493 The holoprosencephaly (HPE) is a heterogeneous entity of CNS anomalies caused by the impaired midline cleavage of the embryonic forebrain. The incidence is estimated to be 1 in 16,000 live births and observed in 1 of 250 spontaneous abortions.
GENETICS/BASIC DEFECTS
1. Isolated and sporadic in most cases
2. Genetically heterogeneous involving at least 12 loci on eleven chromosomes. There are at least five putative loci for HPE:
a. HPE1
i. Map locus: 21q22.3
ii. Familial alobar holoprosencephaly b. HPE2 (SIX3)
i. Map locus: 2p21
ii. Chromosome 2 form of holoprosencephaly, includ- ing midline cleft syndrome and DeMyer sequence iii. Caused by mutations in the homeo box-containing
SIX3 gene
c. HPE3 on 7q36-qter, characterized as the locus con- taining the human sonic hedgehog gene (SHH)
i. Either loss-of-function mutation or disruption of one of the sonic hedgehog alleles at 7q36 (hap- loinsufficiency) shown to cause variable pheno- type of holoprosencephaly
ii. A broad spectrum of holoprosencephaly present in patients with de novo 7q, or with autosomal dominant holoprosencephaly having a linkage on 7q36
iii. 7q deletion syndrome without typical holopros- encephaly in some patients
iv. Interaction of partial trisomy 3p and partial monosomy 7q: invariably associated with severe forms of holoprosencephaly and facial dysmor- phism. This delineates an autosomal imbalance syndrome or a dosage effect involving distal 3p duplication/terminal 7q deletion and dysmor- phogenesis of the forebrain and mid-face d. HPE4 (TG-interacting factor, TGIF) on 18p11.3.
Mutations of TGIF have been associated with holo- prosencephaly and premaxillary agenesis
e. HPE5 (ZIC2) on 13q32 3. Other known HPE-associated genes
a. PTCH
i. Patched mutations in humans result in haploin- sufficiency
ii. A few of such mutations cause holoprosencephaly b. DHCR7
i. Mutations resulting in reduced serum cholesterol and accumulation of 7-dehydrocholesterol in autosomal recessive Smith-Lemli-Opitz syndrome
ii. 4% of cases with Smith-Lemli-Opitz syndrome have holoprosencephaly
4. Subtypes of holoprosencephaly and the range of possible craniofacial features
a. Alobar holoprosencephaly
i. Cyclopia (a single eye or partially divided eye in a single orbit with or without proboscis above the eye)
ii. Ethmocephaly (extreme ocular hypotelorism with proboscis located between the eyes) iii. Cebocephaly (ocular hypotelorism with a single-
nostril nose)
iv. Premaxillary agenesis (ocular hypotelorism with median cleft lip and palate)
v. Bilateral cleft lip
vi. Ocular hypotelorism only
vii. Anophthalmia or microophthalmia viii. Relatively normal facial appearance b. Semilobar holoprosencephaly
i. Bilateral cleft lip with median process represent- ing the philtrum-premaxilla anlage
ii. Flat nasal bridge iii. Absent nasal septum
iv. Flat nasal tip
v. Midline cleft lip and/or palate vi. Ocular hypotelorism
vii. Flat nose
viii. Anophthalmia/microophthalmia ix. Relatively normal facial appearance c. Lobar holoprosencephaly
i. Bilateral cleft lip with median process ii. Ocular hypotelorism
iii. Flat nose
iv. Relatively normal facial appearance 5. Causes
a. Detectable chromosome abnormalities (24–45%) i. Numerical chromosomal abnormalities
a) Trisomy 13 (most common) b) Trisomy 18
c) Triploidy
ii. Structural chromosomal abnormalities: reported in virtually all chromosomes. The most frequent ones are as follows:
a) Involving 13q [del(13q), r(13)]
b) Del(18p)
c) Del(7)(q36) (20%) d) Dup(3)(p24-pter) (10%) e) Del(2)(p21)
f) Del(21)(q22.3) g) Del(22q11)
h) Partial monosomy 14q
b. Monogenic holoprosencephaly (18–25%) i. Autosomal dominant
a) Pallister-Hall syndrome b) Rubinstein-Taybi syndrome c) Kallmann syndrome
d) Martin syndrome (with club foot and spinal anomalies)
e) Steinfeld syndrome (with congenital heart disease, absent gallbladder, renal dysplasia, and radial defects)
f) Ectrodactyly and hypertelorism ii. Autosomal recessive
a) Meckel-Gruber syndrome b) Smith-Lemli-Opitz syndrome c) Pseudotrisomy 13 syndrome d) XK aprosencephaly syndrome e) Heterotaxy and holoprosencephaly
f) Genoa syndrome (with craniosynostosis) g) Lambotte syndrome (with microcephaly, pre-
natal growth retardation, and hypertelorism) h) Hydrolethalus syndrome (with hydrocephalus,
