Central nervous system malformations can be divided into 4 groups:
1. Neural tube defects and associated spinal cord malformations
2. Disturbances in structural differentiation (gray matter anomalies, neuronal migration disorders)
3. Disorders of the posterior fossa, brain stem and cerebellum
4. Developmental disorders of the brain and skull
Although these disorders are part of any syndrome, they can also be associated with non-syndromic or single gene disorders.
Neural Tube Defects
• Neural tube defects are malformations of the developing brain and spinal cord. occur in weeks 3 and 4 of pregnancy.
• These defects often show transition with multifactorial inheritance type.
o Folic acid deficiency is one of the leading causes.
o Other causes include hyperthermia, drugs such as valproic acid, malnutrition, maternal vitamin B12 deficiency.
• A-fetoprotein (AFP) and acetylcholine esterase (more specific) elevations in maternal serum and amniotic fluid are important in prenatal diagnosis. Early diagnosis can also be made by fetal ultrasonography.
• Since the best known risk factor is folate deficiency, starting before conception and giving 0.4 mg/day folate for the first 12 weeks after conception reduces the risk.
In the presence of additional risk factors (family history/use of valproic acid), the dose is increased to 4 mg/day.
Encephalocele
• It is the herniation of the brain tissue out of the cranium. It is most common in the occipital region.
Anencephaly
• It is the closure defect in the anterior upper region of the neural tube. It is the most severe form of neural tube defect.
Spina Bifida
• It is the type that has closure defect in L5-S1 only radiologically and does not show clinical findings. There may be hair growth and dermal sinus on the defect.
• In case of detection of some of the skin lesions accompanying spine bifida ocuta, there is an indication for imaging, especially with ultrasonography. Ultrasonography is the screening method in the neonatal period, but MRI is the best examination in all or groups.
Meningocele
Meningomyelocele
Diastometamilia
Tethered Cord (Tethered Spinal Cord Syndrome)
Syringomyelia
Sacral Dysnesia
• It is seen in 1% of children of diabetic mothers. The most important neurological disorders are urinary incontinence and muscle weakness in the lower extremities. Treatment is symptomatic.
Neurodermal Sinus
• It does not often cause any neurological problems. Despite this, early detection and closure is necessary, as the mass may expand from the skin to the spinal cord and cause recurrent meningitis.
Additional Anomalies That Can Accompany Neural Tube Defects
Arnold-Chiari Malformation
• It is the downward herniation of the medullary and cerebellar tissue from the foramen magnum to the cervical vertebrae. This condition is often accompanied by a meningomyelocele.
Chiari Type-1 is an isolated protrusion of cerebellar tissue. Chiari Type-2 has meningomyelocele in addition to Type-1 and hydrocephalus also occurs. In addition to these defects, Chiari Type-3 has "cranium bifidum anomaly".
Dandy-Walker Malformation
• Cystic enlargement of the 4th ventricle with obstructive hydrocephalus secondary to block and atresia of the foramen Magendi and foramen Luschka. A shunt attempt is almost always required.
Joubert Syndrome
• Being an autosomal recessive disease, significant genetic heterogeneity is also dominant.
In Joubert syndrome, it is characterized by hypoplasia of the cerebellar vermis, brain tomography in the pontomesencephalic region and molar finding on brain MRI. Other clinical findings are hypotonia, ataxia starting in infancy, episodic apnea and hyperpnea, neuromotor developmental delay, nystagmus, strabismus, and oculomotor apraxia.
Pontocerebellar hypoplasia
• It is a group of diseases characterized by developmental disorders of the cerebellar and pons.
• Clinical findings are nonspecific, hypotonia, feeding difficulties, growth retardation, respiratory distress may be seen.
• Pontocerebellar hypoplasia type 1 (anterior horn involvement)-2 (acquired microcephaly+extra pyramidal finding), Walker-Warburg syndrome, Muscle-eye-brain disease, congenital glycosylation defect type 1A, mitochondrial cytopathies, congenital CMV infection, 3-methylglutaric aciduria, PEHO syndrome (progressive encephalopathy, edema, hypsarrhythmia, optic atrophy) are some pontocerebellar hypoplasia syndromes.
Meckel-gruber syndrome, Rhombencephalosyniasis, and Lhermite duclos disease are other diseases accompanying neural tube defects.
Anterior Midline Defects
• Also known as holoprosencephaly. Infants of diabetic mothers and Trisomy 13 are causes of holoprosencephaly. May cause hypothalamus and single ventricular hypoplasia. Disturbances of thermoregulation in the form of central fever, symptoms such as apnea and severe psychomotor retardation suggest anterior midline defect.
