The blockage of cerebrospinal fluid (CSF) flow may also cause a syrinx to form, eventually leading to syringomyelia. Central cord symptoms such as hand weakness, dissociated sensory loss, and, in severe cases, paralysis may occur.

Syringomyelia is a chronic progressive degenerative disorder characterized by a fluid-filled cyst located in the spinal cord. Its symptoms include pain, weakness, numbness, and stiffness in the back, shoulders, arms or legs. Other symptoms include headaches, the inability to feel changes in the temperature, sweating, sexual dysfunction, and loss of bowel and bladder control. It is usually seen in the cervical region but can extend into the medulla oblongata and pons or it can reach downward into the thoracic or lumbar segments. Syringomyelia is often associated with Chiari malformation type I and is commonly seen between the C-4 and C-6 levels. The exact development of syringomyelia is unknown but many theories suggest that the herniated tonsils in Chiari malformation type I form a "plug" which does not allow an outlet of CSF from the brain to the spinal canal. Syringomyelia is present in 25% of patients with Chiari malformation.

The key features of this syndrome are an enlargement of the fourth ventricle; complete absence of the cerebellar vermis, the posterior midline area of cerebellar cortex responsible for coordination of the axial musculature; and cyst formation near the internal base of the skull. An increase in the size of the fluid spaces surrounding the brain as well as an increase in pressure may also be present. The syndrome can appear dramatically or develop unnoticed.

Symptoms, which often occur in early infancy, include slower motor development and progressive enlargement of the skull. In older children, symptoms of increased intracranial pressure such as irritability, vomiting, and convulsions and signs of cerebellar dysfunction such as unsteadiness and lack of muscle coordination or jerky movements of the eyes may occur. Other symptoms include increased head circumference, bulging at the back of the skull, problems with the nerves that control the eyes, face and neck, and abnormal breathing patterns.

Dandy–Walker syndrome is frequently associated with disorders of other areas of the central nervous system including absence of the corpus callosum, the bundle of axons connecting the two cerebral hemispheres, and malformations of the heart, face, limbs, fingers and toes.

The Dandy–Walker complex is a genetically sporadic disorder that occurs one in every 30,000 live births. Prenatal diagnosis and prognosis of outcomes associated with Dandy–Walker can be difficult. Prenatal diagnosis is possible with ultrasound. Because the syndrome is associated with an increased risk for fetal karyotype abnormalities, amniocentesis can be offered after prenatal diagnosis. There is a relative contraindication of taking Warfarin during pregnancy, as it is associated with an increased risk of Dandy–Walker syndrome if taken during the first trimester.

The DWS malformation is the most severe presentation of the syndrome. The posterior fossa is enlarged and the tentorium is in high position. There is complete agenesis of the cerebellar vermis. There is also cystic dilation of the fourth ventricle, which fills the posterior fossa. This often involves hydrocephalus and complications due to associated genetic conditions, such as Spina Bifida.

Classification systems for malformations of the cerebellum are varied and are constantly being revised as greater understanding of the underlying genetics and embryology of the disorders is uncovered. A classification proposed by Patel S in 2002 divides cerebellar malformations in two broad groups; those with cerebellar hypoplasia and; those with cerebellar dysplasia.

- I. Cerebellar hypoplasia

- A. Focal hypoplasia

- 1. Isolated vermis

- 2. One hemisphere hypoplasia

- B. Generalized hypoplasia

- 1. With enlarged fourth ventricle (“cyst,”), Dandy-Walker continuum

- 2. Normal fourth ventricle (no “cyst”)

- a. With normal pons

- b. With small pons i. Normal foliation

- a) Pontocerebellar hypoplasias of Barth, types I and II

- b) Cerebellar hypoplasias, not otherwise specified

Macrocephaly-capillary malformation (M-CM) is a multiple malformation syndrome causing abnormal body and head overgrowth and cutaneous, vascular, neurologic, and limb abnormalities. Though not every patient has all features, commonly found signs include macrocephaly, congenital macrosomia, extensive cutaneous capillary malformation (naevus flammeus or port-wine stain type birthmark over much of the body; a capillary malformation of the upper lip or philtrum is seen in many patients with this condition), body asymmetry (also called hemihyperplasia or hemihypertrophy), polydactyly or syndactyly of the hands and feet, lax joints, doughy skin, variable developmental delay and other neurologic problems such as seizures and low muscle tone.

