclampsia in 27.3% (RR 70.7) and birth weight below the 2.3rd percentile in 52.6% (RR 21.5), and CPM 20 with preeclampsia in 10.5% (RR 27.2) and planned caesarean delivery in 38.9% (RR 5.2) [30]. The Italian cohort of Grati (2020; 181 CPM and 757 controls, with outcome known in 124 and 468) confirmed the risk in trisomy 16 (birth weight below the 3rd percentile, odds ratio [OR] 11.2; preterm birth, OR 10.2) but found no strong associations for the other RATs and concluded that genome-wide RAT screening offers minimal benefit [136]. In the Australian cohort of Raymond (Melbourne, 2022–2025; 60 false-positive cfDNA results vs. 120 low-risk controls), CPM was confirmed in 57.9% (11/19) after RAT; the median birth weight percentile was lower in confirmed CPM (20.1 vs. 43.5), with no significant increase in SGA or other adverse outcomes [137]. In Benn's compilation of five studies (2019), there was FGR or low birth weight in 14.6% of pregnancies with RAT at screening [28]. There is agreement that type III CPM confers a risk of FGR [2].

3.9. Pigmentary mosaicism and hypomelanosis of Ito

Skin. The lesions are hypopigmented (or hyperpigmented) streaks and whorls along the lines of Blaschko, with streaks predominating on the limbs and whorls on the trunk, much more visible under ultraviolet light (Wood's lamp) [14, 29]. There is no preceding vesicular or inflammatory phase, unlike incontinentia pigmenti; the lesions are usually not visible in the neonatal period and become apparent in the first months (80%), sometimes only on first sun exposure or when other symptoms appear [4]. In the review by Kromann and colleagues (651 patients published between 1985 and 2017, 54% female), there was hyperpigmentation in 43%, hypopigmentation in 50%, and both in 7%; the distribution was blaschkoid in 79% and phylloid, patchy, checkerboard, or sash-like in 6%; among the 378 with known age at onset, 75% had onset by the first year (174 at birth) and 25% later, 38 after 2 years of age [6]. A family history was present in 4% [6]. The figure in Smith's shows a 14-month-old child with developmental delay, hypotonia, and seizures and irregular streaky hypopigmentation (description from the caption) [138]. Other changes in the skin and adnexa include café-au-lait macules, cutis marmorata, angiomatous naevi, hypertrichosis, alopecia, dystrophic nails, and dental dysplasia [4, 17].

Extracutaneous manifestations. In the Kromann review, 56% (367/651) had extracutaneous manifestations, more often with hypopigmentation (73%) than with hyperpigmentation (32%) and more often when both coexisted (83%); the most frequent were developmental delay (54% of the 367), skeletal deformities (38%), seizures or an abnormal electroencephalogram (37%), and facial dysmorphism (31%) [6]. These figures exceed those of smaller series (0%, 8%, and 30%), and the authors attribute the difference to publication bias [6]. Smith's reports ID in 30–50%, autistic behaviour, and generalised tonic-clonic, partial, and myoclonic seizures and infantile spasms, which appear in the first years; about 70% of reported cases have some associated anomaly, but apart from ID, seizures, and cerebral atrophy, each occurred in only a few patients [4]. The Spanish series of Pascual-Castroviejo (76 children followed in a paediatric neurology department over 30 years) found ID in 57%, autistic behaviour in 10%, a borderline intelligence quotient (IQ) in 21% and an IQ above 85 in 22%, seizures in 49%, infantile spasms in 8%, macrocephaly with coarse facies in 12 patients, and microcephaly in 6 [139]. The prospective Mexican series of Ruiz-Maldonado (41 children over 20 years) found extracutaneous disease that was mainly neurological and musculoskeletal, and chromosomal abnormalities in 3 of the 19 studied [140].

MTOR-related HI. In the French MUSTARD cohort of Carmignac (71 patients with patterned dyspigmentation and extracutaneous manifestations), deep exome sequencing of skin and blood in 31 patients identified mosaic MTOR in 1, a mosaic chromosomal abnormality in 7, TFE3 in 1, postzygotic RHOA in 2, and other candidate genes in 4, and was negative in 16; targeted ultra-deep sequencing of MTOR in a further 40 patients with blaschkoid hypopigmentation and epilepsy or ID was positive in 14 (35.0%) [5]. The 15 patients with an MTOR variant (10 female, aged 1 to 30 years) had linear blaschkoid hypopigmentation in 14, woolly or curly hair in 4, psychomotor delay in 12 (all with later ID), autism spectrum disorder in 4, macrocephaly (head circumference ≥+3 standard deviations) in 8, and seizures in 10; of the six with seizures and MRI, all had hemimegalencephaly, and 80% had macrocephaly or (hemi)megalencephaly [5]. There were no angiomyolipomas or renal cysts [5]. The spectrum overlaps with that of constitutional SKS, in which HI does not occur; in SKS, hyperpigmented naevi and pigmentary mosaicism are described mainly in individuals with a mosaic variant, and the published series records delay or ID in 95%, macrocephaly in 90%, brain malformations in 79%, and epilepsy in 61% [5, 19].

RHOA-related mosaic ectodermal dysplasia. Vabres's seven French patients had linear blaschkoid hypopigmentation and hypotrichosis, symmetric or asymmetric facial dysmorphism (microstomia, malar hypoplasia, downslanting fissures), acral anomalies (brachydactyly, syndactyly, broad great toe), dental anomalies (oligodontia, microdontia, conical teeth), and ocular anomalies (microphthalmia, strabismus, myopia), and diffuse cystic leukoencephalopathy on MRI in three, without ID or neurological deficit [9]. Yigit and colleagues added four patients with body asymmetry and limb hemihypotrophy [70].

GNA13-related syndrome. El Masri's four patients (aged 22 months to 24 years) had linear fusiform, guttate, flag-like, or phylloid hypopigmentation, without the typical V-, S-, or whorl-shaped lines; facial asymmetry or asymmetric limb hypoplasia; polysyndactyly in 2; hypotrichosis or madarosis in 3; intestinal atresia (jejunal or colonic) in 3; iris or eyelid coloboma or unilateral microphthalmia in 3; hearing loss in 2; and delayed wound healing in the affected areas in 2; none had ID or seizures [10].

ACTB-related HI. A 5-year-old boy with "splash-like" hypopigmented streaks on the right side since the first month, macrocephaly (+2.9 standard deviations), axial hypotonia, and speech and learning delay, and a 10-year-old girl with linear and whorled hypopigmentation on the trunk and all four limbs, dysmorphism, ectopic teeth, and moderate tricuspid regurgitation, both with normal MRI, illustrate the phenotype [11].

