X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) is the most severe phenotype on the L1 spectrum and is predominantly known for its major feature: profound hydrocephalus, typically beginning before birth. Due to its prenatal onset (i.e. before the bones of the skull have fused together), hydrocephalus associated with HSAS results in progressive macrocephaly (abnormal enlargement of the skull) due to markedly increased intracranial pressure. The signs and symptoms of hydrocephalus can vary depending on severity and age of onset, however irritability (due to pain) and vomiting are common amongst infants with the condition. Without treatment, congenital hydrocephalus can be fatal in infancy. In less severe cases of untreated hydrocephalus, a child may progress beyond infancy but often experiences nausea and vomiting, missed developmental milestones (both physical and cognitive/social), diplopia (double vision), and papilledema (swelling of the optic disc) which can progress to permanent visual impairment due to increased intracranial pressure if definitive treatment is withheld. Neurological damage, caused by both hydrocephalus and poor neuronal development because of defects in the L1 cell adhesion molecule, results in nearly all people with HSAS experiencing severe intellectual disability.People living with HSAS will also frequently experience spasticity, a condition causing some muscles to be continuously contracted, thereby causing stiffness of the body and challenges with walking and speaking.
Spasticity is also known to cause difficulty in performing activities of daily living such as bathing and showering, dressing, and self-feeding.Despite HSAS frequently being considered an isolated disorder of the central nervous system, its genetic basis also causes musculoskeletal defects that result in more than half of males with HSAS displaying thumbs that are adducted (clasped, or brought inwards towards the palm). Specifically, this abnormal presentation of the hand is due to congenital malformations in the extensor pollicis brevis and/or extensor pollicis longus muscle of forearm. MASA syndrome
MASA syndrome is named after its four principle features: mental retardation, adducted thumbs (clasped, or brought inwards towards the palm), shuffling gait, and aphasia (a language disability affecting the comprehension and production of speech as well as reading and writing abilities). Diagnosis
A healthcare provider, usually a medical geneticist (a physician with special training in diagnosing and managing genetic disorders) can provide a clinical diagnosis of L1 syndrome by examining a patient and ordering certain imaging studies, however the presence of L1 syndrome can only be confirmed when a molecular diagnosis has been made through genetic testing.Often, the diagnostic odyssey for a person with L1 syndrome begins prenatally (before they are born) when prenatal ultrasounds reveal non-specific brain abnormalities, ventriculomegaly, or a non-existent or underdeveloped corpus callosum. Fetuses with X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) will typically have hydrocephalus severe enough to be discovered upon routine fetal ultrasound as early as 18–20 weeks gestation.