Hereditary multiple exostoses: anatomical distribution and burden of exostoses is dependent upon genotype and gender

Abstract

Background and aims

We describe the novel anatomical distribution of exostoses in patients with hereditary multiple exostoses according to their gender and genotype.

Methods and results

A prospective database of 143 patients from 65 families with hereditary multiple exostoses was compiled. Patient demographics, genotype and number of exostoses according to anatomical site were recorded. The hand was affected by the greatest proportion of exostoses for both EXT1 (19%) and EXT2 (14%) genotypes and was the most prevalent site for exostoses in patients with an EXT1 genotype (92%). Patients with an EXT1 genotype had a significantly greater number of exostoses compared to those with an EXT2 genotype (2680 vs. 1828, p = 0.006); however, this was only significantly different for 10 of the 19 anatomical regions examined. Male patients with an EXT1 genotype had a significantly (p < 0.05) greater number of exostoses affecting their hands, distal radius, proximal humerus, scapular and ribs compared to female patients with the same genotype and males with an EXT2 genotype.

Conclusion

The anatomical distribution of exostoses varies according to genotype and gender; however, the reason for this difference is not clear and may relate to different biochemical pathways.

Keywords

Hereditary multiple exostoses EXT gender anatomical distribution

Introduction

Hereditary multiple exostoses (HME) is one of the more common inherited musculoskeletal conditions that present to musculoskeletal services, with an approximate incidence of one in 50,000.¹ HME has an autosomal dominant inheritance pattern with variable penetrance² and is clinically characterised by numerous benign exostoses that typically occur at the metaphysis of long bones. Exostoses are present, both clinically and radiographically, around the knee and proximal humerus in more than 90% of patients with HME.^1,3,4 The prevalence of exostoses in other anatomical regions vary from 4% at the distal humerus to 85% at the distal radius.³

The genes that cause HME are termed EXT1 and EXT2 and code for exostosins, which are transmembrane glycosyltransferases found in the endoplasmic reticulum and Golgi apparatus.⁵ These proteins are involved in the biosynthesis of heparan sulphate proteoglycans. EXT1 and EXT2 are located on chromosome 8 and 11, respectively, and are present in more than 85% of patients with HME.^6,7 A more severe phenotype, according to function and deformity, is associated with the EXT1 genotype.² Phenotype severity is also independently associated with gender, with male patients suffering a greater degree of functional limitation and deformity.² EXT1 genotype and male gender are both associated with an increased burden of exostoses throughout the skeletal system.^2,8,9 It is not known, however, if the distribution of exostoses in relation to anatomical site varies according to genotype or gender for patients with HME.

The total number of exostoses suffered by an individual has been used as a clinical marker of phenotype severity in patients with HME.^8,9 Due to the scarcity of HME patients and their wide spread geographical distribution, clinical examination is logistically difficult. If a specific area of the body could be identified that directly correlated with the anatomic burden of exostoses, this area could be assessed by the patients themselves and reported to the clinician or researcher without the need to review and physically examine every patient.

The primary aim of this study was to describe the anatomical distribution of exostoses in patients with HME according to their gender and genotype. Our secondary aim was to identify anatomical regions that predicted the total exostoses burden.

Patients and methods

During a five-year period, a prospective database was compiled, which enrolled 172 patients diagnosed with HME from 78 families. The patients were identified and referred by orthopaedic surgeons, geneticists and by self-presentation. Patients with an isolated exostosis were excluded.

Demographic details and family pedigree were recorded. A single examiner collected all the clinical data. The number of palpable exostoses affecting 19 defined anatomical sites was recorded. This has been shown to correlate with radiographic assessment of the number of osteochondromas.¹⁰ The number and site of surgical excisions and malignant transformation were also recorded. Surgical excision was performed for symptomatic exostoses, or more rarely as an excisional biopsy.

