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.