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Stress-related growth failure
THE LANCET
COMMENTARY
Stress-related growth failure See page 353 In 1967 Powell et al described a remarkable case-series of 13 children with aberrant and bizarre behaviours, adverse home environments, and linear growth failure with evidence of hypopituitarism.1,2 The behaviours, the growth failure, and the endocrine abnormalities were all completely reversed upon removal of the children from their stressful home environments. This description was the first of a clinical syndrome that has been called psychosocial dwarfism or short stature. An important aspect of this case-series was that it provided measurable anthropometric and biochemical evidence of the impact of psychological stress on physiological processes in children. Thus, the syndrome offered an intriguing model for the study of the interaction between psychological and physical processes. Unfortunately, although the validity of a syndrome of stress-induced growth failure with neuroendocrine abnormalities has been confirmed by reports from other investigators, there has been little progress in the past 25 years towards a fundamental understanding of its pathophysiology. However, the report by Skuse et al in this issue of The Lancet marks a significant contribution to diagnostic nosology that should facilitate progress in our understanding of this syndrome. Such progress has been hindered by a lack of clear diagnostic criteria, the heterogeneity of reported samples, and a confusing nomenclature. What Skuse and his colleagues have accomplished is to provide specific criteria for a “new” neurobehavioral syndrome, which they term hyperphagic short stature and which mirrors Powell’s original description. The clinical criteria were taken from previous reports of children with “psychosocial dwarfism”. They then applied these criteria to a sample of children referred to hospital with short stature and to a comparison group of children with short stature from a regional epidemiological survey, and calculated a symptom score. Using this symptom score, they divided the patients into 29 hyperphagic (28 of whom were hospital referrals), 23 non-hyperphagic hospital-referred, and 31 communitycomparison children. The nine behaviours that discriminated the groups were all appetite-related. They validated the clinical syndrome on the basis of other nonappetite-related behaviours and abnormalities of growthhormone secretion. Unfortunately, biochemical data were not available on all patients. Despite this drawback, the methods employed seem sound and the findings are significant. From their data, the authors propose a clinical algorithm for the diagnosis of hyperphagic short stature based solely on age, anthropometric data, and behavioral criteria. They demonstrate, convincingly, that the algorithm is discriminative and predictive: discriminative of a group of short children with growth-hormone abnormalities, and predictive of children whose behaviour, growth, and growth-hormone concentrations become normal upon removal from the home environment. Although the algorithm still needs to be used by other investigators and the findings replicated, it seems to be a useful clinical tool for both the care of children and research. Skuse and colleagues have proposed more than simply a change in terminology. They have developed valid diagnostic criteria for the identification of a group of 348
children with a specific stress-induced neurobehavioural and neuroendocrine syndrome that is reversible. They propose the descriptive term, hyperphagic short stature, to clearly separate it from the much larger group of children with psychosocial ills who present with poor growth and, commonly, malnutrition. The ability to discriminate a homogeneous group of children is an important contribution that will facilitate patient care and further research, which in turn might lead to substantive progress, perhaps over the next 25 years or so, in our understanding of this fascinating entity and our knowledge of how psychological and physiological factors interact.
Richard D Stevenson Kluge Children's Rehabilitation Center and Research Institute, University of Virginia School of Medicine, Charlottesville, VA 22903, USA 1
2
Powell GF, Brasel JA, Blizzard RM. Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. I. Clinical evaluation of the syndrome. N Engl J Med 1967; 276: 1271-78. Powell GF, Brasel JA, Raiti S, Blizzard RM. Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. II. Endocrinologic evaluation of the syndrome. N Engl J Med 1967; 276: 1279-83.
The naming of cats—and alpha-interferons As T S Elliot memorably pointed out, “the naming of cats is a difficult matter, it isn’t just one of your holiday games”, for . . . “a cat must have THREE DIFFERENT NAMES”. No doubt he would have said the same about the human alpha-interferons (IFN-alpha), for their nomenclature is the source of considerable confusion. The interferons are classed as type I (alpha, omega, and beta interferons) and type II (interferon-gamma). Biochemical evidence suggests that during the evolution of the mammals over the past 80 million years, the previously single prototype alpha gene gave rise to many variants,1 and all mammals have multiple IFN-alpha genes. It is now established there are 13 human IFN-alpha genes that give rise to functional proteins. These genes, all on chromosome 9, are designated IFNA1, IFNA2, IFNA4, and so on up to IFNA21, gaps in the sequence being due to earlier errors or artifacts. The interferons formed are named correspondingly IFN-alpha1, IFN-alpha2, and so on.2 These 13 subtypes (chemical species) of human IFNalpha are very similar in many respects: they share 100 or more of the 165 or 166 aminoacids that form their polypeptide chain; nearly all react with a single monoclonal antibody; and they all bind to a common complex receptor on the cell surface. Nevertheless, each subtype is to some extent unique in its chemical composition2 and in in-vitro antiviral and immunological properties.3 IFN-alpha preparations for clinical use can be obtained in three ways. When suitably stimulated with a virus or other inducer, human cells, blood leucocytes,4 or cultured lymphoblastoid cells5 give rise to a mixture of many of the subtypes. An IFN-alpha preparation can also be obtained by introducing a single human IFNA gene into Escherichia coli, for instance.6 Three preparations of recombinant IFN-alpha2 made this way are in used in the clinic (rIFNalpha2a, rIFN-alpha2b, and rIFN-alpha2c, each differing from the two others by single aminoacid). No other subtype has as yet been used for therapy, probably because of the costs needed for regulatory approvals. However, in a small phase I study, rIFN-alpha1 (then termed rIFN-