TFE3-related disease. Lehalle's 17 individuals (12 female) had blaschkoid pigmentary changes, severe ID, epilepsy, coarse storage disease–like facial features, growth delay, and recognisable dysmorphism [12]. In the founding series of five patients, severe ID was present in 5/5, coarse facies in 4/5, and blaschkoid pigmentary mosaicism in 4/5, and MRI was normal in 5/5; two girls described by Diaz were initially investigated for a lysosomal disease, with negative enzyme screening [21, 141].

Linear and whorled naevoid hypermelanosis. LWNH presents with congenital or infantile reticulated macular hyperpigmentation, bilateral and in whorls and streaks along Blaschko lines on the trunk, limbs, head, and neck, sparing the palms, soles, and mucous membranes, with no preceding inflammation, vesicles, or atrophy; it is occasionally associated with autism, seizures, heart disease, skeletal anomalies, and delay, and histology shows basal and suprabasal melanosis without pigmentary incontinence [18]. A French multicentre cohort of 33 patients was published in 2026 [142].

4. Clinical Recognition and Red Flags

4.1. When to suspect after birth

Screening for mosaicism is not routinely performed on karyotype, except in girls with Turner syndrome; it is up to the clinician to request targeted investigation in the presence of suggestive signs [29]. Clues on examination are a milder phenotype of a known chromosomal syndrome (the usual way mosaic trisomy 21 is detected), asymmetry, especially of the limbs, patchy or streaky pigmentary changes, sparse hair at the temples (Pallister-Killian), ear malformation with preauricular tags (mosaic trisomy 22), syndactyly and finger contractures, deep plantar creases with hypoplastic patellae (mosaic trisomy 8), and supernumerary nipples [29]. In the dysmorphic child, one should ask specifically about "birthmarks" and look for pigmentary changes [143]. A limb length discrepancy greater than 1 cm with a measurable difference in circumference is abnormal, and hemihypoplasia with developmental delay and dysmorphism points towards chromosomal mosaicism [116]. A child with seizures and developmental delay should be examined with a Wood's lamp, because pigmentary anomalies along Blaschko lines are a cutaneous sign of mosaic disease [144]. In mosaic trisomy 20 diagnosed before birth, vertebral anomalies, constipation, and hypotonia should be sought even when the neonatal examination is normal [67]. In atypical Temple syndrome, mosaic trisomy 14 should be tested for [120].

4.2. Skin examination

The history of pigmentary changes includes a three-generation pedigree with targeted questions about skin lesions, presence since birth, increase in number or size, deafness, neurological signs, delay, seizures, and Hirschsprung disease or chronic constipation since birth [101]. The examination documents the skin photographically, the margins (well or poorly defined), the distribution (lines of Blaschko or another embryological pattern), the number of areas, and midline crossing; it looks for lesions of tuberous sclerosis or neurofibromatosis type 1, atrophic areas without adnexa (late stage of incontinentia pigmenti, Goltz syndrome), a white forelock, or premature greying; and it examines the nervous system and the eye (retinal hamartoma in TSC; heterochromia in Waardenburg syndrome) [101]. Wood's light accentuates the lesions [6, 29]. In fair-skinned children, hypopigmentation may become visible only after sun exposure [4]. The distinction between narrow-band Blaschko lines (HI, chromosomal causes, MTOR, RHOA, ACTB) and flag-like, phylloid, or fusiform patterns (for example, GNA13) guides the aetiological diagnosis [6, 10].

4.3. When to suspect before birth

In genome-wide cfDNA screening, a RAT result occurs in 0.18–0.32% of pregnancies and in most cases corresponds to CPM; the positive predictive value (PPV) for fetal RAT was 4.1% in Belgium, 6% (first year) and 7.7% (two years) in the Netherlands, and 11.46% in an ISPD meta-analysis [27, 30, 32, 89]. At CVS, chromosomal mosaicism is present in 1–2% of samples and RAT mosaicism in 0.6% [78, 145]. The detailed anomaly scan guides the assessment of severity: multiple malformations suggest a high level in several tissues; agenesis of the corpus callosum in mosaic trisomy 8 indicates brain involvement; and each chromosome has a pattern to look for (cardiac, renal, and brain anomalies and microphthalmia in trisomy 9; cardiac and renal anomalies, ear malformation, and preauricular tags in trisomy 22; FGR in trisomy 16; the "coat-hanger" sign of the thorax in paternal UPD14) [2, 47, 92].

4.4. Red flags and emergency signs

4.5. Newborn screening

There is no newborn screening for mosaic trisomies or for pigmentary mosaicism; these conditions are identified through prenatal screening, clinical examination, or the investigation of developmental delay.

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Criteria

There are no validated formal clinical criteria for mosaic trisomies or for pigmentary mosaicism: the diagnosis is cytogenetic or molecular and depends on demonstrating two cell lines [17, 29]. In 1992 Ruiz-Maldonado proposed criteria for a presumptive and definitive diagnosis of HI, which are no longer in current use [140]. In SKS there are likewise no consensus clinical criteria, and a variant of uncertain significance (VUS) in MTOR neither establishes nor excludes the diagnosis [19].

5.2. Tests and their limitations

A negative result in blood does not exclude mosaicism. In MTOR-related HI, the variant was absent from blood in half of patients (median VAF 21% in skin and 0% in blood) [5]; in the RHOA, GNA13, and ACTB syndromes, blood was negative in all patients tested [9–11]; in four children with focal cortical dysplasia type 2a, Mirzaa found the low-level mosaic variant only in brain tissue (VAF 0.012–0.086), and negative blood does not exclude a brain-confined variant [87, 110].

5.3. Choice of tissue

The Oxford Desk Reference, reviewed on this point by Veronica Kinsler (Great Ormond Street), cautions that in mosaic conditions paired blood and skin samples play an important role, but fibroblasts may not be the right cells to test, and specialist advice should be sought [101]. In HI, Kromann and colleagues recommend analysing fibroblasts from light and dark skin as well as lymphocytes, counting many metaphases or, preferably, performing microarray on uncultured cells, and using sequencing for monogenic causes [6].

