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Patau Syndrome (Trisomy 13)

Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13. As the 3rd most common trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations, Patau syndrome has an incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of 1 in 10,000 live births and is more common in women. Most cases of Patau syndrome are diagnosed prenatally by maternal screening Screening Preoperative Care and ultrasound. More than half of the pregnancies result in spontaneous abortions. If pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care reaches term, it is recommended that a specialized center handle delivery and neonatal care. In the neonate Neonate An infant during the first 28 days after birth. Physical Examination of the Newborn, findings include craniofacial and cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) malformations, severe intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman's compensation benefits. ABCDE Assessment, and greatly reduced life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids. 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.

Last updated: Mar 24, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13 or Patau syndrome is defined by the presence of 3 copies of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13.

Epidemiology

  • 3rd most common autosomal trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations
  • 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 Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13: presence of 3 copies of the 13th chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics
  • There are 2 types of trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13: 
    • “True” trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13: presence of 47 chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure in each cell due to an extra 13th chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics
    • Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13 mosaicism Mosaicism The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. Chromosome Testing: presence of 46 chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure in some cells and 47 chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure in others (with an extra 13th chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics)
    • Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13 from unbalanced Robertsonian translocation results in 2 copies of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13 and an extra copy of a segment (i.e., long arm Arm The arm, or “upper arm” in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm: Anatomy) of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13 due to translocation.

Mnemonic

“At 13 you enter Puberty”: P as in Patau syndrome or 13 for Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13

Pathophysiology

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

  • Chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure contain genetic material.
  • Human cells:
    • 46 chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure (23 pairs of chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure, with 1 homolog each from the mother/egg and father/sperm)
    • Chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 1–22: autosomes
    • Chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 23: 2 sex chromosomes Sex chromosomes The homologous chromosomes that are dissimilar in the heterogametic sex. There are the X chromosome, the Y chromosome, and the w, z chromosomes (in animals in which the female is the heterogametic sex (the silkworm moth bombyx mori, for example)). In such cases the w chromosome is the female-determining and the male is zz. Basic Terms of Genetics 
      • Female: XX
      • Male: XY
  • Meiosis Meiosis The creation of eukaryotic gametes involves a DNA replication phase followed by 2 cellular division stages: meiosis I and meiosis II. Meiosis I separates homologous chromosomes into separate cells (1n, 2c), while meiosis II separates sister chromatids into gametes (1n, 1c). Meiosis
    • DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication is followed by reproductive cell division Cell Division A type of cell nucleus division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. Cell Cycle, in which cells separate the chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure before reproduction (from 46 → 23 chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure).
    • The normally diploid Diploid The chromosomal constitution of cells, in which each type of chromosome is represented twice. Symbol: 2n or 2x. Basic Terms of Genetics (2 sets of chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure) cells divide into gametes (egg or sperm) and become haploid Haploid The chromosomal constitution of cells, in which each type of chromosome is represented once. Symbol: n. Basic Terms of Genetics (single set of chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure).
  • During fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week, a diploid Diploid The chromosomal constitution of cells, in which each type of chromosome is represented twice. Symbol: 2n or 2x. Basic Terms of Genetics zygote Zygote The fertilized ovum resulting from the fusion of a male and a female gamete. Fertilization and First Week is formed when a haploid Haploid The chromosomal constitution of cells, in which each type of chromosome is represented once. Symbol: n. Basic Terms of Genetics egg and haploid Haploid The chromosomal constitution of cells, in which each type of chromosome is represented once. Symbol: n. Basic Terms of Genetics sperm unite.

Nondisjunction Nondisjunction The failure of homologous chromosomes or chromatids to segregate during mitosis or meiosis with the result that one daughter cell has both of a pair of parental chromosomes or chromatids and the other has none. Basic Terms of Genetics

