Miscellaneous Sequences

Arrhinencephaly-Cebocephaly-Cyclopia: Primary Defect in Prechordal Mesoderm

Holoprosencephaly results from incomplete cleavage of the prosencephalon between the eighteenth and twenty-eighth day of gestation. Neuroanatomically it is divided—based on the extent to which the forebrain has failed to separate—into alobar (the most severe type), semilobar, lobar, and middle interhemispheric type (the mildest type). In the alobar type the prosencephalon fails to cleave sagittally into cerebral hemispheres, transversely into telencephalon and diencephalon, and horizontally into olfactory tracts and bulbs. As a consequence of, and associated with, these severe defects in brain development, varying degrees of midline facial development occur. Cyclopia represents a severe deficit in early midline facial development. The eyes fuse, the olfactory placodes consolidate into a single tube-like proboscis above the eye, and the ethmoid and other midline bony structures are missing. Less severe deficits result in hypotelorism and varying degrees of inadequate midfacial and incomplete forebrain development that are more common than cyclopia and frequently include midline cleft lip and palate. The important clinical point is that incomplete midline facial development—such as hypotelorism, absence of the philtrum or nasal septum, a single central incisor, congenital nasal pyriform aperture stenosis, and/or a missing frenulum of the upper lip—suggests the possibility of a serious anomaly in brain development and function. Endocrine disorders, including diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia, hypoglycemia, precocious puberty, growth hormone defects, and short stature, are common. In addition, seizures and autonomic instability affecting temperature control, heart rate, and respiration have been reported. Finally, neural tube closure defects, ptosis, coloboma, choanal atresia, cleft lip and palate, genitourinary defects including micropenis, cryptorchidism, and ambiguous genitalia, and renal anomalies, as well as thymic hypoplasia, common mesentery, single umbilical artery, diaphragmatic hernia, gallbladder agenesis, esophageal atresia, intestinal stenosis, a variety of skeletal abnormalities, and cardiac defects occur. Nonalcoholic fatty acid disease has recently been associated.

Although the defect is isolated in the vast majority of cases, holoprosencephaly is etiologically heterogeneous with both genetic and environmental causes identified. Aneuploidy syndromes—including trisomies 13 and 18, as well as several structural chromosome aberrations, including del2p21, dup3pter, del7q36, del13q, del18p, and del21q22.3—should be considered. Autosomal dominant mutations in a number of genes have been identified in “nonsyndromic” holoprosencephaly. Mutations in four genes that have been identified in both sporadic and familial cases are responsible for most of these nonsyndromic cases. These four genes are SHH, ZIC2, SIX3, and TGIF. Sonic hedgehog ( SHH ), responsible for 12% of cases, is associated with wide variability of expression and is located at 7q36. Mutations in ZIC2, located at 13q32, occur in 9% of cases and are associated with a specific facial phenotype, including bitemporal narrowness, upslanting palpebral fissures, a flat nasal bridge, a short nose with anteverted nares, a broad and deep philtrum, and large ears. Mutations in SIX3, located at 2p21 and associated with an increase in renal anomalies, occur in up to 5% of cases, and mutations in TGIF, located at 18p11.3, occur in 1% to 2% of cases. Mutations in a number of genes involved in signaling pathways important for brain development, including PATCHED1 and GLI2 , as well as TDGF1 and FAST1 , which are involved in the Nodal/transforming growth factor β (TGF-β) pathway, occur far less frequently. Parents of an affected child should be checked for mild manifestations, such as a single central incisor, a missing upper lip frenulum, and absence of the nasal cartilage. Finally, holoprosencephaly has been seen as one feature of multiple malformation syndromes, such as Meckel-Gruber syndrome and Smith-Lemli-Opitz syndrome, in the offspring of diabetic women, and as an occasional feature in fetal alcohol spectrum disorder. The prognosis for central nervous system function in individuals with this type of defect is very poor.

A significant number of infants with holoprosencephaly survive into childhood and even adulthood. Factors associated with long-term survival include holoprosencephaly subtype (lobar, semilobar, and middle interhemispheric), female gender, and a milder facial phenotype.

Primary Defect in Neural Tube Closure

The initiating malformation appears to be a defect in closure of the neural groove to form an intact neural tube, which is normally completely fused by 28 days. Anencephaly represents a defect in closure at the anterior portion of the neural groove. The secondary consequences are these: (1) the unfused forebrain develops partially and then tends to degenerate; (2) the calvarium is incompletely developed; and (3) the facial features and auricular development are secondarily altered to a variable degree, including cleft palate and frequent abnormality of the cervical vertebrae.

Defects of closure at the mid or caudal neural groove can give rise to meningomyelocele and other secondary defects, as depicted. Of greatest concern relative to outcome for independence and survival is the hydrocephalus and other manifestations of the Chiari II malformation, which is present in virtually all cases.

Defects of closure in the cervical and upper thoracic region can culminate in the iniencephaly sequence, in which secondary features may include retroflexion of the upper spine with short neck and trunk, cervical and upper thoracic vertebral anomalies, defects of thoracic cage, anterior spina bifida, diaphragmatic defects with or without hernia, and hypoplasia of lung and/or heart. Evidence suggesting that there may be four sites of anterior neural tube closure explains the variations observed in their location, recurrence risk, and etiology. Most commonly, no specific etiology is appreciated. The recurrence risk is 1.9% for parents who have had one affected child. Measurement of alpha fetoprotein (AFP) in maternal serum in conjunction with detailed ultrasonography allows prenatal diagnosis in the vast majority of cases.

Encouraging results have been reported from the Management of Myelomeningocele Study (MOMS), a multicenter, randomized, controlled trial that compared in utero prenatal closure to postnatal closure. The study was published in 2011 and long-term outcomes continue to be documented. The study so far has demonstrated a decrease in hindbrain herniation resulting in a decreased need for ventriculoperitoneal (V-P) shunting for hydrocephalus, decreased pressure on the hindbrain, and improvement in motor function in the prenatal repair group compared with those who received surgery postnatally.

The United States Public Health Service has recommended that women of childbearing age should consume 0.4 mg of folic acid daily to reduce their risk of conceiving a child with a neural tube defect. For women who previously have had an affected infant, it has been recommended that 4.0 mg daily of folic acid should be consumed from 1 month before conception through 3 months of pregnancy.