5.4. Postnatal algorithm for suspected mosaic trisomy

The first step is chromosomal microarray on blood, alerting the laboratory to the suspicion of mosaicism; in Li's trisomy 9 cohort, all microarrays and FISH studies were abnormal and karyotype made the diagnosis in only 44%, so the authors recommend microarray when the condition is suspected [29, 31]. In trisomy 12, microarray detected ~25% trisomic cells in a child with 50 normal metaphases on karyotype [55]. Karyotype serves to confirm the array finding and characterise rearrangements, with an extended cell count [29]. If suspicion persists with a normal array and lymphocyte karyotype, another lineage is studied: fibroblasts, DNA from a skin biopsy, saliva, or FISH on a buccal smear [29]. In hemihypotrophy, the Oxford Desk Reference recommends chromosomal analysis with mosaicism screening at the highest available resolution, and a skin biopsy if there is delay, especially with syndactyly or HI, and a normal blood karyotype [147]. When faced with a mosaic trisomy of an imprinted chromosome, the ACMG recommends considering UPD testing in the euploid line [47]. Ring chromosomes 14 and 20 are studied by karyotype [144]. When the trisomy involves an acrocentric chromosome, parental karyotyping excludes a Robertsonian translocation [2, 47].

5.5. Algorithm for pigmentary mosaicism

The approach proposed by Kromann comprises skin examination with Wood's light, systematic clinical examination, karyotype of many metaphases or, preferably, microarray on uncultured cells, with exome sequencing as an increasingly used alternative, and exclusion of the differentials; it recommends testing patients without extracutaneous manifestations as well, because 32% of those tested in this group had an abnormal karyotype (vs. 43% of those with manifestations; difference not significant) [6]. The Oxford Desk Reference advises blood and skin arrays when there is developmental delay or malformations, and genomic analysis (panel, exome, or genome) depending on availability [101]. The ACMG (2021) recommends exome or genome sequencing as a first- or second-tier test in children with global delay, ID, or multiple congenital anomalies, a recommendation echoed by the SKS GeneReviews chapter, with the caveat that standard depth may miss mosaic variants [19, 148]. Skin histology shows pilosebaceous anomalies and dyskeratosis according to Síndromes Genéticas: Reconhecer para Tratar, and more melanin in hyperpigmented areas and less in hypopigmented areas in the Kromann review; it plays a supporting role and does not establish the cause [6, 13, 17]. Smith's recommends a karyotype of affected skin when HI is accompanied by delay or structural anomalies [4]. Carmignac and colleagues recommend ultrasensitive MTOR sequencing on DNA from skin or another affected tissue in HI with macrocephaly, megalencephaly, or hemimegalencephaly [5]. In TFE3-related disease, exome sequencing on blood is usually diagnostic in girls, and affected skin should be tested in a clinically typical boy with negative blood; the triad of coarse facies, severe ID, and blaschkoid pigmentation with negative lysosomal screening should point towards TFE3 [21]. In practice, the combined yield in the MUSTARD cohort was 15 patients with MTOR, 7 with a chromosomal abnormality, 2 with RHOA, and 1 with TFE3 out of 71, with 16 negative deep exomes out of 31, showing that a substantial fraction remains undiagnosed [5].

5.6. Report content

The cytogenetic report describes the lines in ISCN with the cell count for each and the tissue analysed; the microarray report indicates the estimated fraction of abnormal cells and, for SNP arrays, the regions of homozygosity [31, 47]. The UPD report indicates the chromosome, the parental origin, the type (iso- or heterodisomy, whole-chromosome or segmental), and the ISCN notation, for example upd(15)mat [47]. For sequence variants, it indicates the gene, the versioned transcript (MANE Select), the Human Genome Variation Society (HGVS) c. and p. notation, the VAF in each tissue tested, the sample type, and the classification according to the ACMG/AMP criteria; a VUS in MTOR neither establishes nor excludes the diagnosis [19, 106].

5.7. Prenatal diagnosis

Classification of mosaicism in culture. At amniocentesis, level I mosaicism (a single abnormal cell) is almost always an artefact and is not routinely reported; level II (two or more cells with the same abnormality in a single flask or colony) is almost always pseudomosaicism and is reported case by case; level III (the same abnormality in more than one independent culture) corresponds to probable true mosaicism, although not necessarily fetal [47, 77, 92]. In the Canadian study by Worton and Stern (>12,000 amniocenteses), the frequencies were 7.1%, 1.1%, and 0.3%, and 60% of level III cases reflected true fetal mosaicism [77, 84]. The New York protocol examines 20 to 40 additional cells from one or two more flasks when there is one abnormal cell, and in 12,000 cases it found single-cell pseudomosaicism in 6.68%, multicell pseudomosaicism in 1.05%, and true mosaicism in 0.2% [85]. Overall, mosaicism is present in 0.3% of amniocenteses and in slightly more than 2% of CVS samples (CPM 1.9%; true fetal mosaicism 0.19%) [94].

Probability of fetal involvement. The combined probability of TFM for autosomal trisomies detected in mosaic form at CVS is 9.6% (153/1587), varying by chromosome: trisomy 21 40.7%, 18 15.3%, 16 10.9%, 13 7.1%, with risk also increased for 8, 9, 20, and 22, and trisomies 2, 3, and 7 mostly confined to the placenta [3]. In Grati's series of 52,673 CVS samples, only 8/316 (2.53%) mosaic RATs were confirmed at amniocentesis [78], and according to the ISPD, 97% of RATs detected at CVS appear to be confined to the placenta [32]. Confirmation at amniocentesis was more likely when the RAT came from cfDNA screening (9.3%) than from CVS (3.0%) [28]. According to the Society for Maternal-Fetal Medicine (SMFM), true fetal mosaicism occurs in about 10–15% of CPM cases, varying by chromosome, and type I is the least associated with fetal involvement; CPM is associated with 2% of trisomy 21 results and with up to 59% of monosomy X results [145]. At CVS, a non-mosaic aneuploidy confined to the cytotrophoblast was associated with fetal mosaicism in 8.9%, and a mosaic one in the cytotrophoblast in 2.9% [2, 149]. Pertile and colleagues associated high RAT fractions in cfDNA with a higher risk of adverse outcome (miscarriage, true fetal mosaicism, FGR, UPD) [2, 150].

Amniocentesis and other tests. Amniocytes are the accessible tissue that best reflects the fetus; the laboratory combines interphase FISH on uncultured cells, microarray, and karyotype of cultured cells [2, 3]. There is no indication to repeat an amniocentesis that has shown mosaicism [57, 96]. Fetal blood sampling has limited value, except perhaps in trisomies 8 and 9 (in trisomy 8, because of a real risk of a false-negative amniocentesis) [151]; a normal result does not exclude low-level mosaicism and adds a risk of pregnancy loss; in trisomy 20, trisomic cells do not appear in blood [2, 39, 92, 96]. A normal amniocentesis is reassuring for most RATs but does not exclude low-grade fetal mosaicism or mosaicism confined to tissues without contact with the amniotic fluid, such as the brain; false negatives have been described in trisomy 8, trisomy 9 (with paternal isodisomy), and trisomy 15 [2, 3]. In Hsu's series (1997), confirmation was more frequent in abnormal outcomes in fibroblasts (81% vs. 55%) and in placental cells (88% vs. 46%), and reached 85% when fibroblasts and placenta were studied in the same case [39]. False negatives at CVS are extremely rare and result mainly from analysis of the direct preparation alone [3]. Sex chromosome mosaicism raises issues of its own (genitalia, fertility, gonadal tumour risk); in mosaic balanced autosomal translocations, true mosaicism is rare and the phenotypic risk low, and in unbalanced rearrangements the risk is higher and is assessed case by case [96]. Cell-based testing of circulating extravillous trophoblasts, marketed since May 2026 as a "confirmatory test," merely reaffirms the presence of abnormal trophoblast and does not distinguish CPM from a fetal abnormality [152].