Genomic deoxynucleic acid (DNA) was obtained from either blood or buccal swabs, and analysis was performed as described by Porter et al.⁸ EXT1 and EXT2 exons were amplified by polymerase chain reaction from the DNA. The analysis was originally performed using confirmative sensitive gel electrophoresis and fluorescent single strand conformational polymorphism analysis. However, the majority of the DNA analysis was performed using denaturing high-performance liquid chromatography. There were 143 patients from 65 families with EXT1 and EXT2 genotypes which formed our study cohort. Patients without these genotypes were excluded, as analysis of this group may present a false distribution of exostoses due to the unknown genetic origin which may be heterogeneous for this group.

The genotype data were collected by an observer blinded to the outcome of phenotype data and vice versa for those collecting phenotype data. Ethical approval was obtained for DNA sample collection and genetic analysis (Central Oxford Research Ethics Committee 93.257). All patients were informed and gave their consent to participate in the study.

Statistical analysis

Statistical analysis was performed using Statistical Package for Social Sciences version 17.0 (SPSS Inc., Chicago, IL, USA). Parametric and non-parametric tests were used as appropriate to assess continuous variables for significant differences between groups. An unpaired Student’s t-test and Mann–Whitney U test were used to compare linear variables between groups. A Spearman’s rank correlation was used to compare linear variables. Dichotomous variables were assessed using a Chi square. A p-value of ≤0.05 was taken as the level of statistical significance.

Results

The study cohort consisted of 76 female and 67 male patients, with a mean age of 28.2 years (range 3–76 years, SD 19.2). A total of 4508 exostoses were identified for all 143 patients, with an average of 31.5 (range 2–172, SD 25.6) per individual. There were 71 patients with an EXT1 and 72 with an EXT2 genotype, with a mean age of 27.8 years and 28.6 years, respectively (p = 0.78, t-test). Subgroup analysis of age demonstrated significant differences between male patients with EXT1 and EXT2 genotypes and between male and female patients with an EXT1 genotype (Table 1). There were no significant differences observed for the prevalence of surgical excision between genotypes (p = 0.5, chi square) or genders (p = 0.39, chi square).

Table 1.

Mean age according to gender and genotype.

Gender	Genotype		p-value*
Gender	EXT1	EXT2
Male (years, SD)	21.1 (16.5)	29.8 (19.1)	0.05
Female (years, SD)	32.9 (19.7)	27.4 (20.0)	0.24
p-value*	0.009	0.61

Unpaired t-test.

The number of exostoses varied according to anatomical site (Figure 1). The hand was affected by the greatest proportion of exostoses and accounted for 19.4% of all exostoses in patients with EXT1 and 14.3% of exostoses in patients with EXT2 genotypes (Figure 1). The hand was also the most prevalent site affected by exostoses in patients with an EXT1 genotype, whereas the distal radius and distal femur were equally the most prevalent sites for patients with an EXT2 genotype (Figure 2). Patients with an EXT1 genotype had a greater mean number of exostoses for all anatomical sites examined, except for the proximal femur and distal fibula (Figure 3). However, this increased burden of exostoses in patients with an EXT1 genotype was only significantly different for 10 of the 19 anatomical sites examined (Table 2).

Figure 1.

The percentage of all exostoses (n = 4508) according to the anatomical site for patients with EXT1 and EXT2 genotypes.

Figure 2.

The percentage of patients affected by exostoses for each of the 19 anatomical sites with EXT1 and EXT2 genotypes.

Figure 3.

Mean number of exostoses according to anatomical site for patients with EXT1 and EXT2 genotypes.

Table 2.

The distribution and comparison of the number of exostoses by anatomical site for patients with EXT1 and EXT2 genotype.

