RESEARCH REVIEW
X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED): Clinical and Diagnostic Insights from an International Patient Registry Mary Fete,1* Julie Hermann,2 Jeffrey Behrens,2 and Kenneth M. Huttner2 1
National Foundation for Ectodermal Dysplasia, Mascoutah, Illinois
2
Edimer Pharmaceuticals Inc., Cambridge, Massachusetts
Manuscript Received: 8 October 2013; Manuscript Accepted: 1 December 2013
The web-based Ectodermal Dysplasia International Registry (EDIR) is a comprehensive patient-reported survey contributing to an understanding of ectodermal dysplasia (ED). XLHED is the most common of the genetic ED syndromes and was the primary diagnosis reported by 223/835 respondents (141 males and 82 females). Overall, 96% of XLHED registrants reported as least one other affected family member and 21% reported a family history of infant or childhood deaths, consistent with the published mortality data in this disorder. In general, XLHED is diagnosed by the triad of decreased sweating, reduced hair, and hypodontia (present in 89%, 74%, and 74% of XLHED respondents). Additionally, the registry dataset confirmed a spectrum of life-long XLHED clinical complications including recurrent sinus infections (49% males, 52% females), nasal congestion often foul smelling and interfering with feeding (73% males, 27% females), eczema (66% males, 40% females), wheezing (66% males, 45% females), and a hoarse, raspy voice (67% males, 23% females). The Registry results also highlighted features consistently differentiating XLHED from the non-hypohidrotic ED syndromes including the frequency of infant/childhood deaths, the presence of limb/digit abnormalities, feeding issues related to nasal discharge, dentures, and a diagnosis of asthma. These results represent the largest collection of data on a broad-spectrum of health-related issues affecting ED patients. This project provides information for expanding knowledge of the natural history of XLHED, and as such may facilitate the diagnosis and treatment of its varied and lifelong medical challenges. Ó 2014 Wiley Periodicals, Inc.
Key words: ectodermal dysplasias; XLHED; patient advocacy group; registry
INTRODUCTION In 2010 the U.S. National Foundation for Ectodermal Dysplasias (NFED, www.nfed.org), in conjunction with 13 international patient support groups (Acknowledgements), launched the Ectodermal Dysplasias International Registry (EDIR), a patientreported research tool providing information for expanding knowledge of the natural history of ectodermal dysplasia (ED).
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Fete M, Hermann J, Behrens J, Huttner KM. 2014. X-linked hypohidrotic ectodermal dysplasia (XLHED): Clinical and diagnostic insights from an international patient registry. Am J Med Genet Part A 9999:1–6.
This comprehensive, web-based questionnaire was designed to capture relevant medical history across all major organ systems, and to identify specific signs and symptoms that would aide health care providers in the differential diagnosis of the ED. As of May 2011, 835 individuals had entered data into the EDIR, equally divided between males and females (419 vs. 416). Hypohidrotic ectodermal dysplasia (HED) is the most common form of ED, and the majority of HED cases are associated with mutations or deletions in the ectodysplasin (EDA) gene inherited on the X-chromosome [Wright et al., 2011]. Males with X-linked HED (XLHED) are hemizygous for EDA gene abnormalities and usually express the full-blown HED phenotype of hypotrichosis, hypohidrosis, oligodontia, and a predisposition to respiratory disorders. Females with XLHED are heterozygous for an EDA gene abnormality (homozygosity possible but not yet reported in the literature) and present with a phenotype ranging from mild HED with hypodontia to the severe form seen in hemizygous males. Several reports in the literature summarize the range and frequency of clinical findings in XLHED [Clarke et al., 1987; Vincent et al., 2001] but these usually include small numbers of patients and a limited breadth of outcome measurements. Conflict of interest: none. Correspondence to: Mary Fete, National Foundation for Ectodermal Dysplasias, 6 Executive Dr., Ste.2, Fairview Heights, IL 62208. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36436
1
2 The first analysis of data from this International Registry confirms a number of clinical findings common in XLHED, highlights similarities and differences between XLHED males and females, and provides insights into diagnostic clues differentiating XLHED from less common ED.
METHODS The EDIR is a central, online database conceived and developed by the National Foundation for Ectodermal Dysplasias (http://nfed. org/index.php/research/ectodermal_dysplasias_international_registry) with the participation of international ectodermal dysplasia groups (listed below). It contains 17 sections including a comprehensive, systems approach to clinical issues relevant to any of the ED. It’s stated goal is to identify and register patients with any form of ED, to enter their information under conditions of informed consent and strict confidentiality, and to build a resource for investigators seeking to enhance patient diagnosis, education, and treatment. The database is held by Innolyst (http://www. innolyst.com/). De-identified data are available for researcher review, with IRB and Scientific Review Board approval required to follow-up with registry participants. The EDIR was launched on March 1, 2010, and as of May 24, 2011, had collected information from 835 ED patients. The data were downloaded to an Excel spreadsheet for analysis. Diagnosis groups were subdivided based on registrant identification as XLHED, HED, non-HED (any specified ED diagnosis that did not fall into one of the HED categories), and unknown (no diagnosis specified, or diagnosis unknown). The HED patient group included all XLHED in addition to autosomal recessive, autosomal dominant, immune deficiency, and unknown types. Test for statistical differences in population proportions used a two-proportion z-test. In this analysis, proportions of symptom frequencies were compared between males and females selfreporting with a diagnosis of XLHED, and then between XLHED males and males in each of the other diagnostic groups. No correction was made for multiple comparisons in this hypothesis-generating analysis.
