King–Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene

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Abstract

King–Denborough syndrome (KDS), first described in 1973, is a rare condition characterised by the triad of dysmorphic features, myopathy, and malignant hyperthermia susceptibility (MHS). Autosomal dominant inheritance with variable expressivity has been reported in several cases. Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been implicated in a wide range of myopathies such as central core disease (CCD), the malignant hyperthermia (MH) susceptibility trait and one isolated patient with KDS.

Here we report clinical, pathologic and genetic features of four unrelated patients with KDS. Patients had a relatively uniform clinical presentation but muscle biopsy findings were highly variable. Heterozygous missense mutations in RYR1 were uncovered in three out of four families, of which one mutation was novel and two have previously been reported in MH. Further RyR1 protein expression studies performed in two families showed marked reduction of the RyR1 protein, indicating the presence of allelic RYR1 mutations not detectable on routine sequencing and potentially explaining marked intrafamilial variability.

Our findings support the hypothesis that RYR1 mutations are associated with King–Denborough syndrome but that further genetic heterogeneity is likely.

Introduction

King–Denborough syndrome (KDS) was first described by King and Denborough in 1973 [1] and is characterised by a susceptibility to malignant hyperthermia (MH), delayed motor development, short stature, cryptorchidism, skeletal abnormalities, and variable dysmorphic features. Skeletal abnormalities include scoliosis, kyphosis, lumbar lordosis, and pectus carinatum/excavatum. Additional findings such as vertebral fusion, eventration of the diaphragm and spinal cord tethering have been reported in few individuals with suggestive clinical features [2], [3]. Variable dysmorphic features include ptosis, down-slanting palpebral fissures, malar hypoplasia, high-arched palate, dental crowding/malocclusion, micrognathia, low-set ears, and webbing of the neck [2]. Some of these features overlap with Noonan syndrome and it has been suggested that there may be a link between the two syndromes [4]. However, whilst moderate CK elevations and a MH reaction have been reported in isolated cases with a clinical but genetically unconfirmed diagnosis of Noonan syndrome [5], [6], kyphoscoliosis is uncommon in the latter and heart defects are not usually a feature in KDS.

Various diagnostic studies support the conclusion that King–Denborough syndrome is, at least in part, a myopathy. Resting CPK levels are elevated in some KDS patients [1], [7] and muscle biopsies have shown a variety of myopathic features, most commonly fibre size variation and few, small, or atrophic type I muscle fibres [2], [8]. Central cores, the diagnostic hallmark of central core disease (CCD) and also often seen in MH patients, are uncommon in KDS.

Many patients with KDS have a family history of MH and/or of dysmorphic features; thus, it has been suggested that KDS is inherited in an autosomal dominant manner [7]. However, siblings with apparently unaffected parents and a severe phenotype with prenatal onset have been subsequently reported [9], [10], [11], suggesting either recessive inheritance, mosaicism or highly variable penetrance. There also seems to be a predominance of males with KDS [2] but the reason for this finding is uncertain.

At this time, the genetic basis for KDS is unclear in the majority of patients. One prior case was published demonstrating a de novo mutation in the skeletal muscle ryanodine receptor (RYR1) [12] gene. RYR1 encodes the principal sarcoplasmic calcium release channel with a crucial role in excitation–contraction coupling and has been associated with several neuromuscular conditions, including MH [13], central core disease (CCD) [14], multi-minicore disease (MmD) [15] and centronuclear myopathy (CNM) ([16].

Here we describe the clinical, pathologic and genetic features of four patients with features suggestive of KDS and provide evidence for prominent RYR1 involvement but also possible genetic heterogeneity.

Section snippets

Patients

Patients with King–Denborough syndrome (KDS) were included in this study and selected for RYR1 screening based on a combination of suggestive dysmorphic features and presence of a myopathy with or without a personal or family history of malignant hyperthermia (MH). The main clinical, histopathological and genetic features of our patients are summarised in Table 1.

Discussion

Here we report the clinical, pathologic and genetic findings in three patients with features of King–Denborough syndrome (KDS) harbouring likely pathogenic, non-polymorphic RYR1 sequence variants, and a fourth with identical clinical features in whom RYR1 mutations could not be identified on routine sequencing. In one of the families with RYR1-related KDS, unaffected relatives were found to harbour the same change.

It is of note that in two families (Families 3 and 4) there was no history of

Acknowledgements

The authors do not have any conflict of interest to declare. J.J.D. is funded by a career development award from MDA and NIH (NIAMS) 1K08AR054835. Part of this work was supported by a grant from the Guy’s and St Thomas’ Charitable Foundation to S.A. and H.J. (Grant No. 070404) and of the Muscular Dystrophy Association (MDA) of the USA to H.J. and F.M. (Grant No. 68762). Support from the National Commissioning Group (NCG) of the United Kingdom to the Dubowitz Neuromuscular Centre and Guy’s

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