polydactyly, and other anomalies) i) Facial clefts and brachial amelia
iii. X-linked recessive (holoprosencephaly-fetal hypokinesia/akinesia)
c. Agnathia-otocephaly (10%) d. Fronto-nasal dysplasia (6.7%) e. Sirenomelia association
f. Holoprosencephaly, ectopia cordis, and embryonal neoplasms
6. Nongenetic risk factors
a. Maternal diabetes: 1–2% of newborn infants of dia- betic mothers develop holoprosencephaly
b. Retinoic acid
i. CNS anomalies, particularly hydrocephalus ii. Holoprosencephaly
c. Ethyl alcohol
i. Holoprosencephaly/arhinencephaly ii. Agnathic cyclopia
iii. Midline cerebral dysgenesis with hypothalamic- pituitary dysfunction
iv. Hydrocephalus
v. Agenesis of the corpus callosum and anterior commissure
d. Salicylates e. Estrogen/progestin
f. Anticonvulsants
g. Low-calorie weight reduction diets h. Prenatal infections
i. Cytomegalovirus ii. Rubella
iii. Toxoplasma i. Poverty
j. Previous pregnancy loss
CLINICAL FEATURES
1. Variable expression, ranging from a small brain with a single cerebral ventricle and cyclopia to clinically unaf- fected carriers in familial holoprosencephaly
2. Face: Holoprosencephaly is often associated with distinct facial appearance (holoprosencephaly facies syndrome).
The face predicts the brain approximately 80% of the time. In decreasing order of severity:
a. Absence of eye(s) (the most severe form) b. Cyclopia
i. The most severe dysmorphism
ii. A median monophthalmia (a single midline eye) iii. Synophthalmia (fusion of two eyes in a single
midline orbit) iv. Anophthalmia
v. Presence of a single median orbit (sine qua non for the diagnosis)
vi. Without or with proboscis (single or double pro- truding from the glabella, just above the median eye)
vii. Complete arhinia with no nose, no nasal bones viii. Degree of facial dysmorphism strongly correlated
with the severity of brain malformation (facial and the oculo-orbital phenotype reflect the underlying central nervous system pathology) c. Ethmocephaly
i. Rarest type
ii. Close-set eyes (ocular hypotelorism) located in two separate orbits
iii. A median proboscis between the two eyes as a rudimentary tube-like nose
iv. Hypoplastic or absent median facial bones d. Cebocephaly
i. Close-set eyes (ocular hypotelorism) into sepa- rate orbits
ii. A nose with a single nostril iii. No cleft lip
e. Premaxillary agenesis
i. Close-set eyes (ocular hypotelorism) ii. Median cleft lip and palate
3. Eyes
a. Anophthalmia b. Microphthalmia c. Cyclopia d. Fused eyes e. Coloboma
f. Hypotelorism g. Bulging eyes
h. Other eye malformations i. Fused lids
ii. Optic disk hypoplasia iii. Cataract
4. Nose
a. Proboscis
b. Arhinia with or without proboscis c. Flat nose
i. With proboscis
ii. Absent or nonpatent nares iii. Other malformations 5. Mouth
a. Median cleft lip b. Bilateral cleft lip c. Unilateral cleft lip d. Cleft palate alone e. Cleft lip with cleft palate
f. Cleft lip alone
g. Cleft uvula h. Microstomia
i. Macrostomia j. Agnathia k. Microganthia 6. Ear
a. Fused ears
b. Other ear malformations 7. Neurodevelopmental deficits
a. Hoarse or “barking” voice, high-pitched crying b. Major feeding problems with choking spells c. Common growth delay
d. Seizures
e. Spasticity or floppy muscle tone
f. Brain-stem dysfunction with irregular breathing and heart rate and erratic body temperature control g. Profound developmental delay with very limited
expressive language and minimal attainment of motor skills
h. Behavioral problems 8. Endocrine disorders
a. Occasional diabetes insipidus with episodes of dehy- dration
b. Rare panhypopituitarism
9. Presence of microforms of holoprosencephaly in relatives of patients with holoprosencephaly
a. Microcephaly
b. Single central maxillary incisor c. Ocular hypotelorism
d. Anosmia/hyposmia secondary to absent olfactory tracts and bulbs
e. Iris coloboma
f. Absent superior labial frenulum g. Midface hypoplasia
h. Congenital nasal pyriform aperture stenosis i. Developmental delay
10. Prognosis
a. Infants born with cyclopia, ethmocephaly, and cebo- cephaly: virtually all die within a week of birth b. Infants born with premaxillary agenesis, unilateral or
bilateral cleft lip, or more normal facies i. Half of the patients die before 4–5 months ii. 20–30% of the patients live to one year of age.
