LAUSR

Myhre syndrome (MS; OMIM 139210) is a rare congenital disorder first reported in 1981, which mainly affects connective tissues. The clinical characteristics include mental and growth deficiencies, muscular hypertrophy, joint restriction, and facial deformities. Restrictive cardiopulmonary complications, such as tracheal stenosis and pericarditis may be life threatening. MS also involves mild, but distinctive, skeletal alterations, such as thick calvaria, large pedicles, abbreviated long bones, and brachydactyly. Recently, SMAD4 was identified as the disease-causing gene. Most patients have missense mutations involving the Ile500 residue located on the MAD homology 2 domain. To date, more than 50 affected individuals have been reported. It is intriguing that most patients were diagnosed at school age, and the youngest patient was a 4year-old girl. This raises suspicion that MS is a late-onset disorder with postnatal progression. Here, we report on a Japanese boy with MS, in whom the dysmorphic features came to medical attention in early childhood, but in whom the final diagnosis was made after the clinical features fully manifested over the mid-childhood period. The boy was born to healthy, non-consanguineous parents at 38 weeks of gestation. Birthweight, length, and occipitofrontal circumference were 2,432 g ( 1.75 SD), 46 cm ( 1.28 SD), and 30 cm ( 2.30 SD), respectively. At 3.5 years of age, he was referred to us because of short stature and mild intellectual disability. At this point, his height was 88 cm ( 2.40 SD) and weight was 13.4 kg ( 0.74 SD). He had mild brachydactyly (Fig. 1a) and thick skin. Short philtrum, thin upper lip, prognathism, and mild obesity were observed (Fig. S1a). Radiology indicated a thick calvarium (not shown), brachymetacarpia (Fig. 1a), and fusion of the C2–C3 vertebrae (not shown). No specific diagnosis was made. Thereafter, his growth was persistently retarded (height, < 3 SD; Fig S1d). He had progressive joint contracture and skin thickness with hyperkeratosis (Fig. S1b,c). On repeated skeletal survey, a b