Patau Syndrome (Trisomy 13)

Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births and is more common in women. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. If pregnancy reaches term, it is recommended that a specialized center handle delivery and neonatal care. In the neonate, findings include craniofacial and cardiac malformations, severe intellectual disability, and greatly reduced life expectancy. Most babies do not survive beyond 3 months. With no treatment available and a null expectancy of survival, the family is given supportive management and resources to navigate through the natural course of the disease.

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Overview

Definition

Trisomy 13 or Patau syndrome is defined by the presence of 3 copies of chromosome 13.

Epidemiology

  • 3rd most common autosomal trisomy
  • 1 in 10,000 live births
  • More common in women than men
  • Risk increases with maternal age
  • 60% of fetuses will spontaneously abort in the 2nd trimester.

Etiology

  • Trisomy 13: presence of 3 copies of the 13th chromosome
  • There are 2 types of trisomy 13: 
    • “True” trisomy 13: presence of 47 chromosomes in each cell due to an extra 13th chromosome
    • Trisomy 13 mosaicism: presence of 46 chromosomes in some cells and 47 chromosomes in others (with an extra 13th chromosome)
    • Trisomy 13 from unbalanced Robertsonian translocation results in 2 copies of chromosome 13 and an extra copy of a segment (i.e., long arm) of chromosome 13 due to translocation.

Mnemonic

“At 13 you enter Puberty”: P as in Patau syndrome or 13 for Trisomy 13

Pathophysiology

Genetics

  • Chromosomes contain genetic material.
  • Human cells:
    • 46 chromosomes (23 pairs of chromosomes, with 1 homolog each from the mother/egg and father/sperm)
    • Chromosome 1–22: autosomes
    • Chromosome 23: 2 sex chromosomes 
      • Female: XX
      • Male: XY
  • Meiosis: 
    • DNA replication is followed by reproductive cell division, in which cells separate the chromosomes before reproduction (from 46 → 23 chromosomes).
    • The normally diploid (2 sets of chromosomes) cells divide into gametes (egg or sperm) and become haploid (single set of chromosomes).
  • During fertilization, a diploid zygote is formed when a haploid egg and haploid sperm unite.

Nondisjunction

  • Most common mechanism: 90% of cases
  • In nondisjunction:
    • Failure of proper separation of 2 homologous chromosomes or the sister chromatids
    • Diploid cell (with a pair of chromosomes) divides → a gamete ends up with 2 chromosomes while the other cell has none (not viable)
    • Nondisjunction results in aneuploidy, a state of chromosomal imbalance.
  • Trisomy 13:
    •  All or a particular region of chromosome 13 is present 3 times (or has 3 copies).
    • Can occur when either:
      • The egg with a pair of chromosome 13 is fertilized by a normal haploid cell (2 from the egg and 1 from the sperm = 3). 
      • The sperm with a pair of chromosome 13 fertilizes a normal haploid cell (2 from the sperm and 1 from the egg = 3).

Robertsonian translocation

  • Found in < 20% of trisomy 13
  • Not related to maternal age
  • Translocation occurs when a part of the chromosome is attached to another chromosome, or is interchanged with a segment of another chromosome.
  • Robertsonian translocation involving chromosome 13:
    • Translocation occurring between:
      • Chromosome 13 AND 
      • Another acrocentric chromosome (chromosomes with very small, short arms) including 14, 15, 21, and 22
    • Results in:
      • Loss of their short arms (no deleterious effect as short arms carry redundant genes)
      • Fusion of their long arms → resulting in a single chromosome
    • The carrier of the translocation, though phenotypically unaffected, is at risk of having children with genetic abnormalities:
      • Carrier will have an affected gamete carrying 2 copies of chromosome 13.
      • When the affected gamete (with 2 copies) is fertilized or fertilizes a normal gamete (with 1 copy) → zygote will have 3 copies.

Mosaicism

  • Not all cells are trisomic.
  • Some cells have the normal 2 copies of chromosome 13.
  • Stems from a mitotic nondisjunction error
  • Unrelated to maternal age
  • Severity of the condition is dependent on the number and type of cells with trisomy.

