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Hyaluronidase 2 deficiency due to novel compound heterozygous variants in HYAL2: a case report of siblings with HYAL2…

Abstract

This study reports the first Asian case of syndromic cleft lip and palate resembling CHARGE-like syndrome, caused by novel compound heterozygous variants of the HYAL2 gene. Hyaluronidase-2 (HYAL2) plays a critical role in hyaluronic acid degradation and tissue remodelling. A 2-year-old Japanese boy presented with growth deficiency, congenital heart disease, craniofacial dysmorphism, micropenis, and developmental delays–features that overlapped with those of CHARGE syndrome. Genetic analysis identified two rare HYAL2 missense variants (c.1133G>A, p.Arg378His; c.1271A>G, p.His424Arg), classified as “likely pathogenic” based on ACMG/AMP criteria. This case highlights the importance of considering HYAL2 deficiency in the syndromic presentation of cleft lip and palate with congenital heart disease, particularly in the absence of CHD7 abnormalities. This study also emphasizes potential primary testicular dysfunction in male patients with HYAL2 deficiency and underscores the need for further research to clarify genotype-phenotype correlations and pathology.

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Fig. 1: Phenotypic and genetic analysis of the cases.

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Acknowledgements

We are deeply grateful to Prof. Kenjiro Koseki and the Initiative on rare and undiagnosed diseases for supporting genetic diagnosis.

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Authors and Affiliations

Department of Pediatrics and Developmental Biology, Institute of Science Tokyo, Tokyo, Japan

Ryuta Orimoto, Eriko Adachi, Yoko Saito, Haruki Yamano, Hisae Nakatani, Shizuka Kirino, Kengo Moriyama, Yohei Yamaguchi, Tomoko Mizuno, Taku Ishii, Kenichi Kashimada & Kei Takasawa

Department of Life Science and Bioethics, Institute of Science Tokyo, Tokyo, Japan

Maki Gau & Masayuki Yoshida

Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan

Kenichi Kashimada

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Ryuta Orimoto

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