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

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).

Scalp-Ear-Nipple syndrome: first report of a Potassium channel tetramerization domain-containing 1 in-frame insertion and review of the literature.

OBJECTIVES: Pathogenic missense variants in the potassium channel tetramerization domain-containing 1 (KCTD1) gene are associated with autosomal dominant Scalp-Ear-Nipple syndrome (SENS), a type of ectodermal dysplasia characterized by aplasia cutis congenita of the scalp, hairless posterior scalp nodules, absent or rudimentary nipples, breast aplasia and external ear anomalies. We report a child with clinical features of an ectodermal dysplasia, including sparse hair, dysmorphic facial features, absent nipples, 2-3 toe syndactyly, mild atopic dermatitis and small cupped ears with overfolded helices. We also review the published cases of SENS with molecularly confirmed KCTD1 variants. METHODS AND RESULTS: Using whole-exome sequencing, we identified a novel, de novo in-frame insertion in the broad-complex, tramtrack and bric-a-brac (BTB) domain of the KCTD1 gene. By comparing to the previously reported patients, we found that our patient's clinical features and molecular variant are consistent with a diagnosis of SENS. CONCLUSIONS: This is only the 13th KCTD1 variant described and the first report of an in-frame insertion causing clinical features, expanding the mutational spectrum of KCTD1 and SENS.