Environmental Causes
The most common teratogen in humans known to cause holoprosencephaly (HPE) is maternal diabetes mellitus. Infants of diabetic mothers have a 1% risk (a 200-fold increase) for HPE [Barr et al 1983]. Other teratogens, including alcohol and retinoic acid, have been associated with HPE in animal models, although their significance in humans is not established [Johnson & Rasmussen 2010].
More recently, cholesterol-lowering agents (i.e., statins) have been associated with HPE, although a causal relationship between prenatal statin use and HPE in the infant has not yet been proven [Edison & Muenke 2004a, Edison & Muenke 2004b].
An animal model of maternal hypocholesterolemia has been shown to cause HPE. Preliminary studies in humans show that maternal hypocholesterolemia can be associated with HPE in her offspring [Edison & Muenke 2003; Kelley & Muenke, unpublished].
Heritable Causes
Cytogenetic Abnormalities Approximately 25%-50% of individuals with HPE have a chromosomal abnormality. Chromosomal abnormalities are nonspecific and either numeric or structural. Those with HPE and a normal karyotype cannot be distinguished from those with an abnormal karyotype on the basis of craniofacial abnormality or subtype of HPE; however, individuals with HPE as a result of a cytogenetic abnormality are more likely to have other organ system involvement [Olsen et al 1997].
Numeric chromosomal abnormalities include trisomy 13, trisomy 18, and triploidy. Arrhinencephaly is seen in approximately 70% of individuals with trisomy 13, which has a birth prevalence of 1:5000. Defects of the corpus callosum have been reported with trisomy 18 [Muenke & Beachy 2001, Solomon et al 2010c].
Structural chromosomal abnormalities associated with HPE have been reported in virtually all chromosomes, but the most frequent in descending order are deletions or duplications involving various regions of 13q, del(18p), del(7)(q36), dup(3)(p24-pter), del(2)(p21), and del(21)(q22.3) [Muenke & Beachy 2001, Dubourg et al 2007]. Many of these regions are known to harbor known genes associated with autosomal dominantnonsyndromic HPE (Table 1). Significant phenotypic variation exists among individuals with a similar cytogenetic deletion [Schell et al 1996].
Molecular Abnormalities
Copy number variants (CNVs). Array genomic hybridization (array GH) has identified copy number variants (CNVs) in 10% to 20% of all individuals with HPE [Bendavid et al 2009; Author, unpublished data]. These CNVs can include loci already known to be associated with HPE, as well other loci whose relationship to HPE is less well understood [Bendavid et al 2009; Author, unpublished data]. (Detection rates of CNVs may vary among testing laboratories and based on methodologies.) Because of changes in the availability, pricing, and power of array GH, this test has replaced karyotyping as one of the first-line tests in many situations; nonetheless, karyotyping is useful (e.g., to detect balanced translocations) and is an efficient and economical way to evaluate for many chromosome disorders that cause HPE [Pineda-Alvarez et al 2010, Solomon et al 2010c].
Mutations in Single Genes
Syndromic HPE. Approximately 18%-25% of individuals with HPE have a mutation in a single gene causing syndromic HPE. At least 25 different conditions have been described in which HPE is an occasional finding; the majority of these disorders are rare. Some of the more common include the following, categorized by mode of inheritance [Dubourg et al 2007]:
The most common teratogen in humans known to cause holoprosencephaly (HPE) is maternal diabetes mellitus. Infants of diabetic mothers have a 1% risk (a 200-fold increase) for HPE [Barr et al 1983]. Other teratogens, including alcohol and retinoic acid, have been associated with HPE in animal models, although their significance in humans is not established [Johnson & Rasmussen 2010].
More recently, cholesterol-lowering agents (i.e., statins) have been associated with HPE, although a causal relationship between prenatal statin use and HPE in the infant has not yet been proven [Edison & Muenke 2004a, Edison & Muenke 2004b].
An animal model of maternal hypocholesterolemia has been shown to cause HPE. Preliminary studies in humans show that maternal hypocholesterolemia can be associated with HPE in her offspring [Edison & Muenke 2003; Kelley & Muenke, unpublished].
Heritable Causes
Cytogenetic Abnormalities Approximately 25%-50% of individuals with HPE have a chromosomal abnormality. Chromosomal abnormalities are nonspecific and either numeric or structural. Those with HPE and a normal karyotype cannot be distinguished from those with an abnormal karyotype on the basis of craniofacial abnormality or subtype of HPE; however, individuals with HPE as a result of a cytogenetic abnormality are more likely to have other organ system involvement [Olsen et al 1997].
Numeric chromosomal abnormalities include trisomy 13, trisomy 18, and triploidy. Arrhinencephaly is seen in approximately 70% of individuals with trisomy 13, which has a birth prevalence of 1:5000. Defects of the corpus callosum have been reported with trisomy 18 [Muenke & Beachy 2001, Solomon et al 2010c].
Structural chromosomal abnormalities associated with HPE have been reported in virtually all chromosomes, but the most frequent in descending order are deletions or duplications involving various regions of 13q, del(18p), del(7)(q36), dup(3)(p24-pter), del(2)(p21), and del(21)(q22.3) [Muenke & Beachy 2001, Dubourg et al 2007]. Many of these regions are known to harbor known genes associated with autosomal dominantnonsyndromic HPE (Table 1). Significant phenotypic variation exists among individuals with a similar cytogenetic deletion [Schell et al 1996].
Molecular Abnormalities
Copy number variants (CNVs). Array genomic hybridization (array GH) has identified copy number variants (CNVs) in 10% to 20% of all individuals with HPE [Bendavid et al 2009; Author, unpublished data]. These CNVs can include loci already known to be associated with HPE, as well other loci whose relationship to HPE is less well understood [Bendavid et al 2009; Author, unpublished data]. (Detection rates of CNVs may vary among testing laboratories and based on methodologies.) Because of changes in the availability, pricing, and power of array GH, this test has replaced karyotyping as one of the first-line tests in many situations; nonetheless, karyotyping is useful (e.g., to detect balanced translocations) and is an efficient and economical way to evaluate for many chromosome disorders that cause HPE [Pineda-Alvarez et al 2010, Solomon et al 2010c].
Mutations in Single Genes
Syndromic HPE. Approximately 18%-25% of individuals with HPE have a mutation in a single gene causing syndromic HPE. At least 25 different conditions have been described in which HPE is an occasional finding; the majority of these disorders are rare. Some of the more common include the following, categorized by mode of inheritance [Dubourg et al 2007]:
- Autosomal Dominant
- Pallister-Hall syndrome
- Rubinstein-Taybi syndrome
- Kallmann syndrome
- Martin syndrome (with clubfoot, spinal anomalies)
- Steinfeld syndrome (with congenital heart disease, absent gallbladder, renal dysplasia, radial defects) (OMIM 184705)
- Ectrodactyly and ocular hypertelorism
- Pallister-Hall syndrome
- Autosomal recessive
- "Pseudotrisomy 13 syndrome," in which affected individuals have a normal karyotype and polydactyly. Other commonly seen features of trisomy 13, including scalp defects, overlapping fingers, and nail hypoplasia, are not generally observed [Cordero et al 2008].
- Smith-Lemli-Opitz syndrome [Kelley et al 1996, Weaver et al 2010]
- Meckel syndrome
- Genoa syndrome (with craniosynostosis) (OMIM 601370)
- Lambotte syndrome (with microcephaly, prenatal growth retardation, ocular hypertelorism) (OMIM 245552)
- Hydrolethalus syndrome (with hydrocephalus, polydactyly, and other anomalies) (OMIM236680)
- Facial clefts and brachial amelia (OMIM 601357)
- "Pseudotrisomy 13 syndrome," in which affected individuals have a normal karyotype and polydactyly. Other commonly seen features of trisomy 13, including scalp defects, overlapping fingers, and nail hypoplasia, are not generally observed [Cordero et al 2008].
- Autosomal dominant vs multifactorial
- Microtia-anotia (OMIM 600674) and other anomalies
- HPE-agnathia spectrum disorders
- Microtia-anotia (OMIM 600674) and other anomalies
- Unknown mode of inheritance
- Caudal dysgenesis [Martinez-Frias et al 1994]
- Caudal dysgenesis [Martinez-Frias et al 1994]