Skull Base Developmental Anomalies
platybasi
• It is the upward displacement of the skull base. It causes narrowing of the foramen magnum. Because of cervical cord compression, spasticity in the lower extremities, pain in the arms and weakness in the proximal arm muscles occur. The treatment is surgical decompression.
Klippel-Feil Syndrome
• It occurs as a result of the absence or fusion of several cervical vertebral bodies.
Symptoms are similar to those seen in platibaside. It is mostly seen with anomalies such as genitourinary anomalies, spina bifida, syringomyelia, sensorineural hearing loss, scoliosis, sprengel deformity and congenital heart disease.
Cellular Migration and proliferation disorders
• Although they can be seen as a result of toxic substance (alcohol, phenytoin) intake during pregnancy as well as chromosomal or other genetic anomalies, they can also occur due to an unknown reason.
Agenesis of the Corpus Callosum (CCA)
• It can manifest itself clinically with seizures and severe mental retardation, or it can be completely asymptomatic.
• Colpocephaly is an abnormal enlargement of the occipital horns of the ventricular system and often accompanies agenesis of the corpus callosum. It is also associated with microcephaly and Sotos syndrome with megancephaly.
• Some important accompanying diseases;
- Trisomy 8, 18
- Aicardi syndrome (CCA, chorioretinal lacunae, infantile spasm, mental retardation)
- Pyridoxine-dependent epilepsy
- Pyruvate dehydrogenesis deficiency/Pyruvate decarboxylase deficiency
- Vici syndrome (CCA, albinism, recurrent infections, mental retardation)
- Meckel-Gruber syndrome (CCA, encephalocele, polydactyly, polycystic kidney)
- Rubinstein-Taybi syndrome (large thumbs and big toes, mental retardation, microcephaly, CCA)
- Sotos syndrome (physical overgrowth, mental retardation, craniofacial changes, CCA)
- Nonketotic hyperglycinemia (CCA, cerebral and cerebellar atrophy, myoclonus, progressive encephalopathy)
Hydranencephaly
• It is the event of severe necrosis of the cerebral cortex and accumulation of CSF occurring in the uterus. The midbrain and brainstem are preserved. The etiology is not completely clear.
It can cause migration disorder and bilateral internal carotid artery occlusion.
After the first year of life, the survival rate is low.
• May be related to fetal stroke, most commonly associated with deceased twin partner.
Megalencephaly
• It is an anatomical developmental brain anomaly in which the brain volume is >98% or >2 standard deviations for age. It is often accompanied by macrocephaly. It is closely related to storage diseases and degenerative diseases. The most common form is benign familial megalencephaly. It is quickly diagnosed with a family history.
• It is associated with many prenatal postnatal somatic overgrowth syndromes such as Sotos, Simpson-Golabl-Behmel, fragile X, Weaver, macrocephaly-cutis marmorata telangiectatica congenita. In addition, it can be seen in metabolic diseases such as Alexander, Canavan, Tay Sachs, Gangliosidosis, MSUD and MLD.
• The most common megalencephalic syndrome is Sotos syndrome (cerebral gigatism). Macrocephaly is also present in the prenatal period in 50% of patients with Sotos syndrome. 100% of patients are diagnosed with macrocephaly up to 1 year of age. Early postnatal overgrowth normalizes towards adulthood. It is characterized by frontal bossing, hypertelorism, downward localization of the palpebral fissures, long flat face type, and flushing in the malar region. In addition, hypotonia, speech, mental and neural developmental retardation are frequently observed in these patients.
Lissencephaly
• Absence of cerebral sulci, underdeveloped sylvian fissures with large ventricles. It occurs as a result of migration defect.
• There are growth retardation, microcephaly and severe convulsions.
• Miller-Dieker syndrome and Walker-Warburg syndrome are the most important syndromes in which lissencephaly is seen.
Schizencephaly
• Unilateral or bilateral clefts in the cerebral hemispheres. Often there is microgyri.
• There are microcephaly, spastic quadriparesis, severe mental retardation and convulsions.
Schizencephaly is also a neuronal migration defect.
• Unilateral schizencephaly is among the common causes of congenital hemiparesis.
Porencephaly
• There are cysts and cavities in the parenchyma. It is a migration defect.
