Fetal Cystic Hygroma and Increased Nuchal Translucency of Genetic Cause

First-trimester fluid collections of the fetal neck, from nuchal translucency above the 95th centile to septated cystic hygroma: ultrasound markers of aneuploidies, copy number variants, RASopathies, congenital lymphatic anomalies and other monogenic disorders, with an evaluation ranging from invasive testing with chromosomal microarray to fetal exome or genome sequencing.

Literature and regulatory information updated: 17 October 2026.

0. Initial Reference Table

Main causal entities

1. Introduction

1.1. From the first descriptions to the concept of nuchal translucency

The association between neck oedema, short stature and sexual abnormalities predates ultrasound. In 1922, Rössle recorded the association between short stature and ovarian defect («sexual dwarfism»), and in 1949 Otto Ullrich described patients whose appearance resembled a mouse strain bred by Bonnevie, with webbed neck and lymphoedema; the designation «Bonnevie-Ullrich syndrome» spread mainly in Europe and covered, for decades, patients who are now classified as Turner syndrome or Noonan syndrome, while the term «male Turner» wrongly suggested that the second condition did not occur in females [8, 51]. Webbed neck (pterygium colli), low posterior hairline, ptosis and redundant nuchal skin were later interpreted as sequelae of fetal oedema and hydrops [36, 51].

The founding series of the ultrasound era was published by Chervenak and colleagues in 1983 in the New England Journal of Medicine: the authors defined CH as a congenital malformation of the lymphatic system, with single or multiloculated cavities mainly in the neck, attributed to failure of communication between the lymphatic and venous systems in the neck, and described 15 consecutive cases detected by second-trimester ultrasound, none of which survived, 13 of which were hydropic at diagnosis and 11 (73%) of which had a karyotype consistent with Turner syndrome [52]. In 1991, Bernstein and colleagues (San Francisco, 55 fetuses) observed aneuploidy in about two thirds and a strong association between septation and aneuploidy; only five fetuses reached term and were born alive [53]. These second-trimester series, biased towards severe cases, defined the prognosis of CH for a decade.

The concept of NT emerged in 1992, when Nicolaides and colleagues (King's College, London) studied 827 fetuses karyotyped at 10–14 weeks: among 51 fetuses (6%) with NT of 3–8 mm, 35% had chromosomal abnormalities, compared with 1% of the remaining 776, and NT ≥3 mm was proposed as a marker [54]. In 1993, Bronshtein and colleagues, in Haifa, separated septated from non-septated CH on transvaginal scans in the first and early second trimester, showing that the two forms differ in location, morphology, histology, frequency of aneuploidy and prognosis [20]. In 2005, the FASTER trial (First and Second Trimester Evaluation of Risk), in the United States, provided the first estimate of the prevalence of septated CH in a general obstetric population and the paediatric outcome of survivors [18]. At around the same time, the review by Souka and colleagues for the Fetal Medicine Foundation (FMF) systematised the significance of increased NT with a normal karyotype [5].

1.2. From cytogenetics to genomics

Until the end of the 2000s the evaluation was limited to karyotyping, and the European series from Oxford (1996), London (2004) and Reims (2007) described about half of CH as euploid, without distinguishing submicroscopic or monogenic causes [37, 55, 56]. CMA added detection of copy number variants, and from 2013 Dutch and Italian studies showed that a fraction of euploid fetuses with increased NT or CH had variants in RAS/MAPK pathway genes [57–59]. In 2019 the PAGE (Prenatal Assessment of Genomes and Exomes, England and Scotland) and Columbia (New York) studies established the yield of exome sequencing in fetal structural anomalies and showed that isolated NT is the phenotype with the lowest yield [60, 61]. In 2020, the San Francisco study by Sparks and colleagues included CH and increased NT in the NIHF spectrum and found diagnostic variants in 29% of unexplained cases, with RASopathies as the most frequent group [62]. In 2026, SMFM Consult Series #75 and the global ESHG and ISPD recommendations consolidated genomic sequencing in the evaluation of fetal effusions, with divergence regarding isolated NT [25, 26].

1.3. Nomenclature and definitions

NT is the echolucent region at the back of the fetal neck visible at 11–14 weeks and measured in a mid-sagittal section according to the standardised FMF technique; the ISUOG checklist considers NT normal below the 95th centile for CRL [1]. The former ACOG Practice Bulletin 226, now withdrawn, defined increased NT as ≥3.0 mm or above the 99th centile for CRL [3]. The Souka review showed that, in euploid fetuses, the risk of adverse perinatal outcome only increases statistically significantly from 3.5 mm (above the 99th centile) [5]. The 3.5 mm threshold is the one that American and British sequencing cohorts use as an eligible fluid collection [62, 63]. A Brazilian textbook gives normality as below 2.5 mm and an isolated sensitivity of 70% for trisomy 21, values that correspond to old fixed-cut-off conventions and not to current guidelines [28, 64].

CH is an anomaly of the lymphatic vascular system, septated or non-septated, and both forms are associated with aneuploidy [65]. Practice Bulletin 226 described CH as increased NT extending along the length of the fetus, with visible septations, or as large single or multilocular fluid cavities in the nuchal region that may extend along the length of the fetus [3]. In the Duke cohort (2013–2023), the operational distinction between CH and increased NT was based on the presence of septations or extension of the collection beyond the posterior nuchal region, superiorly to the skull or inferiorly along the back [4]. Definitions vary between studies, but analyses restricted to studies that required septations and to first-trimester CH gave results consistent with the overall analysis in the meta-analysis by Wang and colleagues [22].

The separation between increased NT and CH in the first trimester has been questioned: Bilardo and colleagues considered it of limited clinical relevance, because management is identical, and Mastromoro and colleagues treated the two as presentations of the same phenotypic spectrum [2, 28]. The «non-septated» CH of the Israeli series at 14–16 weeks (lateral cervical collections, unilateral or bilateral) is not equivalent to increased NT measured at 11–14 weeks and has its own prognosis [20, 66]. In the second trimester, a thickened nuchal fold measures ≥6 mm from the outer edge of the occipital bone to the skin, in the midline, at 15–20 weeks [3]. Other discrete fluid collections at the sides of the neck correspond to dilated jugular lymphatic sacs [1]. The SMFM defines NIHF as abnormal fluid in at least two fetal compartments and calls a single effusion attributed to a systemic process the «NIHF spectrum»; the San Francisco studies underpinning the guideline included NT ≥3.5 mm and CH among eligible collections [25, 67].

1.4. Scope

CH and increased NT are not diseases; they are ultrasound findings with heterogeneous aetiology. Aneuploidies, RASopathies and NIHF, including PIEZO1- and EPHB4-related lymphatic dysplasias, enter the differential diagnosis. The approach to multiple congenital anomalies applies when CH is associated with other malformations. The following content focuses on the first-trimester nuchal finding, its interpretation, testing strategy, prognosis and counselling. Persistent cervical lymphatic malformation in children, usually associated with somatic PIK3CA variants, is a distinct postnatal entity and is mentioned only as a differential [68].

2. Molecular Genetics and Pathophysiology

2.1. Jugular lymphatic development and the formation of nuchal collections

The lymphatic system of the neck develops from the jugular lymphatic sacs, which drain into the venous system; failure of this communication was the explanation proposed by Chervenak for CH, which frequently progresses to hydrops and fetal death [52]. The Oxford Desk Reference considers that the reason why fetuses with chromosomal abnormalities develop nuchal oedema, CH or hydrops remains poorly understood, and that CH appears to result from lymphatic dysplasia and is particularly associated with monosomy X [65]. Fluid accumulation between 11 and 14 weeks may also occur before lymphatic development is complete, before the intervillous circulation is established and before renal function matures, which explains why increased NT normalises before 14 weeks in about one in five fetuses [28].

The mechanisms described in the spectrum of fetal effusions are imbalance of fluid movement between the vascular and interstitial compartments, increased interstitial fluid production, lymphatic dysplasia with reduced lymphatic return, right heart failure or volume overload, anaemia, and visceromegaly with obstruction of venous return in metabolic disorders [25, 62, 69]. Bellini and Hennekam grouped the mechanisms of hydrops into fetal hypomobility, congestive heart failure and obstruction of lymphatic flow, three pathways that are also recognisable among the causes of increased NT: neuromuscular and akinesia disorders, heart defects and lymphatic dysplasias [65].

The immunohistochemical comparison by Bekker and colleagues showed that the nuchal oedema of trisomy 21 and that of Turner syndrome look similar but result from different lymphatic anomalies: in trisomy 21, the jugular lymphatic sac is present and enlarged and the skin has numerous dilated lymphatics; in Turner syndrome, the jugular lymphatic sac is absent, cutaneous lymphatics are sparse and small, and the nuchal cavities, negative for endothelial markers, are very large [70]. The SMFM attributes the effusions of trisomy 21 and monosomy X to aberrant communications between the lymphatic and venous systems, and adds that transient abnormal myelopoiesis, present in about 10% of infants with trisomy 21, can cause fetal anaemia and effusions [25].

