ESPE Abstracts

Introduction: In 1950s - 1960s, the thalidomide disaster resulted in congenital malformations in more than 10,000 children. Derivative of thalidomide interferes with early embryonic transcriptional regulation due to selective degradation of SALL4 protein and thus, thalidomide embryopathy phenocopies pathogenic variants of the SALL4 gene. Their phenotypes range from phocomelia, reduced radial ray, to defects of the heart, kidneys, eye, and cerebral midline. SALL4, together with GLI3, downregulate the SHH signaling pathway that is essential for pituitary development and function. We report on a family with a SALL4 pathogenic variant leading to vertical transmission of radial hypoplasia, kidney dystopia, and short stature due to growth hormone deficiency (GHD).

Clinical Case: Our proband was born at 39th GW small for gestational age (BW 2550 g/BL 47 cm, both≤-2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb), an ectopically placed lower canine and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma or Duane anomaly. He was examined for progressive growth failure at the age of 3.9 years, where his IGF-1 was 68 mg/l (-1.0 SDS), and growth hormone (GH) after stimulation 6.2 mg/l. Other pituitary hormones and brain CT were normal. GH therapy was started at 6.5 years when his height was 109 cm (-2.8 SDS), and he experienced catch-up growth as expected in GHD. Puberty started spontaneously and progressed normally. At age 13 his height was 158.7 cm (-0.2 SDS). His mother’s and father’s heights are 152.3 cm (-2.4 SDS) and 177.8 cm (-0.4 SDS) respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; -2.3 SDS) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype in the paternal grandfather’s mother and sister. IGF-1 in proband's mother was 153 mg/l (-0.3 SDS) and in paternal grandfather 69 mg/l (-1.9 SDS), which is supportive of GHD. Whole exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather.

Conclusion: This is the first case demonstrating a patient with a congenital upper limb defect based on a pathogenic variant of the SALL4 gene where an isolated GHD was detected and has been successfully treated with GH. Thus, SALL4 joins the candidate gene list for monogenic syndromic pituitary insufficiency.