Non-progressive early onset ataxia and poor motor learning are the commonest presentation.

Cerebellar agenesis is a rare condition in which a brain develops without the cerebellum. The cerebellum controls smooth movement, and when it does not develop, the rest of the brain must compensate, which it cannot do completely. The condition is not fatal on its own, but people born without a cerebellum experience severe developmental delays, language deficits, and neurological abnormalities. As children with cerebellar agenesis get older, their movements usually improve. It can co-exist with other severe malformations of the central nervous system, like anencephaly, holoprosencephaly, and microencephaly.

The condition was first reported in 1831. 10 cases had been reported as of 1998. Agenesis of one half or another part of the cerebellum is more common than complete agenesis.

Cerebellar agenesis can be caused by mutations in the PTF1A gene.

Congenital hydrocephalus is present in the infant prior to birth, meaning the fetus developed hydrocephalus in utero during fetal development. The most common cause of congenital hydrocephalus is aqueductal stenosis. Aqueductal stenosis occurs when the narrow passage between the third and fourth ventricles in the brain is blocked or too narrow to allow sufficient cerebral spinal fluid to drain. Fluid accumulates in the upper ventricles, causing hydrocephalus.

Other causes of congenital hydrocephalus include neural tube defects, arachnoid cysts, Dandy-Walker syndrome, and Arnold-Chiari malformation.

The cranial bones fuse by the end of the third year of life. For head enlargement to occur, hydrocephalus must occur before then. The causes are usually genetic but can also be acquired and usually occur within the first few months of life, which include 1) intraventricular matrix hemorrhages in premature infants, 2) infections, 3) type II Arnold-Chiari malformation, 4) aqueduct atresia and stenosis, and 5) Dandy-Walker malformation.

In newborns and toddlers with hydrocephalus, the head circumference is enlarged rapidly and soon surpasses the 97th percentile. Since the skull bones have not yet firmly joined together, bulging, firm anterior and posterior fontanelles may be present even when the patient is in an upright position.

The infant exhibits fretfulness, poor feeding, and frequent vomiting. As the hydrocephalus progresses, torpor sets in, and the infant shows lack of interest in their surroundings. Later on, the upper eyelids become retracted and the eyes are turned downwards ("sunset eyes") (due to hydrocephalic pressure on the mesencephalic tegmentum and paralysis of upward gaze). Movements become weak and the arms may become tremulous. Papilledema is absent but there may be a reduction of vision. The head becomes so enlarged that the child may eventually be bedridden.

About 80-90% of fetuses or newborn infants with spina bifida—often associated with meningocele or myelomeningocele—develop hydrocephalus.

This condition is acquired as a consequence of CNS infections, meningitis, brain tumors, head trauma, toxoplasmosis, intracranial hemorrhage (subarachnoid or intraparenchymal) and is usually painful.

Microlissencephaly Type B or Barth microlissencephaly syndrome: is a microlissencephaly with thick cortex, severe cerebellar and brainstem hypoplasia. The Barth-type of MLIS is the most severe of all the known lissencephaly syndromes.

This phenotype consists of polyhydramnios (probably due to poor fetal swallowing), severe congenital microcephaly, weak respiratory effort, and survival for only a few hours or days. Barth described two siblings with this type as having a very low brainweight, wide ventricles, a very thin neopallium, absent corpus callosum and absent olfactory nerve.