5.8. Guidelines on cfDNA screening and RAT

SMFM table 3 guides management by result category: for trisomies 1, 2, 3, 4, 5, 7, 8, 9, 10, 12, 16, 17, 19, and 22, amniocentesis if the first-trimester ultrasound is normal and CVS if abnormal, with a third-trimester growth scan, especially in trisomy 16; for trisomies 6, 7, 11, 14, 15, and 20, CVS followed by amniocentesis if abnormal and, with a fetus with a normal karyotype, methylation or UPD studies (trisomy 7 appears in both rows of the original table); for multiple aneuploidies, investigate for maternal malignancy if the fetus is unaffected [145]. The divergence from the ISPD is explicit: the ISPD prefers amniocentesis with UPD testing for imprinted chromosomes, because CVS has a high probability of reflecting CPM and UPD can be assessed only in the fetus; the SMFM proposes starting with CVS for these chromosomes [32, 145]. The Netherlands chose to stop reporting RATs because of the low PPV, a decision the ISPD considers possibly not generalizable, and in Belgium first-line genome-wide screening is reimbursed for all pregnant women and reports RATs [32, 89]. The SMFM lists as causes of a false-positive result fetal, placental, or maternal mosaicism, maternal copy-number variants (CNVs), a vanishing twin, maternal malignancy, prior transplantation, fibroids, recent transfusion, statistical chance, and technical error, and recalls the US Food and Drug Administration (FDA) warning of 19 April 2022 about false positives [145]. The ISPD recommends at least one early ultrasound before screening and diagnostic testing with microarray, regardless of screening, in fetuses with ultrasound anomalies, including nuchal translucency ≥3.5 mm [32]. In the Chinese cohort of Liu (2026; 64,889 pregnancies), the theoretical mosaicism ratio calculated from cfDNA had poor discrimination for adverse outcome (area under the curve 0.643), and the authors restrict it to complementary use [153].

5.9. Mosaic embryos and preimplantation diagnosis

In trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A), a mosaic result has a very low predictive value for true mosaicism in the fetus or newborn; cutoffs of 40% and 50% separate low (20–39%) from high (40–80%) mosaicism, and mosaicism above 50% is often associated with full aneuploidy [154]. The European Society of Human Reproduction and Embryology (ESHRE, 2022) recommends offering counselling about prenatal diagnosis to all pregnant women after PGT, considers that low-level mosaicism in the trophectoderm is not in itself an indication for invasive diagnosis, advises against rebiopsy and against discarding embryos with low-level mosaicism, and accepts genome-wide cfDNA screening as first-line surveillance [154]. The ACMG (2020), by contrast, recommends prenatal studies including UPD testing after transfer of an embryo mosaic for chromosomes 6, 7, 11, 14, 15, or 20 [47]. In the ESHRE survey, 95% of centres recommended prenatal diagnosis after transfer of a mosaic embryo, 62.9% by amniocentesis [154].

5.10. Uniparental disomy testing

The ACMG recommends UPD testing at prenatal diagnosis in the following situations: level II or III mosaicism for trisomy or monosomy of chromosomes 6, 7, 11, 14, 15, or 20 at amniocentesis or CVS; level II or III mosaicism for these chromosomes at CVS followed by a normal amniocentesis; transfer of an embryo mosaic for these chromosomes; compatible ultrasound findings ("coat-hanger" thorax; omphalocele, macroglossia, visceromegaly, enlarged adrenals, or macrosomia, preferably using native amniotic fluid for UPD11); a Robertsonian translocation or isochromosome of 14 or 15; and a non-Robertsonian translocation involving an imprinted chromosome [47]. After birth, it recommends testing in the presence of delay or ID with a balanced Robertsonian translocation or a marker derived from 14 or 15, suspected Silver-Russell syndrome, Beckwith-Wiedemann syndrome with loss of methylation at IC2 and gain at IC1, pseudohypoparathyroidism 1B with abnormal GNAS methylation, and prenatal mosaic trisomy or monosomy of a chromosome associated with a UPD phenotype [47]. The Oxford Desk Reference, citing Kotzot (2008), recommends considering prenatal UPD testing, after counselling, when mosaicism involves chromosomes 6, 7, 11, 14, 15, or 20 [92, 155].

6. Differential Diagnosis

6.1. Chromosomal and growth differential

In the following tables, AD denotes autosomal dominant inheritance and AR autosomal recessive inheritance.

9p duplication is the classic differential of mosaic trisomy 9: the correlation described in Smith's shows that severity increases with the extent of the triplicated segment and that, when it reaches 9q31-32, the phenotype no longer corresponds to that of trisomy 9p and approaches that of mosaic trisomy 9 [156]. In practice, microarray distinguishes the two. In a child with asymmetry and pigmentary changes, the distinction between chromosomal mosaicism and mosaic overgrowth rests on the direction of the asymmetry (hemihypoplasia vs. hemihypertrophy), the cutaneous pattern (lines of Blaschko vs. capillary malformation), and the tissue tested [116, 159]. MVA should be considered when the karyotype shows aneuploidies of several chromosomes rather than a single trisomy, because it changes counselling (25% recurrence risk) and mandates cancer surveillance [14].

6.2. Differential of pigmentary changes

The most frequent distinction in practice is from incontinentia pigmenti, whose hyperpigmented stage also follows the lines of Blaschko from 3 to 6 months of age; the absence of a preceding vesicular or verrucous stage, occurrence in both sexes, and the possibility of primary hypopigmentation point towards pigmentary mosaicism [4, 13, 160]. A single hypopigmented macule occurs in 6% of normal children and 4% of adults under 45 years of age, and fewer than 1% have multiple macules, so isolated lesions do not warrant genetic investigation [101]. Among the genic mosaicisms, ID and epilepsy with macrocephaly point towards MTOR and, with coarse facies, towards TFE3; absence of ID with dental, acral, and ocular anomalies points towards RHOA; and intestinal atresia with phylloid or flag-like patterns points towards GNA13 [5, 9, 10, 12].

