Chromosomal and monogenic diseases
Fetal genetic anomalies are divided into chromosomal (changes in chromosome number or structure) and monogenic (mutations in specific genes inherited according to Mendelian laws).
Key chromosomal pathologies include:
- Patau syndrome and Edwards syndrome (trisomy 18): accompanied by multiple malformations (heart, bones, skull) and marked hypotrophy. The prognosis is unfavorable, resulting in death in the first weeks or months of life.
- Turner syndrome (monosomy 45,X0): the only form of monosomy in live-born girls (incidence up to 5.5 per 10,000). In newborns, it manifests as a short webbed neck and lymphedema of the extremities. In older age, short stature, ptosis, gonadal dysgenesis, primary amenorrhea, and infertility are characteristic. One-quarter of patients exhibit heart and kidney malformations.
Monogenic diseases (over 5,000 types are known) are most commonly inherited in an autosomal dominant manner. The main representatives include:
- Phenylketonuria: deficiency of the enzyme phenylalanine hydroxylase (chromosome 12). Children are healthy at birth, but upon ingestion of phenylalanine from breast milk, they develop seizures, hypertonia, a "mousetrap" odor, and later microcephaly and intellectual disability.
- Cystic fibrosis: a mutation in chromosome 7 disrupts chloride and sodium ion transport, causing hypersecretion of thick mucus in the bronchi, gastrointestinal tract, and pancreas.
- Connective tissue disorders: Marfan syndrome (lens dislocation, skeletal and vascular anomalies) and Ehlers-Danlos syndrome (impaired collagen synthesis, tissue hyperextensibility).
- X-linked disorders: Duchenne muscular dystrophy (dystrophin deficiency, muscle necrosis) and hemophilia A (factor VIII deficiency, impaired coagulation).
Polygenic diseases and CNS malformations
Polygenic pathologies arise from the interaction of allele combinations and exogenous factors. They do not follow Mendelian laws, and genetic risk is calculated using empirical tables. The most frequent group of such anomalies is CNS malformations (neural tube defects), which form before the 28th day of gestation.
Risk factors include diabetes mellitus, maternal hyperthermia, exposure to teratogens (valproic acid, methotrexate), and chromosomal anomalies.
Main nosologies:
- Anencephaly: absence of the cerebral hemispheres and cranial vault due to failure of the anterior neuropore to close at 3–4 weeks. Incidence is 1:1000. The defect is absolutely lethal; pregnancy termination is indicated. (It is differentiated from acrania, which is the absence of vault bones with a preserved brain).
- Cephalocele: herniation of the meninges through a cranial defect. If brain tissue is present in the hernial sac, the pathology is called encephalocele.
- Spina bifida (Spina bifida): a neural tube closure defect, most commonly in the lumbosacral region.
- By content: meningocele (meninges only) and meningomyelocele (with neural tissue).
- By form: Spina bifida cystica (with a visible hernial sac) and Spina bifida occulta (hidden form).
Separately, hydrocephalus (ventricular dilation with increased intracranial pressure and head enlargement due to impaired CSF outflow) and ventriculomegaly (isolated ventricular dilation) are distinguished. In hydrocephalus without associated anomalies, in utero shunting is possible.
Facial and chest anomalies
Facial structural anomalies form at 4–10 weeks of gestation due to incomplete fusion of the frontonasal and maxillary prominences. The most common variant is cleft lip combined with cleft palate. The risk increases with maternal diabetes and the use of alcohol or phenytoin. Diagnosis requires 3D ultrasound and mandatory karyotyping.
Thoracic organ malformations:
- Congenital diaphragmatic hernia: a defect in the closure of the pleuroperitoneal canal. Abdominal organs displace into the chest cavity, compressing the lungs and causing hypoplasia. In utero surgical correction is possible, but strictly before the end of the second trimester.
- Congenital cystic adenomatoid malformation (hamartoma): a cystic or solid mass in the lungs, often accompanied by fetal hydrops. For large cysts, thoracoamniotic shunting is performed.
- Pulmonary sequestration: a segment of the lung develops separately from the airways and receives its blood supply from an aberrant vessel originating directly from the aorta. Treatment consists of postnatal segmentectomy or lobectomy.
Briefly: answers to topical questions
What anatomical forms of pulmonary sequestration exist?
- Intralobar (intralobar) — the separated segment is located within the lobe, and its isolation from the lung parenchyma is impossible.
- Extralobar (extralobar) — the sequestered part has its own vessel originating directly from the aorta, and venous drainage goes into the systemic venous system.
Which specific genes are mutated in Marfan syndrome and Ehlers-Danlos syndrome?
- Marfan syndrome — mutations in the FBN1 gene, and in 5% of cases, mutations in the COL1A2 gene are detected.
- Ehlers-Danlos syndrome — pathogenesis is associated with impaired collagen synthesis due to mutations in various collagen genes; in the vascular type (type IV), mutations in the COL3A1 and COL1A2 genes are identified.
What specific malformations are characteristic of Patau syndrome?
- CNS — microcephaly, arhinencephaly, holoprosencephaly, aplasia and hypoplasia of the corpus callosum and cerebellum.
- Eyes — microphthalmia, retinal dysplasia, iris and choroidal colobomas, lens malformations, cartilage ectopia.
- Kidneys — excessively lobulated microcystic kidney, which is a characteristic sign of this syndrome.
- Face and skeleton — cleft lip or palate, polydactyly, and congenital heart defects.
What are the selection criteria and indications for in utero surgical correction of congenital diaphragmatic hernia?
In congenital diaphragmatic hernia, indications for in utero surgical correction include a normal fetal karyotype and the absence of associated anomalies. The main selection criteria is that the intervention must be performed strictly no later than the second trimester of pregnancy.
To remember Spina bifida forms: Occulta — Out (sac absent/hidden form), Cystica — Complete sac outside (cystic form).
Class and exam questions
What is the difference between hydrocephalus and ventriculomegaly?
In hydrocephalus, the cerebral ventricles enlarge against the background of increased intracranial pressure, leading to an increase in the fetal head size. Ventriculomegaly is an isolated ventricular enlargement without changes in skull size.
When and why does phenylketonuria manifest?
Children with phenylketonuria appear visually healthy at birth. The disease manifests in the first weeks of life when phenylalanine begins to enter the child's body via breast milk and cannot be metabolized due to enzyme deficiency.
What is the obstetric management when anencephaly is detected?
Anencephaly is classified as an absolutely lethal malformation. Upon confirmation of this diagnosis, pregnancy termination is strongly recommended to the woman.
What else to study on this topic
- Pathogenesis and forms of adrenogenital syndrome (21-hydroxylase deficiency)
- Ultrasound diagnosis of Spina bifida and hydrocephalus in the II–III trimesters
- Clinical manifestations of myotonic dystrophy and neurofibromatosis
- Techniques for in utero surgical correction of diaphragmatic hernia
- Differential diagnosis of pulmonary sequestration using color Doppler flow imaging
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