Management

ZIC2-associated HPE does not conform to the typical dogma of ‘the face predicts the brain’, as individuals with pathogenic ZIC2variants often present with significant brain malformations in the absence of severe craniofacial anomalies. As a result, ZIC2-associated cases may be underrecognised. Therefore, to ensure accurate management, the correct diagnosis must first be made using neuroimaging, coupled with screening of patient probands.

HPE encompasses a wide range of forebrain and midline defects, with an accompanying wide spectrum of clinical manifestations. A coordinated, multidisciplinary care team is required for clinical management of this complex disorder and management is highly variable depending on the severity of the condition. In the case of severe dysmorphisms, such as proboscis and cyclopia, early lethality is the rule. Survival during the first year of life is 54% for isolated HPE cases (non-syndromic) without severe craniofacial abnormalities, but long-term survival is possible even with the alobar or semilobar subtypes.

Middle interhemispheric variant and lobar HPE
In milder subtypes such as MIHV, presentation may not occur until after the age of 1 year with motor or speech delay, intellectual disability and behavioural difficulties. This type of HPE typically requires minimal medical intervention, however, support from speech pathologists, paediatricians and child developmental specialists is often beneficial.

Semilobar and alobar HPE
Individuals with the more severe HPE phenotypes often exhibit complex multisystem clinical manifestations requiring long-term management. Individuals with severe brain malformations commonly experience seizure disorders, diabetes insipidus and other hormonal deficiencies, neurodevelopmental delay and more.

Approximately 50% of children with HPE experience seizures, and 17% require cerebrospinal fluid shunts to manage hydrocephalus. This means close monitoring from neurologists and neurosurgical teams is required.

Further, ~70% of patients with classic HPE experience central diabetes insipidus due to malformation of the pituitary gland. Similarly, hormonal disorders relating to abnormal hypothalamic and pituitary hormones are common and ongoing management by endocrinological teams is needed.

Finally, management from speech and language pathologists, physiotherapists and occupational therapists to manage neurodevelopmental delay, motor impairment and feeding disorders is often required.