Growth Hormone Treatment in Rapadilino/Rothmund-Thomson Syndrome

INTRODUCTION/CASE PRESENTATION We describe two female Caucasian siblings with compound heterozygous mutations in the RECQL4 gene. Both were referred to the Endocrine clinic for severe short stature. The 4 year old has talipes equinovarus, bilateral radial reduction defects, small palpebral fissures, small mouth, and skin changes. She was found to be growth hormone (GH) deficient, with a small pituitary gland on MRI scan, and was treated with biosynthetic GH. Her 22 month old sibling was born with bilaterally absence of her tibias, bilateral radial ray reduction defects, small mouth, and small palpebral fissures, but normal GH. DISCUSSION The RECQL4 gene encodes helicases that are important in DNA replication and repair. Clinically RECQL4 mutations are found in three rare conditions: 1) Rapadilino syndrome (RS), 2) Rothmund Thomson syndrome (RTS) and 3) Baller Gerold syndrome (BGS). These three autosomal recessive conditions have similar characteristics of skeletal abnormalities, and an increase prevalence of cancer, such as osteosarcoma, particularly in RTS and RS. Osteosarcoma development has been reported in growth hormone treated RS and RTS patients. The DNA helicase activity of RECQL4 has been shown to be critical in skeletal development. Animal models of mutated RECQL4 deregulate p53 activity that can possibly explain the predisposition to osteosarcoma. CONCLUSION We report two siblings with a rare disorder due to the RECQL4 gene mutation associated with multiple skeletal abnormalities and predisposition cancer, such as osteosarcoma. In individuals who are deficient, GH has been shown to significantly improve linear growth and quality of life. Although the older sibling has shown a favorable response, because of its mitogenic effects GH should be used with caution in children predisposed to cancer. A better understanding of the pathophysiology of the diseases associated with mutations in the RECQL4 gene is needed to help develop a more effective treatment program.