7. Treatment and Risk Management Strategies

7.1. Principles

There is no targeted treatment for any mosaic trisomy or for pigmentary mosaicism; management is symptomatic, multidisciplinary, and oriented towards quality of life, with an initial system-based evaluation and follow-up guided by the findings [17, 31]. The only published system-based recommendations are those suggested by Li and colleagues for mosaic trisomy 9, which are expert opinion and not a formal guideline [31]. The pigmentary changes require no treatment [17].

7.2. Management by system

Growth and feeding. Feeding difficulties and FGR are common in mosaic trisomy 9; weight, length, and head circumference should be monitored at every visit, swallowing assessed, and gastroenterology referral made when necessary [31]. Short stature in a child born SGA may be an indication for somatropin according to the label criteria (section 7.3); in mosaic trisomy 14, a 2026 report describes its use [122].

Heart. Congenital heart disease is among the most frequent manifestations in the class (two thirds in mosaic trisomy 9, 14/15 in mosaic trisomy 14, 14/25 in mosaic trisomy 22) and requires an echocardiogram at diagnosis; surgical repair follows the usual indications, and in the Fujimoto series one child with tetralogy of Fallot improved after a Blalock-Taussig shunt, whereas another died at 3 years of age after cardiac surgery [31, 50, 59, 69].

Kidney and urinary tract. Baseline renal ultrasound in mosaic trisomy 9 and in the evaluation of any mosaic trisomy with malformations; monitor testicular descent in the first year [31].

Nervous system and epilepsy. Neurologic evaluation and brain and spinal MRI are performed according to symptoms [31]. Seizures in HI include generalised tonic-clonic, partial, and myoclonic seizures and infantile spasms, and may be drug-resistant [4, 139]. The sources consulted describe no trials of antiseizure medications specific to HI or mosaic trisomies; the choice follows the seizure type. For infantile spasms, vigabatrin has an approved indication regardless of cause (section 7.3). In MTOR-related hemimegalencephaly or focal cortical dysplasia with refractory epilepsy, mTOR inhibitors are off-label (section 7.4), and focal areas of brain malformation may be targeted by epilepsy surgery, as in the Karaca case, operated on at 5 years of age [34, 144].

Hearing, vision, and teeth. Audiologic and ophthalmologic evaluation at diagnosis and annually (mosaic trisomy 9), and ophthalmologic and dental referral in HI because of the frequent ocular and dental anomalies [4, 17, 31].

Orthopaedics. Hip ultrasound in the newborn with mosaic trisomy 9; surveillance for scoliosis and kyphosis; in mosaic trisomy 20, evaluation of the spine (stenosis, vertebral fusion, kyphosis) and of constipation [31, 67].

Endocrinology. Central precocious puberty occurs in HI and in Temple syndrome associated with mosaic trisomy 14 [4, 99].

Development and education. Supportive therapies and an individualised education plan, reviewed annually; augmentative communication for non-verbal patients [31].

7.3. Drugs and dosing

None of the following drugs has an approved indication for mosaic trisomy or pigmentary mosaicism. Vigabatrin is used on-label (infantile spasms, whatever the cause); the others are off-label or extrapolated from an analogous condition, and each row identifies the source of the dose and the difference between the reference dose and the label dose.

Vigabatrin doses differ little between the US label and the Portuguese SmPC: both start at 50 mg/kg/day and allow up to 150 mg/kg/day, but the FDA label sets titration every 3 days and defines 150 mg/kg/day as the maximum [164, 165]. For everolimus, the European SmPC adds a higher starting dose below 6 years of age [167]. For sirolimus, the trough target of the SKS series (<3 ng/mL) is lower than the label's therapeutic range (5–15 ng/mL), and the series dose is the reference for the condition, with the label only for comparison [19, 169]. For somatropin, the maximum dose on the US label is almost double the usual dose in the European SmPC [171, 172].

7.4. mTOR inhibitors in mosaic MTOR-related disorders

The biological rationale is direct: the variants activate mTORC1, and the neuronal hypertrophy caused by the Mirzaa variants was reversed by everolimus in cultured neurons [87]. The clinical evidence is limited. GeneReviews reports seven individuals with SKS treated off-label with sirolimus at 0.5–2 mg/day, with parent-reported improvements in verbal skills, attention, self-injury, and hyperphagia, and sleep-wake disturbances with troughs above 3 ng/mL [19, 176]. Bonniaud and colleagues (2025) treated a 12-year-old boy with megalencephaly, pigmentary mosaicism, and MTOR p.(Ser2413Ile) (23% of skin cells) with 1.3 mg twice daily for a severe behavioural disorder, with no improvement at 6 months on family reports and neuropsychological scales; before them, only three genotyped patients had been treated, with conflicting results [33]. Karaca and colleagues (2026) reported a 9-year-old monozygotic twin girl with operated, recurrent focal cortical dysplasia, faint Blaschko lines, and a somatic MTOR variant detected only by RNA sequencing of brain tissue, with about a 50% reduction in seizures and autistic and verbal improvement on sirolimus (dose not stated in the abstract) [34]. Carmignac and colleagues consider efficacy still inconclusive and note that topical sirolimus repigments the hypomelanotic macules of TSC, with no equivalent data in HI [5]. GeneReviews recommends assessing the biochemical and functional impact of the variant before using an mTOR inhibitor, noting that the generations of inhibitors differ in mechanism and off-target effects, and points to the University of Washington Rx-Matcher platform for sharing experience with off-label use [19]. A phase 2 crossover trial of everolimus vs. placebo in refractory focal cortical dysplasia type II (NCT03198949, Korea, n = 23) has been completed, with no results located in the sources consulted [177].

7.5. Comparative regulatory status

7.6. Studies supporting prenatal management

There are no randomised clinical trials of therapeutic interventions in mosaic trisomies or pigmentary mosaicism. Management of pregnancies with RAT or CPM rests on the following cohort studies.

These studies measure different things and should not be compared with one another: TRIDENT-2 compares CPM with the general Dutch obstetric population, whose incidence of pre-eclampsia (0.5%) is low relative to international reviews (3–8%), which inflates the RRs; Grati used controls from the same laboratory and had outcome data for only 69% of cases; Raymond studied an average-risk cohort with systematic placental biopsies [30, 136, 137]. The high RRs should be read alongside the absolute rates: in TRIDENT-2, 91.5% of pregnancies with CPM did not develop pre-eclampsia [30]. The Hsu and Wallerstein series assessed outcome mainly at birth or at termination, without developmental assessment, and pool cases from various sources [39, 57]. Trial NCT04311749 (University of California, San Francisco; expanded cfDNA in pregnancies with FGR or severe pre-eclampsia) ended in 2024, with no results located in the sources consulted [177].

