Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders

Abstract

Lethal short‐limb skeletal dysplasia Al‐Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al‐Gazali type, is an ultra‐rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al‐Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short‐limb skeletal dysplasia Al‐Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease‐causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al‐Gazali skeletal dysplasia and identifies it as a semi‐lethal part of the spectrum of ADAMTSL2‐related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease‐causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

ADAMTSL2 mutations determine the phenotypic severity in Geleophysic Dysplasia

“…Human and animal model data indicate that the total absence of ADAMTSL2 is incompatible with life, as seen in KO mice resembling the lethal phenotype observed in Al-Gazali skeletal dysplasia, the most severe form of GD1 ( 12 , 21 ). In humans with GD, most of the described variants are missense, and no reported patient was homozygous or compound heterozygous for complete loss-of-function variants (e.g., nonsense or frameshift indel).…”

“…Retrospective data indicate that the phenotypic spectrum of GD1 is variable, ranging from very severe cases incompatible with life to mild cases of patients diagnosed as adults ( 2 , 21 , 23 – 27 ). GD001 is a 4-year-old boy with a prenatal history of polyhydramnios, delivered at term with short stature (40.7 cm, 0.1th centile) at birth.…”

“…In myoblast-derived cells with stable knockdown of ADAMTSL2 , there is no increase in TGF-β activity ( 34 ). Finally, no change in TGF-β signaling in dermal fibroblasts from a patient with an ADAMTSL2 mutation was also reported ( 21 ). Taken together, these results suggest either TGF-β signaling is not different in all ADAMTSL2 mutations or there are other factors or conditions not fully defined to explain the observed discrepancy.…”

“…An association of mutated ADAMTSL2 with an increased TGF-β signaling has been reported in humans and mouse models, suggesting that the mechanism underpinning the disease is through the dysregulation of the TGF-β pathway ( 5 , 12 , 18 , 19 ). However, other reports indicated that TGF-β increase exists in some but not all GD cases ( 20 , 21 ).…”

“…However, these animals do not survive after birth, limiting their use for further characterization. The KO model likely represents the most severe end of the phenotypic spectrum caused by ADAMTSL2 mutations ( 21 ). Therefore, there is a need to generate animal models that reproduce the phenotype as characterized in most patients.…”