Growth Hormone Deficiency: Extending the Phenotypic Spectrum of SALL4-Related Disorders

Background: The SALL4 gene encodes sal-like protein 4, a transcription factor with eight zinc finger motifs that is essential for the development of the epiblast and primitive endoderm. In association with TBX5 (T-box), SALL4 is responsible for the establishment and morphogenesis of the thumb. Pathogenic SALL4 variants have been reported to cause Duane-radial ray syndrome (also known as Okihiro syndrome), acro-renal-ocular syndrome and Holt-Oram syndrome. Hereby, we report on a family with radial hypoplasia and kidney dystopia in members of 4 consecutive generations, and short stature due to growth hormone deficiency (GHD) in the proband. Clinical Case: The male proband was born from the 3rd normal pregnancy at 39th week of gestation. He has no biological siblings. He was born small for gestational age (birth weight 2550 g, length 47 cm - both < 2SD) and had bilateral asymmetrical radial ray malformation consisting of radial hypoplasia, ulnar flexure and bilateral aplasia of the thumb, and pelvic dystopia of his right kidney. He had no cardiac malformations, clubfoot, ocular coloboma or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 ug/l (-1.0 SD), and peak GH in two stimulation tests was 6.2 ug/l. Other pituitary hormones were normal. His mother’s and father’s heights are 152.3 cm (-2.4 SD), and 177.8 cm (-0.4 SD), respectively. His father has malformation of the forearm that is milder than that of the son. The paternal grandfather is affected as well, with a radial defect with missing opposition of the thumb and height 164 cm (-2.3 SD). The family reports that the phenotype of radial dysplasia was apparent in the paternal grandfather’s mother as well. Due to the suggestive monogenic dominant transmission of the developmental abnormality, we carried out whole exome sequencing that revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. The proband was started with regular GH therapy at age 6.5 years and experienced catch-up growth as expected in GHD. By the age 11 years, his height stabilized at about the 25th percentile in accordance to the mid-parent height with a target height of 171.5 +/- 8.5 cm. Puberty started spontaneously at the age 12.5 years. 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 growth hormone deficiency (GHD) was detected and has been successfully treated with growth hormone. Acknowledgements: Genetic testing was funded by AZV grant NV18-07-00283.