RESULTS Among the 835 subjects represented in the Registry, 429 (51%) classified themselves as having HED (259 males and 170 females). Further questioning yielded 223 of the 429 HED subjects who selfidentified as XLHED (141 males and 82 females). Geographic distribution of the individuals in each subgroup is presented in Figure 1. We elected to focus on the XLHED population as it represents the largest cohort within the ED, is considered to be associated with mutations in a single gene (ectodysplasin or EDA) and has relevant literature for comparison. Sensitivity analyses comparing all outcomes for the XLHED subset with the larger HED cohort demonstrated no statistically-significant differences (data not shown). Table I presents key demographic data for the XLHED cohort, subdivided by gender. The average age of XLHED male registrants was younger than for female registrants, means of 17.8 yrs versus 32.1 yrs and medians of 13.1 yrs versus 33.0 yrs. Overall, 96% of all
AMERICAN JOURNAL OF MEDICAL GENETICS PART A XLHED subjects reported a positive family history for this genetic disorder, and 21% were aware of infant/childhood deaths, consistent with prior literature [Clarke et al., 1987; Friere-Maia and Pinheiro, 1990]. Males were diagnosed more often in early childhood (88% vs. 41%), likely to be the result of a more severe and recognizable phenotype (Fig. 2). While geneticists were involved in diagnosis of XLHED in the majority of cases (57% of males and 68% of females), confirmation by genetic testing was far less common in this cohort (44% of males and 42% of females). Table II reports the frequency of both major and minor XLHED clinical issues, and highlights statistical differences between XLHED males and females. Hypohydrosis, hypotrichosis, and hypodontia are considered the common ectodermal manifestations in the severe form of XLHED, and they were reported by 98%, 80%, and 74% of the male XLHED registrants. Having nearly a quarter of male registrants not reporting hypodontia may reflect the younger age of this cohort (median age 13 yrs). While abnormalities in sweating and hair were less common in the XLHED females, they still were reported by the majority of female registrants (75% and 63%). Missing permanent teeth, often the first clue to diagnosis in XLHED females, were equally common in the males and females. These findings in the XLHED female population are a validation of studies in prior cohorts [Clarke et al., 1987; Clarke et al., 1990]. Reviews of the spectrum of clinical issues in XLHED [Soderholm and Kaitila, 1985; Clarke et al., 1987] reported a number of less common but medically significant complications that impact the quality of life in individuals affected by this disorder. These are confirmed and extended in the Registry data. Grouped by organ system they include diet and growth, skin and nails, respiratory, ocular, and dental. Diet and growth- both “failure-to-thrive as an infant” and “underweight as an adolescent” were reported as relatively common in XLHED males (40% and 44%) but also in XLHED females (26% and 33%). Multiple factors contributing to the growth issues in infancy may include: (1) nasal congestion interfering with feeding; (2) dry mouth and swallowing difficulties secondary to salivary gland hypoplasia [Lexner et al., 2007b; Wells et al., 2010]; (3) gastroesophageal reflux; (4) and late or absent primary dentition [Crawford et al., 1991; Mortier and Wackens, 2004]. The physiologic under-pinnings for “underweight in adolescence,” reported in a prior study as well [Motil et al., 2005], have yet to be fully explained, with anecdotal experience not consistently associated with either an intake or malabsorptive mechanism. Skin and nails- while eczema is common in XLHED males and females, often with onset within the first year of life, significant nail issues are generally not recognized [Nakata et al., 1980] although reported in some literature reviews [Mortier and Wackens, 2004] and by half of all registrants in this study. Respiratory- primarily an issue for XLHED males, respiratoryrelated health issues began in infancy lasting through adulthood and include foul smelling nasal discharge (67%), respiratory infections requiring antibiotics (52%), recurrent pneumonias (19%), wheezing (66%), recurrent sinus infections (49%), and raspy/ hoarse voice (67%). The XLHED female registrants reported all of these less commonly, with the one exception being recurrent sinus infections (52%). Given the abnormalities in craniofacial bone structure associated with XLHED, both a deficiency in nasal
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FIG. 1. A: Number of Registrants by Country (total n ¼ 835). “Others ” represents 23 countries with 1 or 2 registrants. B: Number of XLHED Registrants by Country (total with response, n ¼ 223). “Others ” represents 11 countries with 1 or 2 XLHED registrants.
secretions and sinus outlet compromise may contribute to the sinusitis risk. Ocular- dry eye syndrome was reported by nearly a third of XLHED registrants, but corneal abrasions were rare. This may change in late adulthood but no data is available currently. Anecdotal experience is that XLHED males may not tolerate the wearing of contact lenses, possibly secondary to the combined decrease in lacrimation and Meibomian gland secretions [Kaercher, 2004]. Dental- the literature suggests that XLHED males will present with severe oligodontia (absence of six or more permanent teeth) and XLHED females are likely to have milder hypodontia [Crawford et al., 1991; Lexner et al., 2007a]. The registry data is consistent with this clinical experience in that dentures and dental implants are much more common in the XLHED males.