2.2. Sequelae of fetal oedema

Even when fetal lymphoedema regresses, distension and displacement of tissues can leave dysmorphic features: webbed neck, nuchal skin folds, hypertelorism, epicanthic folds, low-set ears and widely spaced nipples [65]. In Turner syndrome, the short, broad, webbed neck, ptosis and low posterior hairline are secondary to fetal oedema or hydrops; congenital lymphoedema usually regresses in early childhood, the skin is lax at birth, especially at the nape, and the redundant skin may persist as webbed neck, while residual oedema of the dorsum of the fingers and toes occurs in more than 80% [36, 51]. Some structural heart defects, such as coarctation of the aorta and hypoplastic left heart, have been interpreted as possible sequelae of fetal lymphoedema [65]. Birth weight in children with Noonan syndrome is normal or increased because of oedema, and in Costello syndrome prenatal oedema results in weight loss after birth [71, 72].

2.3. Aetiological architecture

The distribution of causes depends on the entry phenotype (increased NT, CH, single effusion or NIHF), gestational age and the tests applied. The following table brings together the estimates from the sources consulted, without adding them up, because each measures a different denominator.

2.4. Aneuploidies and copy number variants

Turner syndrome affects 1/2500 female live births; up to 99% of 45,X conceptions are lost as spontaneous miscarriages and intrauterine lethality between 12 and 40 weeks is about 65% [36]. In 80% of 45,X cases the retained X chromosome is maternal, so the error occurs mainly in paternal meiosis, and the frequency of 45,X is inversely related to maternal age [36]. Mosaicism does not guarantee survival to term, but it is more frequent in live births than in miscarried 45,X fetuses [51]. Among 45,X/46,XY mosaics diagnosed in amniotic fluid, 95% (72/76) had normal male genitalia and one of the normal male fetuses had CH [73]. In the Chervenak series, one fetus with CH had female genitalia and a 46,XY karyotype [52].

Trisomy 21 is the most frequent aneuploidy in several cohorts of CH and increased NT: in the Croatian series of 405 CH it was the most common chromosomal abnormality (p<0.001), in the Chinese series of 180 NT ≥2.5 mm it accounted for 76.2% of aneuploidies, and in the Reims series it corresponded to 36.8% of the 38 chromosomal abnormalities [21, 39, 56]. Between 11 weeks and term, 43% of pregnancies with trisomy 21 are lost spontaneously [74]. Trisomy 18 has an incidence of 1/7900 live births in a defined UK population, a female excess and maternal origin in 85%; spontaneous loss from the second trimester onwards is 36% [75]. Most conceptions with trisomy 13 end in spontaneous miscarriage [76].

CMA detects submicroscopic copy number variants: in a meta-analysis with an in-house series of 96 fetuses, the incremental yield of CMA over karyotype in isolated NT was 2.35% for NT ≥2.5 mm, 3.89% for ≥3 mm and 4.1% for ≥3.5 mm [2]. Balanced reciprocal translocations may be found on a karyotype performed for increased NT, but are not detected by microarrays or by maternal plasma cell-free DNA (cfDNA) screening, and karyotyping remains necessary to demonstrate the structural rearrangement giving rise to an imbalance, with implications for recurrence risk [25, 77].

2.5. RASopathies

RASopathies result from gain-of-function variants in RAS/MAPK pathway genes. In Noonan syndrome, the proportions by gene are: PTPN11 50%, SOS1 10–13%, LZTR1 about 8% (AD or AR), RAF1 5%, RIT1 5%, SOS2 about 4%, KRAS <5%, BRAF <2%, MAP2K1 <2%, and MRAS, NRAS and RRAS2 <1% each; intragenic deletions and duplications have hardly been described, so testing for intragenic CNV is rarely diagnostic [8]. The lymphatic anomaly with increased nuchal oedema is most common with PTPN11 [71]. The table by Brouillard and colleagues attributes lymphoedema to 54% of patients with PTPN11 and 63% of patients with SOS1 [78, 79]. Advanced paternal age has been observed in cohorts with sporadic Noonan syndrome [8].

The prenatal distribution differs from the postnatal one. In an Italian and Canadian series of 352 fetuses with normal CMA tested for RASopathies, the genes involved were PTPN11 (30%), RIT1 (16%), RAF1 (14%) and HRAS (12%); HRAS, LZTR1 and RAF1 correlated with hydrops and effusions and RIT1 with prenatal-onset hypertrophic cardiomyopathy [59]. In 71 Chinese fetuses with confirmed RASopathy, 16 genes were involved, with PTPN11 in 43.7% and RAF1 in 8.5% [80]. In an American six-institution series (46 pregnancies with RASopathy and a fluid collection), increased NT or CH was more frequent with SOS1 (100% vs 44%, p=0.049) and contractures more frequent with HRAS (63% vs 24%, p=0.044) [81]. In the meta-analysis of the FIND study (Fetal hydrops and the Incremental yield of Next-generation sequencing over standard prenatal Diagnostic testing), PTPN11 accounted for 44.4% of RASopathies diagnosed in NIHF [82].

Costello syndrome results from variants in HRAS and cardiofaciocutaneous syndrome from variants in BRAF, MAP2K1 or KRAS; both share with Noonan syndrome the perinatal findings of lymphatic dysplasia [12, 13, 83]. Among the exome diagnoses in NIHF in San Francisco, 68% of the variants were AD and, of these, 88% were de novo [62]. The relationship of SHP2 (the tyrosine phosphatase encoded by PTPN11) with neural crest cell function has been proposed as the basis of the cardiac and cranial anomalies of Noonan syndrome [28].

2.6. Congenital lymphatic anomalies

Primary lymphatic anomalies are, in general, AD with reduced penetrance, variable expressivity and variable age at onset [78]. The table by Brouillard, Boon and Vikkula (2014), reproduced in the Oxford Desk Reference, summarises the genes known up to that date:

Source: [78, 79]. The table dates from 2014 and does not include PIEZO1, EPHB4, FAT4 or ADAMTS3.

In PIEZO1-related generalised lymphatic dysplasia, biallelic loss-of-function variants deprive the endothelium of the shear-stress mechanosensor that guides lymphatic development; gain-of-function variants in the same gene cause AD dehydrated hereditary stomatocytosis, an allelic disorder [44, 84]. EPHB4 variants lacking tyrosine kinase activity cause AD lymphatic-related hydrops fetalis, with high mortality in the two families described; Ephb4 is required for lymphovenous valves in the mouse [45, 46].

CCBE1 and ADAMTS3 take part in the proteolytic activation of vascular endothelial growth factor C (VEGF-C); in Hennekam syndrome, CCBE1 explains about 25% of cases (13/29 in a series of patients with classic Hennekam), FAT4 was identified in five CCBE1-negative families and ADAMTS3 defines type 3 [49, 78, 85]. In a prospective San Francisco cohort of 303 pregnancies with at least one effusion studied by exome or genome sequencing, 8 (3%) had AD lymphoedema or generalised lymphatic dysplasia, detectable from the first to the third trimester; four fetuses inherited the variant from a parent (one asymptomatic, three with milder symptoms), and heterozygous PIEZO1 variants were associated with more favourable perinatal outcomes [10]. In a targeted analysis of lymphatic anomaly genes in 71 undiagnosed cases of fetal oedema, pathogenic or likely pathogenic variants were found in 7% (RASA1, SOS1, PTPN11 and a novel PIEZO1 variant) and variants of uncertain significance (VUS) in 45% (CELSR1, EPHB4, TIE1, PIEZO1, ITGA9, SOS1, SOS2, RAF1) [86]. In a review of genome sequencing, a pathogenic 1.3 kb intragenic deletion in MED13L was identified in a fetus with a lymphatic malformation [87].

2.7. Other monogenic disorders with increased NT or CH

The list of syndromes described with increased NT grows continuously; most are sporadic and have a prevalence of 1:10,000 or lower, which prevents specific associations from being demonstrated, but the relationship with increased NT is established for Noonan syndrome, Smith-Lemli-Opitz syndrome, spinal muscular atrophy and other musculoskeletal disorders [28]. Increased NT is a non-specific indicator of abnormal development, common to several pathological pathways [28].

The Bilardo review added, between 2005 and 2009, descriptions of increased NT in Pallister-Killian, Apert, Walker-Warburg, Coffin-Siris, Fryns, Ritscher-Schinzel, cardiofaciocutaneous, multiple pterygium, orofaciodigital type IV, arthrogryposis-renal dysfunction-cholestasis, androgen insensitivity and thrombocytopenia-absent radius syndromes, in ectrodactyly, diastrophic dysplasia, spondyloepiphyseal dysplasia congenita, Ellis-van Creveld chondroectodermal dysplasia and thanatophoric dysplasia, and in unbalanced translocations, deletions and marker chromosomes [28]. The Souka review also covers diaphragmatic hernia, omphalocele, spinal muscular atrophy, Zellweger syndrome, mucopolysaccharidosis type VII, Blackfan-Diamond and Fanconi anaemias, homozygous alpha-thalassaemia and parvovirus infection [5].

Inborn errors of metabolism associated with hydrops and increased NT include congenital disorders of glycosylation (CDG; PMM2, ALG1, ALG8, ALG12), Farber, Gaucher and Niemann-Pick A and C diseases, galactosialidosis, glycogen storage disease IV, GM1 gangliosidosis, mucolipidosis II, mucopolysaccharidoses I, IV and VII, multiple sulfatase deficiency, Salla disease and sialic acid storage disease, sialidosis, Wolman disease, transaldolase deficiency (TALDO), SGPL1 deficiency and Pearson syndrome [65, 117].

2.8. Nomenclature of the variants cited

The article by Zhen and Li does not state the transcript; correspondence with MANE was inferred from the agreement of the predicted proteins, and the GRCh38 genomic coordinates are NC_000001.11:g.42757831A>T and NC_000001.11:g.42747397_42747400delinsAAGC (P3H1) and NC_000004.12:g.122250439del and NC_000004.12:g.122229943C>T (BLTP1) [119]. The two PTPN11 deletions were described only at the protein level in the original articles (Yoshida 2004; Lee 2005) [8].

