Definition: A 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, which occurs with a frequency of about 1 in 16,000 live births and about 1 in 200 spontaneous abortions, is an etiologically heterogeneous entity.

Synopsis

 cyclopia
 ethmocephaly
 cebocephaly
 agenesis of nasal bones
 ocular hypotelorism
 facial cleft
 median cleft lip/palate
 alobar holoprosencephaly
 endocrine dysgenesis

• absent pituitary gland
• hypoplastic adrenal glands

 micropenis

Etiology

 teratogenic causes

• maternal diabetes (diabetic embryopathy) (RR x200)

 chromosomal diseases

• del(2)(p21)
• 2q37.1-2q37.3 deletion (HPE6)
• dup(3pter)
• 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)

 non-syndromic holoprosencephaly

• 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)
• 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

 syndromic holoprosencephaly

• Meckel syndrome
• pseudotrisomy 13 syndrome
• Smith-Lemli-Opitz syndrome (MIM.270400)
• dysgnathia complex (MIM.202650)
• pseudotrisomy 13 syndrome (MIM.264480)
• semilobar holoprosencephaly with craniosynostosis (MIM.601370)

Associations

 fetal akinesia/hypokinesia sequence (MIM.306990)
 pituitary anomalies with holoprosencephaly-like features (MIM.165230): GLI2 mutations
 limb reduction defects

• Steinfeld syndrome

References

 Roessler E, Muenke M. How a Hedgehog might see holoprosencephaly. Hum Mol Genet. 2003 Apr 2 ;12(Suppl 1) :R15-25. PMID : #12668593#