Contrast with Other Ectodermal Dysplasias Table III highlights the key clinical and potentially diagnostic findings related to the diagnoses of XLHED, non-HED, and unknown ED. Given the range of clinical outcomes in XLHED males
versus XLHED females, we have selected comparisons between males in each category (N ¼ 141, 88, 72 respectively). In general, all ED registrants reported a high incidence of affected family members but a low percentage of genetic confirmation. Key distinguishing features of XLHED in males included minimal or absent sweating, family history of infant/childhood deaths, very rare occurrence of limb/digit abnormalities, frequent need for dentures, and most consistently respiratory issues. The respiratory issues are especially significant in the areas of chronic, foul smelling nasal congestion interfering with feeding, a diagnosis of asthma, and recurrent sinusitis. Non-HED male registrants rarely had a family history of childhood loss, were almost twice as often born preterm as compared to XLHED males, had nearly twice the frequency of nail issues, and were less prone to respiratory issues. The presence of limb/digital abnormalities was the most common finding differentiating non-HED from the XLHED and unknown cohorts. It is revealing that non-HED male registrants reported many of the cardinal features of HED, that is, minimal or no sweat (54%), hypotrichosis of scalp or eyebrows (56%), and missing permanent
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. XLHED Demographics Number enrolled Mean age (yrs) Family hx for disorder Hx of infant/childhood deaths Dx by geneticist Genetic testing confirmation Dx by age 2 yrs
XLHED males 141 17.8 15.1 95% 17% 57% 44% 88%
teeth (61%). While there remains the question of confirmation of diagnosis in any registry with patient-reported outcomes, these findings do suggest that there may exist considerable overlap in the biologic pathways that regulate ectodermal development and are defective in the various forms of ED.
DISCUSSION Cross-sectional survey data captured in an international, webbased Registry can be a valuable tool for identifying common and medically-important health outcomes in rare disorders. These study results reflect the commitment and investment of families for the betterment of patients with these rare disorders. The efforts of well-organized, international patient-support groups can be translated into valuable outreach programs to enhance rare disorder diagnosis and care in developing countries. Hence, it is important to analyze and disseminate registry outcomes as they may relate to patient care, patient education, and research. The inherent weaknesses of a patient-reported registry are selfselection for inclusion in the Registry and lack of medical history documentation in patient-reported outcomes. The percentage of
XLHED females 82 32.1 16.3 99% 26% 68% 42% 41%
All XLHED 223 22.9 16.9 96% 21% 61% 43% 71%
All HED 429 22.2 16.9 95% 15% 56% 35% 71%
registrants reporting under each diagnostic category may not reflect their prevalence in the general population, but instead their active participation in organizations and social media sites through which the Registry might be announced. This in turn may bias their reported health issues either towards the more severe or more detailed. Importantly for developmental disorders, certain medical issues may not arise until patients attain a specific age, and hence would be under-reported in younger populations, for example, permanent dentition, sinus infections, and hair loss. In the case of XLHED-affected registrants, findings from the Registry analysis update and extend the data from prior, smaller datasets [Soderholm and Kaitila, 1985; Clarke et al., 1987; Clarke et al., 1990] and thus reaffirm key medical issues including: (1) significant infant/childhood mortality; (2) nutritional and growth challenges; (3) lifelong nasal/respiratory problems in both male and females affected by XLHED; and (4) dental interventions (and associated costs) that continue to be a common and significant health issue for XLHED patients. Physical and historical findings that differ between XLHED and other ED syndromes will facilitate their differential diagnosis. The data presented in this analysis on less-commonly appreciated aspects of the ED disorders are
FIG. 2. Age at diagnosis for XLHED male and female registrants. Percentages are within each gender, with totals of males n ¼ 140 and females n ¼ 82 responding to the question.
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TABLE II. XLHED Clinical Issues XLHED males General # of subjects Minimal/no sweat Absent/sparse haira Missing permanent teeth Growth/feeding FTTb Underweight adolescent Nasal congestion affecting feeding Dry mouth Swallowing difficulty Feeding problems GE reflux Skin/nails Eczema Nail issues Respiratory Foul smelling nasal discharge Hospitalizations for fevers Respiratory infections requiring antibiotics Recurrent pneumonias Recurrent sinus infections Raspy/hoarse voice Wheezing Asthma Ocular Dry eyes Corneal abrasions Dental Dentures Dental implants a
XLHED females
TABLE III. XLHED vs. Non-HED and Unknown ED Diagnosis (Males Only) P-values
141 98% 80% 74%
82 75% 63% 73%
2.01E-07 0.0045 N.S.
