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To date, a total of 22 patients from 11 unrelated families, of all origins, have been reported in the literature with pathogenic variants in EIF2S3. Only male patients are affected while carrier females are asymptomatic.

The phenotype is heterogeneous ranging from a severe, complete phenotype, which is associated to a recurrent frameshift variant (p.(Ile465Serfs*4), to a less severe and/or incomplete phenotype associated with various missense variants. Patients with missense variants present with inconstant features including developmental delay (90%), growth retardation (83%), microcephaly (83%), and more variably epilepsy (33%), and obesity (33%). Endocrinopathy including low growth hormone level, hypopituitarism and hypogonadism was described in 66%. Although intellectual disability is common in patients with missense variants, its severity varied from mild to moderate or severe, while all patients with the frameshift variant shared severe to profound intellectual disability. Early-onset diabetes is a recurrent feature found in patients with the recurrent frameshift variant, while hypoglycaemia and glucose dysregulation are not constant in patients with EIF2S3 missense variant.

MEHMO syndrome is caused by pathogenic variants in EIF2S3 (Xp22.11). The gene encodes the gamma subunit of the eukaryotic translation initiation factor-2, eIF2, essential for protein translation. Families with a recurrent frameshift variant p.(Ile465Serfs*4) in EIF2S3 exhibit a severe, full phenotype of MEHMO syndrome. The majority of patients with missense variants exhibit a less severe and/or incomplete phenotype.

The diagnosis is usually found by next generation sequencing (e,g Whole Exome Sequencing).

Differential diagnosis includes Wolcott-Rallison syndrome caused by pathogenic variants in EIF2AK3; primary microcephaly-mild intellectual disability-young-onset diabetes syndrome caused by TRMT10A or PPP1R15B; primary microcephaly-epilepsy-permanent neonatal diabetes syndrome caused by IER3IP1 pathogenic variants.

Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.

Transmission is X-linked recessive. Genetic counseling should be offered to at-risk couples (where the mother is a healthy carrier of a disease-causing variant) informing them that there is a 50% risk of having an affected male child at each pregnancy. Intrafamilial phenotypic variation is observed, most particularly concerning EIF2S3 missense variants.

Multidisciplinary care is needed for this multisystemic disorder; initially including neonatal care, and then with regular pediatric, endocrinology and neuropediatric follow-up. Regular glycemic controls are suggested.

The prognosis depends on the severity of the syndrome. Patients with missense variants usually have a normal lifespan while severely affected patients (in particular with the recurrent frameshift variant p.(Ile465Serfs*4)) could present a poor life prognosis.