Neurocutaneous melanosis is associated with the presence of either giant congenital melanocytic nevi or non-giant nevi of the skin. It is estimated that neurocutaneous melanosis is present in 2% to 45% of patients with giant congenital melanocytic nevi. Patients with non-giant congenital melanocytic nevi seem to have a much lower, but undefined risk. Of these patients, only a small number are symptomatic, usually displaying symptoms before the age of 2.

These symptoms are the result of melanocytic lesions being present in the leptomeninges of the central nervous system.

Symptoms can include:

- Papilledema

- Cranial palsies

- Headache

- Vomiting

- Seizures

Others symptoms may also exist that are related to an increase in intracranial pressure. These symptoms seem to be present regardless of the malignancy of the melanin deposits within the central nervous system.

Approximately 10% of patient with neurocutaneous melanosis also present the Dandy–Walker syndrome and associated Dandy-Walker malformation. This malformation involves an enlargement of the posterior fossae and fourth ventricle along with agenesis of the cerebellar vermis. The abnormalities of the leptomeninges during fetal development due to neurocutaneous melanosis may be the cause of this increased incidence of the Dandy-Walker malformation. The development of hydrocephalus is the most common symptom associated with a combination of neurocutaneous melanosis and a Dandy-Walker malformation, occurring in about two out of three patients.

Microlissencephaly with mildly to moderately thick (6–8 mm) cortex, callosal agenesis

Diagnosis is usually based on clinical observation. Various sets of criteria have been suggested to identify the disorder in an individual patient, all of which include macrocephaly and a number of the following: somatic overgrowth, cutis marmorata, midline facial birthmark, polydactyly/syndactyly, asymmetry (hemihyperplasia or hemihypertrophy), hypotonia at birth, developmental delay, connective tissue defect and frontal bossing. Currently no consensus exists about which diagnostic criteria are definitive and so evaluation by a medical geneticist or other clinician with familiarity with the syndrome is usually needed to provide diagnostic certainty. It is not clear if there are some features which are mandatory to make the diagnosis, but macrocephaly appears essentially universal though may not be congenital. The distinctive vascular abnormalities of the skin often fade over time, making the diagnosis challenging in older children with this condition.

The brain can be affected in several ways in this syndrome. Some children are born with structural brain anomalies such as cortical dysplasia or polymicrogyria. While developmental delay is nearly universal in this syndrome it is variable in severity, with the majority having mild to moderate delays and a minority having severe cognitive impairment. Some patients are affected with a seizure disorder. White matter abnormalities on magnetic resonance imaging (MRI), suggesting a delay in white matter myelination, is commonly seen in early childhood. Some patients may have asymmetry of the brain, with one side being noticeably larger than the other.

One interesting phenomenon that seems very common in this syndrome is the tendency for disproportionate brain growth in the first few years of life, with crossing of percentiles on the head circumference growth charts. A consequence of this disproportionate brain growth appears to be a significantly increased risk of cerebellar tonsillar herniation (descent of the cerebellar tonsils through the foramen magnum of the skull, resembling a Chiari I malformation neuroradiologically) and ventriculomegaly/hydrocephalus. Such cerebellar tonsil herniation may occur in up to 70% of children with M-CM.

The medical literature suggests that there is a risk of cardiac arrhythmias in early childhood. The cause for this is unknown. In addition, a variety of different congenital cardiac malformations have been reported in a small number of patients with this disorder.

Like other syndromes associated with disproportionate growth, there appears to be a slightly increased risk of certain types of childhood malignancies in M-CM (such as Wilms' tumor). However, the precise incidence of these malignancies is unclear.

Various degrees of intensity and locations of epilepsy are associated with malformations of cortical development. Researchers suggest that approximately 40% of children diagnosed with drug-resistant epilepsy have some degree of cortical malformation.

Lissencephaly (to which pachygyria is most closely linked) is associated with severe mental retardation, epilepsy, and motor disability. Two characteristics of lissencephaly include its absence of convolutions (agyria) and decreased presence of convolutions (pachygyria). The types of seizures associated with lissencephaly include:

- persisting spasms

- focal seizures

- tonic seizures

- atypical seizures

- atonic seizures

Other possible symptoms of lissencephaly include telecanthus, estropia, hypertelorism, varying levels of mental retardation, cerebellar hypoplasia, corpus callosum aplasia, and decreased muscle tone and tendon reflexes. Over 90% of children affected with lissencephaly have seizures.