General # of subjects Average age (yrs)
40% 44% 73% 42% 38% 30% 35%
26% 33% 27% 18% 16% 9% 23%
0.04 N.S. 4.57E-10 0.0003 0.0006 0.00015 N.S.
Family hx for disorder Infant/childhood deaths Dx by geneticist Minimal/no sweat Absent/sparse haira Missing permanent teeth Growth/feeding Preterm birth FTT Nasal congestion affecting feeding Swallowing difficulty Feeding problems GE reflux Skin/nails/limbs Eczema Nail issues Limb/digit abnormalities Respiratory Foul smelling nasal discharge Respiratory infections requiring antibiotics Recurrent sinus infections Raspy/hoarse voice Asthma Dental Dentures
66% 47%
40% 57%
0.0002 N.S.
67% 33% 52%
20% 9% 34%
1.11E-11 3.07E-05 0.0008
19% 49% 67% 66% 40%
10% 52% 23% 45% 23%
N.S. N.S. 3.74E-10 0.003 0.01
36% 9%
26% 2%
N.S. N.S.
66% 20%
41% 9%
0.0003 0.05
Demonstrates international participation.
XLHED males
All HED males
Non-HED males
Unknown ED dx males
141 17.8 15.1 95% 17% 57% 98% 80% 74%
259 17.4 14.6 94% 14% 51% 94% 77% 73%
88 18.3 15.4 82% 1% 61% 54% 56% 61%
72 19.0 18.0 90% 2% 24% 59% 66% 51%
15% 40% 73%
18% 36% 63%
28% 28% 24%
10% 25% 37%
38% 30% 35%
31% 27% 31%
28% 27% 32%
14% 11% 18%
66% 47% 2%
62% 51% 3%
45% 89% 52%
67%
62%
18%
52%
52%
34%
49% 67% 40%
53% 59% 36%
35% 35% 16%
66%
58%
21%
38% 79% 16% 13% 18%
38% 26% 33% 44%
The are for statistical significance at the P < 0.05 level without adjustment for multiple comparisons.
anticipated to be helpful both to treating clinicians and to investigators in identifying relevant clinical endpoints and including their assessment in clinical study design. To this end, they also can facilitate assessing health care costs due to the genetic disorder over a patient’s lifetime, and potential lifetime cost savings for an intervention.
ACKNOWLEDGMENTS Ectodermal dysplasia advocacy groups and other partners contributing to the design and successful implementation of the EDIR include:
Innolyst, Inc. Edimer Pharmaceuticals Australia—ozED Austria/Germany—Selbsthilfegruppe Ektodermale Dysplasie
Belgium Denmark—Ectodermal Dysplasia Denmark France—Associacion Francaise Dysplasias Ectodermiques (AFDE) Italy—Associazione Nazionale Displasia Ectodermica (A.N. D.E.) Mexico—Asociacion Mexicana de Displasia Ectodermica Netherlands/Belgium/Luxemborg—Ectodermal Dysplasia the Netherlands Norway—Norsk ED-forening Spain—Asociacion de afectados por displasia ectodermica (A.A. D.E.) Sweden—Svenska Ed-foreningen Turkey—Ektodermal Displazi Grubu – Turkiye United Kingdom—Ectodermal Dysplasia Society
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REFERENCES Clarke A, Phillips DI, Brown R, Harper PS. 1987. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child 62: 989–996. Clarke RP, Goff MR, MacDermot KD. 1990. Identification of functioning sweat pores and visualization of skin temperature patterns in X-linked hypohidrotic ectodermal dysplasia by whole body thermography. Hum Genet 86:7–13.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Mortier K, Wackens G. Ectodermal Dysplasia anhidrotic. Orphanet Encyclopedia. September 2004. http://www.orpha.net/data/patho/GB/ukectodermal-dysplasia-anhidrotic.pdf Motil KJ, Fete TJ, Fraley JK, Schultz RJ, Foy TM, Ochs U, Sybert VP. 2005. Growth Characteristics of Children with Ectodermal Dysplasia Syndromes. Pediatrics 116:e229–e234. Nakata M, Koshiba H, Eto K, Nance WE. 1980. A genetic study of anodontia in X-linked hypohidrotic ectodermal dysplasia. Am J Hum Genet 32:908– 919.
Crawford PJM, Aldred MJ, Clarke A. 1991. Clinical and radiographic dental findings in X linked hypohidrotic ectodermal dysplasia. J Med Genet 28:181–185.
Soderholm AL, Kaitila I. 1985. Expression of X-linked hypohidrotic ectodermal dysplasia in six males and in their mothers. Clin Genet 28:136–144.
