Increased Nuchal Translucency

Nuchal translucency is the sonographic measurement of the subcutaneous fluid-filled space at the back of the fetal neck, measured between 11+0 and 13+6 weeks (CRL 45–84 mm).

  • A phenotypic marker, not a diagnosis
  • A reflection of impaired fetal fluid dynamics at that moment in gestation
  • Highly gestational-age dependent
  • The same as cystic hygroma
  • A dynamic first-trimester phenotype
  • A risk marker, not a diagnosis
  • A reflection of temporary imbalance in fetal fluid regulation

Percentile-based (preferred)

  • ≥ 95th centile: abnormal

Pathophysiology: why NT increases

1. Cardiac dysfunction (most important)

  • Structural CHD
  • Arrhythmias
  • Myocardial dysfunction

→ raised venous pressure → neck edema

2. Abnormal lymphatic development

  • Delayed or abnormal jugular lymphatic drainage
  • Seen in Turner syndrome, Noonan spectrum

3. Altered extracellular matrix

  • Collagen and proteoglycan abnormalities
  • Explains association with skeletal dysplasias, RASopathies

4. Fetal anemia or hypoproteinemia

  • Rare but relevant (e.g. alpha-thalassemia major)

5. Early hydrops spectrum

  • NT is often the earliest manifestation of hydrops

Etiological spectrum (the big buckets)

A. Chromosomal abnormalities

Risk rises steeply with NT thickness.

  • NT ≥ 3.5 mm → aneuploidy risk ~20–35%
  • NT ≥ 6 mm → aneuploidy risk >50%
  • Copy number variants (CNVs)
  • 22q11.2 deletion
  • 1p36 deletion
  • 15q duplications
  • Submicroscopic pathogenic CNVs

Yield of CMA in isolated increased NT with normal karyotype: ~3–7%, higher as NT increases.

Single-gene disorders

1. RASopathies (major group)

  • Noonan syndrome
  • Costello syndrome
  • Cardio-facio-cutaneous syndrome

Clues:

  • Persistently increased NT
  • Later cystic hygroma
  • CHD (esp. pulmonary stenosis, HCM)
  • Normal karyotype and CMA

Genes: PTPN11, SOS1, RAF1, RIT1, KRAS

Yield of targeted RASopathy testing: ~10–15% in NT ≥ 5 mm with normal CMA

Skeletal dysplasias

  • COL2A1 disorders
  • Thanatophoric dysplasia (early NT increase may precede limb shortening)

Normal outcome (important for counseling)

Approximate liveborn normal outcome:

  • NT 95–99th centile: ~70–80%
  • NT 3.5–4.4 mm: ~60–70%
  • NT ≥ 6 mm: <30%

Effect of persistence and evolution (often more important than size)

NT resolves by 16 weeks

  • CMA yield unchanged
  • RAS and exome yield drops sharply
  • Prognosis improves significantly

NT persists or becomes cystic hygroma

  • RASopathy yield increases
  • Exome yield rises further
  • Prognosis worsens regardless of genetics

NT + early cardiac anomaly

  • RASopathy yield increases disproportionately
  • Exome yield exceeds CMA yield

Practical escalation algorithm

  • NT ≥3.5 mm → CMA for all
  • NT ≥4.5–5 mm → add RASopathy panel
  • NT ≥5.5–6 mm OR evolving phenotype → consider exome early
  • NT + CHD or hydrops → exome strongly justified

RASopathy genes to NT patterns
RASopathies cause increased NT via:

  • Abnormal lymphatic development
  • Altered extracellular matrix
  • Early cardiac dysfunction

But different genes bias toward different patterns of:

  • NT thickness
  • Persistence vs progression
  • Associated cardiac phenotype
  • Likelihood of hydrops

Summary table

Gene Typical NT Progression Hydrops risk Cardiac bias
PTPN11 3.5–5 mm Often resolves Low PS, ASD
SOS1 3.5–4.5 mm Resolves Very low Mild PS
RAF1 4.5–6 mm Persistent Moderate HCM
RIT1 ≥5–7 mm Progressive High HCM, arrhythmia
KRAS ≥5 mm Progressive Moderate–high Variable
BRAF ≥5.5–6.5 mm Persistent Moderate Complex CHD
MAP2K1/2 ≥5 mm Progressive Moderate Complex
SHOC2 ~4–5 mm Variable Low Variable

Practical testing

  • NT ≥4.5–5 mm, normal CMA → RAS panel justified
  • NT ≥6 mm or rapidly increasing → prioritize genes like RIT1, RAF1, KRAS
  • NT + evolving HCM → RAF1, RIT1 first
  • NT + cystic hygroma / hydrops → RIT1, KRAS, BRAF

Increased NT in RASopathies, Turner syndrome, and 22q11.2 deletion

Feature RASopathies Turner syndrome (45,X) 22q11.2 deletion
Primary mechanism Lymphatic + ECM + cardiac Primary lymphatic failure Cardiac outflow obstruction
NT severity Mild → very severe Often very large Usually mild–moderate
Progression Variable, often persistent Progressive → hygroma/hydrops Often resolves
Septations Absent initially Common Absent
Cardiac driver HCM, PS Coarctation, HLHS Conotruncal defects
Genetic class Single-gene Whole chromosome Microdeletion

Pattern recognition

Feature RASopathies Turner 22q11.2
NT size Variable, gene-dependent Very large Mild–moderate
Persistence Common Progressive Often resolves
Hydrops risk Moderate–high High Low
Septations No (early) Yes No
Cardiac timing Often evolves Often later Often later but severe
Best test after CMA RAS panel Karyotype already diagnostic CMA essential

Huge NT + septations at 12 weeks

→ Turner syndrome until proven otherwise

Moderate-to-large NT that persists despite normal scans

→ Think RASopathy

Borderline NT that resolves but conotruncal CHD appears later

→ Think 22q11.2 deletion

NT that increases despite normal karyotype

→ RASopathy or Turner, not 22q11

Clinical summary

  • Size predicts Turner
  • Persistence predicts RAS
  • Resolution shifts focus to the heart (22q11)