  • Most common mechanism: 90% of cases
  • In nondisjunction Nondisjunction The failure of homologous chromosomes or chromatids to segregate during mitosis or meiosis with the result that one daughter cell has both of a pair of parental chromosomes or chromatids and the other has none. Basic Terms of Genetics:
    • Failure of proper separation of 2 homologous chromosomes Homologous chromosomes Basic Terms of Genetics or the sister chromatids
    • Diploid Diploid The chromosomal constitution of cells, in which each type of chromosome is represented twice. Symbol: 2n or 2x. Basic Terms of Genetics cell (with a pair of chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure) divides → a gamete Gamete Gametogenesis ends up with 2 chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure while the other cell has none (not viable)
    • Nondisjunction Nondisjunction The failure of homologous chromosomes or chromatids to segregate during mitosis or meiosis with the result that one daughter cell has both of a pair of parental chromosomes or chromatids and the other has none. Basic Terms of Genetics results in aneuploidy, a state of chromosomal imbalance.
  • Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13:
    •  All or a particular region of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13 is present 3 times (or has 3 copies).
    • Can occur when either:
      • The egg with a pair of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13 is fertilized by a normal haploid Haploid The chromosomal constitution of cells, in which each type of chromosome is represented once. Symbol: n. Basic Terms of Genetics cell (2 from the egg and 1 from the sperm = 3). 
      • The sperm with a pair of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13 fertilizes a normal haploid Haploid The chromosomal constitution of cells, in which each type of chromosome is represented once. Symbol: n. Basic Terms of Genetics cell (2 from the sperm and 1 from the egg = 3).

Robertsonian translocation

  • Found in < 20% of trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13
  • Not related to maternal age
  • Translocation occurs when a part of the chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics is attached to another chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics, or is interchanged with a segment of another chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics.
  • Robertsonian translocation involving chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13:
    • Translocation occurring between:
      • Chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13 AND 
      • Another acrocentric chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics ( chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure 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 Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure)
      • Fusion of their long arms → resulting in a single chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics
    • The carrier Carrier Vaccination of the translocation, though phenotypically unaffected, is at risk of having children with genetic abnormalities:

Mosaicism Mosaicism The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. Chromosome Testing

  • Not all cells are trisomic.
  • Some cells have the normal 2 copies of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 13.
  • Stems from a mitotic nondisjunction Nondisjunction The failure of homologous chromosomes or chromatids to segregate during mitosis or meiosis with the result that one daughter cell has both of a pair of parental chromosomes or chromatids and the other has none. Basic Terms of Genetics error Error Refers to any act of commission (doing something wrong) or omission (failing to do something right) that exposes patients to potentially hazardous situations. Disclosure of Information
  • Unrelated to maternal age
  • Severity of the condition is dependent on the number and type of cells with trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations.

Related videos

Clinical Presentation

  • Classic triad:
    • Micro/anophthalmia
    • Cleft lip Cleft lip The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate and palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy
    • Polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn
  • In ≥ 50% of individuals with trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13, the following conditions are noted:
    • Holoprosencephaly Holoprosencephaly Anterior midline brain, cranial, and facial malformations resulting from the failure of the embryonic prosencephalon to undergo segmentation and cleavage. Alobar prosencephaly is the most severe form and features anophthalmia; cyclopia; severe intellectual disability; cleft lip; cleft palate; seizures; and microcephaly. Semilobar holoprosencephaly is characterized by hypotelorism, microphthalmia, coloboma, nasal malformations, and variable degrees of intellectual disability. Lobar holoprosencephaly is associated with mild (or absent) facial malformations and intellectual abilities that range from mild intellectual disability to normal. Holoprosencephaly is associated with chromosome abnormalities. Development of the Nervous System and Face with:
      • Incomplete development of the forebrain forebrain The anterior of the three primitive cerebral vesicles of the embryonic brain arising from the neural tube. It subdivides to form diencephalon and telencephalon. Development of the Nervous System and Face, and the olfactory and optic nerves
      • Severe intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
      • Deafness
    • Craniofacial:
      • Scalp defects (cutis aplasia Aplasia Cranial Nerve Palsies)
      • Abnormal auricles
      • Microphthalmia/anophthalmia
      • Colobomata
      • Sloping forehead Forehead The part of the face above the eyes. Melasma ( fissure Fissure A crack or split that extends into the dermis Generalized and Localized Rashes or cleft of the iris, ciliary body Ciliary body A ring of tissue extending from the scleral spur to the ora serrata of the retina. It consists of the uveal portion and the epithelial portion. The ciliary muscle is in the uveal portion and the ciliary processes are in the epithelial portion. Eye: Anatomy, or choroid Choroid The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. Eye: Anatomy)
    • Cutaneous and extremities:
      • Capillary hemangiomata
      • Simian crease
      • Hyperconvex narrow fingernails
      • Polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn of hands and feet
      • Prominent heel
    • Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) (approximately 80% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship):
      • Ventricular septal defect Ventricular Septal Defect Tetralogy of Fallot (VSD)
      • Patent ductus arteriosus Patent ductus arteriosus The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA) ( PDA PDA The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA))
      • Atrial septal defect Atrial Septal Defect Atrial septal defects (ASDs) are benign acyanotic congenital heart defects characterized by an opening in the interatrial septum that causes blood to flow from the left atrium (LA) to the right atrium (RA) (left-to-right shunt). Atrial Septal Defect (ASD) ( ASD ASD Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by poor social skills, restricted interests/social interactions, and repetitive/stereotyped behaviors. The condition is termed a “spectrum” because of the wide variability in the severity of symptoms exhibited. Autism Spectrum Disorder)
      • Dextroposition
    • Urogenital: 
  • Other less-frequent findings:
Male infant with patau syndrome