Friere-Maia N, Pinheiro M. 1990. Precocious mortality in Christ-SiemensTouraine syndrome. Am J Med Genet 37:299.
Vincent MC, Biancalana V, Ginisty D, Mandel JL, Calvas P. 2001. Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia. Eur J Hum Genet 9:355–363.
Kaercher T. 2004. Ocular symptoms and signs in patients with ectodermal dysplasia syndromes. Graefes Arch Clin Exp Ophthalmol 242:495–500. Lexner MO, Bardow A, Hertz JM, Nielsen LA, Kreiborg S. 2007a. Anomalies of tooth formation in hypohidrotic ectodermal dysplasia. Int J Paediatr Dent 17:10–18. Lexner MO, Bardow A, Hertz JM, Almer L, Nauntofte B, Kreiborg S. 2007b. Whole saliva in X-linked hypohidrotic ectodermal dysplasia. Int J Paediatr Dent 17:155–162.
Wells KL, Mou C, Headon DJ, Tuckeer AS. 2010. Recombinant EDA or Sonic Hedgehog rescue the branching defect in Ectodysplasin A pathway mutant salivary glands in vitro. Dev Dyn 239:2674–2684. Wright JT, Grange DK, Richter MK. Hypohidrotic Ectodermal Dysplasia. 2003 Apr 28 [Updated 2013 Jun 13]. In Pagon RA, Adam MP, Bird TD, et al., editors. Gene ReviewsTM [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2014. Available from: http://www.ncbi.nlm. nih.gov/books/NBK1112/
X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED): Clinical and Diagnostic Insights from an International Patient Registry Mary Fete,1* Julie Hermann,2 Jeffrey Behrens,2 and Kenneth M. Huttner2 1
National Foundation for Ectodermal Dysplasia, Mascoutah, Illinois
2
Edimer Pharmaceuticals Inc., Cambridge, Massachusetts
Manuscript Received: 8 October 2013; Manuscript Accepted: 1 December 2013
The web-based Ectodermal Dysplasia International Registry (EDIR) is a comprehensive patient-reported survey contributing to an understanding of ectodermal dysplasia (ED). XLHED is the most common of the genetic ED syndromes and was the primary diagnosis reported by 223/835 respondents (141 males and 82 females). Overall, 96% of XLHED registrants reported as least one other affected family member and 21% reported a family history of infant or childhood deaths, consistent with the published mortality data in this disorder. In general, XLHED is diagnosed by the triad of decreased sweating, reduced hair, and hypodontia (present in 89%, 74%, and 74% of XLHED respondents). Additionally, the registry dataset confirmed a spectrum of life-long XLHED clinical complications including recurrent sinus infections (49% males, 52% females), nasal congestion often foul smelling and interfering with feeding (73% males, 27% females), eczema (66% males, 40% females), wheezing (66% males, 45% females), and a hoarse, raspy voice (67% males, 23% females). The Registry results also highlighted features consistently differentiating XLHED from the non-hypohidrotic ED syndromes including the frequency of infant/childhood deaths, the presence of limb/digit abnormalities, feeding issues related to nasal discharge, dentures, and a diagnosis of asthma. These results represent the largest collection of data on a broad-spectrum of health-related issues affecting ED patients. This project provides information for expanding knowledge of the natural history of XLHED, and as such may facilitate the diagnosis and treatment of its varied and lifelong medical challenges. Ó 2014 Wiley Periodicals, Inc.
Key words: ectodermal dysplasias; XLHED; patient advocacy group; registry
INTRODUCTION In 2010 the U.S. National Foundation for Ectodermal Dysplasias (NFED, www.nfed.org), in conjunction with 13 international patient support groups (Acknowledgements), launched the Ectodermal Dysplasias International Registry (EDIR), a patientreported research tool providing information for expanding knowledge of the natural history of ectodermal dysplasia (ED).
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Fete M, Hermann J, Behrens J, Huttner KM. 2014. X-linked hypohidrotic ectodermal dysplasia (XLHED): Clinical and diagnostic insights from an international patient registry. Am J Med Genet Part A 9999:1–6.
This comprehensive, web-based questionnaire was designed to capture relevant medical history across all major organ systems, and to identify specific signs and symptoms that would aide health care providers in the differential diagnosis of the ED. As of May 2011, 835 individuals had entered data into the EDIR, equally divided between males and females (419 vs. 416). Hypohidrotic ectodermal dysplasia (HED) is the most common form of ED, and the majority of HED cases are associated with mutations or deletions in the ectodysplasin (EDA) gene inherited on the X-chromosome [Wright et al., 2011]. Males with X-linked HED (XLHED) are hemizygous for EDA gene abnormalities and usually express the full-blown HED phenotype of hypotrichosis, hypohidrosis, oligodontia, and a predisposition to respiratory disorders. Females with XLHED are heterozygous for an EDA gene abnormality (homozygosity possible but not yet reported in the literature) and present with a phenotype ranging from mild HED with hypodontia to the severe form seen in hemizygous males. Several reports in the literature summarize the range and frequency of clinical findings in XLHED [Clarke et al., 1987; Vincent et al., 2001] but these usually include small numbers of patients and a limited breadth of outcome measurements. Conflict of interest: none. Correspondence to: Mary Fete, National Foundation for Ectodermal Dysplasias, 6 Executive Dr., Ste.2, Fairview Heights, IL 62208. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36436
1
2 The first analysis of data from this International Registry confirms a number of clinical findings common in XLHED, highlights similarities and differences between XLHED males and females, and provides insights into diagnostic clues differentiating XLHED from less common ED.