7.7. Management of pregnancies with RAT or CPM

After a RAT result at screening or mosaicism at CVS, genetic counselling, specialist ultrasound, and, in the vast majority, amniocentesis follow, according to the guidelines compared in section 5.8 [3, 32, 145]. The TRIDENT-2 authors recommend specialist ultrasound and fetal growth monitoring in all RAT cases and, given the absence of fetal origin in all 60 RAT 7 cases, propose considering forgoing invasive testing for this chromosome [27, 30]. The SMFM recommends a third-trimester growth scan, especially in trisomy 16, and the ISPD recommends fetal surveillance in CPM 16 because of its association with early FGR [32, 145]. TRIDENT-2 and the Lannoo review propose advising low-dose acetylsalicylic acid to reduce pre-eclampsia in CPM; this is an authors' proposal, because the USPSTF and NICE guidelines do not include CPM among the risk factors, and the ACMG considers the utility of identifying CPM before manifestations questionable, with no methods to predict which pregnancies will have an adverse outcome [2, 30, 78, 173, 174]. When amniocentesis is normal, detailed ultrasound follow-up of growth and structural anomalies is recommended [2].

In mosaic T20 with a normal detailed anomaly scan, James and colleagues recommend advising that the risk of an anomaly is below 10% and performing further tests only when clinically indicated [92, 123]. When cfDNA screening shows multiple aneuploidies with an unaffected fetus, maternal malignancy is investigated; it occurs in ~1/1000–1500 pregnancies; in a 2024 National Institutes of Health study, 48.6% of 107 pregnant women with unusual results had cancer, but there is no consensus guideline for the workup [145]. When cfDNA screening reveals a trisomy that is maternal (for example, constitutional trisomy 8 or trisomy associated with an occult malignancy), the result has implications for the pregnant woman herself [2, 30].

7.8. Developments in the past 12 months

Outside this window, but recent and relevant, are the description of GNA13 (2025), the non-mosaic form of RHOA (2025), and Bonniaud's negative sirolimus report (2025) [10, 33, 71].

7.9. Agents to avoid, pregnancy, perioperative care, and transition

The sources consulted identify no drugs specifically contraindicated because of mosaic trisomies or pigmentary mosaicism; precautions derive from the comorbidities (heart disease, epilepsy) and from the labels of the drugs used, such as visual monitoring with vigabatrin and CYP3A4 metabolism of everolimus [164, 168]. In women with mosaicism who become pregnant, the main issue is reproductive (section 8); cfDNA screening may reveal asymptomatic maternal mosaicism, including pathogenic CNVs and mosaic 45,X, with implications for offspring [30, 78]. The sources describe no specific anaaesthetic risks beyond those associated with heart disease and spinal anomalies (spinal stenosis in mosaic trisomy 20) [67]. Transition to adult care is poorly documented; survival into adulthood is common in SKS, there are adults with mosaic trisomies 9 and 14, and survival in HI is not affected, which calls for planning continuity of neurologic, orthopaedic, and social support care [17, 19, 31, 59].

7.10. Comparison of recommendations

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by mechanism

The recurrence risk is negligible when mosaicism results from mitotic non-disjunction or somatic mutation; there is some risk when it results from trisomic rescue, because of the possibility of parental germline mosaicism, but it is usually impossible to distinguish the two mechanisms, and the overall risk for subsequent pregnancies is low [14, 96]. Prenatal diagnosis may be offered in a future pregnancy for reassurance [14, 96].

The germline mosaicism model is useful for counselling: in tuberous sclerosis with unaffected parents, the recurrence risk is about 2% because of germline mosaicism [188]. For postzygotic MTOR, RHOA, GNA13, or ACTB variants, the sources consulted do not quantify the risk of gonadal involvement.

8.2. Testing of parents and family

Parental karyotyping is indicated for a trisomy or rearrangement of an acrocentric chromosome (14, 15, 22), for an X;autosome translocation (de novo X;autosome translocations are usually of paternal origin), and for any unbalanced structural mosaicism [2, 47, 104]. A mosaic marker 22 may be familial, and some carriers have a normal phenotype, so parental karyotypes are important [29]. UPD testing requires samples from at least one parent [47]. In familial HI, Síndromes Genéticas: Reconhecer para Tratar recommends biopsy of affected and unaffected skin when a parent or another child in the family is affected [17]. In disorders due to a postzygotic variant, parental blood testing serves to exclude a constitutional variant, but a negative result does not exclude gonadal mosaicism [19].

8.3. Prenatal and preimplantation diagnosis

Prenatal diagnosis is technically possible in all scenarios with an identified alteration; in MVA it should be offered because of the 25% risk, and in SKS and the other genic disorders it is available once the variant has been identified, through prenatal diagnosis or preimplantation genetic testing [14, 19]. Prenatal diagnosis in patchy hypopigmentation is possible only when the variant or chromosomal abnormality is known [160]. After PGT-A with transfer of a mosaic embryo, ESHRE and the ACMG diverge on the indication for invasive diagnosis, as described in section 5.9 [47, 154]. Live birth rates are lower and miscarriage rates higher after transfer of mosaic embryos, but these embryos are an option when no euploid embryos are available [154].

8.4. Prenatal counselling after RAT or mosaicism

Counselling is difficult because investigations reduce uncertainty but rarely eliminate it: the percentage of abnormal cells at CVS or amniocentesis does not reliably predict fetal mosaicism or severity, and TFM without ultrasound anomalies has an uncertain prognosis [3, 94]. Preparation for the consultation includes discussion with fetal medicine about the ultrasound findings and with the cytogenetics laboratory about the level and type of mosaicism and the investigation plan, consultation of reference works, and a literature search focused on the chromosome [92]. The ACMG recommends that pretest counselling explain the optional nature of screening, the conditions covered and not covered, the types of result (including no result and incidental findings), the predictive values, and the need for diagnostic confirmation, and that it may reveal unknown parental abnormalities [78]. In a 2014 study of more than 30,000 women, about 6% of those with a positive result terminated the pregnancy without confirmation, and the SMFM emphasises that every abnormal result requires diagnostic testing [145]. The Danish qualitative study by Farø (2026) showed that uncertainty (the complexity of mosaicism, probabilistic risk, ambiguous information) dominates the experience of parents who continue the pregnancy after a CPM diagnosis, that clear and empathetic communication helps, and that some worry persists even after the birth of a healthy baby [182]. The non-directive support of organisations such as ARC (Antenatal Results and Choices) is a resource to recommend [96, 189].

