Holoprosencephaly (HPE) is a congenital brain malformation that occurs when the embryonic forebrain fails to properly divide into two separate cerebral hemispheres during early gestation, typically between the 18th and 28th days of pregnancy. This developmental anomaly can affect both brain structure and facial features. While severe forms often lead to poor outcomes in infancy, a spectrum of severity exists, allowing some individuals with milder forms to survive into adulthood.
The Spectrum of Holoprosencephaly
Holoprosencephaly presents across a wide spectrum of severity, categorized into distinct types based on the degree of forebrain division. The most severe form is alobar HPE, characterized by a complete failure of the forebrain to divide, resulting in a single, centrally located ventricle and fused deep gray nuclei.
Semilobar HPE represents a partial division, where the cerebral hemispheres are fused anteriorly but separate posteriorly, and a single ventricular cavity may still be present. Lobar HPE is considered the mildest of the classic forms, with nearly complete brain division, though there may be partial fusion of the frontal horns of the lateral ventricles and an absent septum pellucidum. The middle interhemispheric fusion (MIHF) variant, also known as syntelencephaly, is a distinct type where the posterior frontal and parietal lobes fail to separate, while other brain regions are typically cleaved. Lobar HPE and MIHF are generally associated with better outcomes and higher rates of survival into adulthood compared to the more severe alobar and semilobar forms.
Clinical Manifestations in Adulthood
Adults with milder forms of holoprosencephaly exhibit a range of clinical manifestations, often reflecting the degree of brain involvement. Craniofacial features can be subtle in mild cases, such as closely spaced eyes, a flattened nasal bridge, or a single central incisor. More pronounced facial characteristics, like cleft lip and palate, may also be present.
Neurological issues are common and include seizures, affecting about 50% of individuals with HPE. Motor control difficulties, such as spasticity or poor coordination, are also frequently observed, impacting mobility and daily activities. Hydrocephalus, an accumulation of cerebrospinal fluid in the brain, can occur and may necessitate shunt placement.
Endocrine system dysfunction is common for adults with HPE, particularly issues stemming from the pituitary gland. Diabetes insipidus, a condition affecting water balance, is reported in up to 70% of individuals with classic HPE. Other hormonal imbalances, such as hypothyroidism (affecting 11%), hypocorticism (affecting 7%), and growth hormone deficiency (affecting 5%), are also common and require ongoing management. Cognitive and developmental function varies widely, from severe intellectual disability in more affected individuals to normal or near-normal intelligence in those with the mildest forms. Many adults with milder HPE may experience learning disabilities or challenges with executive functions, but they can often achieve semi-independent or independent living with appropriate support.
Long-Term Health Management
Long-term health management for an adult with holoprosencephaly requires a comprehensive, multidisciplinary approach tailored to their specific needs. Neurologists manage seizures, often with anti-seizure medications. For individuals with hydrocephalus, neurosurgical interventions like ventriculoperitoneal (VP) shunt placement are often necessary.
Endocrinologists manage hormonal imbalances, providing lifelong care for conditions such as diabetes insipidus, growth hormone deficiency, and thyroid or adrenal dysfunctions. Physical and occupational therapists help individuals improve motor skills, manage spasticity or dystonia, and enhance their ability to perform daily living activities. Neuropsychologists offer assessments and support for cognitive and executive function challenges, helping individuals develop strategies for learning and independent living. Regular monitoring, including MRI scans, helps track brain structure changes and identify new or evolving health issues. Nutritional support can be arranged for those with persistent feeding difficulties or gastrointestinal problems.
Prognosis and Life Expectancy
The prognosis and life expectancy for individuals with holoprosencephaly are highly variable, largely dependent on the severity of the brain malformation and associated medical complications. While the most severe form, alobar HPE, is frequently associated with stillbirth or death shortly after birth, individuals with milder forms can survive for many decades.
For those with semilobar or lobar HPE, more than 50% may live beyond 12 months, often surviving into adulthood. Life expectancy in adults with HPE is influenced by the management of health issues like seizures, endocrine dysfunction, and respiratory problems. With consistent and comprehensive medical care, individuals with milder forms of HPE can experience improved quality of life and a longer lifespan.