METHODS The EDIR is a central, online database conceived and developed by the National Foundation for Ectodermal Dysplasias (http://nfed. org/index.php/research/ectodermal_dysplasias_international_registry) with the participation of international ectodermal dysplasia groups (listed below). It contains 17 sections including a comprehensive, systems approach to clinical issues relevant to any of the ED. It’s stated goal is to identify and register patients with any form of ED, to enter their information under conditions of informed consent and strict confidentiality, and to build a resource for investigators seeking to enhance patient diagnosis, education, and treatment. The database is held by Innolyst (http://www. innolyst.com/). De-identified data are available for researcher review, with IRB and Scientific Review Board approval required to follow-up with registry participants. The EDIR was launched on March 1, 2010, and as of May 24, 2011, had collected information from 835 ED patients. The data were downloaded to an Excel spreadsheet for analysis. Diagnosis groups were subdivided based on registrant identification as XLHED, HED, non-HED (any specified ED diagnosis that did not fall into one of the HED categories), and unknown (no diagnosis specified, or diagnosis unknown). The HED patient group included all XLHED in addition to autosomal recessive, autosomal dominant, immune deficiency, and unknown types. Test for statistical differences in population proportions used a two-proportion z-test. In this analysis, proportions of symptom frequencies were compared between males and females selfreporting with a diagnosis of XLHED, and then between XLHED males and males in each of the other diagnostic groups. No correction was made for multiple comparisons in this hypothesis-generating analysis.
RESULTS Among the 835 subjects represented in the Registry, 429 (51%) classified themselves as having HED (259 males and 170 females). Further questioning yielded 223 of the 429 HED subjects who selfidentified as XLHED (141 males and 82 females). Geographic distribution of the individuals in each subgroup is presented in Figure 1. We elected to focus on the XLHED population as it represents the largest cohort within the ED, is considered to be associated with mutations in a single gene (ectodysplasin or EDA) and has relevant literature for comparison. Sensitivity analyses comparing all outcomes for the XLHED subset with the larger HED cohort demonstrated no statistically-significant differences (data not shown). Table I presents key demographic data for the XLHED cohort, subdivided by gender. The average age of XLHED male registrants was younger than for female registrants, means of 17.8 yrs versus 32.1 yrs and medians of 13.1 yrs versus 33.0 yrs. Overall, 96% of all
AMERICAN JOURNAL OF MEDICAL GENETICS PART A XLHED subjects reported a positive family history for this genetic disorder, and 21% were aware of infant/childhood deaths, consistent with prior literature [Clarke et al., 1987; Friere-Maia and Pinheiro, 1990]. Males were diagnosed more often in early childhood (88% vs. 41%), likely to be the result of a more severe and recognizable phenotype (Fig. 2). While geneticists were involved in diagnosis of XLHED in the majority of cases (57% of males and 68% of females), confirmation by genetic testing was far less common in this cohort (44% of males and 42% of females). Table II reports the frequency of both major and minor XLHED clinical issues, and highlights statistical differences between XLHED males and females. Hypohydrosis, hypotrichosis, and hypodontia are considered the common ectodermal manifestations in the severe form of XLHED, and they were reported by 98%, 80%, and 74% of the male XLHED registrants. Having nearly a quarter of male registrants not reporting hypodontia may reflect the younger age of this cohort (median age 13 yrs). While abnormalities in sweating and hair were less common in the XLHED females, they still were reported by the majority of female registrants (75% and 63%). Missing permanent teeth, often the first clue to diagnosis in XLHED females, were equally common in the males and females. These findings in the XLHED female population are a validation of studies in prior cohorts [Clarke et al., 1987; Clarke et al., 1990]. Reviews of the spectrum of clinical issues in XLHED [Soderholm and Kaitila, 1985; Clarke et al., 1987] reported a number of less common but medically significant complications that impact the quality of life in individuals affected by this disorder. These are confirmed and extended in the Registry data. Grouped by organ system they include diet and growth, skin and nails, respiratory, ocular, and dental. Diet and growth- both “failure-to-thrive as an infant” and “underweight as an adolescent” were reported as relatively common in XLHED males (40% and 44%) but also in XLHED females (26% and 33%). Multiple factors contributing to the growth issues in infancy may include: (1) nasal congestion interfering with feeding; (2) dry mouth and swallowing difficulties secondary to salivary gland hypoplasia [Lexner et al., 2007b; Wells et al., 2010]; (3) gastroesophageal reflux; (4) and late or absent primary dentition [Crawford et al., 1991; Mortier and Wackens, 2004]. The physiologic under-pinnings for “underweight in adolescence,” reported in a prior study as well [Motil et al., 2005], have yet to be fully explained, with anecdotal experience not consistently associated with either an intake or malabsorptive mechanism. Skin and nails- while eczema is common in XLHED males and females, often with onset within the first year of life, significant nail issues are generally not recognized [Nakata et al., 1980] although reported in some literature reviews [Mortier and Wackens, 2004] and by half of all registrants in this study. Respiratory- primarily an issue for XLHED males, respiratoryrelated health issues began in infancy lasting through adulthood and include foul smelling nasal discharge (67%), respiratory infections requiring antibiotics (52%), recurrent pneumonias (19%), wheezing (66%), recurrent sinus infections (49%), and raspy/ hoarse voice (67%). The XLHED female registrants reported all of these less commonly, with the one exception being recurrent sinus infections (52%). Given the abnormalities in craniofacial bone structure associated with XLHED, both a deficiency in nasal
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3
FIG. 1. A: Number of Registrants by Country (total n ¼ 835). “Others ” represents 23 countries with 1 or 2 registrants. B: Number of XLHED Registrants by Country (total with response, n ¼ 223). “Others ” represents 11 countries with 1 or 2 XLHED registrants.
