Glossary in Congenital Malformations

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General:

#Agenesis: the complete absence of an organ and its associated primordium.

#Agenesis of corpus callosum:

·         Clinical features: Agenesis of corpus callosum is often associated with marked ventricular dilatation and a large head.

·         Agenesis of the corpus callosum should be reserved to the cases when mechanism(s) by which the axons of the corpus callosum cross the midline in the usual position are absent of deficient (i.e., the agenesis is a primary event but not secondary to other damage or malformation of the neurons or axons up stream to the callosal axons). Probst bundle can be found.

Lipomas and hamartomas: The association of hamartomas and lipomas in some cases support the hypothesis that agenesis of corpus callosum in these cases may be resulted from disruption of outgrowth of corpus callosum by mechanical obstruction.

·         Since the corpus callosum develops in an anterior to posterior fashion, partial agenesis usually involves the posterior part while complete agenesis involves both anterior and posterior portions. If the anterior part of the corpus callosum is absent but the posterior part is present, a destructive mechanism should be seriously considerd. Complete or partial agenesis of the corpus callosum rarely exists as an isolated entity.

·         They are associated with many different malformations of the brain with Aicardi syndrome as the prototype. Agenesis of corpus callosum also has increased association with a midline mass such as lipoma, meningioma, cysts, and hamartoma. They also have increased association with visceral abnormalities.

·         Timing: critical event(s) must have happened no later than 9 to 20 weeks of gestation, the peak time of development of corpus callosum.

#Agenesis of cerebellar vermis: this term essentially means the absence of a cerebellar vermis or that the vermis is not separated from the cerebellar hemispheres. Developmental defects of the paleocerebellum predominantly involve the vermis. This includes several conditions:

·         Dandy-Walker malformations and its variants with partial or complete agenesis of the cerebellar vermis in combination with other malformations.

·         Rhombencephaloschisis: Total or subtotal agenesis of the vermis resulting in the two cerebellar hemispheres being separated by a deep midline cleft.

·         Rhombencephalosynapsis:

·         Major cerebellar abnormality: This is a relatively rare condition characterized by the cerebellar hemispheres being fused across the midline as one mass instead of being separated by either a vermis or a cleft.

·         Other cerebellar abnormalities have been described and include heterotopias, abnormal roof nuclei and fusion of the superior or inferior cerebellar peduncles.

·         Other brain stem abnormalities: fusion of the colliculi, atresia or dilatation of the fourth ventricle, and cranial nerve and inferior olivary nuclei abnormalities.

·         Cerebral abnormalities: hypoplasia of corpus callosum and septum pellucidum; hypoplasia of commissures, optic nerve and tracts; atresia of the third ventricles; fused thalami; hydrocephalus and abnormal gyri; diverticulum of the medial wall of the cerebral hemispheres, absence of the olfactory nerve and tracts; and fibrosis over the exit foramina.

·         Tectocerebellar dysraphia: Characterized by partial or total vermal agenesis, a severe deformation of the midbrain tectum and a cerebelloencephalocele. The occipital encephalocele contains cerebellar tissue with a severe malformation of the tectum. The vermis is either aplstic or represented by a rudimentary anterior portion. There are also other malformation of the cerebellum and the brain stem.

#Agnathia: congenital absence of the mandible.

#Agyria (Lissencephaly): (Liss-, Greek, smooth) Absence of gyri. See also pachygyria.

#Anencephaly: Congenital partial or complete absence of the cranial vault, with the cerebral hemispheres completely missing or reduced to small masses. Some of the calvarial bones are present but they are deformed, displaced, and flat. The skull base is covered by area cerebrovasculosa. The anterior and middle fossa contain no recognizable tissue except for the trigeminal ganglia and limited residual cranial nerve II to V. By definition, there is no membrane covering the brain or remnants thereof and calvarial bones are present. Incidence: Most common congenital malformation of the brain in human fetus.  Timing: the onset of anencephaly is estimated to be no later than 24 days of gestation.

·         Eye: eyes are usually of normal size. However, they appear protruded and give the typical frog face appearance due to the shallow orbits. The photoreceptor layer is complete and the inner nuclear layer contains a normal or reduced density of neurons. The ganglion cell layer shows moderate to total absence of neurons and the nerve fiber layer is hypoplastic. The optic nerve may be very hypoplastic and have prominent, vascularized fibrous septa. Most of them are not connecting with the brain at all.