2.9. Penetrance, expressivity, mosaicism and allelic disorders

In RASopathies, prenatal findings vary with the gene and with gestational age, and a variant inherited from a mildly symptomatic parent in genes with reduced penetrance may be misinterpreted as non-causal [26, 81]. In AD lymphatic anomalies, the variant is often inherited from an asymptomatic or mildly affected parent [10]. In trio sequencing, low-level parental somatic mosaicism was identified in about 5% (4.4% and 5.7% in two studies) of apparently de novo variants, and raises the recurrence risk up to 50% [26]. Confined placental mosaicism affects about 1% of CVS [121]. In sex chromosome aneuploidies, maternal mosaicism may explain discordant cfDNA screening results [73, 122]. PIEZO1 is the most relevant example of allelism: biallelic loss of function in generalised lymphatic dysplasia, gain of function in dehydrated stomatocytosis [44, 84].

3. Clinical Spectrum and Manifestations by System

3.1. Increased NT with a normal karyotype: natural history by thickness

Of fetuses with NT above the 95th centile, about 20–30% have a chromosomal aberration; in euploid fetuses there remains an increased risk of spontaneous fetal loss, isolated anomalies and genetic syndromes [28]. In the Amsterdam cohort (1994–2005), of 675 fetuses with increased NT, known karyotype and outcome, 224 (33%) had a chromosomal abnormality; in the 451 euploid fetuses the overall adverse outcome was 19% and rose with NT from 8% to 80% [29]. The distribution by thickness class, in the original version of Table 4 by Bilardo and colleagues (2010), is as follows:

Source: [28], modified from [29]. The reproduction in the Oxford Desk Reference merges miscarriage or intrauterine death and termination for severe hydrops into a single «fetal death» column (2%, 5%, 9%, 0% and 50%), and leaves blank the cell for the 5.5–6.4 mm class, which in the original corresponds to 0/19 [28, 65]. The absence of deaths in that class results from 19 fetuses and does not mean zero risk: in the combined data of three studies with 4991 euploid fetuses, the prevalence of miscarriage or fetal death rose from 1.6% between the 95th and 99th centiles to about 20% with NT ≥6.5 mm, a value probably underestimated because up to 30% of couples with worsening hydrops opt for termination before fetal death [28].

The prevalence of major anomalies in euploid fetuses rises exponentially with NT, from 2.5% between the 95th and 99th centiles to about 45% with NT ≥6.5 mm [28]. Heart defects predominate, followed by cleft lip and palate, diaphragmatic hernia, skeletal dysplasias and renal anomalies [28]. The prevalence of heart defects is about six times higher with NT ≥99th centile than in an unselected population and rises from 0.6–5% (NT 2.5–3.5 mm) to 64% (NT >8.5 mm), with no association with a specific type of heart defect [28]. In six studies, the mean prevalence of major heart defects in euploid fetuses with NT ≥3.5 mm was 6.27% (range 3.1–12.2%) and, in another eight heart-defect screening studies, 5.88% (2.3–9.7%) [65]. The ISUOG estimates that NT is increased in up to 40% of fetuses with a major heart defect [1]. In a pooled analysis of four centres, NT ≥2.5 mm and ≥3.5 mm was present in 35.5% and 23% of 397 euploid fetuses with a major heart defect; absent or reversed flow in the ductus venosus a-wave triples the probability of a major heart defect and tricuspid regurgitation at 11–13+6 weeks multiplies it eightfold [28].

In the five largest studies published after 2000 (2271 euploid fetuses with increased NT), the mean frequency was 10.6% (2.1–25.8%) for structural anomalies, 4.4% (0.5–6.4%) for genetic disorders detected before birth and 2.5% (2.2–6.5%) for anomalies detected only after birth [28]. In unselected first-trimester screening cohorts, the adverse outcome in fetuses with increased NT ranges from 3% to 6%; in selected referral cohorts it is about 3–6 times higher (approximately 20%) [28]. Sex influences prognosis in the marginal grades: male fetuses with NT between the 95th and 99th centiles are more likely to have an uncomplicated outcome than female fetuses [28].

Nine follow-up studies of chromosomally and anatomically normal fetuses with increased NT reported developmental delay between 0% and 8.7%, with heterogeneous cohorts, thresholds, duration and methods [28]:

Source: [28]. ASQ: Ages and Stages Questionnaire.

In the French prospective study by Senat and colleagues, the 162 children born after NT ≥99th centile with a normal karyotype were assessed at 2 years by clinical examination and ASQ (160 assessed) and had no more developmental delay than 370 external controls [123]. In the Amsterdam series, the seven cases of developmental delay (1.6%) occurred with NT >4 mm, and in only two (0.5%) had the second-trimester scan been completely normal [28, 29].

In about 3% of fetuses with increased NT, nuchal oedema persists at the 20-week scan, isolated or with other collections; in this scenario, parents should be informed of a risk of about 10% of progression to hydrops and perinatal death or of birth with a genetic syndrome, such as Noonan syndrome [28].

3.2. CH: cohorts and natural history

In the cohort of Scholl and colleagues, each additional millimetre of NT was associated with an adjusted odds ratio (OR) of 1.44 (95% CI 1.29–1.60) for abnormal karyotype, 1.26 (1.08–1.47) for major anomaly, 1.47 (1.07–2.02) for perinatal loss and 1.77 (1.15–2.74) for composite abnormal outcome [23]. In FASTER, compared with simple increased NT, septated CH was associated with a fivefold higher risk of aneuploidy, a twelvefold higher risk of cardiac malformation and a sixfold higher risk of perinatal death; among the 65 fetuses without a chromosomal abnormality, there were five fetal deaths (8%) and 15 terminations without evidence of anomaly, and one of the 23 survivors normal at birth (4%) had cerebral palsy and developmental delay; with a median follow-up of 25 months (12–50), most pregnancies with a normal evaluation at the end of the second trimester resulted in healthy infants [18]. In the Belgian series, NT >10 mm and hydrops were associated with a worse outcome [124]. In the Oxford series, the prognosis was favourable when the karyotype was normal, there was no other anomaly and the lesions were small and non-septated [55].

3.3. Septated and non-septated CH

In the Haifa series, non-septated CH (125, 1.6% of scans) were transient in 98%, aneuploid in 5.7% (6/106 karyotyped), hydropic in 1.7% and associated with other anomalies in 15% (17/115), with 94% (108/115) live births; septated CH (25) were transient in 44%, aneuploid in 72% (18/25), hydropic in 40% and associated with anomalies in 52%, with 12% live births [20]. In an Italian series of 11 CH at 9.1–13.4 weeks, the four septated ones had a significantly larger volume (p<0.01) and three ended in fetal death with an abnormal karyotype; five CH regressed by 19 weeks [126]. In the Croatian series, septated CH were significantly more frequent in the group with an abnormal karyotype (71.4%) [21]. In 24,000 transvaginal scans at 14–16 weeks in a predominantly low-risk population, 1254 fetuses (5.2%) had a nuchal fold or non-septated CH; 140 (11.1%) had additional structural anomalies, mainly cardiovascular, and 43 (3.4%) were aneuploid (27 with trisomy 21), with aneuploidy more frequent when there was an associated structural anomaly [127]. Rotmensch and colleagues described, over seven years, 18 families with recurrent non-septated CH in two successive pregnancies (36 siblings), all with normal karyotype, echocardiography and neonatal examination and resolution at 22–24 weeks, which suggests a transient hereditary form of lymphatic development without sequelae [66].

3.4. Resolution of CH

Regression is not synonymous with normality. In the London series, regression occurred in 10% of aneuploid and 17.6% of euploid fetuses and had no diagnostic value; the three normal survivors were euploid male fetuses [37]. In the Duke cohort, of the 284 CH, 59 (21%) resolved and ended in a live birth; median gestational age at diagnosis was 12.0 weeks (interquartile range, IQR, 11.1–12.3) and the latency to resolution 5.6 weeks (IQR 4.6–8.0); of the 46 with diagnostic testing (45 karyotypes, 30 CMA, 20 panels), 15 (33%) had a genetic anomaly (10 aneuploidies, 2 pathogenic deletions, 3 monogenic disorders) [4]. Fetuses with a genetic anomaly had later diagnosis of CH (12.3 vs 11.6 weeks, p=0.007), later resolution (20.1 vs 17.3 weeks, p=0.006), more structural anomalies (67% vs 13%, p=0.001), more fetal growth restriction, earlier delivery and longer neonatal admission [4]. In the Boston cohort, of the 31 CH under expectant management that resolved in the second trimester, 4 (13%) had a genetic anomaly [125].

3.5. Presentation by aetiology

Turner syndrome. Many fetuses are now identified by oedema or hydrops on the 12-week scan; when the syndrome is detected through fetal oedema or hydrops, the probability of spontaneous loss is high, whereas incidental detection without hydrops is associated with longer survival and a milder phenotype; in mosaics, prognosis depends on the proportion of abnormal cells and the cell line involved [36]. Ultrasound signs include CH, hydrops, subcutaneous oedema, femoral shortening, increased NT and cardiac and renal malformations [128]. Cardiovascular anomalies (coarctation, bicuspid aortic valve, atrial and ventricular septal defects) occur in 15–50% and renal anomalies (horseshoe kidney, agenesis, others) in about one third; in Turner syndrome, left-sided heart defects are the rule [8, 36]. In 45,X/46,XY mosaics without an ultrasound anomaly the outcome is generally favourable [73].