Site	EXT1 (n = 71)			EXT2 (n = 72)			Mean difference	p-value*
Site	Total	Mean	SD	Total	Mean	SD	Mean difference	p-value*
Hand	519	7.3	6.6	261	3.6	4.0	3.7	<0.0001
Distal radius	260	3.7	2.8	201	2.8	2.5	0.9	0.05
Distal ulna	131	1.9	1.8	96	1.3	1.6	0.5	0.05
Proximal radius	42	0.6	1.5	13	0.2	0.5	0.4	0.05
Proximal ulna	5	0.1	0.3	4	0.1	0.3	0.0	0.47
Distal humerus	10	0.1	0.4	8	0.1	0.3	0.0	0.75
Proximal humerus	197	2.8	2.5	126	1.8	1.8	1.0	0.01
Clavicle	116	1.6	1.9	62	0.9	1.2	0.8	0.007
Scapular	94	1.3	1.8	45	0.6	1.3	0.7	0.002
Ribs	105	1.5	2.7	63	0.9	1.7	0.6	0.19
Spine	4	0.1	0.3	1	0.0	0.1	0.0	0.3
Pelvis	67	0.9	1.9	12	0.2	0.8	0.8	<0.0001
Proximal femur	5	0.1	0.3	7	0.1	0.5	0.0	0.73
Distal femur	274	3.9	3.6	235	3.3	2.7	0.6	0.56
Proximal tibia	218	3.1	2.7	184	2.6	1.8	0.5	0.52
Proximal fibular	133	1.9	2.0	122	1.7	1.9	0.2	0.61
Distal tibia	248	3.5	3.1	169	2.3	2.6	1.1	0.01
Distal fibular	136	1.9	2.5	155	2.2	2.5	0.2	0.51
Foot	116	1.6	3.1	64	0.9	1.6	0.7	0.04
Total	2680	37.7	29.7	1828	23.3	19.2	14.4	0.006

Mann–Whitney U test.

Male patients with an EXT1 genotype had significantly more exostoses than female patients with the same genotype (Table 3), with male patients suffering a greater mean number of exostoses for all anatomical sites examined, except for the proximal radius and ulna (Figure 4). This difference, however, was only significantly greater for 10 of the 19 anatomical sites examined (Table 3). In contrast, there was no significant difference between the total number of exostoses between genders for those patients with an EXT2 genotype (Table 4). Only three of the 19 anatomical sites, distal humerus, proximal tibia and pelvis, demonstrated a significant difference.

Figure 4.

Mean number of exostoses according to anatomical site for patients with an EXT1 genotype for male and female genders.

Table 3.

The distribution and comparison of the number of exostoses by anatomical site for male and female patients with an EXT1 genotype.

Site	Male (n = 31)				Female (n = 40)				Mean Difference	p-value*
Site	Total	%	Mean	SD	Total	%	Mean	SD	Mean Difference	p-value*
Hand	286	18.7	9.2	7.3	233	20.2	5.8	5.6	3.6	0.04
Distal radius	143	9.4	4.6	3.1	117	10.1	2.9	2.3	2.3	0.02
Distal ulna	59	3.9	1.9	2.0	72	6.2	1.8	1.6	0.3	0.87
Proximal radius	17	1.1	0.5	1.1	25	2.2	0.6	1.7	1.2	0.76
Proximal ulna	2	0.1	0.1	0.2	3	0.3	0.1	0.3	0.2	0.87
Distal humerus	8	0.5	0.3	0.5	2	0.2	0.1	0.2	0.0	0.02
Proximal humerus	113	7.4	3.6	2.7	84	7.3	2.1	2.2	1.5	0.008
Clavicle	78	5.1	2.5	2.2	38	3.3	1.0	1.2	1.4	0.001
Scapular	60	3.9	1.9	2.2	34	2.9	0.9	1.2	0.7	0.03
Ribs	74	4.8	2.4	3.6	31	2.7	0.8	1.6	0.8	0.04
Spine	2	0.1	0.1	0.2	2	0.2	0.1	0.3	0.3	0.43
Pelvis	42	2.8	1.4	2.4	25	2.2	0.6	1.4	0.1	0.11
Proximal femur	3	0.2	0.1	0.3	2	0.2	0.1	0.2	0.1	0.45
Distal femur	173	11.3	5.6	4.2	101	8.8	2.5	2.4	3.2	0.001
Proximal tibia	117	7.7	3.8	2.8	101	8.8	2.5	2.4	1.3	0.01
Proximal fibular	70	4.6	2.3	2.5	63	5.5	1.6	1.6	0.7	0.34
Distal tibia	131	8.6	4.2	3.3	117	10.1	2.9	2.8	1.4	0.08
Distal fibular	85	5.6	2.7	3.3	51	4.4	1.3	1.5	1.2	0.04
Foot	64	4.2	2.1	4.2	52	4.5	1.3	1.7	0.4	0.97
Total	1527	–	49.3	35.3	1153	–	28.8	21.0	28.3	0.005