·         Spinal cord: the pathology of the spinal cord can be quite variable. Abnormalies of the tracts and the level of conus medullaris may be abnormal. Loss of descending tracts in the spinal cord is common and probably secondary to the anencephaly.

·         Pituitary: the pituitary and the sella turcica are almost always present, albeit, markedly deformed. In most specimens, the pituitary is composed solely of the anterior lobe. Folliculostellate cells are not found [Coates PJ and Doniach I, 1988]. The pituitary stalk is almost always missing.

·         Adrenal glands: as a rule, the adrenal glands are extremely small. The cortex is atrophic and the medulla looks prominent, probably secondary to the small size of the cortex. Most likely, there are atrophic changes of both the fetal and permenant cortex. The size of the adrenal is age dependent. Until 20 weeks of gestation, the fetal cortex of the anencephalic has a normal histology. Beginning at about that time, the fetal zone undergoes progressive involution, so that in full-term fetus it is almost absent.

·         CV system: most cardiovascular changes are minor with no identifiable repetitive pattern of malformation.

·         Lung: the lung is hypoplastic.

·         GI tracts: a wide variety of malformations involve the gastrointestinal tract.

·         Diaphramatic hernia: increased incidence.

#Aneurysmal malformation of the great vein of Galen:  This is not a true aneurysm but a consortium of congenital vascular malformations of the neonate that all share dilatation of the vein of Galen as a common feature. It is resulted from abnormal communication between one or several cerebral arteries and the vein of Galen. Such abnormal communication can be deep-seated arteriovenous malformation, an arteriovenous fistula, or a verix. The prognosis and the baby often die of cardiac failure. Embolization appear to show some promise. Rupture is an uncommon event.  

#Anlage: (syn.primodium) an aggregation of cells in the embryo indicating the first trace of an organ or structure.

#Aplasia: the absence of an organ owing to failure of the developmental anlage to develop.

#Aplasia cutis congenita: this is a heterogenous condition recognized at birth on the basis or eroded, absent, or scarred areas of skin at birth. Can be further subtyped into different clinical variants. May combine with other abnormalities. It is a physical finding denoting only that a disruption of skin development has occurred in utero. Can occur in anywhere in the body, but 86% of the solitary lesions occur on the scalp. In severe cases, the calvarium is also missing. Must be distinguished from hypocalvaria/acalvaria cases where skin lesion is absent.

#Aplasia of the internal granular layer: A rare condition described in familial and sporadic forms. THe salient featues are ectopic internal granular cells, lost of granular cells, and relative preservation of Purkinje cells.  The major clinical findings are cerebellar ataxia, dysarthria, and mental retardation. Patients usually die in the first or second decade.  Aplasia of the internal granular layer is featured by an ectopic stratum of granular cells in the thinned molecular layer; a plexus of parallel fibers that is best demonstrated by silver stain or neuofilaments is present in the subpial molecular layer.  Ectopic Purkinje cells can also be seen in the molecular layer. his should be distinguished from primary atrophy of the internal granular layer which is characterized by lost of internal granular cells with preservation of the overall architecture.

#AprosencephalyAtelencephalon:

·         Aprosencephaly: This is the most severe form of holoprosencephaly. The entire prosencephalon (both telencephalon and diencephalon) fails to develop; the hindbrain is largely preserved. The calvarium is present and there is microcephaly. Both the telencephalon and diencephalon are absent and only a small remnant attached to the rudimentary brain stem is present. The diencephalic structures, the eyes, optic nerves, mamillary bodies, hypothalamus, and hypophysis are involved. Facial features are similar to that of holoprosencephaly. An intact, albeit microcephalic, cranial vault is present (otherwise it will be anencephaly or exencephaly). See also telencephalon. This is most likely resulted from a destructive process since there is often gliomesodermal tissue in the location of the cerebral tissue, often with microcalcification.

·         Atelencephaly: The entire cerebral cortex, basal ganglia, and ventricles are absent.