• Identified risk factors for porencephalic cyst formation;
- Hemorrhagic venous infarct
- Various thrombophilia states (protein C deficiency, factor V Leiden mutation)
- Perinatal alloimmune thrombocytopenia
- Von Willebrand's disease
- Use of maternal warfarin
- Maternal cocaine use
- Congenital infections
- Traumatic conditions such as maternal abdominal trauma and amniocentesis
• Familial porencephaly has been described with the COL 4Al mutation.
• Pseudopoencephalic cysts may occur secondary to problems experienced in the perinatal/postnatal period. These are not migration defects. It may present with focal seizures, limp baby, hemiparesis, and sometimes neonatal encephalopathy in the first year of life.
Holoprosencephaly
• It is the defect of the cleft of the forebrain.
• Severe types, which have never been separated into brain lobes, have a high risk of mortality, rarely living for a few years. However, the morbidity and mortality risk is low in mild types.
• It is common in infants of diabetic mothers, Trisomy 13 and 18. In addition, mutations in the 7q region are thought to be related.
Polymicrogyry
• It is the representation of the underdeveloped cortex with many small gyri.
• Drug-resistant forms of epilepsy can be seen.
Cranial Nerve Anomalies
Mobius Syndrome
• With bilateral facial paralysis, n. abducens paralysis also occurs. Rarely, III, V, IX and XII may also be affected.
• If there is pectoral muscle hypoplasia, it is called "Poland-Möbius syndrome".
De Morsier Syndrome
• Optic nerve hypoplasia with septooptic dysplasia. The HESXl gene mutation is thought to be responsible.
Microcephaly
Microcephaly is the head circumference below 3 standard deviations according to age and gender. Many diseases can be involved in the etiology. Basically, it is examined in two groups as primary and secondary.
In the table, the causes of microcephaly are written. In addition to the table, acquired microcephaly can be seen in syndromes with Rett syndrome, Seckel syndrome, Angelman syndrome and encephalopathy.
Causes of microcephaly
PRIMARY
• Familial microcephaly (Autosomal recessive, severe mental retardation and seizures are seen)
Autosomal dominant (mild-borderline mental retardation, controllable seizures, linear growth normal)
Syndromes
• Down syndrome
• Edward's syndrome
• Cri-du-chat (5p-)
• Cornela de Lange
• Rubinstein-Taybi
• Smith-Lemli-Opitz
SECONDARY
Congenital infections
• CMV
• Rubella
• Toxoplasma
• Zika virus
Medicines
• Fetal alcohol
• Fetal hydantoin
Other
• Radiation
• Meningitis/encephalitis
• Malnutrition
• Metabolic
• Hyperthermia
• Hypoxic ischemic encephalic allopathy
Craniosynostoses
• Premature closure of cranial sutures. Most of the cases are sporadic. It is accompanied by genetic syndromes in 10-20% of cases.
• Scaphocephaly is the most common craniosynostosis. The sagittal suture is closed. It has a head structure that is elongated towards the back and pressed from the sides. The anterior fontanelle is small or closed.
• Since it accompanies the syndromes, the genetic basis of this condition has been investigated and the FGFR gene family (most frequently FGFR2 mutation) has been found to be associated. Among the syndromic craniosynostoses, only craniofrontonasal dysplasia shows X-linked transmission.
• Untreated maternal hyperthyroidism can also cause craniosynostosis.
common craniosynostoses
- Suture : sagittal
Deformity: Dolichocephaly or scaphocephaly (most common)
Clinic: Frontal bossing, prominent occiput, occipital frontal measurement is normal and decreased biparietal diameter
- Suture: Coronal
Deformity: Unilateral: Plagiocephaly , Bilateral: brachycephaly, acrocephaly
Clinical: Bilateral Apert and Crouzon syndrome
- Suture : Lambdoid
Deformity: Lambdoid / occipital plagiocephaly
Clinic: Bilateral lower located ear
- Suture : Metopic
Deformity: Trigonocephaly
Clinic: Hypotelorism
- Suture: Multiple
Deformity: Oxycephalus
Clinic: Tower head, increased intracranial pressure
Some syndromes associated with craniosynostosis
- Antler-Bixler syndrome
- Apert syndrome (coronal suture)
- Beare-Stevenson syndrome
- Baller-Gerold syndrome
- Carpenter's syndrome
- Craniofrontonasal dysplasia
- Crouzon syndrome (coronal suture)
- Crouzonomesodermoskeletal syndrome
- Jackson-Weiss syndrome
- Muenke syndrome
- Pfeiffer syndrome
- Saethre-Chotzen syndrome
- Shprintzen-Goldberg syndrome
