Endocrine Abstracts

We present 3 children in a single centre with Myhre syndrome (MS) due to a heterozygous SMAD4 Ile500val mutation. Consistent features were brachydactyly, joint restriction, muscular hypertrophy, genital abnormalities, conductive hearing loss and developmental delay. SGA and height were variable. Diagnosis was made by next generation sequencing in patients 1 and 3 and on the skeletal survey in patient 2. Retrospectively, features of Myhre syndrome were present on the skeletal survey in all 3 patients, at young age.

Discussion: MS has been described in under 100 patients. MS is mostly caused by SMAD4 Ile500Val gain-of-function mutations(GOF) resulting in growth retardation and excessive fibrosis leading to keloid formation, cardiac fibrosis and tracheal stenosis after trauma/intervention. Making early diagnosis is important to avoid non-essential invasive procedures. SMAD4 is the central intracellular mediator of TGF β and BMP signalling and inhibits chondrocyte differentiation and hypertrophy, and mice with SMAD4 deletion in chondrocytes are dwarved. Gain-of-function leads to abnormal extracellular matrix formation, although the effect on growth plate chondrocytes is unclear. Neurosecretory dysfunction and variable response to GH has been described, in line with findings in patient 1. The mechanism for the neurosecretory dysfunction is not known.

Conclusion: MS may be more common than previously thought. SGA and height deficit are variable. GH treatment might increase height but can also accentuate muscular hypertropy. Skeletal surveys in our patients showed features at early age, and skeletal survey may therefore aid early diagnosis.

Clinical characteristics were as follows: