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Keywords:

  • growth;
  • body height;
  • body weight;
  • anthropometry;
  • body fat;
  • ectodermal dysplasia;
  • gastroesophageal reflux;
  • constipation;
  • gastrostomy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC) is a rare genetic disorder due to mutations in the TP63 gene. In the present study, we characterized the pattern of growth and body composition and the nutritional and gastrointestinal aspects of children and adults (n = 18) affected with this disorder using clinical anthropometry and a survey questionnaire. The mean birth weight and height-for-age z-scores of the AEC patients were significantly lower than those of the reference population. The weight-for-age z-score of the AEC cohort increased significantly with advancing age because of increasing body fat. Cleft lip and palate were present in 47% and 94%, respectively, of the AEC cohort; 28% had dentures. One-fourth or more of the AEC cohort reported having nutritional and/or gastrointestinal problems including the need for supplemental formula feedings, gastrostomy placement, gastroesophageal reflux, and constipation. Our observations provide novel clinical information about growth, body composition, and nutritional and gastrointestinal aspects of children and adults with AEC. © 2009 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Ankyloblepharon-ectodermal defect-cleft lip and/or cleft palate (AEC), also known as Hay–Wells syndrome, is a rare genetic disorder that belongs to a heterogeneous group of ectodermal dysplasias (ED) affecting the ectodermal derivatives of the body, including the skin; hair; nails; teeth; and the sebaceous, eccrine, and apocrine glands [Champlin and Mallory, 1989; Masse and Perusse, 1994; Pinheiro and Freire-Maia, 1994; Guckes et al., 1998]. AEC is due to mutations in the TP63 gene which give rise to a variable range of phenotypes affecting skin, limb formation, teeth, and hearing [McGrath et al., 2001]. The manifestations of AEC include ankyloblepharon filiforme adenatum; congenital erthyroderma; scalp erosions; coarse, brittle hair; nail dystrophy; cleft palate with or without cleft lip; conjunctivitis; and obstruction of lacrimal ducts and ear canals. Heat intolerance and hypohidrosis have been reported, but objective evidence to support eccrine dysfunction is lacking. Treatment is supportive and includes protective skin care and prevention of infections.

Growth abnormalities have been described in children with several ED syndromes, including four children with AEC [Motil et al., 2005]. Clinical findings in AEC have been reported [Siegfried et al., 2005]; however, the patterns of growth and body composition and the nutritional and gastrointestinal aspects of this genetic disorder have not been characterized. Because of the paucity of information, the National Foundation for the Ectodermal Dysplasias (NFED) convened a workshop conference at Texas Children's Hospital and Baylor College of Medicine, Houston, TX, on November 8–10, 2006, to review the recent progress in basic and clinical research that has been made in this rare genetic disorder and to consider future research directions. Findings from that conference related to growth, body composition, and nutritional and gastrointestinal function in AEC are summarized in this article.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Patients

All children and adults in attendance at the workshop conference who had the clinical diagnosis of AEC were eligible to participate. The diagnosis of AEC was based on review of medical records and clinical evaluation by physician members of the NFED Scientific Advisory Board. The physicians who confirmed the diagnosis of AEC knew each individual and, as specialists in various disciplines, were familiar with manifestations of AEC. Our sample included 18 individuals (males n = 9, females n = 9). The mean age of the patients was 7.5 ± 7.6 years; the age range was 3 months to 31 years. The racial distribution was characterized as 83% Caucasian (n = 15) and 17% African-American (n = 3); one patient was Hispanic.

The Institutional Review Boards for Human Subject Research at Baylor College of Medicine and St. Louis University each approved the research study. Written, informed consent was obtained from the parents of all children younger than 18 years and directly from all individuals 18 years of age or older.

