Reassessment of holoprosencephaly–diencephalic hamartoblastoma (HDH) association

We report on a 23‐week fetus with a hypothalamic hamartoma, lobar holoprosencephaly, right anophthalmia, and facial asymmetry, features which are consistent with the h oloprosencephaly– d iencephalic h amartoblastoma (HDH) association. In an attempt to better delineate HDH, we reviewed 19 published patients with similar features. The HDH clinical spectrum ranges from classic holoprosencephaly with micro/anophthalmia, multiple additional findings in non‐contiguous structures and early lethality, to isolated microforms of holoprosencephaly. Associated cephalic features mainly include cortical/neuronal migration defects (39%), meningeal anomalies (28%), brainstem/posterior fossa malformations (22%), dysmorphic ears (41%), facial asymmetry (35%), and hypoplastic mandible (29%). Fifty‐three percent of patients have additional extra‐cephalic malformations, for example, vertebral/rib segmentation defects (50%), hypo/aplastic lungs (38%), congenital heart defect (29%), and urinary anomalies (29%). HDH shows etiological heterogeneity, that is, teratogenic exposure, chromosome imbalances, autosomal recessive as well as dominant “de novo” mutations. Several features could directly result from a disruptive sequence caused by an early hamartoma which alters the development of forebrain, hindbrain, meninges, and 1st–2nd branchial arches, although the pleiotropic action of genetic/environmental factors cannot be excluded. HDH does not emerge as a distinct syndrome, but other hypotheses, including separate conditions within a common pathway and the developmental field defect theory, are discussed. © 2007 Wiley‐Liss, Inc.