Endocrine Abstracts

JOINT2279

Myhre syndrome is a multisystem progressive connective disorder with highly distinctive findings of craniofacial dysmorphism, short stature, joint limitation, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis. We report a 3-year-old girl with Myhre syndrome. The girl was born full term with birth weight of 2705gram from a non-consanguineous Chinese couple. Antenatal Down syndrome screening, noninvasive prenatal testing and morphology scan were unremarkable. However, maternal grandparents were consanguineous. Among their 12 children, many suffered from congenital anomalies and succumbed. After birth, parents had no developmental concern. She walked at 11 months. Bow legs had progressively worsened since 15 months. When she was seen at 18 months, body length was 1.3cm below 0.4th centile, body weight at 9th centile, and head circumference at 50th centile. Clinical examination revealed facial dysmorphism – short palpebral fissures, hypoplastic maxilla, short philtrum, narrow mouth, prognathism and small ears. Skeletal examination showed brachydactyly, limited elbow and shoulder extension, genu varum with intercondylar distance measured 10cm, and waddling gait. Bone biochemistry revealed calcium 2.42mmol/l (2.15-2.55), phosphate 1.29 mmol/l (0.72-1.43), ALP 1358IU/L (130-330), total 25-hydroxyvitamin D 38nmol/l (30-49nmol/l mild deficiency), and parathyroid hormone 5.8pmol/l (1.6-6.9). Skeletal survey showed rickets features including metaphyseal fraying and spraying with rachitic rosary over costochondral joints. Other differential diagnosis included chondrodysplasia. There were no obvious features for other skeletal dysplasia or mucopolysaccharidosis. Urinary organic acid, plasma amino acid, serum free carnitine and acylcarnitine pattern were unremarkable. Urine glycosaminoglycan/creatinine ratio measured 27.7g/mol Cr (<29.9) and no pathological pattern detected by electrophoresis. In view of mild vitamin D deficiency, cholecalciferol 1000 IU daily was initiated and daily calcium intake of 500mg was ensured. As mild vitamin D deficiency could not account for craniofacial dysmorphism and joint limitation, genetic testing was arranged. Whole exome sequencing detected a de novo pathogenic heterozygous NM_005359.6(SMAD4):c.1486C>T p.(Arg496Cys) variant. This is a missense variant located in the MH2 domain of SMAD4 gene. Another de novo variant of uncertain significance heterozygous NM_018486.3(HDAC8):c.1133A>G p.(Ter378Trpext*16) was detected. This is a stop loss variant. Echocardiogram at 30 months was unremarkable. Developmental assessment at 42 months revealed a 9-month global developmental delay. Early education and training were continued. After 8-month vitamin D supplementation, bone biochemistry was mostly normal – calcium 2.56mmol/l, phosphate 1.67mmol/l, ALP 402IU/l, and total 25-hydroxyvitamin D 114nmol/l. Serial follow up demonstrated improvement in genu varum – intercondylar distance measured 5cm and 4cm at 24 months and 34 months respectively.