Mary L. Williams, MD, Adjunct Professor of Dermatology and Pediatrics, University of California San Francisco, CA
|Dr. Mary Williams|
It has become apparent to dermatologists who have had the opportunity to see a number of children with ichthyosis that some of these children are small for their age. Less commonly, severe growth failure has been observed during infancy. Severe growth failure is recognized as particularly common in Netherton syndrome, but can also occur in other types of ichthyosis. The basis for this "failure to thrive" has not been previously studied, although it has been suggested that the chronic skin inflammation and increased skin cell production of ichthyosis may be the source of increased energy needs in these children. Some studies of children and adults with severe, widespread skin diseases (similar to some forms of ichthyosis) have shown that gastrointestinal dysfunction, particularly impairment in the ability to absorb fatty foods from the diet, may be a problem. Our study was undertaken to identify the cause(s) of growth failure in children with ichthyosis.
We reasoned at the outset that energy losses due to impaired skin barrier function could be a previously unrecognized cause of growth failure in children with severe ichthyosis. Impaired skin barrier function, as measured by increased rates of water evaporation from the skin surface, has been shown to be present in most people with ichthyosis, due to the abnormally formed outermost layers of skin (the stratum corneum or SC). As water evaporates, it carries with it energy in the form of heat (0.59 Calories /ml). This is why sweating results in cooling of the body. We reasoned that in some children with ichthyosis, the energy lost through their impaired skin barrier might be large enough to cause or contribute to their growth failure. This article will summarize two recent publications resulting from this study:
Ten children with ichthyosis and growth failure, i.e., with height for weight or weight for height in the third, or lower, centile for age, were admitted to the University of California San Francisco Pediatric Research Center for the study. The ages and diagnoses of the participants are given in Table 1. A nutritional evaluation was undertaken that included measuring blood levels of iron, several vitamins, essential fatty acids and other nutrients, as well as some
Table 1: Summary of Patient Characteristics
routine blood chemistries, such as calcium, magnesium, and phosphate levels, and a blood cell count. A history of the child's caloric intake was obtained and caloric intake was recorded over five days of the study. An extensive evaluation of gastrointestinal (GI) function was obtained, including measures of the ability of the GI tract to absorb protein and fat. Upper and lower endoscopies were performed to further evaluate GI status. Skin function was evaluated by measuring transepidermal water loss (TEWL) at multiple body sites to determine an average or "mean basal" transepidermal water loss . The patient's body surface area (BSA) could be determined from their height and weight and, when multiplied by the mean basal TEWL, we could determine daily total transepidermal water loss (TEWL). From this we could calculate daily total caloric losses from skin evaporative water losses (S-EER for Skin Estimated Energy Requirements). We then incorporated the Skin Estimated Energy Requirements into energy balance studies, as follows. The normal or expected energy requirements for each child were obtained from standard tables for children of the same size and age (Normal Expected Energy requirements, N-EER). The total daily caloric requirement (total estimated energy requirements,T-EER) was then calculated as the sum of normal estimated energy requirements (N-EER) plus skin estimated energy requirements (S-EER). Normal estimated energy requirements (N-EER) and total estimated energy requirements (T-EER) were then compared to the child's daily calorie intake, based upon the 5-day calorie counts. To determine if our children were in a hypermetabolic state (i.e., expending more energy at rest) we measured oxygen consumption and carbon dioxide generation at rest and compared the expected (E) resting energy expenditure (REE) for a child of this age and size with our measured (M) resting energy expenditure (REE).
Results: The results of our study are summarized below. For further details, the reader is referred to the original publications 1,2.
Skin Barrier Function:
All the children exhibited impaired skin barriers with elevated mean basal transepidermal water loss (TWEL) (Patients: 39.6 ± 20.6 ml/m²/hr vs. Normal : < 9.7 ml/m²/hr). Children with Netherton and Harlequin ichthyosis had the most severe barrier defects (mean basal TEWL > 40 ml/m²/hr). Those children with CIE and Ichthyosis en confettis had intermediate barrier defects (mean basal TEWL between 20 and 40 ml/m²/hr). And those with lamellar ichthyosis and trichothiodystrophy had the least abnormal barriers (mean basal TWEL between 15-20 ml/m²/hr). We also obtained skin biopsies for electron microscopic evaluation of the structures of the skin that are responsible for the skin barrier ; abnormalities in the quality and quantity of these structures correlated closely with the skin barrier defect (mean basal TEWL). The defective skin barriers can result in large volumes of water lost each day across the skin surface (mean 746 ± 468 ml/day).