8.5. Counselling of minors and affected adults

The sources consulted give no specific guidance on testing minors; because these conditions are usually sporadic and there are no asymptomatic carriers to identify among siblings, cascade testing does not apply, except for parental translocations and MVA (detection of heterozygous carriers) [14]. In adults with mosaicism who are planning to have children, counselling distinguishes the cell line present in the gonads, unknown in most cases, and the nature of the alteration; women with a TFE3 variant have an X-linked transmission risk [12].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

The absence of population estimates is structural: many low-level mosaicisms go undiagnosed because the phenotype is mild, blood is normal, or no other tissue is tested, and the true prevalence is unknown [6, 119]. HI is often considered the fourth most common neurocutaneous syndrome, after NF1, TSC, and Sturge-Weber syndrome, but this ranking is not based on prevalence studies [9, 17].

9.2. Data by region

Netherlands and Belgium. Population data on RATs come mainly from the nationwide implementation of first-line genome-wide cfDNA screening: TRIDENT-2 (2017–2019), in which 74.2% of 149,318 pregnant women chose genome-wide analysis, and the Belgian programme, the first to fully reimburse screening for all pregnant women [30, 89]. In the Netherlands, T7 was the most frequent RAT (32 of 101 in the first year), followed by trisomies 16, 8, and 20 [27].

Italy, Denmark, and Europe. The Italian database of Benn and Grati (76,102 CVS samples over 18 years) and the European EUCROMIC study (1986–1992) defined the frequency and origin of mosaicism at CVS; the Danish cohort of Thomsen (528 cases of placental mosaicism for autosomal trisomies, 1983–2021) is the largest follow-up series [28, 93, 190]. In France, the MUSTARD cohort (NCT01950975), in Dijon, defined MTOR-related HI and the RHOA and GNA13 syndromes [5, 10].

North America. The reference series for mosaicism in amniocytes (Hsu 1991, 1992, 1997; Wallerstein 2000) are North American, and Li's mosaic trisomy 9 cohort comes from Philadelphia and Cincinnati [31, 39, 57, 66, 85]. In Mexico, Ruiz-Maldonado described 41 children with HI [140].

Asia and Oceania. The Chinese cohort of Liu (64,889 pregnancies, 2021–2024) and the Australian cohort of Raymond (2022–2025) are the most recent RAT series; in New Zealand, James described 14 prenatal cases of mosaic trisomy 20 [123, 137, 153].

Portugal. The sources consulted include a case of mosaic trisomy 7 with blaschkoid pigmentary dysplasia published by the Centro Hospitalar e Universitário de Coimbra [129]. No data on the frequency of RATs at Portuguese prenatal screening or series of HI were found in the sources consulted.

Brazil. Zen and colleagues (Porto Alegre) described two patients with mosaic trisomy 9 and prolonged survival [90]. The Brazilian chapter on HI in the book Síndromes Genéticas: Reconhecer para Tratar (Fortaleza, 2021) presents a case of its own with a figure and cites a master's dissertation from Unicamp on cytogenetic investigation in pigmentary mosaicism of the Ito type (2010), the text of which was not consulted [17, 191].

9.3. Special populations

Sex and ancestry. HI was initially described as more frequent in females and in non-Caucasians, but later studies showed no predilection by sex or ethnicity; in the Kromann review, 54% were female [6, 17]. In dark skin, pigmentary mosaicism is more visible, which led Ritter to recommend cytogenetic evaluation in all cases in these populations; in fair skin, a Wood's lamp is needed, and the lesions may appear only after sun exposure [4, 80].

Maternal age. Advanced maternal age increases the likelihood of meiotic trisomy and, through rescue, of mosaicism; in Li's trisomy 9 cohort, the median maternal and paternal ages were 39 years, but other authors found 80% of mothers to be younger than 35 years [29, 31].

Assisted reproduction. The transfer of mosaic embryos after PGT-A creates a growing group of pregnancies with a theoretical risk of fetal mosaicism or UPD; ESHRE notes that only 66.9% of centres reporting mosaicism had validated the technology, and 61.8% of these specifically for mosaicism [154]. A case of mosaic trisomy 12 has been described in a child conceived by in vitro fertilisation [55].

Maternal mosaicism. In TRIDENT-2, 90 findings were of maternal origin, including 12 malignancies and 32 mosaic pathogenic CNVs, asymptomatic but with offspring at risk; mosaic 45,X in lymphocytes increases with age in 46,XX women [30, 78].

9.4. Reference networks and organisations

10. Illustrative Clinical Case

10.1. Mosaic trisomy 14 with maternal uniparental disomy of chromosome 14

In 2016 Balbeur and colleagues published in Clinical Case Reports the case of a 15-year-old girl from Guinea, the fourth child of healthy non-consanguineous parents [99]. She was born at term weighing 2 kg (−3 standard deviations) and measuring 48 cm (−0.8 standard deviations), with hypotonia and a weak suck in the neonatal period; from 2 years of age she had progressive weight gain, she walked at 5 years, had severe speech delay and moderate ID, and thelarche and menarche occurred before 8 years of age [99]. At 15 years she weighed 54.7 kg (+0.33 standard deviations), measured 129 cm (−4.7 standard deviations), and had a body mass index of 32.87 (+5.5 standard deviations), with a broad, depressed nasal root, a short nose, upslanting palpebral fissures, truncal obesity, hyperlaxity of the metacarpophalangeal and proximal interphalangeal joints with camptodactyly of the distal interphalangeal joints, fifth-finger clinodactyly, and irregular hyperpigmentation along the lines of Blaschko [99]. Figure 1 of the article, consulted for this article, shows the short stature with truncal obesity, the blaschkoid hyperpigmentation on the arm, the face, the hyperlaxity with camptodactyly, and the clinodactyly of the fifth fingers.

Low-density lipoprotein (LDL) cholesterol was 146 mg/dL, endocrine tests showed no specific abnormalities, bone age was advanced by 3 years, brain MRI and ophthalmological evaluation were normal, and the echocardiogram showed myxoid degeneration of the mitral valve with mild regurgitation [99]. Electron microscopy of the skin revealed collagen fibres of highly variable calibre, with "cauliflower" fibres, and fragmented elastic fibres [99]. GNAS sequencing excluded McCune-Albright syndrome, and a normal 15q11-q13 methylation profile excluded Prader-Willi syndrome [99].