Longer survival is possible to at least 11 years c. Cases diagnosed in utero will have an extremely poor
neurologic development after birth
d. Causes of death most often due to brain-stem mal- function (unable to control the respiration and heart rate) aggravated by infections and other stresses
DIAGNOSTIC INVESTIGATIONS
1. Neuroimagings (MRI/CT of the brain) a. A single ventricle
b. Absence of olfactory bulb and tracts c. Absence of corpus callosum
d. Absence of inferior frontal and temporal regions e. Fused thalami
f. Absence of optic nerve
g. Incomplete anterior and posterior pituitary
h. Normal brainstem and cerebellum i. Lack of ethmoid bone
2. Cytogenetic analysis
3. Adjunctive molecular analyses of distinct human gene for HPE
4. Necropsy: Holoprosencephaly is generally classified into three types. The distinction among the following three types is not always clear
a. Alobar holoprosencephaly i. The most severe form
ii. Complete failure of brain tissue to develop into the normal right and left cerebral hemispheres iii. The brain consisting of a single fused cerebral
hemispheres located in the frontal region iv. Total absence of interhemispheric fissure and
falx cerebri
v. The brain surface is smooth with sparse convolu- tional markings
vi. A single dilated ventricle communicating with a large dorsal cyst
vii. Absence of the third ventricle, neurohypophysis, olfactory bulbs and tracts
viii. Fused thalami and basal ganglia ix. Migrational anomalies often present b. Semilobar holoprosencephaly
i. The less severe form
ii. Rudimentary cerebral lobes. Only partial separa- tion into two cerebral hemispheres; the hemi- spheres are not separated across the midline in the front part of the brain
iii. A single ventricle
iv. Olfactory bulbs and corpus callosum are usually absent
v. Partial presence of the septum pellucidum and corpus callosum pending on the severity c. Lobar holoprosencephaly
i. The least severe form
ii. Well-formed lobes that may be of normal size iii. Virtual complete separation of the cerebral hemi-
spheres
iv. Various degree of rostral and basilar nonseparation v. Absent, hypoplastic or normal olfactory bulbs,
tracts and corpus callosum
vi. Gray matter heterotopias and other associated migrational anomalies
GENETIC COUNSELING
1. Recurrence risk: depending on the basis for the actual condition
a. Patient’s sib
i. Empirical estimate of 20% for holoprosen- cephaly, 15% for a microform, and 15% for normal phenotype
ii. Increased recurrence risk depending on the type of Mendelian inheritance (autosomal recessive and dominant conditions with holoprosen- cephaly). Existence of incomplete penetrance or an incomplete form or microform of holoprosen- cephaly makes the interpretation of familial occurrence difficult
iii. 50% recurrence risk of having affected siblings with variable clinical symptoms and severity if a parent is affected with holoprosencephaly iv. Germline mosaicism in which apparently unaf-
fected parents with negative family history hav- ing more than one affected child
v. Increased in a case where a parent carries a chro- mosome translocation or other chromosome rearrangement
b. Patient’s offspring
i. Severe cases of prosencephaly: not surviving to reproductive age
ii. Individuals with mild form or microform holo- prosencephaly (with a gene mutation for the autosomal dominant nonsyndromic holopros- encephaly): 50% recurrence risk of having an affected child
2. Prenatal diagnosis
a. Prenatal ultrasonography i. General characteristics
a) Polyhydramnios b) Ocular hypotelorism c) Cleft lip/palate d) Arhinia
e) Cyclopia and proboscis: identifiable at the beginning of the 9th week of gestation by 2-D and 3-D ultrasonography
f) Absence of central falx
g) Demonstration of a single rudimentary cere- bral ventricle
ii. Alobar holoprosencephaly a) Single ventricle
b) Presence or absence of dorsal sac c) Fused thalami
d) Absence of septum cavum pellucidum iii. Semilobar holoprosencephaly
a) Single ventricles with rudimentary occipital horns
b) Presence or absence of dorsal sac c) Fused thalami
