Prevalence and prevention of severe complications of hypohidrotic ectodermal dysplasia in infancy

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Abstract

Objective

To re-evaluate the mortality of hypohidrotic ectodermal dysplasia (HED) and the prevalence of hyperpyrexia and possible neurological sequelae in affected infants.

Study design

A cross-sectional postal survey was conducted among parents of 100 children with ectodermal dysplasia who had been registered with the German–Swiss–Austrian patient support group at any time point within the past 10 years. Detailed questionnaires referring to the first year of life were evaluated statistically.

Results

63% of parents returned completed surveys, identifying 57% of children as patients with X-linked HED and 20% as patients with autosomal HED or HED of unknown origin. Of those two groups, 17 infants had been placed in an incubator after birth, where body temperature recording proved to be of utmost importance. In 94% of all HED patients, episodes of unexplained fever were observed during the first year of life. X-linked HED was associated with frequent airway infections. Febrile seizures occurred in 5.9% of infants with X-linked HED and in 17% of the other HED patients. Developmental retardation was reported for 15% and 25%, respectively. Prognosis depended on the type of genetic defect and the time point of diagnosis. Except for one all patients survived infancy. Early recognition of the disease was aided by vigilant neonatal care and consulting a dermatologist or geneticist. Adequate instruction of the parents and networking with patient support groups also reduced the risks associated with HED.

Conclusions

Today, mortality of HED and the risk of hyperthermic brain damage are still increased, but lower than reported previously.

Introduction

The ectodermal dysplasias are a large, heterogeneous group of hereditary disorders characterized by defective formation of tissues derived from embryonic ectoderm. Mutations that affect the epithelial morphogen ectodysplasin A or its signalling pathway result in hypohidrotic ectodermal dysplasia (HED) [1], where a lack of sweat glands may lead to recurrent severe overheating. This rare condition was first described by Thurman [2] and also documented by Charles Darwin [3] who had received correspondence from India depicting a family in which 10 men had sparse hair, abnormal teeth and unexpected dryness of the skin during hot weather. Absence of sweating was understood as a major hazard when working out in the fields. However, the mortality of HED was found to be highest during the first year of life [4]. Although it has been widely accepted that children with HED are at substantial risk of sudden death in infancy due to fatal hyperpyrexia, few studies have investigated this issue [4], [5], indicating a mortality in early childhood of almost 30% [5]. In addition, there are anecdotal reports of HED cases with mental retardation, possibly as a result of repeated severe hyperthermia [6], [7]. Impressions of frequent mental retardation in persons with HED and claims that their intelligence is different from that of the general population were difficult to dispute and may have been affected by biases against physically unattractive individuals.

However, there have been significant improvements in pediatric care over the past two decades. To complement the information published more than 20 years ago and to assess the prevalence of hyperpyrexia and possible neurological sequelae in affected infants today, patients' neonatal records were reviewed and a cross-sectional postal survey was conducted among parents of children with ectodermal dysplasia.

In our analysis, we distinguished between patients with clearly X-linked HED caused by a defect in the ectodysplasin A gene (EDA) and other HED patients, either carrying a mutation in the autosomal genes EDAR or EDARADD which encode the ectodysplasin A1 receptor or an intracellular signal mediator named EDAR-associated death domain [8], respectively, or suffering from HED of unknown origin. Thus, only the first group represents a well-defined homogeneous cohort, whereas the latter one is a heterogeneous group which may include also individuals with still undetected EDA mutations.

Section snippets

Data collection

Neonatal records of 3 HED patients referred to the Department of Pediatrics of Innsbruck Medical University were reviewed to compile a detailed retrospective questionnaire (75 specific questions) addressing perinatal variables and family characteristics, distinctive features of the patient and parental observations during his first year of life as well as typical diagnostic procedures (Supplementary table). This questionnaire was sent out to the parents of 100 children who had been registered

Results

Overall, 63% of parents (57/91) returned completed surveys on a total of 62 ectodermal dysplasia patients. However, two questionnaires could not be evaluated because of a lack of specific data. The 60 complete data sets identified 23% of affected children as individuals without hypohidrosis and 57% (34/60) as patients with clearly X-linked HED, while the remaining 20% (12/60) were classified as HED of autosomal or unknown origin (Table 1). Considering that autosomal mutations usually underlie

Discussion

Eccrine sweating is an extremely important function in human thermoregulation. Problems affecting either the control of sweating activity or the glands themselves can lead to fatal hyperpyrexia. This applies in particular to the early childhood. Therefore, despite worldwide improvements in pediatric care, the reduced number of sweat glands in HED patients is still assumed to have a strong impact on mortality. An earlier study by Clarke et al. [4] revealed a higher mortality in the first

Conflict of interest statement

The authors declare that they have no conflict of interest.

Acknowledgements

This study was supported by a grant from the German–Swiss–Austrian ectodermal dysplasia patient support group (to H. S.). The authors wish to thank all families who participated in the survey.

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