Disorders of Prosencephalic Development
Fundamental Disorders of Prosencephalic Formation
1. Aprosencephaly
- Complete absence of prosencephalic structures:
- No telencephalon or diencephalon.
- Extremely rare and lethal anomaly.
2. Atelencephaly
- Absent telencephalon; preserved diencephalon (thalami present).
- Rare and invariably lethal anomaly.
Disorders of Prosencephalic Cleavage
Holoprosencephaly (HPE)
Definition
- Spectrum disorder from impaired or incomplete forebrain cleavage into cerebral hemispheres.
- Fundamental issue: disturbed dorsoventral patterning during ventral induction phase.
Pathogenesis and Molecular Basis
- Sonic Hedgehog (SHH) signaling:
- Key ventralising factor in forebrain development.
- SHH disruption leads to failure or incomplete cleavage.
- Bone Morphogenetic Protein (BMP) signaling:
- Dorsalising effects, antagonistic to SHH.
- Excessive BMP may disrupt SHH signaling indirectly.
- Thus, SHH-BMP imbalance underlies HPE spectrum.
Incidence
- Approximately 1:10,000 live births.
- High prevalence (~1:250) in spontaneously aborted fetuses.
Clinical Classification of Holoprosencephaly
1. Alobar HPE (Most Severe)
- Complete failure of prosencephalic cleavage.
- Large monoventricle ("horseshoe-shaped"); dorsal cyst common.
- Absent structures:
- Interhemispheric fissure, third ventricle, corpus callosum, cavum septi pellucidi, olfactory bulbs.
- Fused nuclei: thalamic, hypothalamic, basal ganglia.
- Facial anomalies severe (cyclopia, cebocephaly, ethmocephaly, hypotelorism, cleft lip).
- Vascular: Single anterior cerebral artery (ACA); sometimes absent middle/ACAs.
- Hydrocephalus common.
2. Semilobar HPE
- Partial anterior cleavage failure; posterior hemispheres usually separate.
- Monoventricle anteriorly; partial formation of posterior horns.
- Absent anterior corpus callosum; posterior callosal parts (splenium) often preserved.
- Absent/small third ventricle; partially fused thalami.
- Facial anomalies milder or absent.
- No dorsal cyst.
3. Lobar HPE (Least Severe Classic Form)
- Complete separation except ventral/anterior regions.
- Intact interhemispheric fissure posteriorly; hypoplastic genu/anterior corpus callosum.
- Absent cavum septi pellucidi (key imaging clue).
- Separated thalami; formed (but dysmorphic) third ventricle.
- Rudimentary frontal horns; fused fornices within third ventricle.
- Facial anomalies minimal or absent; olfactory bulbs reduced or absent.
Extended Spectrum of Holoprosencephaly
Additional recognized forms:
- Syntelencephaly (Midline Interhemispheric Fusion Variant)
- Failed cleavage in central frontoparietal hemispheres; basal forebrain typically normal.
- Normal genu/splenium; absent body of corpus callosum.
- Vertically oriented, continuous sylvian fissures.
- Frequent cortical dysplasia/subcortical heterotopia (>50% cases).
- Dorsal-ventral signaling disrupted (excess SHH or reduced BMP).
- Minimal/microform HPE:
- Subtle midline defects; no major MRI findings.
- Interhypothalamic adhesion (forme fruste):
- Mildest phenotype; minimal clinical relevance.
- Septo-optic dysplasia:
- Some controversy regarding inclusion in HPE spectrum; typically considered separately.
Associated Clinical Features
Neurological and Endocrine Complications
- Commonly associated with microcephaly.
- Hydrocephalus due to aqueductal stenosis (~40%).
- Deep grey nuclei non-cleavage frequent:
- Hypothalamus (near universal), caudate nuclei (96%), lentiform nuclei (85%), thalami (67%).
- Endocrine dysfunction:
- Diabetes insipidus, thyroid/adrenal hypoplasia, hypogonadism, growth hormone deficiency.
Extracerebral anomalies:
- Congenital heart defects (transposition of great arteries).
- Limb anomalies (polydactyly, reduction defects).
- Scalp defects.
Genetic and Environmental Factors in HPE
Chromosomal anomalies (up to 45%):
- Trisomy 13 (most common), triploidy, trisomy 18 (rare).
Recognized genetic syndromes (~25%):
- Meckel-Gruber, Aicardi, Pallister-Hall, Smith-Lemli-Opitz, pseudo-trisomy 13, velocardiofacial syndromes.
Single gene mutations (~20%):
- SHH, ZIC2, SIX3, TGIF genes implicated.
- ZIC2 mutations: distinctive facial phenotype (upslanting eyes, short nose, broad philtrum).
Environmental:
- Maternal diabetes increases risk significantly (~200-fold).
Prognosis and Outcomes in Holoprosencephaly
- Prognosis varies significantly based on severity:
- Alobar HPE: ~50% mortality by 5 months; ~30% survive beyond first year.
- Lobar HPE: ~50% learn to walk, use hands, basic language.
- Long-term survivors often experience significant disability:
- Intellectual disability, seizures, endocrine disturbances.
- Presence of dorsal cyst increases hydrocephalus risk and worse outcomes.
Clinical Approach and Management
- Multidisciplinary supportive care (neurology, endocrinology, developmental support).
- Genetic counseling critical due to multifactorial inheritance.