secretions and sinus outlet compromise may contribute to the sinusitis risk. Ocular- dry eye syndrome was reported by nearly a third of XLHED registrants, but corneal abrasions were rare. This may change in late adulthood but no data is available currently. Anecdotal experience is that XLHED males may not tolerate the wearing of contact lenses, possibly secondary to the combined decrease in lacrimation and Meibomian gland secretions [Kaercher, 2004]. Dental- the literature suggests that XLHED males will present with severe oligodontia (absence of six or more permanent teeth) and XLHED females are likely to have milder hypodontia [Crawford et al., 1991; Lexner et al., 2007a]. The registry data is consistent with this clinical experience in that dentures and dental implants are much more common in the XLHED males.
Contrast with Other Ectodermal Dysplasias Table III highlights the key clinical and potentially diagnostic findings related to the diagnoses of XLHED, non-HED, and unknown ED. Given the range of clinical outcomes in XLHED males
versus XLHED females, we have selected comparisons between males in each category (N ¼ 141, 88, 72 respectively). In general, all ED registrants reported a high incidence of affected family members but a low percentage of genetic confirmation. Key distinguishing features of XLHED in males included minimal or absent sweating, family history of infant/childhood deaths, very rare occurrence of limb/digit abnormalities, frequent need for dentures, and most consistently respiratory issues. The respiratory issues are especially significant in the areas of chronic, foul smelling nasal congestion interfering with feeding, a diagnosis of asthma, and recurrent sinusitis. Non-HED male registrants rarely had a family history of childhood loss, were almost twice as often born preterm as compared to XLHED males, had nearly twice the frequency of nail issues, and were less prone to respiratory issues. The presence of limb/digital abnormalities was the most common finding differentiating non-HED from the XLHED and unknown cohorts. It is revealing that non-HED male registrants reported many of the cardinal features of HED, that is, minimal or no sweat (54%), hypotrichosis of scalp or eyebrows (56%), and missing permanent
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. XLHED Demographics Number enrolled Mean age (yrs) Family hx for disorder Hx of infant/childhood deaths Dx by geneticist Genetic testing confirmation Dx by age 2 yrs
XLHED males 141 17.8 15.1 95% 17% 57% 44% 88%
teeth (61%). While there remains the question of confirmation of diagnosis in any registry with patient-reported outcomes, these findings do suggest that there may exist considerable overlap in the biologic pathways that regulate ectodermal development and are defective in the various forms of ED.
DISCUSSION Cross-sectional survey data captured in an international, webbased Registry can be a valuable tool for identifying common and medically-important health outcomes in rare disorders. These study results reflect the commitment and investment of families for the betterment of patients with these rare disorders. The efforts of well-organized, international patient-support groups can be translated into valuable outreach programs to enhance rare disorder diagnosis and care in developing countries. Hence, it is important to analyze and disseminate registry outcomes as they may relate to patient care, patient education, and research. The inherent weaknesses of a patient-reported registry are selfselection for inclusion in the Registry and lack of medical history documentation in patient-reported outcomes. The percentage of
XLHED females 82 32.1 16.3 99% 26% 68% 42% 41%
All XLHED 223 22.9 16.9 96% 21% 61% 43% 71%
All HED 429 22.2 16.9 95% 15% 56% 35% 71%
registrants reporting under each diagnostic category may not reflect their prevalence in the general population, but instead their active participation in organizations and social media sites through which the Registry might be announced. This in turn may bias their reported health issues either towards the more severe or more detailed. Importantly for developmental disorders, certain medical issues may not arise until patients attain a specific age, and hence would be under-reported in younger populations, for example, permanent dentition, sinus infections, and hair loss. In the case of XLHED-affected registrants, findings from the Registry analysis update and extend the data from prior, smaller datasets [Soderholm and Kaitila, 1985; Clarke et al., 1987; Clarke et al., 1990] and thus reaffirm key medical issues including: (1) significant infant/childhood mortality; (2) nutritional and growth challenges; (3) lifelong nasal/respiratory problems in both male and females affected by XLHED; and (4) dental interventions (and associated costs) that continue to be a common and significant health issue for XLHED patients. Physical and historical findings that differ between XLHED and other ED syndromes will facilitate their differential diagnosis. The data presented in this analysis on less-commonly appreciated aspects of the ED disorders are
FIG. 2. Age at diagnosis for XLHED male and female registrants. Percentages are within each gender, with totals of males n ¼ 140 and females n ¼ 82 responding to the question.