d) Absence of septum cavum pellucidum iv. Lobar holoprosencephaly
a) Almost divided ventricles except at frontal horns of lateral ventricles
b) Some enlargement of lateral ventricle c) Flat roof of frontal horns in microtonal view d) Wide communication between the frontal
horns and the inferior third ventricles e) Absence of dorsal sac
f) Divided thalami
g) Absence of septum cavum pellucidum b. Cytogenetic analysis from CVS or amniocytes
i. Parent with a balanced chromosomal rearrangement ii. Fetus with multiple anomalies including holo-
prosencephaly from prenatal ultrasonography c. Molecular analysis on fetal DNA obtained from
amniocentesis or CVS for the disease-causing muta- tion previously identified in the proband in a research laboratory
i. Sequencing of entire coding region for the HPE panel
a) SIX3 gene b) SHH gene c) TGIF gene d) ZIC2 gene
ii. Pallister-Hall syndrome: mutation analysis for mutation panel GLI3 (2023delG and 2012delG) iii. Rubinstein-Taybi syndrome: FISH analysis of
the deletion of the CREBBP gene on chromo- some 16 (16p13.3)
iv. Smith-Lemli-Opitz syndrome
a) Detection of two disease-causing mutations in the DHCR7 gene previously identified in the proband
b) Abnormal concentration of 7-dehydrocho- lesterol levels
d. Preimplantation diagnosis reported for Sonic Hedgehog mutation causing familial holoprosen- cephaly
3. Management
a. Treatment strategies based on the types of brain mal- formations and associated anomalies
i. Lethal entity: no specific treatment available ii. Nonlethal entity
e) Ventriculo-peritoneal shunt for hydrocephalus f) Cleft lip and palate repair if indicated
g) Monitoring of fluid and electrolyte intake in patients with diabetes insipidus
h) Hormone replacement therapy for pituitary dys- function
b. Supportive
i. Multidisciplinary team approach ii. Support and counseling of the parents iii. Seizure management
iv. Gastrostomy tube placement and fundoplication for gastroesophageal reflux and vomiting
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Fig. 1. An aborted embryo with cyclopia.
Fig. 2. A neonate with cyclopia. The infant had holoprosencephaly (arrhinencephaly), agenesis of olfactory and optic nerves, agenesis of pituitary, cor binoculare, left diaphragmatic hernia, bilobar spleen, agenesis of adrenal glands, and absence of right umbilical artery.
Fig. 3. Another neonate with cyclopia.
Fig. 4. An infant with ethmocephaly.
Fig. 5. Postmortem brain with holoprosencephaly (dorsal view) show- ing a dilated single ventricle. The large dorsal cyst was ruptured dur- ing dissection, and the remnants of the membranous cyst wall are vaguely visible at the margins of the ventricle, especially on right side.
Fig. 6. A neonate with cebocephaly.
Fig. 7. A neonate with cebocephaly and 48,XXY,+13.
Fig. 8. A premature neonate with cebocephaly. The infant had anoph- thalmia, bilateral nasal atresia, alobar holoprosencephaly (ventral view) with a 4.5 × 5.5 × 6.0 cm dorsal cyst (not shown), atresia of left external auditory canal with hypoplastic malformed auricle, agenesis of left lung, left kidney and left ureter, hypoplasia of left posterior cra- nial fossa and left cerebellum, multiple skin tags, hemivertebrae, and absence of right umbilical artery.
Fig. 9. Front and lateral view of an infant with arrhinencephaly. The postmortem brain showed absence of olfactory tract and sulci and sep- tum pellucidum and fused thalami.
Fig. 10. A fetus with premaxillary agenesis showing facial dysmor- phism, including hypotelorism, absence of nose, median cleft lip and palate, and low-set ears. In addition, the fetus had thirteen pairs of ribs, and absence of uterus and left kidney. The pregnancy was terminated at 17 weeks gestation because of alobar holoprosencephaly detected by ultrasonography. The postmortem brain showed alobar prosen- cephaly with a cerebral vesicle. Gyri were not developed.
Fig. 12. An infant with hypotelorism and duplicated nose.
Fig. 13. A girl with mild hypotelorism, antimongoloid slant, and a cen- tral incisor.
Fig. 11. Four infants with premaxillary agenesis.