Patients with subcortical band heterotopia (another disorder associated with pachygyria) typically have milder symptoms and their cognitive function is closely linked to the thickness of the subcortical band and the degree of pachygyria present.

The classical triad of symptoms that defines 3C syndrome includes certain heart defects, hypoplasia (underdevelopment) of the cerebellum, and cranial dysmorphisms, which can take various forms. The heart defects and cranial dysmorphisms are heterogeneous in individuals who are all classed as having Ritscher-Schinzel syndrome.

Heart defects commonly seen with Ritscher-Schinzel syndrome are associated with the endocardial cushion and are the most important factor in determining a diagnosis. The mitral valve and tricuspid valve of the heart can be malformed, the atrioventricular canal can be complete instead of developing into the interatrial septum and interventricular septum, and conotruncal heart defects, which include tetralogy of Fallot, double outlet right ventricle, transposition of the great vessels, and hypoplastic left heart syndrome. Aortic stenosis and pulmonary stenosis have also been associated with 3C syndrome.

The cranial dysmorphisms associated with 3C syndrome are heterogeneous and include a degree of macrocephaly, a large anterior fontanel, a particularly prominent occiput and forehead, ocular hypertelorism (wide-set eyes), slanted palpebral fissures, cleft palate, a depressed nasal bridge, cleft palate with associated bifid uvula, low-set ears, micrognathia (an abnormally small jaw), brachycephaly (flattened head), and ocular coloboma. Low-set ears are the most common cranial dysmorphism seen in 3C syndrome, and ocular coloboma is the least common of the non-concurrent symptoms (cleft lip co-occurring with cleft palate is the least common).

Cranial dysplasias associated with 3C syndrome are also reflected in the brain. Besides the cerebellar hypoplasia, cysts are commonly found in the posterior cranial fossa, the ventricles and the cisterna magna are dilated/enlarged, and Dandy-Walker malformation is present. These are reflected in the developmental delays typical of the disease. 75% of children with 3C syndrome have Dandy-Walker malformation and hydrocephalus.

Signs and symptoms in other body systems are also associated with 3C syndrome. In the skeletal system, ribs may be absent, and hemivertebrae, syndactyly (fusion of fingers together), and clinodactyly (curvature of the fifth finger) may be present. In the GI and genitourinary systems, anal atresia, hypospadia (misplaced urethra), and hydronephrosis may exist. Adrenal hypoplasia and growth hormone deficiency are associated endocrine consequences of Ritscher-Schinzel syndrome. Some immunodeficiency has also been reported in connection with 3C syndrome.

Many children with the disorder die as infants due to severe congenital heart disease. The proband of Ritscher and Schinzel's original study was still alive at the age of 21.

A fetus with 3C syndrome may have an umbilical cord with one umbilical artery instead of two.

The degree of cerebral cortex malformation caused by genetic mutations is classified by the degree of malposition and the extent of faulty grey matter differentiation.

Neuronal migration disorders are generally classified into three groups:

- lissencephaly/subcortical band heterotopia

- cobblestone

- ‘other’ heterotopias

The ‘other’ types are associated with corpus callosum agenesis or cerebellar hypoplasia while the cobblestone lissencephalies are associated with eye and muscle disorders.

Classical lissencephaly, also known as type I or generalized agyria-pachygyria, is a severe brain malformation of a smooth cerebral surface, abnormally thick (10-20mm) cortex with four layers, widespread neuronal heterotopia, enlarged ventricles, and agenesis or malformation of the corpus callosum. Classical lissencephaly can range from agyria to regional pachygyria and is usually present along with subcortical band heterotopia (known as ‘double cortex’ to describe the circumferential bands of heterotopic neurons located beneath the cortex). Subcortical band heterotopia is a malformation slightly different from lissencephaly that is now classified under the agyria-pachygyria-band spectrum because it consists of a gyral pattern consistent with broad convolutions and an increased cortical thickness.