Trisomies 21, 18 and 13. Trisomy 18 presents at 11–13 weeks with increased NT and/or omphalocele and, at 19–22 weeks, with growth restriction, choroid plexus cysts, heart defect (large ventricular septal defect), renal anomalies, omphalocele, overlapping fingers and rocker-bottom feet; polyhydramnios occurs in 30–60% [75]. In trisomy 13, the anomaly scan detects about 90% of cases, with increased NT, growth restriction, holoprosencephaly, small orbits, cleft lip, heart defect and polydactyly [76, 129]. Only about 27% of fetuses with trisomy 21 have a major structural anomaly recognisable in the second trimester [3].

RASopathies. The prenatal findings of Noonan syndrome are not specific: polyhydramnios, hydronephrosis, pleural effusion, oedema, heart defect, distended jugular lymphatic sacs, CH and increased NT; CH may be accompanied by scalp oedema, pleural and pericardial effusions, ascites and frank hydrops, and the heart defect is diagnosed prenatally in about 20% [8, 83]. In the Chinese series of 71 RASopathies, the median gestational age at the first finding was 13 weeks (11–34), 40 fetuses (56.3%) had an anomaly in the first trimester (NT ≥3.0 mm in 28, CH in 12), median NT was 5.0 mm (3.1–11.4) and 18 (25.4%) and 13 (18.3%) were identified only in the second and third trimesters [80]. In the American series of 46 pregnancies, CH and jugular sacs appeared in the first trimester and persisted into the second; pleural effusion, skin oedema, ascites and heart defects occurred throughout gestation, and hepatomegaly, polyhydramnios, small or absent stomach and contractures were more frequent in the second and third trimesters [81]. Pulmonary stenosis is difficult to detect on fetal echocardiography [71]. In Costello syndrome, increased nuchal thickness is accompanied by polyhydramnios (>90%), ulnar deviation of the wrists, short humeri and femurs, fetal tachycardia (various forms of atrial tachycardia) and preterm delivery; hydrops, postnatal effusions and severe hypertrophic cardiomyopathy with early lethality are rare, and cases diagnosed prenatally have a more severe phenotype and a high risk of intrauterine death [12, 72]. In cardiofaciocutaneous syndrome, polyhydramnios, macrocephaly, macrosomia, relatively short femurs and increased nuchal fold predominate in the second and third trimesters; neonatal chylothorax and lymphoedema are less frequent [13, 130]. Fetal arrhythmia and neonatal hypoglycaemia are relatively specific to Costello syndrome [83].

Congenital lymphatic anomalies. In Milroy disease, ultrasound may show oedema of the dorsum of the feet, mild pleural effusions that often resolve and, very rarely, hydrops [9]. In PIEZO1-related generalised lymphatic dysplasia, hydrops is frequent and may lead to fetal death or resolve completely after birth, with generalised lymphoedema, intestinal and pulmonary lymphangiectasia, chylothorax and normal intelligence [43]. In CCBE1-related Hennekam syndrome, the spectrum ranges from NIHF to mild forms with segmental intestinal lymphangiectasia [49].

3.6. Maternal and obstetric complications

Mirror syndrome (maternal oedema that reproduces fetal hydrops) occurs in 8–38% of NIHF [25]. In fetal cardiofaciocutaneous syndrome, hyperemesis, gestational diabetes and hypertension, maternal pre-eclampsia and subjectively reduced fetal movements have been described [13]. Clinically significant fetal oedema was associated with preterm delivery, death and maternal pre-eclampsia in the Columbia cohort [86].

4. Clinical Recognition and Warning Signs

4.1. The 11–14-week scan and NT measurement

The ISUOG recommends that the assessment and measurement of NT be part of the 11–14-week scan protocol, whether or not NT is used for risk calculation, because an increased NT may signal rare aneuploidies that cfDNA screening, focused on a limited set of common aneuploidies, does not identify [1]. Measurement is made in a mid-sagittal section, with a magnified image including only the head and thorax, callipers in 0.1 mm increments placed on the echogenic borders, the fetus in a neutral position (extension and flexion alter the measurement) and separate from the amnion; three measurements are obtained on separate images and the largest is recorded, with ongoing quality assurance according to the FMF technique [1, 131]. ACOG Practice Bulletin 226 noted that an undermeasurement of only 0.5 mm can reduce test sensitivity by 18% and required independent accreditation and quality assurance [3]. Measurement performs better at 11–12 weeks when done by qualified sonographers with regular audit [28]. Optimal dating is by CRL at 8–12 weeks [132].

Other discrete fluid collections at the sides of the neck, separate from the NT, correspond to dilated jugular lymphatic sacs and to CH [1]. Identification of a structural anomaly favours an invasive diagnostic approach over non-invasive screening, because cfDNA does not identify structural defects [1].

4.2. When to suspect each aetiological group

4.3. Warning signs

The following are associated with a worse prognosis and a higher probability of a genetic disorder: septation of the CH, NT of large thickness (each millimetre increases the risk of abnormal karyotype, major anomaly and perinatal loss), progression to hydrops or other effusions, the presence of additional structural anomalies, persistence of nuchal oedema into the second trimester, abnormal ductus venosus flow, growth restriction and late diagnosis or resolution of the CH [4, 20, 23, 28, 55]. Maternal mirror syndrome is an emergency that requires a decision on delivery or termination [25].

4.4. History and examination of the parents

The history should include a three-generation pedigree, previous fetal losses, family history of anaemia, consanguinity and ethnic origin (alpha-thalassaemia, glucose-6-phosphate dehydrogenase, G6PD, deficiency); the parents should be examined for Noonan features [65]. A personal or family history of lymphoedema, neonatal oedema or chylothorax points to an AD lymphatic anomaly with mild parental expression [10]. Recent maternal infection, especially in women with young children, warrants infection screening when increased NT evolves in the second trimester into a thickened nuchal fold, generalised oedema or hydrops; infection screening should not be performed routinely for isolated increased NT [28].

4.5. Neonatal period

At birth, oedema of the hands and feet is frequent in Turner syndrome and oedema of the dorsum of the hands and feet is described as a manifestation of lymphatic dysplasia in Noonan syndrome [36, 133]. In Milroy disease, oedema of the dorsum of the feet is present from birth, with deep interphalangeal creases and dysplastic «ski-jump» nails [78]. The newborn who had increased NT or CH should have a targeted clinical examination, with echocardiography and renal ultrasound when the karyotype is 45,X, and postnatal confirmation of the karyotype in sex chromosome mosaics [36, 73]. There is no specific newborn screening for the causes of CH.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Ultrasound criteria and thresholds

There is no single threshold for increased NT. The table brings together the definitions of the sources consulted and the practical consequence that each attributes to them.

The ISUOG and the FMF use the CRL-dependent 95th centile, whereas fixed cut-offs (2.5 mm or 3 mm) were used in older studies; Bilardo and colleagues noted that increased NT is defined in the literature by a fixed cut-off (2.5 or 3 mm), by centile (95th or 99th) or by multiples of the median [1, 28]. The positive predictive value of low cut-offs (2.5 mm, 95th centile) for heart defects is 2–3% [28]. There is also a genetic yield between 3.0 and 3.4 mm: in an Italian cohort of 97 fetuses with complete follow-up, 28.9% had a genetic anomaly and five rare anomalies would not have been detectable by QF-PCR or cfDNA (two by karyotype, two only by CMA, one only by RASopathy panel) [134].

5.2. Evaluation algorithm

The following algorithm combines the recommendations of the ISUOG, SMFM, ESHG/ISPD and ACMG with cohort yields; the steps apply to CH and to NT ≥3.5 mm and, on an individualised basis, to NT between the 95th centile and 3.4 mm.

1. First-trimester scan by a certified operator: confirm the measurement, describe septations, extent, other collections, hydrops and early anatomy (heart, limbs, abdominal wall, central nervous system) [1, 28].
2. Pre-test genetic counselling and offer of invasive diagnostic testing (CVS from 11 weeks or amniocentesis from 15 weeks), with the alternatives and the option to decline [1, 3, 25, 121].
3. Rapid aneuploidy testing by QF-PCR or FISH on the fetal sample, before any sequencing [26].
4. CMA with or without karyotype in all pregnancies with an effusion (GRADE 1C); karyotype when it is important to demonstrate a structural rearrangement or when QF-PCR suggests an aneuploidy that should be characterised [25].
5. If CMA is not diagnostic: RASopathy panel as standard in CH or increased NT (position of a Canadian population-based cohort), or exome/genome in the NIHF spectrum (SMFM, GRADE 1C); if the risk of aneuploidy is low or there is strong monogenic suspicion, it is reasonable to offer exome/genome simultaneously with CMA [25, 27].
6. In truly isolated NT, the ESHG/ISPD does not recommend genomic sequencing, so the next step is serial ultrasound surveillance (14–16 weeks, 18–22 weeks and echocardiography), and sequencing is reserved for when anomalies appear [26, 63, 135].
7. Sequencing preferably as a trio, untargeted, with exclusion of maternal cell contamination and detailed phenotypic information provided to the laboratory [25, 26, 32].
8. Targeted investigation according to context: infection screening if NT evolves into generalised oedema or hydrops; biochemistry of amniotic fluid and cultured amniocytes for lysosomal disorders; exclusion of alloimmunisation and fetal anaemia; examination of the parents [28, 65].
9. In case of fetal death or termination: photography, skeletal radiography, storage of DNA and a fibroblast line, autopsy with placenta, urgent muscle biopsy if akinesia; reanalysis of sequencing data if the phenotype evolves [26, 32, 65].

5.3. Invasive tests and procedural risk

CVS at 11–12 weeks has confined placental mosaicism in about 1% of cases, and amniocentesis is performed at 15–18 weeks [121]. The historical figure of «about 1 in 400» for the risk of miscarriage after amniocentesis has been replaced by meta-analyses of controlled studies [121, 136]. In the updated meta-analysis by Salomon and colleagues (loss before 24 weeks), amniocentesis had 580 losses in 63,723 procedures (0.91%; 95% CI 0.73–1.09) vs 0.58% in controls, with a procedure-attributable risk of 0.30% (95% CI 0.11–0.49); CVS had 1.39% (95% CI 0.76–2.02) vs 1.23%, with an attributable risk of 0.20% (95% CI −0.13 to 0.52); in studies with similar chromosomal risk profiles between groups, the attributable risk was 0.12% (95% CI −0.05 to 0.30) for amniocentesis and −0.11% (95% CI −0.29 to 0.08) for CVS [136]. The earlier meta-analysis by Akolekar and colleagues had estimated attributable risks of 0.11% (95% CI −0.04 to 0.26) and 0.22% (95% CI −0.71 to 1.16) [137]. In both cases the intervals include or approach zero, and the baseline risk of loss in a fetus with CH is much higher than the risk of the procedure.

In CVS, confined placental mosaicism requires dissection of the mesenchymal core or culture, and chorionic tissue has limitations for epigenetic disorders owing to incomplete methylation [26]. Exclusion of maternal cell contamination is mandatory before interpretation of any fetal test [26, 32].

5.4. QF-PCR, karyotype and CMA

Rapid testing identifies most common aneuploidies: in 226 pregnant women in Toronto with NT ≥3.5 mm and invasive testing, QF-PCR identified aneuploidy in 116 (51.3%); in the remaining 110, karyotype or CMA showed a pathogenic change in 9 (8.2%) and VUS in 5 [135]. In a Chinese series of 180 pregnant women with NT ≥2.5 mm studied by karyotype and single nucleotide polymorphism microarray (SNP array), there were 24 chromosomal abnormalities (21 aneuploidies), and the SNP array detected CNV in 13 fetuses with a normal karyotype, one pathogenic, one likely pathogenic and the rest VUS; at follow-up of 10 infants with VUS, two had growth or language delay [39]. In isolated NT, the incremental yield of CMA over karyotype was 2.35–4.1% depending on the threshold [2]. The ACMG estimates that fetuses with structural anomalies have up to a 30% probability of an abnormal karyotype and that CMA adds 4–6% in fetuses with an ultrasound anomaly and a normal karyotype [32]. CMA has become standard in fetal anomalies, but VUS are a greater challenge in the prenatal setting [25, 121].

5.5. Cell-free DNA screening and other screening

cfDNA screening is the most sensitive and specific screening test for trisomies 21, 18 and 13 in any population (SMFM Consult Series #74, GRADE 1B, endorsed by ACOG), but a positive result requires diagnostic testing, and the SMFM does not recommend cfDNA for genome-wide CNV or microdeletion screening in the general population: those who want information on CNV should have diagnostic testing [30, 31]. cfDNA does not detect structural defects, and combined screening or the first-trimester scan may reveal structural anomalies, unexpected genetic diagnoses or a risk of adverse perinatal outcome that cfDNA does not identify [1, 30].

In CH, a low-risk cfDNA result does not exclude a genetic disorder: in the Boston cohort, it was associated with a residual risk of 19% (13/71) of aneuploidy, CNV or another pathogenic finding [125]. Invasive testing remains the standard in septated CH; expanded cfDNA detects CNV >7 Mb and some monogenic disorders, mainly skeletal and neurological, and one case of cfDNA after septated CH led to the diagnosis of previously unrecognised familial Noonan syndrome [19, 138]. cfDNA for selected monogenic disorders, with unique molecular indexing, screens in a commercial panel for 25 AD or X-linked dominant disorders (30 genes, mostly de novo), but it remains screening based on placental DNA, and confirmatory diagnostic testing is mandatory before clinical decisions [139]. If the pregnant woman declines diagnostic testing, the SMFM accepts cfDNA, which requires confirmation [25].

Combined screening (maternal age, gestational age, history, NT, free β-hCG and PAPP-A) with the FMF algorithm screens for the common trisomies, which account for about 50% of genetic anomalies identifiable by microarray, and is effective for Turner syndrome [1]. At 12 weeks, detection of trisomy 21 is 88% for a 2% screen-positive rate [65]. The ISUOG strategy of scanning with NT before cfDNA in all pregnant women, CVS if NT >3.5 mm or anomalies and cfDNA in the remainder, had 100% detection for trisomies 21, 18 and 13, with 0.1% false positives and an additional 2.5% of invasive procedures for NT >3.5 mm or anomalies [1].

5.6. RASopathy panel

The meta-analysis by Powel and colleagues (14 studies, 1800 fetuses with increased NT and normal karyotype or CMA) estimated an overall RASopathy panel yield of 8.1% (95% CI 3.6–13.9%), 3.3% (0.6–7.4%) in isolated NT, 15.1% (1.1–38.1%) with additional ultrasound anomalies (mainly cardiac) and 18.4% (11.0–27.0%) with CH [24]. The series underpinning the testing criteria are as follows.

The yield rises with the thickness and persistence of the NT and with the number of associated findings [58, 59]. The SMFM notes that panels miss 38–89% of the diagnoses identifiable by exome in fetal effusions and that exome was more cost-effective than panels at all gestational ages in one study cited; it recommends panels when exome or genome sequencing is not feasible [25].

5.7. Exome and genome sequencing

P/LP: pathogenic or likely pathogenic variants.

Two patterns are consistent. First, NT that remains isolated on serial scans has a low yield (0–4%), whereas NT or CH with associated anomalies, present at presentation or appearing later, have yields of 22–42% [63, 67, 140, 141]. Second, prior selection by a clinical geneticist increases the yield (42% in those preselected for a monogenic aetiology vs 15% in unselected cases) [140]. In the Sparks series, 68% of diagnoses were AD (88% de novo and 12% inherited), 27% AR (95% inherited), one inherited X-linked recessive case and one of uncertain inheritance [62]. In the Al-Kouatly meta-analysis, inheritance was recessive in 55%, dominant in 41% and X-linked in 4% [69]. The most commonly cited turnaround time for prenatal sequencing is three weeks [26]. Genome sequencing has a small incremental yield over exome sequencing, but often a shorter turnaround time and a lower DNA requirement; the SMFM considers both reasonable depending on availability [25, 145]. In the Boutin study, the new diagnoses resulted mainly from updated tools and literature, not from genome technology itself [145].

5.8. Echocardiography and serial scans

Fetal echocardiography is recommended in all cases with NT ≥3.5 mm and should be considered between 3.0 and 3.4 mm, and in CH [3, 28, 65]. It includes views of the ventricular outflow tracts, valvular Doppler, aorta, pulmonary arteries and pulmonary veins, according to the schedule 11–12 weeks (nuchal assessment), 16 weeks (fetal echocardiography) and 20–22 weeks (review) [132]. In Toronto, among the 92 euploid fetuses with NT ≥3.5 mm and normal genetics, the early scan at 14–16 weeks detected a structural anomaly in 24 (26.1%), the scan at 18–22 weeks in a further 15 (16.3%) and echocardiography a cardiac anomaly in 9 (9.8%) [135]. In experienced hands and with high-resolution equipment, most severe malformations and major heart defects can be detected by the end of the first trimester [28]. Overall ultrasound detection of malformations in an unselected population was about 60% in the Eurofetus study [121].

5.9. Limitations of the tests

CMA does not detect balanced translocations, inversions, low-level mosaicism or sequence variants; karyotyping does not detect submicroscopic CNV; cfDNA screening is not diagnostic and reflects placental DNA [25, 77, 139]. Exome sequencing is not validated for all CNV, so CMA should precede or accompany the exome, unless the laboratory validates CNV analysis in the genomic data, in which case parallel CMA may be unnecessary [26, 146]. In RASopathies, intragenic CNV are exceedingly rare, and a 1.3 kb intragenic deletion in MED13L was detected only by genome sequencing [8, 87]. The fetal phenotype is incomplete and evolving, which limits phenotype-based interpretation; variant classification should consider the fetal phenotype and that of parents and siblings [26, 32]. A negative exome does not exclude a genetic diagnosis and should not be used as a guarantee of a normal outcome [32]. In sequencing studies, VUS ranged from 4% to 42%, with higher values in proband-only analysis [87].

5.10. Report content, VUS and segregation

The report should state the gene, the reference transcript with version, the variant in HGVS nomenclature, zygosity, parental origin and class according to ACMG/AMP criteria. P/LP variants related to the phenotype are reported as diagnostic; severe paediatric P/LP variants unrelated to the phenotype are discussed by a multidisciplinary team; «hot» VUS are reported only in selected scenarios (gene aligned with a very specific phenotype, manifestation expected later, non-genetic confirmatory test available, treatable disorder, informative segregation) and after multidisciplinary discussion [26]. The ACMG recommends reporting P/LP variants in disease genes consistent with the phenotype, considering reporting VUS in genes that fit the phenotype, especially in an AR disorder in trans with a P/LP variant, classifying variants in candidate genes as VUS at most, not reporting variants without a known fetal or childhood phenotype or the fetal carrier status for unrelated AR or X-linked disorders, and reporting high-penetrance variants in unrelated genes that cause moderate to severe disease in childhood [32]. Secondary findings from the ACMG list require consent with an option to decline [32]. Segregation in the parents and manual inspection of parental reads for mosaicism are part of the interpretation [26].

5.11. Prenatal and preimplantation diagnosis in subsequent pregnancies

When the familial variant or chromosomal anomaly is known, prenatal diagnosis by CVS or amniocentesis and preimplantation genetic testing (PGT) are possible; in lymphatic anomalies, prenatal diagnosis is only possible if there is a chromosomal anomaly or a defined variant in the proband [8, 78]. A result classified as VUS may restrict targeted prenatal diagnosis and PGT, depending on laboratory policy [32]. The ACOG points out that PGT is not uniformly accurate and that prenatal screening and diagnosis should be offered regardless of prior PGT [3]. In carrier couples for disorders with a high recurrence risk, NT may serve as an early sign of recurrence or of reassurance [28].

6. Differential Diagnosis

6.1. Comparative table

6.2. Differential of non-genetic causes and focal collections

The SMFM lists as non-genetic causes of fetal fluid collections structural heart defects (8–20% of NIHF before next-generation sequencing, NGS), arrhythmias (supraventricular tachycardia, atrial flutter, bradyarrhythmias), infections (7–8%; parvovirus B19, cytomegalovirus, toxoplasmosis, with PCR on amniotic fluid), thoracic anomalies (5–6%; congenital pulmonary airway malformation, primary chylothorax), twin-to-twin transfusion syndrome (4–5%), placental chorioangioma (2%), anaemias (alpha-thalassaemia major; fetomaternal haemorrhage, with Kleihauer-Betke test and middle cerebral artery peak systolic velocity) and urinary, gastrointestinal and tumour anomalies [25]. Systemic effusion must be distinguished from focal collections, such as urinoma, bladder rupture or oedema due to amniotic bands [25]. The systematic review by Bellini and colleagues (225 articles, 6361 NIHF) estimated the causes of non-immune hydrops:

Source: [147]. The version reproduced in the Oxford Desk Reference refers to 5437 cases and groups syndromes with inborn errors (5.5%) [65]. These data predate sequencing, and the «idiopathic» category is now partly explained by RASopathies, lymphatic anomalies and metabolic disorders.

6.3. Differential of congenital lymphoedema and lymphatic dysplasia

In a child with a history of increased NT or CH and oedema, the differential diagnosis includes Turner syndrome or Turner mosaicism (residual oedema of the hands and feet, redundant nuchal folds), Noonan syndrome (thick eyelids with ptosis, epicanthic folds, webbed neck, low-set posteriorly rotated ears, widely spaced nipples), Milroy disease, GM1 gangliosidosis (AR; coarse facies, oedema of the face, hands and feet, macroglossia, hypotonia), Hennekam syndrome, Aagenaes syndrome (cholestasis-lymphoedema, locus 15q, very rare outside Scandinavia), Klippel-Trenaunay syndrome and microcephaly-lymphoedema-chorioretinopathy (KIF11, AD) [78]. The algorithm by Connell and colleagues separates generalised lymphatic dysplasia or Hennekam (consider CCBE1), multisegmental congenital oedema without systemic involvement, Milroy and Milroy-like (FLT4, KIF11, VEGFC), Parkes-Weber (RASA1), the fibroadipose hyperplasia syndromes of the AKT/PIK3/mTOR pathway, Proteus (AKT1) and late-onset lymphoedema (GJC2, Turner, GATA2, FOXC2) [78, 148]. The GeneReviews entry on Milroy disease adds Hennekam syndrome 3 (ADAMTS3; congenital generalised oedema, facial dysmorphism, protein-losing enteropathy), type 2 (FAT4; oedema in childhood or adulthood, microtia, intellectual disability), hypotrichosis-lymphoedema-telangiectasia syndrome (SOX18; alopecia, palmar telangiectasias, renal defect) and VEGFC-related lymphoedema, clinically indistinguishable from Milroy but with a different lymphoscintigraphy [9]. The investigation includes karyotype (with testing for mosaicism if Turner is suspected with a normal karyotype), genomic analysis, echocardiography, proteinuria, leucocyte enzymes if GM1 or another lysosomal disorder is suspected, ophthalmological assessment and FLT4 if Milroy [78].

6.4. Noonan, Turner and related syndromes

Turner syndrome is distinguished from Noonan syndrome by the sex chromosome anomaly; in Turner syndrome renal anomalies are more common, developmental delay much less frequent and left-sided heart defects are the rule [8]. Cardiofaciocutaneous syndrome has the greatest overlap with Noonan syndrome, with similar cardiac and lymphatic findings, more severe intellectual disability and more likely structural anomalies of the central nervous system [8]. In the differential of Au-Kline syndrome, Noonan syndrome appears with prenatal CH or increased NT, and Simpson-Golabi-Behmel syndrome (GPC3/GPC4, X-linked) with polyhydramnios and overgrowth [17]. Supraventricular or atrial tachycardia and cardiomyopathy with hydrops point to Costello and cardiofaciocutaneous syndromes [149].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no treatment directed at fetal CH or increased NT. Management consists of making every effort to obtain a diagnosis and counselling according to that diagnosis, monitoring for progression to hydrops, treating obstetric complications and planning delivery and neonatal care [25, 65]. In RASopathies, pregnancy complications (polyhydramnios, effusions, hydrops) are managed as in the general population [8]. When there are anomalies, first-trimester detection allows time for additional investigation, counselling and, if that is the option chosen, an unhurried and earlier decision on termination [28]. Bilardo and colleagues also warned of the opposite risk: in their series, 7 of 50 fetuses (14%) with suspicious ultrasound findings had an uncomplicated outcome, and an obsessive search for subtle signs can lead to anxiety and unnecessary terminations of healthy fetuses [28].

7.2. Obstetric management

The SMFM recommends offering all options, including termination of pregnancy, in pregnancies with NIHF (GRADE 1C) [25]. It recommends preterm delivery only for usual obstetric indications, for new or worsening NIHF or when the risks of continuing outweigh those of delivery (1C); antenatal corticosteroids if preterm delivery is anticipated within the next seven days and if neonatal resuscitation is desired or offered (1C); caesarean section for the usual obstetric indications when there is a resuscitation plan (1C); and, in mirror syndrome, individualised counselling on delivery or termination, with expectant management only in rare circumstances (1C) [25]. Needle drainage or thoracoamniotic shunting is considered when the aim is to prolong the pregnancy or when drainage may be beneficial before delivery, and thoracocentesis in primary chylothorax improves outcomes [25]. Aetiology-specific fetal procedures include intrauterine transfusion, maternally administered antiarrhythmics and treatment of thoracic masses.

Some proposals suggested offering termination directly for increased NT with obvious structural anomalies, sparing karyotyping; Bilardo and colleagues advocated karyotyping, not only to define the recurrence risk but also to support the parents' decision [28]. The same logic now applies to CMA and sequencing, because 59% of monogenic diagnoses after non-diagnostic CMA implied a recurrence risk of ≥25% [27].

7.3. Neonatal and postnatal care by aetiology

In Turner syndrome with an ongoing pregnancy, cardiac and renal anomalies are screened for prenatally and renal ultrasound and cardiovascular assessment are performed in the newborn [36]. In Noonan syndrome, cardiac assessment is repeated at least annually until 5 years of age if the initial assessment is normal and then at least every 5 years, according to GeneReviews [8, 150]. In chronic lymphoedema, referral to a specialist clinic and a lymphoedema therapist, complete decongestive therapy according to the 2023 International Society of Lymphology consensus, compression stockings and prevention of cellulitis (the main avoidable harm in Milroy disease) are the mainstay; in intestinal lymphangiectasia a low-fat diet with medium-chain triglyceride supplementation is used [78, 85, 151]. In Hennekam syndrome, protein-losing enteropathy in an infant was treated with parenteral nutrition and transition to a special formula in one reported case [49]. There is no approved therapy for PIEZO1-related disorders; in dehydrated stomatocytosis, splenectomy should be avoided, and for generalised lymphatic dysplasia there are no specific data [84].

7.4. Investigational therapies

MEK inhibition in the lymphatic anomalies of RASopathies. Trametinib, a MEK inhibitor, has been used off-label. Dori and colleagues (2020) described a 14-year-old patient with SOS1-related Noonan syndrome with resolution of mesenteric and retroperitoneal lymphangiectasia and chylothorax and complete remodelling of the lymphatic system [8]. In a series from Bonn (Germany) of six infants with confirmed Noonan syndrome (mean age 0.5 ± 0.72 years), lymphatic anomalies and intractable chylous effusions, after one year of trametinib all improved clinically, none required chest drainage, there was no clinical chylothorax, and magnetic resonance lymphangiography showed reduction of effusions in all (no residual fluid in three and minimal in three) and less pathological pulmonary and pleural lymphatic perfusion (median 3 vs 1), without normalisation of the lymphatic anomalies [152]. The dose is not stated in the sources consulted, and no label with a paediatric indication for lymphatic anomalies was consulted, so no dosing regimens are recorded.

