First case of a Japanese girl with Myhre syndrome due to a heterozygous SMAD4 mutation.

This article reports the first case of a Japanese girl with molecularly confirmed Myhre syndrome (MS). The patient was 9 years old at her first visit, and she had been diagnosed with unknown skeletal dysplasia. Her phenotype fulfilled the clinical and radiological criteria for MS, such as typical facies with prognathism, hearing impairment, short stature, square body shape, and limited joint mobility. The thick calvarium and thick skin were clues to the clinical diagnosis of MS. A heterozygous mutation in the mothers-against-DPP homolog 4 (SMAD4) gene has been reported to cause MS. We sequenced SMAD4 using standard PCR-based technique and identified a recurrent mutation (p.Ile500 Thr). She attained menarche before 11 years of age; however, she developed oligomenorrhea after a few years of 40-day cycles, necessitating hormone replacement therapy. The luteinizing hormone-releasing hormone (LHRH) tests suggested abnormalities related to hypothalamo-hypophyseal malfunction. Previous reports on MS described early menarche in girls and early or delayed puberty and cryptorchidism in boys. Therefore, we recommend performing an endocrinological evaluation of the hypothalamo-hypophyseal-gonadal axis in patients with MS to clarify whether hormonal abnormalities are associated with the syndrome.