The established classification scheme for lissencephaly is based on the severity (grades 1-6) and the gradient.

- Grade 1: generalized agyria

- Grade 2: variable degree of agyria

- Grade 3: variable degree of pachygyria

- Grade 4: generalized pachygyria

- Grade 5: mixed pachygyria and subcortical band heterotopia

- Grade 6: subcortical band heterotopia alone

- Gradient ‘a’: from posterior to anterior gradient

- Gradient ‘b’: from anterior to posterior gradient

Grade 1 and Grade 4 are very rare. Grade 2 is observed in children with Miller-Dieker syndrome (a combination of lissencephaly with dysmorphic facial features, visceral abnormalities, and polydactyly). The most common lissencephaly observed, consisting of frontotemporal pachygyria and posterior agyria, is Grade 3.

Another malformation worth mentioning because of its connections to pachygyria is polymicrogyria. Polymicrogyria is characterized by many small gyri separated by shallow sulci, slightly thin cortex, neuronal heterotopia and enlarged ventricle and is often superimposed on pachygyria.

Brain herniation frequently presents with abnormal posturing a characteristic positioning of the limbs indicative of severe brain damage. These patients have a lowered level of consciousness, with Glasgow Coma Scores of three to five. One or both pupils may be dilated and fail to constrict in response to light. Vomiting can also occur due to compression of the vomiting center in the medulla oblongata.

Vascular tumors, often referred to as hemangiomas, are the most common tumors in infants, occurring in 1-2%. Prevalence is even higher (10%) in premature infants of very low birth weight. Vascular tumors are characterized by overgrowth of normal vessels, which show increased endothelial proliferation. It can be present at birth, but often appears within a couple of weeks after birth or during infancy. There are different kinds of vascular tumors, but the 4 most common types are: infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma and pyogenic granuloma.

Vascular malformation is a collective term for different disorders of the vasculature (errors in vascular development). It can be a disorder of the capillaries, arteries, veins and lymphatic vessels or a disorder of a combination of these (lesions are named based on the primary vessel that is malformed). A vascular malformation consists of a cluster of deformed vessels, due to an error in vascular development (dysmorphogenesis). However, endothelial turnover is stable in these defects. Congenital vascular malformations are always already present at birth, although they are not always visible. In contrast to vascular tumors, vascular malformations do not have a growth phase, nor an involution phase. Vascular malformations tend to grow proportionately with the child. Vascular malformations never regress, but persist throughout life.

Vascular malformations can be divided into slow-flow, fast-flow and complex-combined types.

Usually associated with diaphragmatic hernia,

pulmonary hypoplasia,

imperforate anus,

micropenis,

bilateral cryptorchidism,

cerebral ventricular dilation,

camptodactyly,

agenesis of sacrum,

low-set ear.

- Fryns et al. (1979) reported 2 stillborn sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy corneae, diaphragmatic defects, absence of lung lobulation, and distal limb deformities. A sporadic case was reported by Goddeeris et al. (1980). Fitch (1988) claimed that she and her colleagues were the first to describe this disorder. In 1978 they reported a single infant, born of second-cousin parents, who had absent left hemidiaphragm, hydrocephalus, arhinencephaly, and cardiovascular anomalies.

- Lubinsky et al. (1983) reported a brother and sister with Fryns syndrome who both died in the neonatal period. Facial anomalies included broad nasal bridge, microretrognathia, abnormal helices, and cleft palate. Other features included distal digital hypoplasia, lung hypoplasia, and urogenital abnormalities, including shawl scrotum, uterus bicornis, and renal cysts. They were discordant for diaphragmatic hernia, cleft lip, and Dandy–Walker anomaly.

- Meinecke and Fryns (1985) reported an affected child; consanguinity of the parents supported recessive inheritance. They noted that a diaphragmatic defect had been described in 4 of the 5 reported cases and lung hypoplasia in all. Young et al. (1986) reported a sixth case. The male infant survived for 12 days. These authors listed corneal clouding, camptodactyly with hypoplastic nails, and abnormalities of the diaphragm as cardinal features.

- Samueloff et al. (1987) described a family in which all 4 children had Fryns syndrome and neonatal mortality. Features included hypoplastic lungs, cleft palate, retrognathia, micrognathism, small thorax, diaphragmatic hernia, distal limb hypoplasia, and early onset of polyhydramnios with premature delivery. Schwyzer et al. (1987) described an affected infant whose parents were second cousins.

- Moerman et al. (1988) described infant brother and sister with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies. Both died shortly after birth with severe respiratory distress. Ultrasonography demonstrated fetal hydrops, diaphragmatic hernia, and striking dilatation of the cerebral ventricles in both infants. Post-mortem examination showed Dandy–Walker malformation, ventricular septal defect, and renal cystic dysplasia.

- Cunniff et al. (1990) described affected brothers and 3 other cases, bringing the total reported cases of Fryns syndrome to 25. One of the affected brothers was still alive at the age of 24 months. Bilateral diaphragmatic hernias had been repaired on the first day of life. He required extracorporeal membrane oxygenation therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus. Scoliosis was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a gastrostomy tube was inserted. In addition, because of persistent chylothorax, he underwent decortication of the right lung and oversewing of the thoracic duct.

- Kershisnik et al. (1991) suggested that osteochondrodysplasia is a feature of Fryns syndrome.

- Willems et al. (1991) suggested that a diaphragmatic hernia is not a necessary feature of Fryns syndrome. They described a child with all the usual features except for diaphragmatic hernia; the diaphragm was reduced to a fibrous web with little muscular component. Bartsch et al. (1995) presented 2 unrelated cases with a typical picture of Fryns syndrome but without diaphragmatic hernia. One of these patients was alive at the age of 14 months, but was severely retarded. Bamforth et al. (1987) and Hanssen et al. (1992) also described patients with this syndrome who survived the neonatal period. In the report of Hanssen et al. (1992), 2 older sibs had died in utero. The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. However, mental retardation has been present in all surviving patients.

- Vargas et al. (2000) reported a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had macrocephaly, coarse facial appearance, hypoplasia of distal phalanges, and an extra pair of ribs. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. The authors suggested that absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients.

- Aymé, "et al." (1989) described 8 cases of Fryns syndrome in France. The most frequent anomalies were diaphragmatic defects, lung hypoplasia, cleft lip and palate, cardiac defects, including septal defects and aortic arch anomalies, renal cysts, urinary tract malformations, and distal limb hypoplasia. Most patients also had hypoplastic external genitalia and anomalies of internal genitalia, including bifid or hypoplastic uterus or immature testes. The digestive tract was also often abnormal; duodenal atresia, pyloric hyperplasia, malrotation and common mesentery were present in about half of the patients. When the brain was examined, more than half were found to have Dandy–Walker anomaly and/or agenesis of the corpus callosum. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed retinal dysplasia with rosettes and gliosis of the retina, thickness of the posterior capsule of the lens, and irregularities of Bowman membrane.

- Alessandri et al. (2005) reported a newborn from the Comores Islands with clinical features of Fryns syndrome without diaphragmatic hernia. They noted that diaphragmatic hernia is found in more than 80% of cases and that at least 13 other cases had been reported with an intact diaphragm.

- In a postneonatal survivor of Fryns syndrome, Riela et al. (1995) described myoclonus appearing shortly after birth, which was well controlled on valproate. Progressive cerebral and brainstem atrophy was noted on serial MRIs made at 3 months and after 6 months of age.

- Van Hove et al. (1995) described a boy with Fryns syndrome who survived to age 3 years and reviewed the outcome of other reported survivors (approximately 14% of reported cases). Survivors tended to have less frequent diaphragmatic hernia, milder lung hypoplasia, absence of complex cardiac malformation, and severe neurologic impairment. Their patient had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm associated with profound mental retardation.