Patau syndrome: 37 2/7 week gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care male infant with Patau syndrome demonstrating alobar holoprosencephaly Holoprosencephaly Anterior midline brain, cranial, and facial malformations resulting from the failure of the embryonic prosencephalon to undergo segmentation and cleavage. Alobar prosencephaly is the most severe form and features anophthalmia; cyclopia; severe intellectual disability; cleft lip; cleft palate; seizures; and microcephaly. Semilobar holoprosencephaly is characterized by hypotelorism, microphthalmia, coloboma, nasal malformations, and variable degrees of intellectual disability. Lobar holoprosencephaly is associated with mild (or absent) facial malformations and intellectual abilities that range from mild intellectual disability to normal. Holoprosencephaly is associated with chromosome abnormalities. Development of the Nervous System and Face with cyclopia.
A) Facial features include sloping forehead Forehead The part of the face above the eyes. Melasma with a proboscis superior to a single central palpebral fissure Fissure A crack or split that extends into the dermis Generalized and Localized Rashes.
B) Close-up of the fused eyelids Eyelids Each of the upper and lower folds of skin which cover the eye when closed. Blepharitis and proboscis showing a single nostril
C) Polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn showing six digits
D) Posterior view of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification showing indistinct gyri, fusion of the hemispheres, and occipital Occipital Part of the back and base of the cranium that encloses the foramen magnum. Skull: Anatomy encephalocele Encephalocele Brain tissue herniation through a congenital or acquired defect in the skull. The majority of congenital encephaloceles occur in the occipital or frontal regions. Clinical features include a protuberant mass that may be pulsatile. The quantity and location of protruding neural tissue determines the type and degree of neurologic deficit. Visual defects, psychomotor developmental delay, and persistent motor deficits frequently occur. Neural Tube Defects
E) Transposition of the aorta Aorta The main trunk of the systemic arteries. Mediastinum and Great Vessels: Anatomy (A) and hypoplastic pulmonary trunk Pulmonary Trunk Truncus Arteriosus (P)

Image: “Histogenesis of retinal dysplasia Dysplasia Cellular Adaptation in trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13” by Chan A, Lakshminrusimha S, Heffner R, Gonzalez-Fernandez F. License: CC BY 2.0