Energy Balance Studies:
All children were consuming sufficient calories each day to support growth in a normal child of the same age and size (caloric intake was greater than or equal to normal expected energy requirements, N-EER). However, daily caloric losses due to the skin barrier defect ranged from 84 to 1015 Calories/day, compared to expected rates of 41 to 132 Calories/day for children of same body surface area (BSA) with normal skin barriers. And when skin caloric requirements were added to estimated requirements based upon age and size (total estimated energy requirements, T-EER), 6 patients were in positive energy balance (i.e., consuming enough calories to support growth) and 4 were in negative balance (i.e., they were not consuming enough calories to meet their needs). Resting energy expenditure (REE) was assessed in six patients. In 5 out of 6, measured REE exceeded expected REE based upon norms for age and size, consistent with a hypermetabolic state. Moreover, the percentage difference between M-REE (measured resting energy expenditure) and E-REE (expected resting energy expenditure) was correlated with the severity of the barrier defect (mean basal TEWL). Thus children with more severe barrier defects were more hypermetabolic (expending more energy at rest).
1. Nutritional deficiencies are not common and relatively mild in children with ichthyosis and growth failure.
2. Gastrointestinal function is largely normal in children with ichthyosis and growth failure, but mild fat malabsorption may be present in some. Constipation is a common problem in this group.
|Definitions (in order of appearance)|
Endoscopy - visual examination of the stomach, and upper and lower intestines with a special instrument.
Malabsorption - impaired absorption of nutrients in the intestines.
Lactase deficiency - not enough of the enzyme that breaks down a sugar, lactase, that is found in milk.
Peptic esophagitis - inflammation of the esophagus due to the reflux of acid and pepsin from the stomach.
Hematocrit - the ratio of the volume of red blood cells to plasma in the blood.
3. Skin barrier function is abnormal in these children. Some forms of ichthyosis appear to have more severe barrier abnormalities; these children may loose large volumes of water each day. These children need to compensate by increasing their fluid intake. Whether they do adequately compensate for skin barrier water losses was not examined; the next phase of our research will address this question. It is possible that the chronic constipation in these children may be due in part to inadequate compensatory fluid intake.
4. Increased caloric requirements due to skin evaporative energy losses because of their ichthyosis were present in all and appear to be sufficient to account for the growth failure of most of these children.
5. While these children, at this point in their lives, were consuming sufficient calories to support growth in "normal" children, some of them did not adequately increase their intake to compensate for the calories lost due to their ichthyosis. We suspect that infancy may be a critical time for these children to receive sufficient calories to support growth.
Dr. Melvin Heyman, a pediatric gastroenterologist, was co-investigator on this project.
Dr. Peter M. Elias, assisted by Debra Crumrine, performed the skin electron microscopic studies.
Drs. Ashley Fowler and David Moskowitz coordinated the study and performed the skin and energy consumption measurements.
Dr. Anthony Wong assisted Dr. Heyman.
Ms. Sharon Cohen was the dietician for the study.
Ms. Jeannie Addis was the nurse co-coordinator, and was assisted by staff in the Pediatric Clinical Research Center.
This study is ongoing. If you are interested in having your child participate, please contact Dr. Williams by clicking here. Dr. Williams is Adjunct Professor of Dermatology and Pediatrics, University of California San Francisco.
1-The lay term 'calories' is in scientific terms 'kilocalories'. 'Calories' here refer to kilocalories.
2-Fowler AF, Moskowitz DG, Wong A et al. Nutritional status and gastrointestinal structure and function in children with ichthyosis and growth failure. J Pediatr Gastroenterol Nutr 38(2): 164-9,2004.
3-Moskowitz DG, Fowler AF, Heyman MB et al. Pathophysiologic basis for growth failure in children with ichthyosis: an evaluation of cutaneous ultrastructure, epidermal permeability barrier function, and energy expenditure. J Peds 145: 82-92, 2004.
4-TEWL rates differ normally on different body sites. Also in some forms of ichthyosis, notably Netherton syndrome, the severity of skin involvement may vary over different body sites. Therefore, to obtain a mean TEWL representative of the total body surface, we measured TEWL on multiple body sites then weighted their contribution based upon the approximate percentage of that region of the body to the total body surface area.
5-We used data from the literature for TEWL in normal children. The value of 9.7 represents the upper limit of normal for mean basal TEWL (i.e., plus one standard deviation).
6-Ichthyosis en confettis is a newly described form of ichthyosis, that resembles CIE but in which small (confetti-like) areas of normal skin develop over time . Although the genetic basis has not yet been identified, it appears to be distinct from the CIE/LI family of disorders.
7-The quality and quantity of epidermal lamellar bodies (the organelle that delivers lipid to the SC) and the SC intercellular lipid lamellae was assessed on a 0-4+ scale (4+ = normal). The thickness of the stratum corneum (SC) was also assessed (0-4+). Normal was 4+ and thicker than normal (i.e., most ichthyosis) was also scored as 4+. This is useful, because in Netherton syndrome the SC is typically thinner than normal.
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