MEK inhibition in the hypertrophic cardiomyopathy of RASopathies. Two infants with RIT1 variants and progressive hypertrophic cardiomyopathy showed reversal with trametinib under compassionate use [153]. In the international retrospective analysis by Wolf and colleagues (61 children with RASopathy and severe hypertrophic cardiomyopathy), the group with MEK inhibition (n=30) had lower mortality and morbidity and cardiac improvement compared with standard treatment (n=31), with non-life-threatening and manageable adverse effects [154]. This is postnatal observational evidence.

Postnatal lymphatic malformations. Alpelisib is in a phase 2/3 trial in lymphatic malformations with a PIK3CA variant; sclerotherapy with OK-432 (picibanil) and intralesional bleomycin have been studied in paediatric macrocystic lymphatic malformations and in postnatal cystic hygromas [68, 155, 156]. These interventions are directed at the persistent postnatal lesion and not at fetal CH.

Fetal therapy. A ClinicalTrials.gov search (17 October 2026, terms «cystic hygroma», «nuchal translucency exome», «nonimmune hydrops sequencing», «fetal lymphatic malformation») did not identify trials of fetal pharmacological intervention for CH, RASopathies or lymphatic dysplasias; a negative search of a registry does not demonstrate the absence of studies [157].

7.5. Regulatory status

The sources consulted did not include FDA or EMA labels for these medicines, and their authorisation status in other indications was not verified; the absence of a registered indication in this table refers only to the indications in question.

7.6. Intervention and diagnostic trials and studies

There are no randomised therapeutic trials in fetal CH or increased NT. The MEK inhibition data come from case series and a non-randomised retrospective comparison, with a risk of selection and indication bias, and do not permit extrapolation to the fetus or an estimate of absolute effect. The ongoing diagnostic studies measure yield and clinical utility, not the benefit of an intervention; the three completed postnatal intervention studies have no results in the registry, which prevents any negative results from being known.

7.7. Developments in the last 12 months

7.8. Guideline recommendations and divergences

Sources: [1, 3, 25, 26, 30–32, 146].

The main divergence concerns the place of exome sequencing. The SMFM includes CH and NT ≥3.5 mm in the NIHF spectrum and recommends offering exome or genome sequencing after non-diagnostic CMA, whereas the ESHG/ISPD does not recommend sequencing for isolated increased NT and reserves it for major, multisystem or recurrent anomalies [25, 26]. The divergence is smaller than it appears, because the SMFM relies on cohorts in which isolated NT or CH had a yield of 0% (0/17) and cases with anomalies 42% [67]; in practice, persistent septated CH, hydrops or NT accompanied by anomalies justify sequencing under both positions, and isolated NT that remains isolated justifies it under neither. A second point of divergence is the RASopathy panel: a Canadian cohort proposes it as standard alongside CMA in CH and increased NT, whereas the SMFM considers panels an alternative to exome sequencing when the latter is unavailable, because they miss 38–89% of diagnoses [25, 27]. As regards cfDNA, all sources agree that it does not replace diagnostic testing for increased NT, CH or structural anomaly [1, 25, 30, 125].

7.9. Pregnancy in an affected woman, lactation and agents to avoid

In a pregnant woman with Noonan syndrome, referral to an adult congenital heart disease programme for peripartum assessment and to haematology if there is a history of bleeding or no coagulopathy screening is recommended [8]. In Turner syndrome, natural fertility is rare and prenatal diagnosis should be considered, given the possibly increased risk of trisomy 21 and 45,X [36]. In a pregnancy with a fetus with cardiofaciocutaneous syndrome, high-risk obstetric care is recommended because of polyhydramnios and maternal hypertension [13]. The sources consulted do not identify medicines to avoid specifically because of fetal CH; the MEK inhibitors used postnatally have no safety data in pregnancy or lactation in the sources consulted.

8. Reproductive Options and Family Counselling

8.1. Recurrence risk depends on the diagnosis

Counselling after CH or increased NT is based on the specific diagnosis, and obtaining that diagnosis is the main measure for preventing recurrence [65]. When no laboratory modality demonstrates the aetiology, the recurrence risk may be low (de novo event), 25% (AR disorder) or up to 50% (AD disorder with reduced penetrance or variable expressivity), and parents should be informed of this uncertainty [32].

In the Canadian series, 59% of monogenic diagnoses obtained after non-diagnostic CMA implied a recurrence risk of ≥25% [27]. In the Al-Kouatly meta-analysis, recessive inheritance accounted for 55% of exome diagnoses in NIHF, and the yield was higher with consanguinity [69].

8.2. Evaluation and testing of relatives

Identification of a P/LP variant in the fetus allows at-risk relatives to be tested and future pregnancies to be planned [32]. In RASopathies and AD lymphatic anomalies, examination and testing of the parents are essential, because the variant is often inherited from a mildly affected or asymptomatic parent [10, 71]. Variants inherited from a mildly symptomatic parent in genes with reduced penetrance should not be dismissed as non-causal without evaluation [26]. When a proband sample is unavailable, the ISPD recommends offering sequencing to both parents to identify a shared carrier status for an AR disorder [146]. Trio sequencing may reveal misattributed paternity and undisclosed consanguinity, and laboratories should have policies for communicating these [32].

8.3. Prenatal and preimplantation diagnosis and surveillance in future pregnancies

The ideal time to assess the risk and discuss prenatal diagnosis and PGT is before pregnancy [8]. In Noonan syndrome, prenatal diagnosis by CVS or amniocentesis is possible when the familial variant is known, and in a pregnancy with an a priori risk of 50% high-resolution ultrasound can also be used [8, 71]. In the absence of a molecular diagnosis, surveillance of a subsequent pregnancy is based on early ultrasound, including NT, which may act as an early sign of recurrence [28, 97]. In Turner syndrome, a study of 19 European registries supported NT scanning at 10–14 weeks followed by a search for hydrops as an alternative to invasive diagnosis [36]. The ACOG recommends offering prenatal screening and diagnosis even after PGT, because PGT is not uniformly accurate [3].

8.4. Content of counselling

Pre-test counselling should ideally be provided by a genetics professional and include the types of variants that may be reported, the possibility of a negative result, incidental and secondary findings (with an option to decline) and the turnaround time; consent should involve both parents and be accompanied by written information [26, 32]. Before first-trimester screening, pregnant women should know that it is not limited to Down syndrome and may reveal other risk factors requiring investigation, with the corresponding anxiety [28]. When communicating a sex chromosome aneuploidy, a hasty decision should be discouraged and disclosure of the karyotype limited to those who need to know it [122]. Post-test counselling is recommended for all results, with the possibility of variant reclassification over time [32].

For the most frequent question after increased NT and a normal karyotype («what is the probability of a normal pregnancy?»), the data by thickness class (section 3.1) can be used with couples who understand the concept of risk, and, with a very large NT, parents should know that spontaneous lethality is high and that not all anomalies, especially cardiac ones, are detectable prenatally [28]. Noonan syndrome, one of the most frequent syndromes in this context, generally has a good prognosis in the absence of severe heart disease, with normal intellectual development in the great majority [28]. In Japan, CH was independently associated with the choice of invasive testing (OR 3.10; 95% CI 1.09–9.15), whereas increased NT was negatively associated (OR 0.35; 0.13–0.90), which shows that the way the finding is communicated influences the decision [163].

8.5. Minors and asymptomatic relatives

The ACMG recommends not reporting the carrier status of the fetus for AR and X-linked disorders unrelated to the indication, nor variants without a known fetal or childhood phenotype [32]. Asymptomatic siblings and other relatives in a family with a RASopathy or AD lymphatic anomaly are assessed clinically, and testing is directed at those who derive clinical or reproductive benefit from it [10, 32]. Family support resources include Antenatal Results and Choices (ARC, United Kingdom), which provides non-directive information before, during and after prenatal screening [132].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each estimate measures

Estimates of the frequency of CH depend on the gestational age at the scan, the route (abdominal or transvaginal), the definition (septation, extent) and the population (general screening or referral). Orphanet has no epidemiological data for CH (ORPHA:79486) [6].

The frequency of NT above the 95th centile is, by definition, about 5% in a reference population, but the observed proportion depends on the reference curve and the quality of measurement; referral cohorts do not estimate prevalence. CH cohorts are not national prevalences: they measure the aetiological composition and outcome of cases detected in fetal medicine centres.

9.2. United States and Canada

American data include FASTER (multicentre, general population), the retrospective cohort of 944 CH by Scholl and colleagues, the Boston (294 CH) and Duke (284 CH) cohorts, the San Francisco series of the HYDROPS study (Sparks, Gulrajani, Boutin, Vargo) and the six-institution RASopathy series [4, 10, 18, 23, 62, 67, 81, 125, 145]. Canadian data include the Toronto series with NT ≥3.5 mm and the population-based cohort of a provincial laboratory (2014–2022) [27, 135]. The SMFM notes that the risk of spontaneous loss in early presentations is influenced by the prevalence of aneuploidy and is likely to be higher with less access to termination of pregnancy, which makes outcomes dependent on the legal framework [25].

9.3. Europe

European CH series come from the United Kingdom (Oxford, London), France (Reims), Belgium (Leuven) and Croatia (two centres, 30 years), and the euploid NT studies from Amsterdam and France (Senat) [21, 29, 37, 55, 56, 123, 124]. Prenatal RASopathy studies are mainly Dutch and Italian, and the PAGE study recruited 34 units in England and Scotland [57–60, 134]. Aagenaes syndrome (cholestasis-lymphoedema, AR) is very rare outside Scandinavia, an example of a founder effect among lymphatic anomalies [78].