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Clinical Presentation

  • Classic triad:
    • Micro/anophthalmia
    • Cleft lip and palate
    • Polydactyly
  • In ≥ 50% of individuals with trisomy 13, the following conditions are noted:
    • Holoprosencephaly with:
      • Incomplete development of the forebrain, and the olfactory and optic nerves
      • Severe intellectual disability
      • Deafness
    • Craniofacial:
      • Scalp defects (cutis aplasia)
      • Abnormal auricles
      • Microphthalmia/anophthalmia
      • Colobomata
      • Sloping forehead (fissure or cleft of the iris, ciliary body, or choroid)
    • Cutaneous and extremities:
      • Capillary hemangiomata
      • Simian crease
      • Hyperconvex narrow fingernails
      • Polydactyly of hands and feet
      • Prominent heel
    • Cardiac (approximately 80% of patients):
      • Ventricular septal defect (VSD)
      • Patent ductus arteriosus (PDA)
      • Atrial septal defect (ASD)
      • Dextroposition
    • Urogenital: 
      • Cryptorchidism
      • Bicornuate uterus
  • Other less-frequent findings:
    • Hypo- or hypertonia
    • Cerebral hypoplasia
    • Cyclopsia
    • Micrognathia
    • Polycystic kidney
    • Omphalocele

Patau syndrome: A 37 2/7 weeks gestational age male infant with Patau syndrome shows alobar holoprosencephaly with cyclopia.
A: Facial features include a sloping forehead with a proboscis superior to a single central palpebral fissure.
B: Close-up of the fused eyelids and proboscis showing a single nostril
C: Polydactyly showing 6 digits
D: Posterior view of the brain showing indistinct gyri, fusion of the hemispheres, and occipital encephalocele
E: Transposition of the aorta (A) and hypoplastic pulmonary trunk (P)
F: Trisomy 13 (47, XY, +13) (karyotype by Giemsa banding)

Image: “Histogenesis of retinal dysplasia in trisomy 13” by Chan A, Lakshminrusimha S, Heffner R, Gonzalez-Fernandez F. License: CC BY 2.0

Diagnosis

Maternal screening

  • 1st trimester combined test at 11th–14th week (+ maternal age): 
    • Maternal serum testing:
      • ↓ β-hCG
      • ↓ Pregnancy-associated plasma protein-A
    • Fetal nuchal translucency (FNT):
      • On ultrasound: increased hypoechoic area in the posterior fetal neck
      • Performed between 11 and 13 weeks of gestation
  • 2nd trimester triple test (triple screen) between 15th and 20th week: unchanged/normal 𝛼-fetoprotein, β-hCG, free estriol
  • 2nd trimester quadruple test (quad screen) between 15th and 21st (ideally up to 18th) week: 
    • Best option if the mother presents for prenatal care and is already in the 2nd trimester
    • Finding: unchanged/normal free estriol, 𝛼-fetoprotein, inhibin A, and β-hCG
  • Full integrated test consists of: 
    • Combination of 1st trimester pregnancy-associated plasma protein-A and 2nd trimester quadruple test
    • Ultrasound FNT
  • Serum integrated test: full integrated test but without ultrasound FNT
  • Sequential screening:
    •  1st trimester screening is performed and patient informed of the results
    •  Above a specified threshold, counseling is provided and diagnostic testing is offered.
  • Cell-free fetal DNA test:
    • Noninvasive procedure involving the fetus
    • May be performed anytime after 10 weeks of gestation
    • Fetal DNA is isolated from maternal blood and evaluated for chromosomal abnormalities.
    • May be more accurate and specific than traditional screening tests
    • Also tests for sex of the baby
Table: Maternal screening during 1st and 2nd trimesters
1st trimester2nd trimester
NTPregnancy-associated plasma protein-Aβ-hCGAFPEstriolβ-hCGInhibin A
Trisomy 13↓↓UnchangedUnchangedUnchangedUnchanged
Trisomy 18↑↑↓↓↓↓↓↓↓↓Unchanged
Trisomy 21↑↑↓↓
NT: nuchal translucency
β-hCG: β-human chorionic gonadotropin
AFP: 𝛼-fetoprotein

Diagnostic tests

  • Invasive diagnostic tests:
    • Indicated if: 
      • Positive screening test
      • Prior pregnancy with child with trisomy
      • Known chromosomal translocation or aberration in parent
    • The risks include bleeding, infection, fetal injury, and rarely, fetal loss.
    • Procedures:
      • Chorionic villus sampling: Placenta samples are tested between the 10th and 13th weeks.
      • Amniocentesis: Amniotic fluid is tested between the 15th and 20th weeks.
      • Percutaneous umbilical blood sampling: Umbilical cord blood is tested between the 18th and 22nd weeks. There is a 2% risk of fetal loss.
  • Fetal karyotyping is a confirmatory test (can be done prenatally or postnatally).

