Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations.

Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability.

Severe isolated exudative vitreoretinopathy caused by biallelic FZD4 variants.

Familial exudative vitreoretinopathy (FEVR) is linked to disruption of the Norrin/Frizzled-4 signaling pathway, which plays an important role in retinal angiogenesis. Severe or complete knock-down of proteins in the pathway also causes syndromic forms of the condition. Both heterozygous and biallelic pathogenic variants in the FZD4 gene, encoding the pathway's key protein frizzled-4, are known to cause FEVR.

MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly.

MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date. The disorder is caused by missense variants in the MSMO1 gene encoding methylsterol monooxygenase 1, leading to the accumulation of methylsterols. Clinically, MSMO1 deficiency is characterized by growth and developmental delay, often in association with congenital cataracts, microcephaly, psoriasiform dermatitis and immune dysfunction.