Myhre syndrome

Abstract

Myhre syndrome (MS) is a developmental disorder characterized by typical facial dysmorphism, thickened skin, joint limitation and muscular pseudohypertrophy. Other features include brachydactyly, short stature, intellectual deficiency with behavioral problems and deafness. We identified SMAD4 as the gene responsible for MS. The identification of SMAD4 mutations in Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature (LAPS) cases supports that LAPS and MS are a unique entity. The long-term follow up of patients shows that these conditions are progressive with life threatening complications. All mutations are de novo and changing in the majority of cases Ile500, located in the MH2 domain involved in transcriptional activation. We further showed an impairment of the transcriptional regulation via TGFβ target genes in patient fibroblasts. Finally, the absence of SMAD4 mutations in three MS cases may support genetic heterogeneity.

Myhre-LAPs syndrome and intubation related airway stenosis: keys to diagnosis and critical therapeutic interventions

“…Including our series of 4 patients reported here, 2 of which had previously been described by Lindor et al, the total number of cases of MLS reported in the literature is now 63 [1][2][3][4]7,8]. Of these patients, 8/63 (13%) had laryngotracheal stenosis reported as a manifestation of their disease including the 4 patients described above.…”

“…Two patients (case 1 and case 2) have been described previously at the authoring institution and been reviewed by others [2,3]. In addition, we present two new adult cases of MLS (case 3 and case 4) that have never previously been reported in the literature.…”

“…It is also unfortunate that delayed recognition of rare clinical entities may adversely impact the outcomes of well-intentioned therapeutic efforts and delay management of other organ system involvement. Myhre-LAPS syndrome is a rare condition with approximately 60 patients reported carrying the diagnosis [2,8]. The underlying genetic defect in MLS patients is an SMAD4 mutation which affects the codon for Ile500 which in turn alters the signal transduction pathway of TGF-β and bone morphogenetic protein (BMP) [5,6].…”

“…Myhre syndrome is a rare genetic condition first described in 1981 by Myhre et al which is characterized by short stature, brachydactyly, facial dysmorphism, thick skin, a generalized muscular appearance and restricted joint mobility, among other abnormalities [1,2]. More recently, a syndrome characterized by laryngotracheal stenosis, arthropathy, prognathism and short stature, or LAPS syndrome, was described as a unique clinical entity [3,4].…”

Chondrodysplasias and TGFβ signaling

“…Other features include developmental delay with mental retardation or/and behavioral disturbance, cardiac defects, cryptorchidism and bone anomalies. Skeletal manifestations include thickened calvarium, cone-shaped epiphyses, shortened tubular bones, hypoplastic iliac wings, broad ribs and large vertebrae with short and large pedicles 42,43 (Figure 3). All reported MS cases are sporadic, and advanced paternal age at birth has been reported, supporting de novo dominant mutations.…”