Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation

Hahn, Jin S.; Barnes, Patrick D.

doi:10.1002/ajmg.c.30238

Cited by 143 publications

(152 citation statements)

References 30 publications

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“…7 However, classifying these mild midline abnormalities as HPE may be controversial. 8 Many who study HPE consider the presence of the fornix, septum, and AC to essentially exclude the diagnosis of HPE (personal communication, A. James Barkovich, Jan. 5, 2005), especially when the 2 cerebral hemispheres appear nearly completely separated. Nevertheless, both the preoptic and septal regions are telencephalic structures (with the former being closely related in structure to the hypothalamus, a diencephalic structure).…”

Section: Discussionmentioning

confidence: 99%

Septopreoptic Holoprosencephaly: A Mild Subtype Associated with Midline Craniofacial Anomalies

Hahn¹,

Barnes²,

Clegg³

et al. 2010

AJNR Am J Neuroradiol

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SUMMARY: HPE is a congenital brain malformation characterized by failure of the prosencephalon to divide into 2 hemispheres. We have identified 7 patients who have a mild subtype of HPE in which the midline fusion was restricted to the septal region or preoptic region of the telencephalon. This subtype, which we call septopreoptic HPE, falls in the spectrum of lobar HPE, but lacks significant frontal neocortical fusion seen in lobar HPE. Other imaging characteristics include thickened or dysplastic fornix, absent or hypoplastic anterior CC, and single unpaired ACA. The SP was fully formed in 4, partially formed in 2, and absent in 1. Mild midline craniofacial malformation, such as SMMCI and CNPAS were found in 86% and 71%, respectively. Patients outside of infancy often manifested language delay, learning disabilities, or behavioral disturbances, while motor function was relatively spared.ABBREVIATIONS: AC ϭ anterior commissure; ACA ϭ anterior cerebral artery; CC ϭ corpus callosum; CNPAS ϭ congenital nasal piriform aperture stenosis; FSPGR ϭ fast-spoiled gradient-recalled; HPE ϭ holoprosencephaly; IHF ϭ interhemispheric fissure; MPR ϭ multiplanar reconstructed; SMMCI ϭ single median maxillary central incisor; SP ϭ septum pellucidum; SPGR ϭ spoiled gradient-recalled; V3 ϭ third ventricle H PE is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into 2 hemispheres, a process normally complete by the fifth week of gestation.1 As the name "HPE" implies, these nonseparated prosencephalic structures involve parts of the telencephalon and diencephalon. HPE has traditionally been classified according to DeMyer's 3 grades of severity: alobar, semilobar, and lobar.2 In addition to these classic forms, a subtype of HPE, the middle interhemispheric variant or syntelencephaly, has been characterized. 3,4 In these types of HPE, there is significant nonseparation of the neocortex of the cerebral hemispheres. In the alobar type, the entire hemispheres are involved, and in the semilobar and lobar types, the frontal lobes are primarily involved. In the middle interhemispheric variant, there is nonseparation of the posterior frontal and anterior parietal lobes in the perirolandic region. We report a series of patients who have a very mild form of HPE, in which the nonseparation is restricted to the septal (subcallosal) and/or preoptic regions or both regions (Fig 1). Patients with this type of HPE often present initially with mild midline craniofacial malformations, including SMMCI and CNPAS. Our aim was to characterize the neuroimaging and clinical findings of a mild subtype of HPE that has less neocortical fusion than classic lobar HPE. Materials and MethodsWe searched the neuroimaging data base of the Carter Centers for Research in Holoprosencephaly and Related Malformations for patients who met the criterion for a mild subtype that we call "septopreoptic HPE." The imaging criterion for inclusion was abnormal fusion restricted to the septal (subcallosal) and preoptic telencephalic re...