Mann–Whitney U test.

Table 4.

The distribution and comparison of the number of exostoses by anatomical site for male and female patients with an EXT2 genotype.

Site	Male (n = 36)				Female (n = 36)				Mean difference	p-value*
Site	Total	%	Mean	SD	Total	%	Mean	SD	Mean difference	p-value*
Hand	107	11.8	3.0	3.9	154	16.7	4.3	4.0	1.3	0.09
Distal radius	102	11.2	2.8	2.4	99	10.8	2.8	2.6	0.1	0.76
Distal ulna	45	5.0	1.3	1.5	51	5.5	1.4	1.8	0.2	0.79
Proximal radius	4	0.4	0.1	0.4	9	1.0	0.3	0.6	0.1	0.28
Proximal ulna	0	0.0	0.0	0.0	4	0.4	0.1	0.4	0.1	0.08
Distal humerus	7	0.8	0.2	0.4	1	0.1	0.0	0.2	0.2	0.03
Proximal humerus	59	6.5	1.6	1.8	67	7.3	1.9	1.7	0.3	0.48
Clavicle	30	3.3	0.8	1.3	32	3.5	0.9	1.2	0.1	0.55
Scapular	20	2.2	0.6	1.0	25	2.7	0.7	1.5	0.1	0.99
Ribs	26	2.9	0.7	1.2	37	4.0	1.0	2.1	0.3	0.8
Spine	0	0.0	0.0	0.0	1	0.1	0.0	0.2	0.0	0.32
Pelvis	12	1.3	0.3	1.1	0	0.0	0.0	0.0	0.3	0.02
Proximal femur	5	0.6	0.1	0.7	2	0.2	0.1	0.2	0.1	0.97
Distal femur	132	14.5	3.7	2.9	103	11.2	2.9	2.3	0.8	0.26
Proximal tibia	112	12.3	3.1	1.8	72	7.8	2.0	1.6	1.1	0.01
Proximal fibular	63	6.9	1.8	2.0	59	6.4	1.6	1.8	0.1	0.98
Distal tibia	90	9.9	2.5	2.5	79	8.6	2.2	2.7	0.3	0.39
Distal fibular	72	7.9	2.0	2.4	83	9.0	2.3	2.6	0.3	0.66
Foot	22	2.4	0.6	1.1	42	4.6	1.2	1.9	0.6	0.29
Total	908	–	25.2	18.6	920.0	–	25.6	20.1	0.4	0.95

Mann–Whitney U test.

Male patients with an EXT1 genotype had a significantly greater total number of exostoses than male patients with an EXT2 genotype (Table 5). Analysis by anatomical site illustrated that males with the EXT1 genotype had a significantly greater number of exostoses for 10 of the 19 regions examined compared to males with an EXT2 genotype (Table 5). In contrast, there was no significant difference in the total number of exostoses between genotypes for female patients (Table 6), with exostoses affecting the pelvis demonstrating a significant difference.

Table 5.

The distribution and comparison of the number of exostoses by anatomical site for male patients with an EXT1 and EXT2 genotypes.

