Trigonocephaly With Short Stature And Developmental Delay

Clinical Features

Say and Meyer (1981) observed trigonocephaly in 3 males in 3 maternally related sibships, consistent with X-linked recessive inheritance. Autosomal dominant inheritance with low expressivity in women could not be excluded. The oldest of the 3, aged 30, was 162 cm tall and was moderately mentally retarded. The other 2, nephews of this man, had a closed posterior fontanel, very small anterior fontanel, and a marked frontal vertical ridge; narrow forehead; hypotelorism and marked retardation in weight, height, head circumference, and psychomotor development. Normally the major sutures of the cranial vault close between 28 and 32 years of age; the metopic suture closes much earlier, usually during the second or third year of life. Say and Meyer (1981) found no similar reported case and specifically distinguished the disorder from the trigonocephaly with minor anomalies reported in mother and son by Hunter et al. (1976) and from the Opitz trigonocephaly syndrome (211750).

Inheritance

The transmission pattern of SAMES in the family reported by Say and Meyer (1981) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 2 brothers, born of unrelated Indian parents, with features suggestive of Say-Meyer syndrome, including X-linked recessive inheritance, trigonocephaly, short stature, dysmorphic facial features, and impaired intellectual development, Muthusamy et al. (2019) identified a hemizygous splice site mutation in the HUWE1 gene (300697.0010). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; it was found in the unaffected mother. The molecular findings, as well as clinical features, confirmed that the patients had the Turner-type of X-linked mental retardation syndrome (MRXST; 309590). However, these patients were not part of the original family reported by Say and Meyer (1981).