Novel Inactivating Homozygous PAPSS2 Mutation in Two Siblings With Disproportionate Short Stature

E Melissa Perez-Garcia; Philip Whalen; Nursen Gurtunca

doi:10.1016/j.aace.2021.11.003

Novel Inactivating Homozygous PAPSS2 Mutation in Two Siblings With Disproportionate Short Stature

AACE Clin Case Rep. 2021 Nov 24;8(2):89-92. doi: 10.1016/j.aace.2021.11.003. eCollection 2022 Mar-Apr.

Authors

E Melissa Perez-Garcia¹, Philip Whalen², Nursen Gurtunca^{3

4}

Affiliations

¹ Division of Pediatric Endocrinology, University of South Alabama, Mobile, Alabama.
² Section on Growth and Development, National Institute of Child Health and Development, NIH, Bethesda, Maryland.
³ Division of Pediatric Endocrinology and diabetes, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
⁴ University of Pittsburgh, Pittsburgh, Pennsylvania.

Abstract

Background/objective: Variants in PAPSS2 (3'-phosphoadenosine 5'-phosphosulfate synthetase 2) present with varying degrees of brachyolmia (short trunk, platyspondyly, mild long-bone abnormalities). Our objective is to present the phenotype of male and female siblings with the same novel inactivating variant in PAPSS2.

Case report: A Jordanian female (case 1), born to consanguineous parents, was referred at 10 years of age for short stature (SS). She had a normal laboratory workup, including normal growth hormone stimulation testing. Spinal x-rays done for clinical scoliosis revealed platyspondyly. She attained an adult height of 143.5 cm (-3 SD). Years later, her brother (case 2) was referred at 21 months of age for SS. His laboratory workup and bone age were normal. His growth velocity declined at 6 years of age, but normal growth factors did not suggest growth hormone deficiency. When he returned during puberty, disproportionate body measurements were noted. A skeletal survey revealed platyspondyly, increasing suspicion of growth plate pathology. Exome sequencing in the family revealed a homozygous variant, p.His496Pro (H496P) in PAPSS2 (NM_004670.3:c.1487A>C). Both parents carried the same variant.

Discussion: PAPSS2 assists with the sulfonation of dehydroepiandrosterone (DHEA) to DHEA sulfate and the sulfonation of proteoglycans in the cartilage, necessary for endochondral bone formation. PAPSS2-inactivating variants present with skeletal dysplasia and elevated DHEA levels.

Conclusion: This novel variant in PAPSS2 manifested with mild brachyolmia but disproportionate SS in male and female siblings. Biochemical phenotype with low circulating DHEA sulfate and high DHEA levels reflect a sulfonation defect.

Keywords: DHEA; DHEA, dehydroepiandrosterone; DHEA-S; DHEA-S, dehydroepiandrosterone sulfate; PAPSS2; PAPSS2, 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 gene; PAPSS2, 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 protein; SS, short stature; disproportionate short stature; idiopathic short stature.

Publication types

Case Reports