Oligonucleotide microarray and FISH with IGH (14q32) probes demonstrated mosaic trisomy 14, with different proportions by tissue: 31% in blood, 42% in urine, 49% in saliva, 2.5% in hyperpigmented skin, and 2% in normal skin, the latter two being non-significant [99]. Figure 3 shows the FISH on blood. The SNP array on skin showed proximal and distal maternal isodisomy and central maternal heterodisomy of chromosome 14, and microsatellites revealed a paternal allele in blood, urine, and saliva (the trisomic line) that was absent from skin (Figure 4) [99]. The authors propose a double crossover in maternal meiosis I followed by sister chromatid non-disjunction in meiosis II, with fertilisation of a disomic gamete and subsequent loss of the paternal chromosome 14 in a proportion of cells (Figure 5) [99]. They attribute the delay, pigmentation, and dysmorphism to mosaic trisomy 14, and the low birth weight, short stature, precocious puberty, hyperlaxity, and truncal obesity to maternal UPD14 (Temple syndrome); this was the first published case of mosaic trisomy 14 coexisting with maternal UPD14 in a living patient [99]. Article page: https://pmc.ncbi.nlm.nih.gov/articles/PMC4771849/.

The case illustrates four points of this article: blaschkoid pigmentation as a clue to chromosomal mosaicism; unpredictable tissue distribution, here with skin almost devoid of trisomic cells and blood, urine, and saliva positive, contrary to the usual pattern of preferential detection in skin; trisomic rescue as the simultaneous origin of the mosaicism and the UPD; and the recommendation to look for mosaic trisomy 14 in atypical Temple syndrome [99, 120]. The report describes no therapeutic management beyond the diagnostic evaluation.

10.2. Complementary case: MTOR-related HI

In the Carmignac cohort, patient P12 had broad-band linear hypopigmentation on the left lower limb and left hemimegalencephaly (enlarged thalamus, caudate, and white matter); the MTOR variant NM_004958.4:c.7255G>A p.(Glu2419Lys) was present in 28% of exome reads from hypopigmented skin, 29% on targeted ultra-deep sequencing, 41% in cultured fibroblasts, and less than 1% in blood, and was de novo [5, 106]. Patient P11 had unilateral broad-band linear and whorled hypopigmentation with a sharp boundary at the abdominal midline, accentuated by Wood's light [5]. The images are in Figure 2 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC8354853/), described in the text reviewed but not opened individually for this article.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis by entity

The level of mosaicism measured in blood has weak prognostic value in trisomy 9, and the percentage in amniocytes has some value only for some chromosomes (12, 15, 16, 20) [2, 31]. Multiple malformations on ultrasound or at birth indicate involvement of several tissues and a worse prognosis [2].

11.2. Surveillance

Renal surveillance in HI with hemihypertrophy requires an explicit decision. Smith's records hemihypertrophy in 7% of patients with HI, with an increased risk of abdominal tumours, especially Wilms tumour, but proposes no protocol [4]. The AACR update (2024) recommends renal ultrasound every 3 months from birth or diagnosis until 7 years of age in syndromes with a Wilms tumour risk of 1% or more, includes isolated lateralised overgrowth in the Beckwith-Wiedemann spectrum, and, for the PIK3CA-related overgrowth spectrum (1.6% risk), proposes shared decision-making; it makes no recommendation for HI or for mosaic trisomies, and in Europe the usual threshold is 5% [146]. Applying this protocol to HI with hemihypertrophy is an extrapolation, and the absence of specific data does not demonstrate an absence of risk. In MVA, the Wilms tumour risk above 85% (MVA type 1) justifies surveillance every 3 months until 8 years of age, as indicated in the GeneReviews chapter on Wilms tumour predisposition [15].

11.3. Long-term follow-up and transition

Long-term data are scarce for almost all mosaic trisomies and come from reports of survivors (trisomies 9, 14, and 4) and from follow-up of prenatal diagnoses (trisomy 20, up to 10 years) [59, 118, 123, 133]. The Lannoo review identifies as gaps neurodevelopmental follow-up after prenatal diagnosis and fetal risk in low-risk populations [2]. In adulthood, the main issues are independence, epilepsy, scoliosis, and reproductive counselling, and coordination through the European reference networks (ERN ITHACA and ERN-Skin) facilitates continuity [35, 36].

12. Summary and Concluding Remarks

Mosaic autosomal trisomies form a class in which the chromosome involved, the origin of the error (mitotic, or meiotic with rescue), the distribution of the trisomic line across tissues, and any uniparental disomy determine the phenotype. Almost all autosomes can give rise to mosaicism compatible with birth, with trisomies 1 and 19 being virtually nonviable exceptions; trisomies 9, 14, 15, and 22 carry a high risk of abnormal outcome when present in the fetus, trisomy 20 has a normal outcome in about 90% of prenatal diagnoses, and trisomy 7 is almost always confined to the placenta. Genome-wide prenatal cell-free DNA screening detects RATs in about 0.2–0.3% of pregnancies, with a positive predictive value for fetal trisomy of 4–11%; most correspond to confined placental mosaicism, which may be associated with placental dysfunction—consistently in trisomy 16 and debatably for the other chromosomes.

Postnatal diagnosis rests on microarray, preferably SNP-based, and on the choice of tissue: blood may be normal, and saliva, buccal mucosa, urine, fibroblasts, or affected skin may be needed. In prenatal diagnosis, amniocentesis reflects the fetus better than CVS or cfDNA screening but does not exclude low-level mosaicism or mosaicism confined to tissues without contact with the amniotic fluid, and UPD should be tested for chromosomes 6, 7, 11, 14, 15, and 20. Professional societies diverge on RAT screening (ACMG with no recommendation, ISPD against routine use, SMFM with utility not established), on the first invasive test for imprinted chromosomes (CVS for the SMFM, amniocentesis for the ISPD), and on the follow-up of transferred mosaic embryos (ACMG and ESHRE).

Pigmentary mosaicism along the lines of Blaschko, formerly hypomelanosis of Ito, is no longer an entity and is now regarded as a sign of mosaicism with chromosomal and genic causes. Mosaic MTOR explains more than one third of patients with HI and seizures in a French cohort and is associated with macrocephaly and hemimegalencephaly; RHOA and GNA13 cause ectodermal syndromes without ID; ACTB was added in 2026; and TFE3 causes an X-linked disorder with severe ID. Textbook statements that HI has no monogenic basis are outdated. The test of choice for genic causes is deep sequencing of affected skin, because blood is often negative.

There is no targeted treatment. Management is multidisciplinary and system-based, with an echocardiogram and renal ultrasound at diagnosis, audiological, ophthalmological, and developmental evaluation, and treatment of epilepsy according to seizure type. mTOR inhibitors are off-label in MTOR-related disorders, with conflicting results in isolated reports. Wilms tumour surveillance is established in mosaic variegated aneuploidy, an autosomal recessive disorder with a 25% recurrence risk, and is an extrapolation in HI with hemihypertrophy. The recurrence risk of mosaic trisomies and postzygotic pigmentary mosaicism is low, except when there is a parental chromosomal rearrangement.

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