Myhre syndrome

Myhre syndrome is a rare genetic disorder.

History

This disorder was first reported in 1981.^[1]

First described in 1981 by Myhre, Ruvalcaba and Graham, the Myhre syndrome is characterized by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism, short philtrum), thick skin, generalized muscle hypertrophy and restricted joint mobility ^[2].

Genetics

It is inherited as an autosomal dominant disorder.

It is due to mutations in the SMAD4 gene.^[3] This gene encodes a protein - transducer mediating transforming growth factor beta.

The patients of this disease exhibit hypertrophic phenotype in their muscle tissues. Myostatin target genes are found to be downregulated while bone morphogenetic protein (BMP) target genes display both upregulated and downregulated genotypes. ^[4].

SMAD4 encodes a protein belonging to the eightmember family of SMADs, which is divided into three functional classes: the receptorregulated SMADs (RSMADs: SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8), the co-mediator SMAD (SMAD4) and the inhibitory SMADs (SMAD6 and SMAD7). SMAD2 and SMAD3 respond to TGF-β and activin, and SMAD1, SMAD5 and SMAD8 function in BMP signaling pathways. After being activated, receptor-regulated SMADs form heterodimers with SMAD4 and translocate into the nucleus to induce or repress the expression of TGF-β and BMP target genes ^[5].

Clinical

The clinical presentation is variable but includes

developmental and growth delay
athletic muscular built
skeletal anomalies
joint stiffness
characteristic facial appearance
deafness
variable cognitive deficits

The facial abnormalities include:

blepharophimosis (an abnormally narrow gap between the upper and lower eyelids)
maxillary hypoplasia (underdevelopment of the upper jaw)
prognathism (prominent lower jaw)

The skeletal abnormalities include:

short stature
square body shape
broad ribs
iliac hypoplasia
brachydactyly
flattened vertebrae
thickened calvaria

Congenital heart disease and undescended testes have also been reported in association with this syndrome.

References

^ Myhre SA, Ruvalcaba RHA, Graham CB (1981) A new growth deficiency syndrome. Clin Genet 20: 1-5
^ Myhre SA, Ruvalcaba RH and Graham CB. A new growth deficiency syndrome. Clin Genet 1981: 20: 1-5.
^ Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M (2014) Novel SMAD4 mutation causing Myhre syndrome. Am J Med Genet A doi: 10.1002/ajmg.a.36544
^ Le Goff, Carine.; et al. (2012). "Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome". NATURE GENETICS. 44: 85–88. {{cite journal}}: Explicit use of et al. in: |first1= (help)
^ Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nature genetics. 2012;44(1):85-8.

[Myhre1981-1] Myhre SA, Ruvalcaba RHA, Graham CB (1981) A new growth deficiency syndrome. Clin Genet 20: 1-5

[2] Myhre SA, Ruvalcaba RH and Graham CB. A new growth deficiency syndrome. Clin Genet 1981: 20: 1-5.

[Caputo2014-3] Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M (2014) Novel SMAD4 mutation causing Myhre syndrome. Am J Med Genet A doi: 10.1002/ajmg.a.36544

[4] Le Goff, Carine.; et al. (2012). "Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome". NATURE GENETICS. 44: 85–88. {{cite journal}}: Explicit use of et al. in: |first1= (help)

[5] Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nature genetics. 2012;44(1):85-8.

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