King-Denborough syndrome: a clinicogenetic case report

Ariya Venu; Reshma Anna Philip; Joseline Joseph; Manju George Elengical

doi:10.18203/2349-3291.ijcp20262433

Authors

Ariya Venu Department of Paediatrics, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla, Kerala, India
Reshma Anna Philip Department of Paediatrics, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla, Kerala, India
Joseline Joseph Department of Paediatrics, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla, Kerala, India
Manju George Elengical Department of Paediatrics, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla, Kerala, India

DOI:

https://doi.org/10.18203/2349-3291.ijcp20262433

Keywords:

King–Denborough syndrome, RYR1 gene, Congenital myopathy, Hypotonia, Malignant hyperthermia, Developmental delay

Abstract

King–Denborough syndrome is a rare RYR1-related congenital myopathy characterized by dysmorphic features, muscle weakness, and susceptibility to malignant hyperthermia, often posing a diagnostic challenge in early infancy. We report a one-year-old female child presenting with developmental delay and generalized hypotonia. Clinical evaluation revealed craniofacial dysmorphism, bilateral ptosis, and esotropia, raising suspicion of an underlying congenital myopathy. Initial laboratory and imaging workup were inconclusive except for transient elevation of creatine kinase. Whole exome sequencing identified a heterozygous missense variant in the RYR1 gene (c.14126C>T; p.Thr4709Met), along with a likely pathogenic FOXP1 variant. In view of the characteristic clinical phenotype, a diagnosis of King–Denborough syndrome was considered. The child was managed with supportive therapy and developmental interventions, and caregivers were counselled regarding the risk of malignant hyperthermia. This case underscores the importance of clinicogenetic correlation in diagnosing rare myopathies and highlights the need for early recognition to enable appropriate counselling and prevention of anaesthetic complications.

References

North KN, Wang CH, Clarke N, Jungbluth H, Vainzof M, Dowling JJ, et al. Approach to the diagnosis of congenital myopathies. Neuromuscul Disord. 2014;24(2):97-116.

King JO, Denborough MA. Anesthetic-induced malignant hyperpyrexia in children. J Pediatr. 1973;83(1):37-40.

Dowling JJ, Lawlor MW, Dirksen RT. Triadopathies: an emerging class of skeletal muscle diseases. Neurotherapeutics. 2014;11(4):773-85.

Treves S, Jungbluth H, Muntoni F, Zorzato F. Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm. Curr Opin Pharmacol. 2008;8(3):319-26.

Jungbluth H. Central core disease. Orphanet J Rare Dis. 2007;2:25.

Lozano R, Gbekie C, Siper PM, Srivastava S, Saland JM, Sethuram S, et al. FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring. J Neurodev Disord 2021;13:18.

Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93.

Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJA, et al. King–Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2011;21:420-7.

Joseph MR, Theroux MC, Mooney JJ, Falitz S, Brandom BW, Byler DL. Intraoperative presentation of malignant hyperthermia (confirmed by RYR1 gene mutation, c.7522C>T; p.R2508C) leads to diagnosis of King-Denborough syndrome in a child with hypotonia and dysmorphic features. A A Case Rep. 2017;8(3):55-7

Wang CH, Dowling JJ, North K, Schroth MK, Sejersen T, Shapiro F, et al. Consensus Statement on Standard of Care for Congenital Myopathies. J Child Neurol. 2012;27:363-82.

Litman RS, Rosenberg H. Malignant Hyperthermia. JAMA. 2005;293:2918.