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  • Updated 11.05.2023
  • Released 10.21.1994
  • Expires For CME 11.05.2026




In this updated review of holoprosencephaly, the author discusses basic diagnostic anatomical features, pathogenetic and etiologic factors, as well as genetic, epidemiologic, and other data essential to understanding this complex disorder. Research indicates that the diverse phenotypic variations may stem from a host of genetic mutations and is further suggestive of gene-environment interactions. In severe forms, the disease is lethal. The treatment of patients with less severe forms continues to be refined but can be substantial.

Key points

• Holoprosencephaly is the most common congenital malformation to affect the forebrain and often the face in liveborn infants.

• In its most severe forms, holoprosencephaly is lethal; in milder forms, prolonged survival is possible but may require specialized, long-term care.

• Hydrocephalus may occur because of atresia of the third ventricle or midbrain cerebral aqueduct.

• Causes are diverse and include teratogens (maternal diabetes mellitus, ethyl alcohol, cholesterol requirements for hedgehog signaling), chromosomal abnormalities (most often trisomy 13), and gene mutations (most commonly SHH, SIX3, ZIC2, and TGIF), with gene-environmental interactions hypothesized. Most mutations occur de novo, and nearly three-quarters of cases do not have a recognized genetic cause.

• Despite this, a genetic diagnosis is lacking in some 80% to 90% of patients without aneuploidy. Environmental factors and maternal exposure to teratogenic toxins in early pregnancy are epigenetic factors that may interact with genetics.

Historical note and terminology

The earliest references to holoprosencephaly were from ancient mythology and generally involved cyclopic individuals.

These writings presumably had a basis in fact, for cyclopia occurs naturally in humans and a variety of animals. During the 16th and 17th centuries, several of the natural philosophers described cyclopic individuals, but these were still pictured with both real and imaginary features. The late 18th and 19th centuries brought more accurate portrayals. Sommering's atlas contains a precise line drawing of a full-term hydrocephalic cranium with a rudimentary, single nostril nose; olfactory nerves were absent (277). In 1832, Isidore Geoffrey Saint-Hilaire produced a detailed if somewhat arbitrary morphological classification of holoprosencephaly, the "cyclocephalians," whose details remain largely valid today (92; 278). Taruffi reworked Geoffrey Saint-Hilaire's scheme, using a now defunct term, "hypoproso-aplasia" (288).

By the late 19th century, the external facial features of holoprosencephaly were well documented. The first experimental production of holoprosencephaly was by Dareste (70), and in 1882 Kundrat described the cerebral changes of holoprosencephaly, including absent olfactory nerves, coining the term "arrhinencephaly" (152).

The 20th century brought further developments, first in the anatomic and clinical delineation of the disorder and later in cytogenetics. Yakovlev used the term "holotelencephaly" to describe a cerebrum that had failed to develop into separate hemispheres (312). DeMyer and Zeman first used the term "holoprosencephaly," feeling that the word more accurately described the anomaly as being prosencephalic rather than telencephalic in origin and scope (73). DeMyer and Cohen steadfastly contributed to the clinical understanding of the disorder, and Siebert and colleagues added to the fund of morphologic knowledge. Munke (or Muenke) and colleagues have extended the genetic understanding of this disorder considerably, mapping several genes associated with holoprosencephaly (193; 231).

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