- Fryns and Moerman (1998) reported a second-trimester male fetus with Fryns syndrome and midline scalp defects. The authors stated that the finding of a scalp defect in Fryns syndrome confirms that it is a true malformation syndrome with major involvement of the midline structures.

- Ramsing et al. (2000) described 2 sibships with 4 fetuses and 1 preterm baby of 31 weeks' gestation affected by a multiple congenital disorder suggestive of Fryns syndrome. In addition to the diaphragmatic defects and distal limb anomalies, they presented with fetal hydrops, cystic hygroma, and multiple pterygias. Two affected fetuses in 1 family showed severe craniofacial abnormalities with bilateral cleft lip and palate and cardiovascular malformation.

- Arnold et al. (2003) reported a male fetus with Fryns syndrome and additional abnormalities, in particular, multiple midline developmental defects including gastroschisis, central nervous system defects with left arrhinencephaly and cerebellar hypoplasia, midline cleft of the upper lip, alveolar ridge, and maxillary bone, and cleft nose with bilateral choanal atresia.

- Pierson et al. (2004) reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of them. They also described 3 new patients with Fryns syndrome, 1 of whom demonstrated unilateral microphthalmia and cloudy cornea.

- Slavotinek et al. (2005) noted that Fryns syndrome may be the most common autosomal recessive syndrome in which congenital diaphragmatic hernia (see DIH2, 222400) is a cardinal feature. The autosomal recessive inheritance in Fryns syndrome contrasts with the sporadic inheritance for most patients with DIH.

The condition usually consists of:

Sensation to the face is preserved, due to the sparing of the trigeminal nucleus.

The syndrome is said to be "alternating" because the lesion causes symptoms both contralaterally and ipsilaterally. Sensation of pain and temperature is preserved, because the spinothalamic tract is located more laterally in the brainstem and is also not supplied by the anterior spinal artery (instead supplied by the posterior inferior cerebellar arteries and the vertebral arteries).

Neurocutaneous melanosis is a congenital disorder characterized by the presence of congenital melanocytic nevi on the skin and melanocytic tumors in the leptomeninges of the central nervous system. These lesions may occur in the amygdala, cerebellum, cerebrum, pons, and spinal cord of patients. Although typically asymptomatic, malignancy occurs in the form of leptomeningeal melanoma in over half of patients. Regardless of the presence of malignancy, patients with symptomatic neurocutaneous melanosis generally have a poor prognosis with few treatment options. The pathogenesis of neurocutaneous melanosis is believed to be related to the abnormal postzygotic development of melanoblasts and mutations of the NRAS gene.

3C syndrome, also known as CCC dysplasia, Craniocerebellocardiac dysplasia or Ritscher–Schinzel syndrome, is a rare condition, whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.

In "central herniation", the diencephalon and parts of the temporal lobes of both of the cerebral hemispheres are squeezed through a notch in the tentorium cerebelli. Transtentorial herniation can occur when the brain moves either up or down across the tentorium, called ascending and descending transtentorial herniation respectively; however descending herniation is much more common. Downward herniation can stretch branches of the basilar artery (pontine arteries), causing them to tear and bleed, known as a Duret hemorrhage. The result is usually fatal. Other symptoms of this type of herniation include small, dilated, fixed pupils with paralysis of upward eye movement giving the characteristic appearance of "sunset eyes". Also found in these patients, often as a terminal complication is the development of diabetes insipidus due to the compression of the pituitary stalk. Radiographically, downward herniation is characterized by obliteration of the suprasellar cistern from temporal lobe herniation into the tentorial hiatus with associated compression on the cerebral peduncles. Upwards herniation, on the other hand, can be radiographically characterized by obliteration of the quadrigeminal cistern. Intracranial hypotension syndrome has been known to mimic downwards transtentorial herniation.