Description

Scientific background

Patients with Lujan-Fryns syndrome (LFS), also known as X-linked intelligence reduction (XLMR) with Marfanoid habitus, present with Marfanoid habitus, craniofacial features, generalized muscle hypotonia, developmental delay, behavioral problems, and nasal speech. Thus, there is clinical overlap with other connective tissue disorders such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS). Inheritance is X-linked recessive, resulting in predominantly male patients, while female carriers are usually clinically inconspicuous.

The genetic cause are hemizygous variants in the MED12 gene, which encodes mediator complex subunit 12. Allelic disorders with MED12 variants include FG syndrome type 1 (FGS1) and X-linked Ohdo syndrome (XLOS). Subsequently, variants in the UPF3B and ZDHHC9 genes have also been described in patients with intelligence impairment and marfanoid habitus. These patients only partially exhibited the characteristic LFS facial abnormalities such as a long narrow face, prominent forehead, broad nasal root, short philtrum, micrognathia, and high palate.

References

Charzewska et al. 2018, Clin Genet 94:450 / Hackmann et al. 2016, Am J Med Genet 170A:94 / Lyons In: Pagon, Adam, Ardinger, et al., (eds). GeneReviews® (Updated 2016 Aug 11) / Callier et al. 2013, Clin Genet 84:507 / Schwartz et al. 2007, J Med Genet 44:472 / Tarpey et al. 2007, Nat Genet 39:1127 / Raymond et al. 2007, Am J Hum Genet 80:982