HARD Syndrome

HARD is an acronym for hydrocephalus, agyria, and retinal dysplasia. Very rare and severe autosomal recessive syndrome quickly lethal, with major neurologic impairment. It is characterized by type II lissencephaly in association with retinal dysplasia, obstructive hydrocephalus, and agenesis of the corpus callosum. Affected infants typically have severe growth failure, severe microcephaly, seizures, microphthalmia, and cataracts.

Walker-Walburg Syndrome; Warburg Syndrome; Chemke Syndrome; Pagon Syndrome (different from Pagon Bird Detter Syndrome); Cerebroocular Dysgenesis (COD); Cerebroocular Dysplasia Muscular Dystrophy Syndrome (COD MD).

Autosomal recessive.

Caused by mutation in the gene encoding protein O-mannosyl transferase. Could be related to a primitive meningeal pathology (neurocristopathy).

Clinical features. Prenatal diagnosis is possible.

Present at birth with polyhydramnios, decreased fetal movement and growth retardation. It is usually lethal within the first few months of life. This complex polymalformative disease involves the head with neurologic malformations (microcephaly, microtia, agyria, hydrocephalus type II, lissencephaly, corpus callosum and pellucidum agenesis, disorganized brain cytoarchitecture, cerebellar malformation, ventriculomegaly and polymicrogyria), ear (absent auditory canals, low-set and bat ears), eyes (retinal detachment, cataract, microphthalmia, retinal pigmentary changes, anterior chamber malformation, hyperplastic primary vitreous, optic nerve hypoplasia, coloboma, glaucoma, and corneal clouding), and mouth (cleft lip/palate). Profound mental retardation and seizures are constant. Other features can include imperforate anus, genital abnormalities (cryptorchidism, small penis and testes), renal dysplasia, congenital contractures, and muscular dystrophy.

Evaluate neurologic function (clinical, history, CT, MRI, EEG), renal function (clinical, echography laboratory investigations including urea, creatinine, electrolytes), and muscular function (clinical, serum creatine kinase level).

Careful intraoperative positioning is needed because of contractures and muscular anomalies. Avoid procedures that can increase intracranial or intraocular pressure, considering the neurologic and ocular malformations. Ocular signs for measurement of the depth of anesthesia cannot be used in these patients.

Atropine must be avoided because of ocular lesions. Consider interaction between antiepileptic treatment and anesthetic drugs. Succinylcholine use is not recommended because of muscular dystrophy and risk of hyperkalemic response. Ketamine probably should be avoided because of its effect on intracranial and intraocular pressure.

HARDE Syndrome (Walker-Walburg Harrod Doman Keele Syndrome): Presents all the characteristics of the HARD syndrome plus encephalocele. Lissencephaly, malformation of the cerebellum, mental impairment, seizures, hypotonia, and eventually spastic quadriplegia accompany the clinical presentation. Dandy-Walker malformation, cleft lip/palate, microcephaly, and microphthalmia occasionally present.

Harrod Syndrome: Autosomal recessive condition characterized by mental retardation, unusual facial appearance, hypotelorism, high arched palate, numerous genitourinary anomalies, hydrocephalus, and pyloric stenosis.