Procedures

Individual heights, weights, head and arm circumferences, and triceps, biceps, subscapular, and suprailiac skinfold thicknesses were obtained by direct measurement at the time of examination. Standing height measurements (without shoes) were obtained on children 2 years of age or older and were recorded to the nearest 0.1 cm. Length measurements, reclining without shoes, were obtained on children younger than 2 years and were recorded to the nearest 0.5 cm. Weight measurements were obtained using an electronic scale; values were recorded to the nearest 0.1 kg. Heavy clothes and shoes were removed before weighing. Body mass index (BMI) was calculated as the ratio of weight divided by height squared (kg/m2) for children 2 years of age or older. Birth length and weight were ascertained from parental recall or available medical records. z-Scores for birth length and weight, height (length)-for-age, weight-for-age, and BMI-for-age were calculated from the reference growth standards for the United States (U.S.) population established by the National Center for Health Statistics and the Centers for Disease Control and Prevention [National Center for Health Statistics, 2000]. Head circumference was measured from the glabella to the maximal occipital protuberance using a non-stretchable tape and converted to a centile value based on age- and gender-appropriate reference data [Nellhaus, 1968]. Arm circumference was measured at a point mid-way between the tip of the acromion and olecranon processes using a non-stretchable tape. The triceps, biceps, subscapular, and suprailiac skinfold thicknesses were measured with skinfold calipers (Lange, Cambridge Scientific Industries, Inc., Cambridge, MD) using standard anthropometric techniques [Motil et al., 2006]. Arm muscle area was calculated from arm circumference and triceps skinfold measurements [Frisancho, 1981]. Triceps skinfold thickness and arm muscle area centiles were calculated based on age- and gender-appropriate reference data from the U.S. Health and Nutrition Examination Survey I [Frisancho, 1981]. Body fat, expressed as a proportion of body weight, was calculated from the triceps, biceps, subscapular, and suprailiac skinfold thickness measurements [Durnin and Rahaman, 1967].

A survey questionnaire was distributed to each participant or parent. Nutritional and gastrointestinal concerns included questions about cleft deformities, the use of dentures, feeding problems, and gastrointestinal symptoms and diagnoses.

Data Analysis

Statistical analysis was performed with MiniTab statistical software (Version 13.0; MiniTab, Inc., State College, PA). Descriptive statistics (mean ± SD) were used to characterize the growth and anthropometric measures. We applied one-sample t-tests to detect differences (P < 0.05) in the mean birth length and weight, height (length)-for-age, weight-for-age, and BMI-for-age z-scores and the mean arm muscle area and triceps skinfold thickness centiles between the AEC patients and reference populations [Frisancho, 1981; National Center for Health Statistics, 2000]. We used paired t-tests to detect differences in the mean height (length)-for-age and weight-for-age z-scores between birth and current measurements. We used descriptive statistics to determine the sample proportions for individual nutritional and gastrointestinal problems identified.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Measures of growth and body composition are shown in Table I. The mean z-score for birth weight, but not birth length, of the AEC patients was significantly lower than that of the reference population [National Center for Health Statistics, 2000]. The mean z-score for height-for-age, but not weight-for-age or BMI-for-age, of the AEC patients was significantly lower than that of the reference population [National Center for Health Statistics, 2000]. The mean z-score for weight-for-age (n = 17, 0.6 ± 1.2, P < 0.05), but not height-for-age (n = 13, −0.3 ± 1.6, P > 0.05), of the AEC patients increased between birth and conference measurements. The mean head circumference centile of the AEC patients was not different from that of the reference population [Nellhaus, 1968]. The mean arm muscle area centile was not different and the mean triceps skinfold thickness centile was significantly higher in the AEC patients than the median values for these measures in the reference population [Frisancho, 1981]. Body fat as a proportion of body weight averaged 23 ± 6% in the AEC patients.

Table I. Measures of Growth and Body Composition in Children and Adults With Ankyloblepharon-Ectodermal Defect-Cleft Lip and/or Palate Syndrome
MeasureNumberValuea
  • a

    Values expressed as mean ± SD.

  • **

    P < 0.001, AEC cohort versus reference population (8).

  • +

    P < 0.01, AEC cohort versus reference population (8).

  • ++

    P < 0.07, AEC cohort versus reference population (8).

  • +++

    P < 0.05, AEC cohort versus reference population (11).

Birth length (cm)1348.4 ± 3.8
z-Score13−0.5 ± 1.5
Birth weight (kg)172.77 ± 0.57
z-Score17−1.2 ±1.0**
Head circumference (cm)1750.3 ± 5.8
Percentile1750 ± 34
Height (cm)18110.9 ± 35.7
z-Score18−0.7 ± 0.9+
Weight (kg)1826.4 ± 24.2
z-Score18−0.6 ± 1.4++
Body mass index (kg/m2)1218.4 ± 5.6
z-Score120.03 ± 1.5
Arm circumference (cm)1818.8 ± 6.6
Arm muscle area (mm2)181,822 ± 1,211
Centile1838 ± 30
Triceps skinfold thickness (mm)1814 ± 7
Centile1867 ± 28+++
Biceps skinfold thickness (mm)189 ± 5
Subscapular skinfold thickness (mm)1811 ± 9
Suprailiac skinfold thickness (mm)1812 ± 10
Body fat (% body weight)1823 ± 6

Four children with AEC had gestational ages at birth between 33 and 35 weeks. When these children were excluded, the mean z-score for birth weight (n = 13, −1.0 ± 1.0, P < 0.01), but not birth length (n = 11, −0.1 ± 1.3, P > 0.05), of the AEC patients was lower than that of the reference population [National Center for Health Statistics, 2000]. The mean z-score for height-for-age (n = 14, −0.7 ± 0.9, P < 0.05), but not weight-for-age (n = 14, −0.6 ± 1.5, P > 0.05) or BMI-for-age (n = 10, 0.02 ± 1.5, P > 0.05), of the AEC patients was lower than that of the reference population [National Center for Health Statistics, 2000]. The mean centile for arm muscle area (n = 14, 35 ± 30, P > 0.05) was not different and the mean centile for triceps skinfold thickness (n = 14, 69 ± 30, P < 0.05) was higher in the AEC patients than the median values for these measures in the reference population [Frisancho, 1981].

