KS has a wide and variable clinical spectrum. Cranio-facial features include elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows with the lateral third displaying sparseness or notching; short columella with depressed nasal tip; large, prominent or cupped ears; cleft lip/palate or high-arched palate; and dental anomalies. If the stature is normal at birth, neonates soon present with growth delay and frequent failure to thrive of variable severity. Microcephaly is inconstant. Musculo-skeletal anomalies include brachydactyly V, brachymesophalangy, clinodactyly of fifth digits, spine abnormalities and joint hypermobility and dislocations. Dermatoglyphic abnormalities with persistence of fetal fingertip pads are another cardinal sign of KS. Almost all patients have mild to moderate intellectual deficit and may present with neurological manifestations such as hypotonia or seizures. Global developmental delay is frequent. Autism traits and hyperactivity have been observed but do not seem to be higher than general population rates. Hearing loss is frequent and may have a sensorineural cause or be a consequence of chronic otitis media due to craniofacial malformation or susceptibility to infection. Ocular findings are occasional and include blue sclerae, strabismus, ptosis, coloboma and corneal abnormalities. Congenital heart defects such as left-sided obstructive lesions or septal defects are frequent. Renal and urinary tract anomalies are less common but are present in approximately 25% of KS patients. In girls, premature thelarche can occur but does not require treatment unless there are other signs of premature puberty. Immune dysfunction, leading to autoimmune disorders and increased susceptibility to infection, has also been reported, mostly in adolescents.
KS is associated, in 45 to 80% of cases, with mutations in the MLL2 gene. KDM6A gene deletions have also been reported in a few cases.
