Thursday 20 November 2003
Definition: Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/200-1/250 conceptuses.
It is set of developmental anomalies that are associated with impaired midline cleavage of the embryonic forebrain, the absence of the olfactory bulbs and tracts, and midline dysplasia of the face, which is frequently associated with cleft lip and palate.
Holoprosencephaly is an etiologically heterogeneous entity.
Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported.
In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms.
Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent.
severe facial malformations
- cyclopia (alobar holoprosencephaly)
- ethmocephaly (alobar holoprosencephaly)
- cebocephaly (alobar holoprosencephaly)
- agenesis of nasal bones
- ocular hypotelorism
- facial cleft
- median cleft lip/cleft palate
midline skeletodental anomalies (malformations of midline structures anterior to the sella turcica comprising suture development and cartilage development)
- partial absence of the intermaxillary suture (in the region anterior to the central incisor)
- absence of the internasal suture
- partial absence of the metopic suture (caudal part)
- single midline nasal bone
- midline maxillary central incisor
- short nasal septum
- absence of crista galli
- partial absence of cartilaginous tissue anterior to the sella turcica
NB: In semilobar and lobar HPE, the brain is larger and there is partial separation of the hemispheres. Such cases are associated with variable psychomotor retardation depending on the pathology. Diabetes insipidus is frequent in these patients.
cebocephalic holoprosencephaly (one nostril)
To date, seven genes have been positively implicated in HPE: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and TDGF1. A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes SHH, ZIC2, SIX3 and TGIF. Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA).
In about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a "multiple-hit hypothesis" of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability.
- maternal diabetes (diabetic embryopathy) (1% RR x200)
- cholesterol metabolism defect ?
- alcohol ?
- retinoic acid ?
chromosomal diseases (25-50%)
- 2q37.1-2q37.3 deletion (HPE6)
- del(7)(q36) (HPE3)
- trisomy 13 (HPE5)
- del(13q) (HPE5)
- trisomy 18 (HPE4)
- 18p11.3 anomalies: del(18p) (HPE4)
- deletion of 21q22.3: del(21)(q22.3) (HPE1)
genetic non-syndromic holoprosencephaly (18-25%) (SHH, ZIC2, SIX3, TGIF, PTCH, GLI2, FAST1, TDGF1, DHCR7)
- HPE1 at 21q22.3 (MIM.236100)
- HPE2 at 2p21 (MIM.157170): mutations in the homeobox-containing SIX3 gene (603714)
- HPE3 at 7q36 (MIM.142945): mutations in the gene encoding the human sonic hedgehog homolog (SHH) (MIM.600725) (13% of cases; 50% of point-mutations; 38% of deletions/duplications)
- HPE4 at 18p11.3 (MIM.142946): mutations in the TGIF gene (MIM.602630)
- HPE5 at 13q32 (MIM.603073): mutations in the ZIC2 gene (MIM.603073)
- HPE6 at 2q37.1-q37.3 (MIM.605934)
- HPE7 at 9q22.3 (MIM.601309): mutations in PTCH gene coding for Patched protein
- Meckel syndrome (MKS)
- Smith-Lemli-Opitz syndrome (MIM.270400) (DHCR7 mutations at 11q12-q13 MIM.602858)
- dysgnathia complex (MIM.202650)
- pseudotrisomy 13 syndrome (MIM.264480)
- semilobar holoprosencephaly with craniosynostosis (MIM.601370)
fetal akinesia/hypokinesia sequence (MIM.306990)
pituitary anomalies with holoprosencephaly-like features (MIM.165230): GLI2 mutations
limb reduction defects
- Steinfeld syndrome
Between the fourth to sixth week of gestation, the forebrain (prosencephalon) is divided into the two hemispheres. Absence of this cleavage results in a spectrum of malformations called holoprosencephaly (HPE).
HPE is rare among live born infants but very common in embryogenesis. It has genetic and environmental causes.
Most cases are sporadic but there are also autosomal dominant, recessive, and X-linked forms. HPE also occurs as a component of multiple malformation syndromes and in several chromosomal abnormalities.
Genetic HPE is associated with four genes and has been linked to seven additional chromosomal loci. The best known HPE gene is the Sonic Hedgehog (SHH) gene on 7q36 which is important for ventral patterning of the forebrain. Mutations of this gene cause autosomal dominant HPE.
Defective cholesterol synthesis inhibits SHH signaling resulting in HPE-like malformations. Retinoic acid participates in the SHH system.
Excess retinoic acid during embryogenesis (from administration of Accutane for acne) inhibits SHH and causes HPE and other malformations.
The HPE-associated gene TG-interacting factor (TGIF) on 18p11, regulates retinoic acid. Mutations of TGIF result in unrestrained retinoic acid activity and HPE. The multitude of genes and chromosomal loci associated with HPE underlines the complexity of genetic programs that are involved in embryonic patterning and the intricate interaction between genes and environmental factors.
The chemical messages that induce the forebrain to divide into two hemispheres, including SHH, are first expressed in the prechordal plate, an area rostral to the notochord that gives rise to the facial mesoderm. SHH is also involved in craniofacial development.
Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V. Holoprosencephaly. Orphanet J Rare Dis. 2007 Feb 2;2:8. PMID: 17274816
Roessler E, Muenke M. How a Hedgehog might see holoprosencephaly. Hum Mol Genet. 2003 Apr 2 ;12(Suppl 1) :R15-25. PMID : 12668593