Site	EXT1 (n = 31)				EXT2 (n = 36)				Mean difference	p-value*
Site	Total	%	Mean	SD	Total	%	Mean	SD	Mean difference	p-value*
Hand	286	18.7	9.2	7.3	107	11.8	3.0	3.9	6.3	<0.0001
Distal radius	143	9.4	4.6	3.1	102	11.2	2.8	2.4	1.8	0.01
Distal ulna	59	3.9	1.9	2.0	45	5.0	1.3	1.5	0.7	0.19
Proximal radius	17	1.1	0.5	1.1	4	0.4	0.1	0.4	0.4	0.046
Proximal ulna	2	0.1	0.1	0.2	0	0.0	0.0	0.0	0.1	0.13
Distal humerus	8	0.5	0.3	0.5	7	0.8	0.2	0.4	0.1	0.71
Proximal humerus	113	7.4	3.6	2.7	59	6.5	1.6	1.8	2.0	0.001
Clavicle	78	5.1	2.5	2.2	30	3.3	0.8	1.3	1.7	<0.0001
Scapular	60	3.9	1.9	2.2	20	2.2	0.6	1.0	1.4	0.003
Ribs	74	4.8	2.4	3.6	26	2.9	0.7	1.2	1.7	0.03
Spine	2	0.1	0.1	0.2	0	0.0	0.0	0.0	0.1	0.13
Pelvis	42	2.8	1.4	2.4	12	1.3	0.3	1.1	1.0	0.009
Proximal femur	3	0.2	0.1	0.3	5	0.6	0.1	0.7	0.0	0.55
Distal femur	173	11.3	5.6	4.2	132	14.5	3.7	2.9	1.9	0.06
Proximal tibia	117	7.7	3.8	2.8	112	12.3	3.1	1.8	0.7	0.5
Proximal fibular	70	4.6	2.3	2.5	63	6.9	1.8	2.0	0.5	0.4
Distal tibia	131	8.6	4.2	3.3	90	9.9	2.5	2.5	1.7	0.03
Distal fibular	85	5.6	2.7	3.3	72	7.9	2.0	2.4	0.7	0.37
Foot	64	4.2	2.1	4.2	22	2.4	0.6	1.1	1.5	0.05
Total	1527	–	49.3	35.3	908	–	25.2	18.6	24.1	0.001

Mann–Whitney U test.

Table 6.

The distribution and comparison of the number of exostoses by anatomical site for female patients with an EXT1 and EXT2 genotypes.

Site	EXT1 (n = 40)				EXT2 (n = 36)				Mean difference	p-value*
Site	Total	%	Mean	SD	Total	%	Mean	SD	Mean difference	p-value*
Hand	233	20.2	5.8	5.6	154	16.7	4.3	4.0	1.5	0.23
Distal radius	117	10.1	2.9	2.3	99	10.8	2.8	2.6	0.2	0.61
Distal ulna	72	6.2	1.8	1.6	51	5.5	1.4	1.8	0.4	0.15
Proximal radius	25	2.2	0.6	1.7	9	1.0	0.3	0.6	0.4	0.45
Proximal ulna	3	0.3	0.1	0.3	4	0.4	0.1	0.4	0.0	0.87
Distal humerus	2	0.2	0.1	0.2	1	0.1	0.0	0.2	0.0	0.62
Proximal humerus	84	7.3	2.1	2.2	67	7.3	1.9	1.7	0.2	0.69
Clavicle	38	3.3	1.0	1.2	32	3.5	0.9	1.2	0.1	0.77
Scapular	34	2.9	0.9	1.2	25	2.7	0.7	1.5	0.2	0.13
Ribs	31	2.7	0.8	1.6	37	4.0	1.0	2.1	0.3	0.90
Spine	2	0.2	0.1	0.3	1	0.1	0.0	0.2	0.0	0.96
Pelvis	25	2.2	0.6	1.4	0	0.0	0.0	0.0	0.6	0.001
Proximal femur	2	0.2	0.1	0.2	2	0.2	0.1	0.2	0.0	0.91
Distal femur	101	8.8	2.5	2.4	103	11.2	2.9	2.3	0.3	0.41
Proximal tibia	101	8.8	2.5	2.4	72	7.8	2.0	1.6	0.5	0.52
Proximal fibular	63	5.5	1.6	1.6	59	6.4	1.6	1.8	0.1	0.94
Distal tibia	117	10.1	2.9	2.8	79	8.6	2.2	2.7	0.7	0.11
Distal fibular	51	4.4	1.3	1.5	83	9.0	2.3	2.6	1.0	0.1
Foot	52	4.5	1.3	1.7	42	4.6	1.2	1.9	0.1	0.37
Total	1153	–	28.8	21.0	920.0	–	25.6	20.1	3.2	0.39

Mann–Whitney U test.