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Section: Discussionmentioning

confidence: 99%

Septopreoptic Holoprosencephaly: A Mild Subtype Associated with Midline Craniofacial Anomalies

Hahn¹,

Barnes²,

Clegg³

et al. 2010

AJNR Am J Neuroradiol

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“…Inherited forms are classically autosomal dominant with a wide range of phenotypic expression. At the more severe end of the spectrum, patients may have frank HPE, with incomplete cerebral hemispheric separation and accompanying midline craniofacial anomalies related to abnormal signaling from the region of the developing forebrain [Cohen, 2006;Hahn and Barnes, 2010;Roessler and Muenke, 2010;Solomon et al, 2010;Mercier et al, 2011]. At the mildest end of the spectrum, often termed 'microform' HPE, patients may have normal brains by conventional neuroimaging, but display subtle craniofacial anomalies consistent with a midline defect, including hypotelorism (closely spaced eyes), a flat or sharp nasal bridge, choanal stenosis, or a single maxillary central incisor (SMCI) [Cohen, 2006;Lacbawan et al, 2009;Solomon et al, 2009Solomon et al, , 2010Mercier et al, 2011].…”

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confidence: 99%

High Intellectual Function in Individuals with Mutation-Positive Microform Holoprosencephaly

et al. 2012

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Holoprosencephaly is the most common malformation of the forebrain and typically results in severe neurocognitive impairment with accompanying midline facial anomalies. Holoprosencephaly is heterogeneous and may be caused by chromosome aberrations or environmental factors, occur in the context of a syndrome or be due to heterozygous mutations in over 10 identified genes. The presence of these mutations may result in an extremely wide spectrum of severity, ranging from brain malformations incompatible with life to individuals with normal brain findings and subtle midline facial differences. Typically, clinicians regard intellectual disability as a sign that a parent or relative of a severely affected patient may be a mildly affected mutation ‘carrier’ with what is termed microform holoprosencephaly. Here we present 5 patients with clear phenotypic signs of microform holoprosencephaly, all of whom have evidence of above-average intellectual function. In 4 of these 5 individuals, the molecular cause of holoprosencephaly has been identified and includes mutations affecting SHH, SIX3, GLI2, and FGF8. This report expands the phenotypic spectrum of holoprosencephaly and is important in the counseling of patient and affected families.

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“…Overall, the neuroimaging findings in the propositus were consistent with classic lobar-type holoprosencephaly [Hahn and Barnes, 2010]. We attempted to evaluate the correlation between development and neuroimaging characteristics among previously reported patients with Hartsfield syndrome.…”

Section: Discussionmentioning

confidence: 91%

Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting

Tamura¹,

Okuno²,

Kosaki³

et al. 2012

American J of Med Genetics Pt A

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The combination of holoprosencephaly and ectrodactyly, also known as Hartsfield syndrome, represents a unique genetic entity. An X-linked recessive mode of transmission has been suggested for this condition based on the observation that male patients have preferentially been affected. Thus far, no candidate genes have been suggested on the X chromosome. We report a male patient with a full-blown Hartsfield syndrome phenotype who had microduplication at Xq24 involving four genes. He presented with bilateral ectrodactyly of the hands (both hands had four fingers with a deep gap between the 2nd and 3rd digits), cleft lip and palate, and a depressed nasal bridge. Magnetic resonance imaging of the brain revealed lobar holoprosencephaly. His G-banded karyotype was normal. Array comparative genomic hybridization (CGH) using the Agilent 244K Whole Human Genome CGH array revealed a microduplication at Xq24 of 210 kb. Parental testing revealed that the deletion was derived from the asymptomatic mother. Of the genes on the duplicated interval, the duplications of SLC25A43 and SLC25A5 appeared to be the most likely to explain the patient's phenotype. From a clinical standpoint, it is important to point out that the propositus, who performs relatively well with holoprosencephaly and has a developmental quotient around 70, has survived multiple life-threatening episodes of hypernatremia. Awareness of the risk of hypernatremia is of great importance for the anticipatory management of patients with ectrodactyly and an oral cleft, even in the absence of overt hypotelorism.

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Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation

Cited by 143 publications

References 30 publications

Septopreoptic Holoprosencephaly: A Mild Subtype Associated with Midline Craniofacial Anomalies

Septopreoptic Holoprosencephaly: A Mild Subtype Associated with Midline Craniofacial Anomalies

High Intellectual Function in Individuals with Mutation-Positive Microform Holoprosencephaly

Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting

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