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.

FIG. 1

Craniofacial phenotypes in patients with holoprosencephaly. From left to right: (a) synophthalmia and a proboscis in a patient with alobar holoprosencephaly; (b) severe hypotelorism, flat nasal bridge, bilateral colobomas, and midline cleft lip and palate in a patient with alobar holoprosencephaly; (c) hypotelorism, flat nasal bridge, and closely spaced nostrils in a patient with lobar holoprosencephaly; (d) hypotelorism, sharp nasal bridge, and single maxillary central incisor in an individual with a microform of holoprosencephaly. (Adapted from [20] and [25] with permission from Nature Publishing Group and BMJ Publishing Group, Ltd., respectively.)

Fig 2

Axial sections through cranial MR images of patients with holoprosencephaly, distinguished by type. MIHV: middle interhemispheric variant.(Adapted from [32] with permission from Elsevier.)

Fig 3

Recommended clinical protocol for diagnosing and elucidating causes of holoprosencephaly in patients. Each of the six major steps is medically indicated; within each step, bolded items are medically indicated or preferred, while others are performed if suggested by the clinical characteristics of the patient or at the discretion of the clinical laboratory. See text for more details.