The number of exostoses for all anatomical regions assessed directly correlated to the total number of exostoses present, with hand, scapular, distal fibular and proximal fibular having the highest correlation coefficient (Table 7). Subgroup analysis, according to genotype, revealed the number of distal fibular exostoses, and hand exostoses had the greatest correlation with the total number of exostoses present for patients with an EXT1 and EXT2 genotypes, respectively (Table 7).

Table 7.

Correlation of the number of exostoses according to site with the total number observed (all sites) for all patients and for each genotype.

Site	All patients (n = 143)		EXT1 (n = 71)		EXT2 (n = 72)
Site	r	p-value*	r	p-value*	r	p-value*
Hand	0.54	<0.0001	0.33	0.002	0.65	<0.0001
Distal radius	0.39	<0.0001	0.35	0.001	0.44	<0.0001
Distal ulna	0.52	<0.0001	0.39	<0.0001	0.62	<0.0001
Proximal radius	0.31	<0.0001	0.40	<0.0001	0.17	0.08
Proximal ulna	0.19	0.012	0.29	0.008	0.07	0.28
Distal humerus	0.28	<0.0001	0.35	0.001	0.20	0.049
Proximal humerus	0.43	<0.0001	0.34	0.002	0.45	<0.0001
Clavicle	0.49	<0.0001	0.48	<0.0001	0.45	<0.0001
Scapular	0.54	<0.0001	0.48	<0.0001	0.53	<0.0001
Ribs	0.35	<0.0001	0.35	0.001	0.33	0.003
Spine	0.21	0.006	0.29	0.008	0.07	0.284
Pelvis	0.44	<0.0001	0.50	<0.0001	0.28	0.009
Proximal femur	0.14	0.05	0.14	0.13	0.14	0.12
Distal femur	0.43	<0.0001	0.35	0.001	0.57	<0.0001
Proximal tibia	0.45	<0.0001	0.48	<0.0001	0.42	<0.0001
Proximal fibular	0.54	<0.0001	0.58	<0.0001	0.51	<0.0001
Distal tibia	0.44	<0.0001	0.29	0.006	0.51	<0.0001
Distal fibular	0.54	<0.0001	0.59	<0.0001	0.53	<0.0001
Foot	0.53	<0.0001	0.50	<0.0001	0.52	<0.0001

Spearman’s rank correlation.

Discussion

We have demonstrated that the greatest proportion of exostoses in patients with HME involves the hand, for both EXT1 and EXT2 genotypes, and was the most prevalent site for exostoses in patients with an EXT1 genotype. Patients with an EXT1 genotype had a significantly greater number of exostoses compared to those with an EXT2 genotype; however, this was only significantly different for specific anatomical regions. Exostoses affecting the hand demonstrated the greatest and most significant difference between genotypes, as patients with the EXT1 genotype had on average four more exostoses than those with the EXT2 genotype. In addition, male patients with an EXT1 genotype had a significantly greater number of exostoses affecting their hands, distal radius, proximal humerus, scapular and ribs compared to female patients with the same genotype and males with an EXT2 genotype. We also demonstrated that the number of exostoses affecting the hand, scapular, distal fibular or proximal fibular directly correlated to the total burden of exostoses present.