Diagnosis

Maternal screening Screening Preoperative Care

  • 1st trimester combined test at 11th–14th week (+ maternal age): 
    • Maternal serum testing:
      • ↓ β-hCG
      • ↓ Pregnancy-associated plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products protein-A
    • Fetal nuchal translucency Nuchal translucency A prenatal ultrasonography measurement of the soft tissue behind the fetal neck. Either the translucent area below the skin in the back of the fetal neck (nuchal translucency) or the distance between occipital bone to the outer skin line (nuchal fold) is measured. Obstetric Imaging (FNT):
      • On ultrasound: increased hypoechoic Hypoechoic A structure that produces a low-amplitude echo (darker grays) Ultrasound (Sonography) area in the posterior fetal neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess
      • 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 Estriol A hydroxylated metabolite of estradiol or estrogen that has a hydroxyl group at C3, 16-alpha, and 17-beta position. Estriol is a major urinary estrogen. During pregnancy, a large amount of estriol is produced by the placenta. Isomers with inversion of the hydroxyl group or groups are called epiestriol. Noncontraceptive Estrogen and Progestins
  • 2nd trimester quadruple test ( quad screen Quad Screen Prenatal Care) between 15th and 21st (ideally up to 18th) week: 
    • Best option if the mother presents for prenatal care Prenatal care Prenatal care is a systematic and periodic assessment of pregnant women during gestation to assure the best health outcome for the mother and her fetus. Prenatal care prevents and identifies maternal and fetal problems that adversely affect the pregnancy outcome. Prenatal Care and is already in the 2nd trimester
    • Finding: unchanged/normal free estriol Estriol A hydroxylated metabolite of estradiol or estrogen that has a hydroxyl group at C3, 16-alpha, and 17-beta position. Estriol is a major urinary estrogen. During pregnancy, a large amount of estriol is produced by the placenta. Isomers with inversion of the hydroxyl group or groups are called epiestriol. Noncontraceptive Estrogen and Progestins, 𝛼-fetoprotein, inhibin A Inhibin A Glycoproteins that inhibit pituitary follicle stimulating hormone secretion. Inhibins are secreted by the sertoli cells of the testes, the granulosa cells of the ovarian follicles, the placenta, and other tissues. Inhibins and activins are modulators of follicle stimulating hormone secretions; both groups belong to the TGF-beta superfamily, as the transforming growth factor beta. Inhibins consist of a disulfide-linked heterodimer with a unique alpha linked to either a beta a or a beta B subunit to form inhibin a or inhibin b, respectively. Menstrual Cycle, and β-hCG
  • Full integrated test consists of: 
    • Combination of 1st trimester pregnancy-associated plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products protein-A and 2nd trimester quadruple test
    • Ultrasound FNT
  • Serum integrated test: full integrated test but without ultrasound FNT
  • Sequential Sequential Computed Tomography (CT) screening Screening Preoperative Care:
    •  1st trimester screening Screening Preoperative Care is performed and patient informed of the results
    •  Above a specified threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction, counseling is provided and diagnostic testing is offered.
  • Cell-free fetal DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure test:
    • Noninvasive procedure involving the fetus
    • May be performed anytime after 10 weeks of gestation
    • Fetal DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure is isolated from maternal blood and evaluated for chromosomal abnormalities.
    • May be more accurate and specific than traditional screening Screening Preoperative Care tests
    • Also tests for sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria of the baby
Table: Maternal screening Screening Preoperative Care during 1st and 2nd trimesters
1st trimester 2nd trimester
NT Pregnancy-associated plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products protein-A β-hCG AFP AFP The first alpha-globulins to appear in mammalian sera during fetal development and the dominant serum proteins in early embryonic life. Hepatocellular Carcinoma (HCC) and Liver Metastases Estriol Estriol A hydroxylated metabolite of estradiol or estrogen that has a hydroxyl group at C3, 16-alpha, and 17-beta position. Estriol is a major urinary estrogen. During pregnancy, a large amount of estriol is produced by the placenta. Isomers with inversion of the hydroxyl group or groups are called epiestriol. Noncontraceptive Estrogen and Progestins β-hCG Inhibin A Inhibin A Glycoproteins that inhibit pituitary follicle stimulating hormone secretion. Inhibins are secreted by the sertoli cells of the testes, the granulosa cells of the ovarian follicles, the placenta, and other tissues. Inhibins and activins are modulators of follicle stimulating hormone secretions; both groups belong to the TGF-beta superfamily, as the transforming growth factor beta. Inhibins consist of a disulfide-linked heterodimer with a unique alpha linked to either a beta a or a beta B subunit to form inhibin a or inhibin b, respectively. Menstrual Cycle
Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13 ↓↓ Unchanged Unchanged Unchanged Unchanged
Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 18 ↑↑ ↓↓ ↓↓ ↓↓ ↓↓ Unchanged
Trisomy 21 Trisomy 21 Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down syndrome (Trisomy 21) ↑↑ ↓↓
NT: nuchal translucency Nuchal translucency A prenatal ultrasonography measurement of the soft tissue behind the fetal neck. Either the translucent area below the skin in the back of the fetal neck (nuchal translucency) or the distance between occipital bone to the outer skin line (nuchal fold) is measured. Obstetric Imaging
β-hCG: β-human chorionic gonadotropin
AFP AFP The first alpha-globulins to appear in mammalian sera during fetal development and the dominant serum proteins in early embryonic life. Hepatocellular Carcinoma (HCC) and Liver Metastases: 𝛼-fetoprotein

Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests

  • Invasive diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests:
    • Indicated if: 
    • The risks include bleeding, infection, fetal injury, and rarely, fetal loss.
    • Procedures:
      • Chorionic villus sampling: Placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity samples are tested between the 10th and 13th weeks.
      • Amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios: Amniotic fluid Amniotic fluid A clear, yellowish liquid that envelopes the fetus inside the sac of amnion. In the first trimester, it is likely a transudate of maternal or fetal plasma. In the second trimester, amniotic fluid derives primarily from fetal lung and kidney. Cells or substances in this fluid can be removed for prenatal diagnostic tests (amniocentesis). Placenta, Umbilical Cord, and Amniotic Cavity is tested between the 15th and 20th weeks.
      • Percutaneous umbilical blood sampling: Umbilical cord Umbilical cord The flexible rope-like structure that connects a developing fetus to the placenta in mammals. The cord contains blood vessels which carry oxygen and nutrients from the mother to the fetus and waste products away from the fetus. Placenta, Umbilical Cord, and Amniotic Cavity blood is tested between the 18th and 22nd weeks. There is a 2% risk of fetal loss.
  • Fetal karyotyping Karyotyping Mapping of the karyotype of a cell. Chromosome Testing is a confirmatory test (can be done prenatally or postnatally).
Trisomy 13 karyotype

A karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System showing trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations of the 13th chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics (red arrow)

Image: “Figure 2” by Luiza E. Dorfman, et al AL Amyloidosis. 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 Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies and chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics studies on parents, especially if planning future pregnancies
  • Support resources (e.g., Support Organization for Trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations (SOFT))

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

  • 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 Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 18 or Edwards syndrome Edwards syndrome Edwards syndrome, or trisomy 18, is a genetic syndrome caused by the presence of an extra chromosome 18. The extra chromosome is either from 3 full copies of chromosome 18 or an additional segment of chromosome 18. As the 2nd most common trisomy, Edwards syndrome is seen in 1 out of every 5,500 live births. Edwards Syndrome (Trisomy 18): the presence of 3 copies of the 18th chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics. Many clinical findings of trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 18 overlap with those of trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13.
  • Pseudotrisomy 13: a rare autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder characterized by holoprosencephaly Holoprosencephaly Anterior midline brain, cranial, and facial malformations resulting from the failure of the embryonic prosencephalon to undergo segmentation and cleavage. Alobar prosencephaly is the most severe form and features anophthalmia; cyclopia; severe intellectual disability; cleft lip; cleft palate; seizures; and microcephaly. Semilobar holoprosencephaly is characterized by hypotelorism, microphthalmia, coloboma, nasal malformations, and variable degrees of intellectual disability. Lobar holoprosencephaly is associated with mild (or absent) facial malformations and intellectual abilities that range from mild intellectual disability to normal. Holoprosencephaly is associated with chromosome abnormalities. Development of the Nervous System and Face, associated midline facial abnormalities, polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn, and cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) abnormalities including atrial and ventricular septal defects. Antenatal diagnosis is by ultrasound. Like trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 13, pseudotrisomy 13 has a poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas.
  • Meckel-Gruber syndrome: a severe autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance developmental disorder caused by multiple genetic mutations Genetic Mutations Carcinogenesis. There is extensive clinical variability and controversy regarding the minimum diagnostic criteria. The presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor of Meckel-Gruber syndrome can include cystic Cystic Fibrocystic Change renal disease and CNS malformation, most commonly occipital Occipital Part of the back and base of the cranium that encloses the foramen magnum. Skull: Anatomy encephalocele Encephalocele Brain tissue herniation through a congenital or acquired defect in the skull. The majority of congenital encephaloceles occur in the occipital or frontal regions. Clinical features include a protuberant mass that may be pulsatile. The quantity and location of protruding neural tissue determines the type and degree of neurologic deficit. Visual defects, psychomotor developmental delay, and persistent motor deficits frequently occur. Neural Tube Defects and polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn. Genital abnormalities and pulmonary hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) (the common cause of fatality) are also observed.
  • Bardet-Biedl syndrome Bardet-Biedl syndrome An autosomal recessive disorder characterized by retinitis pigmentosa; polydactyly; obesity; mental retardation; hypogenitalism; renal dysplasia; and short stature. This syndrome has been distinguished as a separate entity from laurence-moon syndrome. Diabetes Insipidus: a genetic autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance condition owing to mutations in several genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure. Clinical manifestations include progressive visual impairment, polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn, truncal obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism, kidney abnormalities, and learning difficulties. 
  • Smith-Lemli-Opitz syndrome: a congenital Congenital Chorioretinitis syndrome caused by an abnormality in cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism metabolism resulting from deficiency of the enzyme, 7-dehydrocholesterol (7-DHC) reductase. Smith-Lemli-Opitz syndrome is characterized by growth restriction, microcephaly Microcephaly A congenital abnormality in which the cerebrum is underdeveloped, the fontanels close prematurely, and, as a result, the head is small. (desk reference for neuroscience, 2nd ed. ). Fetal Alcohol Spectrum Disorder, moderate-to-severe intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment, and multiple malformations. Malformations include distinctive facial features, cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy, cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) defects, underdeveloped external genitalia in men, postaxial polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn, and 2–3 syndactyly Syndactyly A congenital anomaly of the hand or foot, marked by the webbing between adjacent fingers or toes. Syndactylies are classified as complete or incomplete by the degree of joining. Syndactylies can also be simple or complex. Simple syndactyly indicates joining of only skin or soft tissue; complex syndactyly marks joining of bony elements. Development of the Limbs 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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