A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes

Abstract

Based on the 7-year experience of the Italian Clinical Network for FSHD, we revised the FSHD clinical form to describe, in a harmonized manner, the phenotypic spectrum observed in FSHD. The new Comprehensive Clinical Evaluation Form (CCEF) defines various clinical categories by the combination of different features. The inter-rater reproducibility of the CCEF was assessed between two examiners using kappa statistics by evaluating 56 subjects carrying the molecular marker used for FSHD diagnosis. The CCEF classifies: (1) subjects presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) subjects with muscle weakness limited to scapular girdle or facial muscles (category B subcategories B1, B2), (3) asymptomatic/healthy subjects (category C, subcategories C1, C2), (4) subjects with myopathic phenotype presenting clinical features not consistent with FSHD canonical phenotype (D, subcategories D1, D2). The inter-rater reliability study showed an excellent concordance of the final four CCEF categories with a κ equal to 0.90; 95 % CI (0.71; 0.97). Absolute agreement was observed for categories C and D, an excellent agreement for categories A [κ = 0.88; 95 % CI (0.75; 1.00)], and a good agreement for categories B [κ = 0.79; 95 % CI (0.57; 1.00)]. The CCEF supports the harmonized phenotypic classification of patients and families. The categories outlined by the CCEF may assist diagnosis, genetic counseling and natural history studies. Furthermore, the CCEF categories could support selection of patients in randomized clinical trials. This precise categorization might also promote the search of genetic factor(s) contributing to the phenotypic spectrum of disease.

Keywords: Clinical phenotype; Diagnostic criteria; Disease classification; Disease registry; FSHD.

Figures

Fig. 1

CCEF Section 3: Clinical Diagnostic Form

Fig. 2

CCEF Section 4: Clinical Categories

Fig. 3

Examples of clinical categories: case reports. a Category A1: male, 38-year old, showing severe upper and lower facial weakness (unable to close both eyelids completely, puff cheeks and protrude lips), and impairment of upper limb abduction with winged scapula. b Category A2: female, 31-year old, with moderate upper (partial ability to close eyes, without the presence of widened palpebral fissures) and lower facial weakness (partial ability to puff out cheeks), impairment of upper limb abduction with winged scapula. c Category A3: male, 60-year old, with moderate lower facial weakness (partial ability to protrude lips), impairment of upper limb abduction with winged scapula. d Category B1: male, 66-year old, with impairment of upper limb abduction with winged scapula, no facial weakness. e Category B2: female, 34-year old, with moderate lower facial weakness (partial ability to puff out cheeks and to protrude lips), no scapular weakness. f Category C1: female, 55-year old, presenting asymmetric scapular winging on forward flexion without motor impairment (FSHD score 0). g Category C2: male, 56-year old, without motor impairment or other FSHD typical signs of muscle atrophy/weakness (FSHD score 0). h Category D1: male, 66-year old: onset after 50 age at shoulder girdle, without facial motor impairment and “bent spine”. i Category D2: male, 75-year old, with isolated bent spine syndrome, without signs suggestive of FSHD

Fig. 4

Clinical characterization of families in which a DRA segregates. Five families are presented. For each subject carrying a 4qA-type DRA on a permissive haplotype, age at evaluation, size of the DRA, clinical category and FSHD score are reported