The nutritional and gastrointestinal concerns of the AEC patients are summarized in Table II. Cleft palate was found in nearly all of the AEC patients; cleft lip was present in almost one-half of the patients. Denture use was less common. Nutritional formula supplements were administered to nearly two-thirds of the AEC patients at some point throughout the lifespan, but were less common at the time of assessment. Gastrostomy placement was found in more than one-fourth of the AEC patients; fundoplication was uncommon. At least one-half of the AEC patients had a diagnosis of gastroesophageal reflux. Symptoms such as vomiting and constipation were reported frequently. One individual had an anteriorly placed anus that did not require surgery.

Table II. Nutritional and Gastrointestinal Features of Children and Adults With Ankyloblepharon-Ectodermal Defect-Cleft Lip and/or Palate Syndrome
FindingNumber of “yes” responsesProportion (%) with finding
Cleft lip8/1747
Cleft palate17/1894
Dentures5/1828
Nutritional supplements
 Previous use11/1861
 Current use4/1724
Gastrostomy placement5/1828
Gastroesophageal reflux10/1856
Fundoplication1/186
Vomiting7/1839
Diarrhea1/186
Constipation5/1828
Anal surgery0/180
Other (anterior placed anus)1/186

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Here we have shown that linear growth abnormalities presented at an early age in children with AEC. Weight deficits at birth improved with advancing age because of increasing body fat. Nutritional and gastrointestinal problems occurred in one-fourth or more of affected individuals. These findings underscore the importance of careful observation and early clinical intervention in the care of children affected with AEC.

Growth abnormalities commonly occur in children affected with the ED syndromes, particularly those with hypohidrotic ED (HED) [Motil et al., 2005]. As a group, weight deficits occur at an early age and deviate significantly from the growth pattern of healthy children. By contrast, height deficits occur predominately in children affected with ED syndromes other than HED. In the present study, the growth pattern of the subset of children affected with AEC paralleled that of all children affected with the ED syndromes. Birth weight z-scores were lower in the AEC and HED cohorts, while height-for-age z-scores were lower in the AEC and non-HED cohorts. This pattern of growth was unchanged even after adjustment for prematurity. Moreover, the pattern of improvement in weight deficits with advancing age was similar between the AEC and HED cohorts [Motil et al., 2005]. Clinical anthropometry provided a crude estimate of increased body fat in the AEC patients. Although subject to inter-observer variability, we find good correlation (r = 0.80) between this clinical technique and other methods such as dual-energy X-ray absorptiometry in children affected with rare genetic disorders [Motil et al., 2008]. The explanation for altered growth and body composition in AEC is unknown, but presumably has a nutritional and/or genetic basis.

Gastrointestinal issues have been described rarely in the ED syndromes [Executive and Scientific Advisory Boards of the National Foundation for Ectodermal Dysplasias, 1995]. A brief survey conducted by the NFED suggested that individuals with HED may have constipation more frequently than unaffected individuals; a small number was diagnosed with gastroesophageal reflux and failure to thrive rarely requiring a feeding gastrostomy [Executive and Scientific Advisory Boards of the National Foundation for Ectodermal Dysplasias, 1995]. In the present study, constipation was documented in nearly one-fourth of the AEC patients, while gastroesophageal reflux had been diagnosed in more than one-half of the children. Gastrostomy placement was common in the AEC patients; more than one-fourth of the children had a gastrostomy, presumably because of feeding difficulties associated with the near-universal finding of cleft palate with or without cleft lip. Dentures were worn by more than one-fourth of the children. As a consequence of tooth and palate anomalies, nearly two-thirds of the AEC patients consumed formula supplements to meet their nutritional needs.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

This work is a publication of the United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX. This project has been funded in part from the National Foundation for Ectodermal Dysplasias and with federal funds from the Agricultural Research Service of the United States Department of Agriculture under Cooperative Agreement number 58-7MN1-6-100. The contents of this publication do not necessarily reflect the views or policies of the National Foundation of Ectodermal Dysplasias or the United States Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States government. The authors thank the families who participated in the research workshop.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
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