A karyotype showing trisomy of the 13th chromosome (red arrow)

Image: “Figure 2” by Luiza E. Dorfman, et al. License: CC BY 4.0

Management and Prognosis

Management

  • Plan for delivery in a specialized center with a neonatologist
  • Supportive management:
    • Intervention dependent on the type of abnormalities
    • Hospice care
  • Genetic counseling and chromosome studies on parents, especially if planning future pregnancies
  • Support resources (e.g., Support Organization for Trisomy (SOFT))

Prognosis

  • 60% of pregnancies are spontaneously aborted in the 2nd trimester.
  • Usual survival is 7–10 days.
  • 80% of offspring born alive will die within the 1st 3 months.

Differential Diagnosis

  • Trisomy 18 or Edwards syndrome: the presence of 3 copies of the 18th chromosome. Many clinical findings of trisomy 18 overlap with those of trisomy 13.
  • Pseudotrisomy 13: a rare autosomal recessive disorder characterized by holoprosencephaly, associated midline facial abnormalities, polydactyly, and cardiac abnormalities including atrial and ventricular septal defects. Antenatal diagnosis is by ultrasound. Like trisomy 13, pseudotrisomy 13 has a poor prognosis.
  • Meckel-Gruber syndrome: a severe autosomal recessive developmental disorder caused by multiple genetic mutations. There is extensive clinical variability and controversy regarding the minimum diagnostic criteria. The presentation of Meckel-Gruber syndrome can include cystic renal disease and CNS malformation, most commonly occipital encephalocele and polydactyly. Genital abnormalities and pulmonary hypoplasia (the common cause of fatality) are also observed.
  • Bardet-Biedl syndrome: a genetic autosomal recessive condition owing to mutations in several genes. Clinical manifestations include progressive visual impairment, polydactyly, truncal obesity, hypogonadism, kidney abnormalities, and learning difficulties. 
  • Smith-Lemli-Opitz syndrome: a congenital syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme, 7-dehydrocholesterol (7-DHC) reductase. Smith-Lemli-Opitz syndrome is characterized by growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple malformations. Malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in men, postaxial polydactyly, and 2–3 syndactyly of the toes. The clinical spectrum is wide; individuals with normal development and only minor malformations have also been described.

References

  1. Cunningham, F., et al. (Eds.). (2018). Williams Obstetrics, 25e. McGraw-Hill.
  2. Giersch, A. (2019). Congenital cytogenetic abnormalities. UpToDate. Retrieved March 23, 2021, from https://www.uptodate.com/contents/congenital-cytogenetic-abnormalities.
  3. Jones, K.L., et al. (2013). Smith’s Recognizable Patterns of Human Malformation. 7th edition. Elsevier Saunders.
  4. McCarthy, J.J., Mendelsohn, B.A. (Eds.). (2016). Pregnancy. Precision Medicine: A Guide to Genomics in Clinical Practice. McGraw-Hill.
  5. Genetic Testing Registry (GTR). Meckel Syndrome Type 1. https://www.ncbi.nlm.nih.gov/gtr/conditions/C3714506/
  6. Meeks, N., et al. (2018). Genetics & Dysmorphology. In William, H. Jr., et al. (Eds.). Current Diagnosis & Treatment: Pediatrics. 24th ed., McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1153315258
  7. Noriega, M.A., Siddik, A.B. (2021). Trisomy 13. StatPearls. Retrieved March 23, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK559091/
  8. Spagnoli, C., Kugathasan, U., Brittain, H., Boyd, S.G. (2015). Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. Brain & development. 37(7),704–713. https://doi.org/10.1016/j.braindev.2014.10.007
  9. Genetic testing registry (GTR). Smith-Lemli-Opitz Syndrome. https://www.ncbi.nlm.nih.gov/gtr/conditions/C0175694/

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