Novel homozygous ALX4 mutation causing frontonasal dysplasia‐2 in a patient with meningoencephalocele

Identification of a novel homozygous ALX4 mutation in two unrelated patients with frontonasal dysplasia type‐2

“…To date, five different homozygous mutations in the ALX4 gene were described in patients with FND‐2 (Alanay et al, ; Kariminejad et al, ; Kayserili et al, ; Kayserili, Altunoglu, Ozgur, Basaran, & Uyguner, ; Meloni et al, ). Our patients and those described before share the consistent clinical phenotype of calvarial defect, alopecia, broad and depressed nasal bridge, notched alae nasi, hypertelorism, blepharophimosis, and cryptorchidism (Supporting Information Table S1).…”

“…Despite these malformations of the occipital lobes, our patients and those described in the literature are free of neurological abnormalities. Furthermore, bilateral cystic masses (simulating the meningocele) over the PEM with intact meningeal membranes were observed either with heterozygous (c.730C > T and c.418C > T) or homozygous (c.207delG) ALX4 mutations (Mavrogiannis et al, ; Meloni et al, ; Saraç Sivrikoz et al, ). These meningocele‐like cysts were similarly observed in Patient 1 that increased in size with age.…”

“…Indeed, ALX4 acts in a dosage‐sensitive manner suggesting that milder loss of function mutations may lead to a milder phenotype. This was evidenced by the presence of mild phenotype reported with homozygous missense mutation (Kariminejad et al, ) when compared with those with homozygous ALX4 truncating mutations (nonsense and frameshift) (Alanay et al, ; Kariminejad et al, ; Kayserili et al, ; Meloni et al, ). Furthermore, heterozygous mutations of ALX4 gene were assumed to yield a PFM that is segregated in an autosomal dominant mode of inheritance with full penetrance (Bertola et al, ; Mavrogiannis et al, ; Saraç Sivrikoz et al, ; Valente et al, ).…”