Holoprosencephaly: A guide to diagnosis and clinical management

Abstract

Context Holoprosencephaly affects 1 in 8,000 live births and is the most common structural anomaly of the developing forebrain, resulting in facial dysmorphism, neurologic impairment, and additional clinical sequelae. Given the increasing relative contribution of genetic diseases to perinatal morbidity and mortality in India, proper recognition and management of holoprosencephaly can improve care for a significant number of affected Indian children. Evidence Acquisition We used the PubMed database (search terms: “holoprosencephaly,” “HPE,” “holoprosencephaly India”) and cross-referenced articles regarding holoprosencephaly, using our research group’s extensive experience as a guide for identifying seminal papers in the field. Results Holoprosencephaly is classified into four types based on the nature of the brain malformations as seen on neuroimaging and/or pathologic examination, with typically recognizable craniofacial phenotypes. Despite the identification of several genetic loci and other etiologic agents involved in pathogenesis, additional causes are elusive. Moreover, satisfactory explanations for phenomena such as incomplete penetrance and variable expressivity are lacking. Conclusions For each patient, pediatricians should follow a diagnostic protocol including dysmorphology examination, complete family history and ascertainment of risk factors, and neuroimaging. Many medical issues, including hypothalamic dysfunction, endocrinologic dysfunction, motor impairment, respiratory issues, seizures, and hydrocephalus should be prioritized in management. Pediatricians should work with genetic specialists to identify syndromic forms and to perform cytogenetic investigation, molecular screening, and genetic counseling in order to fully characterize prognosis and recurrence risk.

Diffusion Tensor Imaging and Fiber Tractography in Syntelencephaly

“…8,9 This embryologic process is normally complete by the fifth week of gestation. The etiology of HPE is very heterogeneous and includes environmental and genetic causes.…”

Early two-stage repair of clefts in holoprosencephaly

“…Trisomy 13 and other chromosomal abnormalities accounted for 50% of HPE, while mutations in Sonic Hedgehog (SHH) accounted for 17% of familial cases (Bullen et al, 2001). Improvements in our understanding and medical management have improved outcomes, particularly for less severe phenotypes (Chaudhary et al, 2011, Raam et al, 2011. This is evidenced by a hundred percent of lobar HPE patients surviving year one with an average age of 4.6 years-of-age at last follow up (Bullen et al, 2001).…”

Incidence and Magnetic Resonance Imaging

“…In a large series of 4,157,224 births, the same authors observed 370 infants with suspected holoprosencephaly (0,009%) stressing that isolated HPE was homogeneous among the 11 sampled countries, increasing from 0.5/10,000 births to 1/10,000 births between 1967 and 2000% [6]. The early embryonic occurrence may be even higher with prevalence of 1:250 in embryos [7] but may not be detected due to most fetuses aborting in early gestation [2]. In our small series of 4000 MRI explorations in children of different ages (from newborns to 15 years old) only three cases harboring HPE were diagnosed, accounting for almost 0.05%.…”

“…Both genetic and teratogen factors are responsible for the development of HPE [1]. Rare in absolute terms, HPE is the most common brain abnormality and is seen in 1 per 8000-16,000 live births [2][3][4]. In an analysis of 21 HPE epidemiologic articles Orioli IM and Castilla EE [5] found that the pregnancy outcomes had relevant impact on the incident rate of HPE, being lower than 1 per 10,000 in live and stillbirth and between 40-50 per 10000 in aborted embryos.…”