Previous studies have reported that the most prevalent anatomical sites for exostoses in patients with HME are around the knee and proximal humerus.^1,3,11 We have affirmed these figures; however, we have also demonstrated the hand to be the most prevalent site in patients with an EXT1 genotype and fourth most prevalent in those with an EXT2 genotype. The prevalence of hand exostoses in the literature varies from 30%^1,11 to 79%³ in epidemiological reports, and one radiographic study found that of the 42 hands examined, only four did not have exostoses.¹² This variation may reflect the case-mix variables among these reports, as we have demonstrated that EXT1 genotype and male gender are associated with a greater burden of exostoses affecting the hand. Solomon³ reported a 79% prevalence rate of hand exostoses in patients with HME, a figure that is similar to our overall prevalence rate of 82% (n = 116/142). In Solomon’s original paper, he also describes one family where six members were predominantly affected by exostoses of the hand, with limited involvement of long bones.³ This observation he hypothesised was due to the involvement of a different gene, when compared to the rest of the HME cohort he examined.

Numerous studies have identified that HME patients with the EXT1 genotype have a more severe phenotype relative to those with an EXT2 genotype,^2,8,9 which we have also demonstrated in terms of the total number of exostoses suffered by an individual. A unique aspect of our study was the variability in the anatomical distribution of the exostoses according to genotype, with only some sites demonstrating a significant difference. The cause of the variation in distribution of the exostoses according to genotype is not clear, but it would seem that the field effect of the EXT1 and EXT2 genes differs. The anatomical variation does not seem to be related to the rate of growth of the epiphysis as there was no difference observed for exostoses around the knee, although there was a significant difference of those affecting the distal radius and proximal humerus. It would however seem that smaller and thinner growth plates (hand, distal radius) are affected more severely than larger thicker growth plates (distal femur, proximal tibia) in patients with the EXT1 genotype compared to those with an EXT2 genotype.

EXT1 and EXT2 genes have different roles in the biosynthesis of heparin sulphate, which in-turn controls the gradient of Indian Hedgehog protein across the growth plate and ultimately controlling chondrocyte differentiation.^13,14 This gradient would seem to be paradoxically more readily disrupted across smaller growth plates in patients with an EXT1 mutation, which may relate to cell density and number within the growth plate. An explanation for this may be due to growth plates with more chondrocytes that are able to produce more heparin sulphate, all be it with defective genes, and to maintain a threshold level of Indian Hedgehog across the growth plate. In contrast with smaller numbers of chondrocytes, in thinner growth plates, the threshold level of Indian Hedgehog may not be reached leading to defective chondrocyte differentiation and result in the formation of exostoses.

Male gender is associated with a more severe phenotype¹⁵ and more recently was identified as an independent predictor of disease severity in patients with HME.² We also observed an increase in the exostoses burden for male patients, relative to female patients. In addition, we also demonstrated that male patients with the EXT1 genotype had a significantly greater number of exostoses affecting their hands, distal radius, proximal humerus, scapular and ribs compared to males with an EXT2 genotype. It would seem from our results that an EXT1 genotype and male gender are additive factors that result in a more severe phenotype. Possible explanations why male gender is associated with an increased phenotype severity may relate to physeal closure at an older age, prolonging the effects of the EXT gene, hormonal differences between genders, or X-linked genes that may interact and accentuate the effect of the EXT1 and EXT2 genotypes. This latter explanation may be the locus of Solomon’s³ hypothesised gene mutation associated with hand exostoses, which is still to be identified.

Clinical assessment of patients with HME is difficult due to the low prevalence of the disorder and sporadic distribute of this population.¹ A simple tool or marker to assess disease burden would offer the possibility of allowing patients to self-assess and grade the severity of their disorder, without the need to be clinically assessed. Numerous anatomical sites correlated with the overall disease burden according to the number of exostoses; however, not all of these sites are easily accessible to patients. Potentially the number of exostoses affecting the hand, being easy to assess by the patient, could be used to evaluate the total burden of exostoses present in each patient, as there was a significant direct correlation between these two variables. This would however need to be affirmed in future studies.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of conflicting interests

None declared.

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