#Area cerebrovasculosa: The mass of dark reddish irregular tissue attached to the base of the cranium in anencephaly. The mass is cystic and contains CSF; with a midline dorsal aperture opening to the exterior. It is composed of vascular tissue with multiple cavities containing CSF. There are also irregular masses of neural tissue, mainly glia with some neuroblasts or neurons, ependymal and tufts of choroid plexus and numerous thin-walled blood vessel.

#Area medullovasculosa: In meningomyelocele, the spinal cord at the site of the bony defect forms a flat discoidal, highly vascular mass, the area medullovasculosa, which become epithelialized after birth. It is composed of highly vascular connective tissue admixed with neurons, glia, and ependyma.

#Arthrogryposis: Persistent flexure of a joint.

#Arthrogyrposis multiplex congenita: This term refer to a heterogeneous group of conditions that share the common feature of congenital immobilization of several joints. There are multiple fixed joint contractures at more than one level, excluding talipes equinovarus in meningomyelocele. Arthrogyrposis form in betwen the 12th week of development and birth. Most cases of neruogenic origins, a few are myogenic. Neurogenic causes include a wide variety of malformations and acquired destructive lesions.  Most cases are sporadic but autosomal recessive, autosomal dominant, and X-linked forms have all been reported. Involvement is variable; it can be diffuse or localized. The most common one is Pena-Sokeir syndrome. [Lebenthal E et al., Arthrogryposis multiplex congenita- 23 cases in an Arab kindred”. Pediatrics 1970 46:891-899]

#Association: occurrence of a nonrandom combination of multiple abnormalities.

·         CHARGE association: coloboma, heart disease, atresia choanae, and retarded growth and development. Other associated abnormalities include holoprosencephaly, genital and ear anomalies, tracheoesophageal fistula, facial palsy, micrognathia, cleft lip, cleft palate, omphalocele, and congenital cardiac defects.

·         MURCS association: mullerian duct aplasia, renal aplasia, and cervicothoracic somite malformation, which cause cervicothoracic vertebral defects, especially from C5 to T1.

·         VATER association (aka. VACTERL association): Frequently seen in stillborns, especially infants of diabetic mothers. The may also be hydrocephalus.

·         Vascular (75%): VSD, ASD, tetralogy of Fallot, patent ductus arteriosus

·         Vertebral (60%): hemivertebrae or absent pedicles.

·         Anus (60%): imperforate

·         Tracheo-Esophageal fistula (60%)

·         Renal (75%): hydronephrosis, agenesis, horseshoe kidney

·         Radius (45%): hypoplastic radii and/or thumbs.

#Atavisms: a (rudimentary) development of anatomic structure known or presumed to have been present in a phylogenetic ancestor and homologous to that observed in a living relative (e.g., the appearance of legs in whales).

#Atresia: absence of an opening, usually of a hollow visceral organ.

#Atresia of 4th ventricle: the fourth ventricle is replaced by multiple small ependymal channels and masses of primitive cells and disarryed cerebellar cortex replacing the normal cerebellum. They are combined with other cerebral malformation frequently. This should be regarded as a diffuse abnormality affecting the cerebellum rather than isolated malformation of the fourth ventricle. 

Syndromes and Sequences:  Head

#Aicardi Syndrome: This is essentially a migration disorder.

·         Genetics: ·         Aicardi syndrome is an X-linked dominant disorder (gene on Xp22) and found in females. (Fatal in males?)

·         Clinical: Aicardi syndrome consists of infantile spasm associated with mental retardation, chorioretinal "lacunae" that are often associated with retinal coloboma and micro-ophthalmia, vertebral anomalies, and complete or partial agenesis of the corpus callosum. Imaging techniques may reveal heterotopia and other evidence of a migration disorder. Vertebrocostal abnormalities are present in half of the cases. The outcome is poor.

·         Pathology: It is characterized by heterotopia and polymicrogyria of the unlayered type, agenesis of corpus callosum (an inconstant feature), and eye lesions (choroid cyst). Ependymal cysts are frequently found around the third ventricle and may reach a large size.

#Amnion rupture sequence: This is an umbrella term that covers three very similar but overlapping conditions namely amniotic band syndrome, amniotic adhesion sequence, and limb-body wall complex. They are probably disruptive sequences secondary to vascular disruption or tissue necrosis and adhesion. The spectrum of pathology includes encephalocele and defects of cranium, cleft palates and other facial abnormalities, autoamputation of digits and limbs, and body wall defects with anomalies of internal organs. The brain is usually normal but cases with developmental abnormalities have also been reported. Karyotypes of affected individuals are normal.