9.4. Other regions and populations with consanguinity

Israel contributed the series of transient non-septated CH and the description of the benign familial form [20, 66, 127]. Recent Chinese series describe fetal RASopathies, CNV in increased NT and exome sequencing in isolated NT, and Japan the effect of the finding on the choice of test [11, 39, 80, 143, 163]. In the exome meta-analysis in NIHF, the yield was higher with consanguinity, which corresponds to the predominance of AR disorders in populations with frequent consanguineous unions [69].

9.5. Portugal and Brazil

The sources consulted contain no Portuguese series of CH or increased NT. From Brazil, a textbook of genetic syndromes uses the 2.5 mm cut-off for NT and describes CH among the ultrasound signs of Turner syndrome, and a Brazilian case of a stillborn infant with Neu-Laxova syndrome is cited in a textbook of metabolic diseases [64, 116, 128]. Absence from the sources consulted does not demonstrate the absence of published data.

9.6. European networks and patient organisations

ERN ITHACA covers malformation syndromes and intellectual disability, and VASCERN, through the vascular anomalies working group (VASCA-WG), postnatal lymphatic anomalies [33, 34]. The FMF manages NT certification and quality assurance [131]. The patient and family organisations identified include Antenatal Results and Choices (https://www.arc-uk.org/), the Turner Syndrome Support Society (United Kingdom, https://tss.org.uk/), the Turner Syndrome Society of the United States (https://www.turnersyndrome.org/), the Noonan Syndrome Association (United Kingdom, https://noonansyndrome.org.uk/), the Noonan Syndrome Foundation (USA, https://teamnoonan.org/), the Lymphatic Education & Research Network (https://lymphaticnetwork.org/), the Lymphatic Malformation Alliance (formerly the Lymphangiomatosis & Gorham's Disease Alliance, LGDA; USA, https://lmalliance.org/) and the Fetal Health Foundation (USA, https://www.fetalhealthfoundation.org/) [36, 132, 165].

10. Illustrative Clinical Case

Zhen and Li (Guangzhou, China) described two families with recurrent first-trimester CH, normal chromosomes and an AR disorder identified by trio exome sequencing [11].

In the first case, a 27-year-old woman, in her second pregnancy with one previous termination, from a healthy non-consanguineous couple, had fetal CH at 12 weeks (Figure 1a of the article); CVS with CMA showed no imbalance. At 16 weeks, the anatomy was normal and the nuchal fold measured 6.0 mm; at 21 weeks severe shortening and bowing of the long bones, femur and tibia appeared (Figure 1b–c). Trio exome sequencing identified, in P3H1 (NM_022356.4), the variants c.1032T>A p.(Tyr344Ter), of maternal origin, and c.1927_1930delinsGCTT p.(Pro643delinsAlaTer), of paternal origin, both classified as pathogenic, which established the diagnosis of osteogenesis imperfecta type VIII. The couple opted for termination at 21 weeks, and the male fetus had short extremities. The previous pregnancy had been terminated at 13 weeks for CH with normal CMA, and the stored DNA of that fetus confirmed both variants [11, 119]. The figure is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC11978256/figure/jmu_128_23-f001/ (first-trimester CH, short and bowed femur and tibia, pedigree).

In the second case, a 27-year-old woman, in her third pregnancy with two previous adverse outcomes, had CH at 12 weeks and normal CMA on CVS at another centre. At 20 weeks, the nuchal CH persisted and there was a flat face, bilateral ventriculomegaly (17.4 and 16.8 mm), micrognathia, cleft palate, scoliosis, clenched hands and clubfeet (Figure 2). After termination, the female fetus had facial dysmorphism, CH, clenched hands, overlapping fingers, diffuse fixed contractures and clubfoot. Trio exome sequencing (fetal skin and parental blood) identified in BLTP1 (KIAA1109; NM_001384125.1) the variants c.5788del p.(Val1930CysfsTer2), maternal, and c.3055C>T p.(Arg1019Ter), paternal, consistent with Alkuraya-Kucinskas syndrome. The first pregnancy had ended in early miscarriage without a karyotype and the second had been terminated at 13 weeks for CH with a normal karyotype; the stored DNA confirmed the variants [11, 119]. The figure is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC11978256/figure/jmu_128_23-f002/.

The authors concluded that recurrent CH with a normal karyotype strongly suggests an AR disorder and proposed considering early exome sequencing, before the appearance of second-trimester structural anomalies [11]. Recurrence of similar anomalies after non-diagnostic karyotype or CMA is one of the sequencing criteria of the ESHG/ISPD and ISPD recommendations, so the management in the report is consistent with the guidelines; sequencing of a first isolated CH, without recurrence or anomalies, is not recommended by the ESHG/ISPD [26, 146]. The case also shows the value of storing fetal DNA: in both families, it was the DNA stored from the previous pregnancy that confirmed the recurrence of the same genotype [11, 65]. The discussion in the article attributes to the FASTER study a series of 410 CH that does not correspond to the original publication, of 134 septated CH, and that figure was not used [11, 18].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis depends mainly on the aetiology, septation and thickness, the presence of structural anomalies and progression to hydrops. In CH, 55% of fetuses have a genetic diagnosis and 42% major structural anomalies; the overall abnormal outcome was 86.6% in the Scholl cohort, with perinatal loss of 39% in pregnancies not terminated, and confirmed survival with a normal paediatric outcome was 17% in FASTER [18, 22, 23]. In NIHF, spontaneous loss or fetal death reaches 15–21%, and up to 62–86% in some series when there are effusions or CH in the first and second trimesters; survival of live-born infants with NIHF is 36–68%, with neurological impairment in up to 48% and major morbidity in up to 39%; the outcome is more favourable when the cause is lymphatic dysplasia, tachyarrhythmias, parvovirus or pulmonary masses, and worse with trisomies 13 and 18, inborn errors of metabolism and heart defects [25].

In euploid fetuses with increased NT, the probability of a live birth without defects ranges from 92% (95th centile–3.4 mm) to 20% (≥6.5 mm) [28]. In the Amsterdam series, the adverse outcome in fetuses with a normal scan at 20 weeks was 4%, divided between intrauterine deaths, undetected heart defects and genetic syndromes, and the probability of a healthy child with a completely normal scan was 98% [28, 29]. Souka and Bilardo concluded that, if the 20–22-week scan shows no sign of abnormal development (including persistence of nuchal oedema or pericardial effusion), the risk of adverse outcome and developmental delay is not increased relative to the general population, regardless of the initial NT; the authors themselves stress that survivors with a very large NT are few, that longer follow-up is needed and that one case of Noonan syndrome with mild pulmonary stenosis was only diagnosed at 3 years [5, 28]. Senat and colleagues recorded postnatal anomalies in 18/179 (11%) of fetuses with a negative scan [28, 65]. Among the euploid fetuses in Toronto with normal genetics and known outcome, 83.1% (69/83) were born alive, 8.4% had fetal death and 8.4% termination [135].

Turner syndrome detected through oedema or hydrops has a high probability of spontaneous loss, and that detected without hydrops has longer survival and a milder phenotype [36]. In Noonan syndrome, the prognosis is generally good without severe heart disease [28]. Costello syndrome diagnosed prenatally has a more severe phenotype and a high risk of intrauterine death, and Fryns syndrome is lethal in the prenatal or neonatal period in 17/17 cases [14, 72]. Heterozygous PIEZO1 variants were associated with more favourable perinatal outcomes than other lymphatic anomalies [10]. In trisomy 13, median survival of live-born infants was 7–10 days in a US population-based study, with 5–10% surviving beyond 12 months [76].

11.2. Surveillance

12. Summary and Final Considerations

Fetal CH and increased NT are first-trimester ultrasound expressions of a disturbance of jugular lymphatic development or fluid balance common to many disorders. About half of CH have a genetic diagnosis, mainly Turner syndrome and trisomies 21, 18 and 13; among euploid fetuses, RASopathies are the most frequent monogenic cause, followed by congenital lymphatic anomalies, neuromuscular and akinesia disorders, skeletal dysplasias and inborn errors of metabolism. Septation, thickness, hydrops, associated anomalies and persistence into the second trimester increase the probability of disease and adverse outcome, and resolution of the CH does not exclude a genetic cause.

Evaluation begins with a certified measurement and counselling, followed by invasive testing with QF-PCR and CMA; cfDNA screening does not replace diagnosis. After non-diagnostic CMA, the RASopathy panel or trio exome/genome sequencing has a high yield when the collection is septated, persistent or accompanied by other anomalies, and a low yield when the NT remains isolated, the point on which the SMFM and the ESHG/ISPD diverge. Fetal echocardiography and scans at 14–16 and 18–22 weeks identify the anomalies that change the indication for sequencing and the prognosis.

In a euploid fetus whose NT regresses and whose 20–22-week scan and echocardiography are normal, the probability of a healthy child approaches that of the general population, with the caveat of few survivors with a very large NT and of late diagnoses, such as mild Noonan syndrome. The recurrence risk is determined by the diagnosis, ranges from very low in free aneuploidies to 25% in AR disorders and up to 50% in inherited AD disorders or with parental mosaicism, and justifies storing fetal DNA and reanalysis before a new pregnancy. There is no therapy directed at fetal CH; MEK inhibition for the postnatal lymphatic and cardiac complications of RASopathies remains experimental.

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