FETE ET AL.
5
TABLE II. XLHED Clinical Issues XLHED males General # of subjects Minimal/no sweat Absent/sparse haira Missing permanent teeth Growth/feeding FTTb Underweight adolescent Nasal congestion affecting feeding Dry mouth Swallowing difficulty Feeding problems GE reflux Skin/nails Eczema Nail issues Respiratory Foul smelling nasal discharge Hospitalizations for fevers Respiratory infections requiring antibiotics Recurrent pneumonias Recurrent sinus infections Raspy/hoarse voice Wheezing Asthma Ocular Dry eyes Corneal abrasions Dental Dentures Dental implants a
XLHED females
TABLE III. XLHED vs. Non-HED and Unknown ED Diagnosis (Males Only) P-values
141 98% 80% 74%
82 75% 63% 73%
2.01E-07 0.0045 N.S.
General # of subjects Average age (yrs)
40% 44% 73% 42% 38% 30% 35%
26% 33% 27% 18% 16% 9% 23%
0.04 N.S. 4.57E-10 0.0003 0.0006 0.00015 N.S.
Family hx for disorder Infant/childhood deaths Dx by geneticist Minimal/no sweat Absent/sparse haira Missing permanent teeth Growth/feeding Preterm birth FTT Nasal congestion affecting feeding Swallowing difficulty Feeding problems GE reflux Skin/nails/limbs Eczema Nail issues Limb/digit abnormalities Respiratory Foul smelling nasal discharge Respiratory infections requiring antibiotics Recurrent sinus infections Raspy/hoarse voice Asthma Dental Dentures
66% 47%
40% 57%
0.0002 N.S.
67% 33% 52%
20% 9% 34%
1.11E-11 3.07E-05 0.0008
19% 49% 67% 66% 40%
10% 52% 23% 45% 23%
N.S. N.S. 3.74E-10 0.003 0.01
36% 9%
26% 2%
N.S. N.S.
66% 20%
41% 9%
0.0003 0.05
Demonstrates international participation.
XLHED males
All HED males
Non-HED males
Unknown ED dx males
141 17.8 15.1 95% 17% 57% 98% 80% 74%
259 17.4 14.6 94% 14% 51% 94% 77% 73%
88 18.3 15.4 82% 1% 61% 54% 56% 61%
72 19.0 18.0 90% 2% 24% 59% 66% 51%
15% 40% 73%
18% 36% 63%
28% 28% 24%
10% 25% 37%
38% 30% 35%
31% 27% 31%
28% 27% 32%
14% 11% 18%
66% 47% 2%
62% 51% 3%
45% 89% 52%
67%
62%
18%
52%
52%
34%
49% 67% 40%
53% 59% 36%
35% 35% 16%
66%
58%
21%
38% 79% 16% 13% 18%
38% 26% 33% 44%
The are for statistical significance at the P < 0.05 level without adjustment for multiple comparisons.
anticipated to be helpful both to treating clinicians and to investigators in identifying relevant clinical endpoints and including their assessment in clinical study design. To this end, they also can facilitate assessing health care costs due to the genetic disorder over a patient’s lifetime, and potential lifetime cost savings for an intervention.
ACKNOWLEDGMENTS Ectodermal dysplasia advocacy groups and other partners contributing to the design and successful implementation of the EDIR include:
Innolyst, Inc. Edimer Pharmaceuticals Australia—ozED Austria/Germany—Selbsthilfegruppe Ektodermale Dysplasie
Belgium Denmark—Ectodermal Dysplasia Denmark France—Associacion Francaise Dysplasias Ectodermiques (AFDE) Italy—Associazione Nazionale Displasia Ectodermica (A.N. D.E.) Mexico—Asociacion Mexicana de Displasia Ectodermica Netherlands/Belgium/Luxemborg—Ectodermal Dysplasia the Netherlands Norway—Norsk ED-forening Spain—Asociacion de afectados por displasia ectodermica (A.A. D.E.) Sweden—Svenska Ed-foreningen Turkey—Ektodermal Displazi Grubu – Turkiye United Kingdom—Ectodermal Dysplasia Society
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