·         Amniotic adhesion: condition where parts of the fetus and placenta, usually the head and amnion, adhere to each other.

·         Amniotic band: amniotic bands are threads or strings formed from amnion that has ruptured. They can encircle various embryonic fetal parts and cause disruptions.

·         Limb-body-wall complex: this is a complex malformation that consists of two or three of the following: exencephaly or encephalocele with facial clefts, thoracic or abdominal schisis, and limb defects; there is a short umbilical cord and a single umbilical artery.

·         There are two different kinds of craniofacial anomalies, one probably due to the frontonasal dysplasia sequence and the other to asymmetrical lateral facial clefts of various types.

#Andermann Syndrome: Autosomal recessive. The cardinal clinical features include mental retardation and progressive sensorimotor neuropathy, and anterior horn cell disease. There is a characteristic square facies. Hypotonia and areflexia occur and are secondary to the neuropathy. There is complete or partial agenesis of corpus callosum in over half of the cases. Vesicular axonal swellings are present in white matter. Nerve roots contain focal axonal swelling up to 120 micron. Myelin sheaths are absent or thin. Numerous onion bulbs are also noted. Anderman syndrome is seen in French Canadians in the Lake St. John region.

#Angelman syndrome: Angelman syndrome is also known as the "Happy puppet syndrome". These patients are happy, frequently simile and with paroxysms of laughter. They also have unusual but characteristic posture characterized by flexion at the wrists and elbows when the arms are raised such that they resemble on a string. Clinically the patients have developmental delay and severe mental retardation, ataxia, seizure, hypotonia, postnatally developing microbrachyencephaly, and a characteristic facial appearance with macrostomia and prognathia. Abnormalities in the cerebrum have been revealed by Golgi impregnantation but very few cases have been studied histologically.

#Anormalous axonal connection (guidance) syndromes: This is a group of syndromes characterized by anormalous axonal connections. They includes ocular miswiring in albinism (oculocutaneous albinism), the gustolacrimal reflex (“crocodile tears”), Marcus Gunn jaw-winking phenomenon, Duane’s syndrome and possibly Wildvanck syndrome.

#Apert Syndrome (Type I acrocephalosyndactyly): The cardinal feature of Apert syndrome is craniosynostosis.

·         Genetics: They almost always result from a new dominant mutation. This disorder is allelic to Crouzon disease and due to different mutation of the FGFR2 gene (fibroblast growth factor receptor 2 gene) on chromosome 10q25-26. [Wilkie AOM et al., Nature Genetics 1995 9:165-172]

·         Clinically characteristized by craniosynostosis with facial malformation and syndactyly.

·         CNS malformations: Different types of malformation of the brain including occipital encephalocele and partial or complete agenesis of the corpus callosum may be seen. There may also be gyral abnormalities, megalencephaly, progressive hydrocephalus had non-progressive ventriculomegaly, absent of olfactory tracts and bulbs, malformation of midline thalamic structures, and others.

#Arnold-Chiari Syndrome: Chiari type II malformation associated with meningocele or meningomyelocele. See Chiari malformatsions.

#Ataxia-telangiectasia syndrome (also known as Louis-Bar syndrome, or Boder-Sedgwick disease): Autosomal recessive. Ataxia-telangiectasia is classified as a chromosome instability syudrome. Chromosome aberrations are frequent (but less frequent than in Bloom syndrome or Faconi syndrome). Random breakage apparently often leads to cell clones with a translocation, involving chromosome 14 in most cases. A characteristic translocation is t(14;14)(q12;q32). The ataxia telangiectasia gene is located on chromosome 11q22-23. Characterized by progressive cerebellar ataxia with progressive loss of Purkinje cells, conjunctival and other facial telangiectases, severe immunodeficiency with anomalies in the immunoglobulins (especially IgA), hypersensitivity to the effects of radiation and a tendency to develop lymphoid tumors. The risk for solid tumors, lymphocytic leukemias, and non-Hodgkin's lymphoma is greatly increased.

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