Vol 348 • August 10, 1996
COMMENTARY
Stress-related growth failure See page 353 In 1967 Powell et al described a remarkable case-series of 13 children with aberrant and bizarre behaviours, adverse home environments, and linear growth failure with evidence of hypopituitarism.1,2 The behaviours, the growth failure, and the endocrine abnormalities were all completely reversed upon removal of the children from their stressful home environments. This description was the first of a clinical syndrome that has been called psychosocial dwarfism or short stature. An important aspect of this case-series was that it provided measurable anthropometric and biochemical evidence of the impact of psychological stress on physiological processes in children. Thus, the syndrome offered an intriguing model for the study of the interaction between psychological and physical processes. Unfortunately, although the validity of a syndrome of stress-induced growth failure with neuroendocrine abnormalities has been confirmed by reports from other investigators, there has been little progress in the past 25 years towards a fundamental understanding of its pathophysiology. However, the report by Skuse et al in this issue of The Lancet marks a significant contribution to diagnostic nosology that should facilitate progress in our understanding of this syndrome. Such progress has been hindered by a lack of clear diagnostic criteria, the heterogeneity of reported samples, and a confusing nomenclature. What Skuse and his colleagues have accomplished is to provide specific criteria for a “new” neurobehavioral syndrome, which they term hyperphagic short stature and which mirrors Powell’s original description. The clinical criteria were taken from previous reports of children with “psychosocial dwarfism”. They then applied these criteria to a sample of children referred to hospital with short stature and to a comparison group of children with short stature from a regional epidemiological survey, and calculated a symptom score. Using this symptom score, they divided the patients into 29 hyperphagic (28 of whom were hospital referrals), 23 non-hyperphagic hospital-referred, and 31 communitycomparison children. The nine behaviours that discriminated the groups were all appetite-related. They validated the clinical syndrome on the basis of other nonappetite-related behaviours and abnormalities of growthhormone secretion. Unfortunately, biochemical data were not available on all patients. Despite this drawback, the methods employed seem sound and the findings are significant. From their data, the authors propose a clinical algorithm for the diagnosis of hyperphagic short stature based solely on age, anthropometric data, and behavioral criteria. They demonstrate, convincingly, that the algorithm is discriminative and predictive: discriminative of a group of short children with growth-hormone abnormalities, and predictive of children whose behaviour, growth, and growth-hormone concentrations become normal upon removal from the home environment. Although the algorithm still needs to be used by other investigators and the findings replicated, it seems to be a useful clinical tool for both the care of children and research. Skuse and colleagues have proposed more than simply a change in terminology. They have developed valid diagnostic criteria for the identification of a group of 348
children with a specific stress-induced neurobehavioural and neuroendocrine syndrome that is reversible. They propose the descriptive term, hyperphagic short stature, to clearly separate it from the much larger group of children with psychosocial ills who present with poor growth and, commonly, malnutrition. The ability to discriminate a homogeneous group of children is an important contribution that will facilitate patient care and further research, which in turn might lead to substantive progress, perhaps over the next 25 years or so, in our understanding of this fascinating entity and our knowledge of how psychological and physiological factors interact.
Richard D Stevenson Kluge Children's Rehabilitation Center and Research Institute, University of Virginia School of Medicine, Charlottesville, VA 22903, USA 1
2
Powell GF, Brasel JA, Blizzard RM. Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. I. Clinical evaluation of the syndrome. N Engl J Med 1967; 276: 1271-78. Powell GF, Brasel JA, Raiti S, Blizzard RM. Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. II. Endocrinologic evaluation of the syndrome. N Engl J Med 1967; 276: 1279-83.
The naming of cats—and alpha-interferons As T S Elliot memorably pointed out, “the naming of cats is a difficult matter, it isn’t just one of your holiday games”, for . . . “a cat must have THREE DIFFERENT NAMES”. No doubt he would have said the same about the human alpha-interferons (IFN-alpha), for their nomenclature is the source of considerable confusion. The interferons are classed as type I (alpha, omega, and beta interferons) and type II (interferon-gamma). Biochemical evidence suggests that during the evolution of the mammals over the past 80 million years, the previously single prototype alpha gene gave rise to many variants,1 and all mammals have multiple IFN-alpha genes. It is now established there are 13 human IFN-alpha genes that give rise to functional proteins. These genes, all on chromosome 9, are designated IFNA1, IFNA2, IFNA4, and so on up to IFNA21, gaps in the sequence being due to earlier errors or artifacts. The interferons formed are named correspondingly IFN-alpha1, IFN-alpha2, and so on.2 These 13 subtypes (chemical species) of human IFNalpha are very similar in many respects: they share 100 or more of the 165 or 166 aminoacids that form their polypeptide chain; nearly all react with a single monoclonal antibody; and they all bind to a common complex receptor on the cell surface. Nevertheless, each subtype is to some extent unique in its chemical composition2 and in in-vitro antiviral and immunological properties.3 IFN-alpha preparations for clinical use can be obtained in three ways. When suitably stimulated with a virus or other inducer, human cells, blood leucocytes,4 or cultured lymphoblastoid cells5 give rise to a mixture of many of the subtypes. An IFN-alpha preparation can also be obtained by introducing a single human IFNA gene into Escherichia coli, for instance.6 Three preparations of recombinant IFN-alpha2 made this way are in used in the clinic (rIFNalpha2a, rIFN-alpha2b, and rIFN-alpha2c, each differing from the two others by single aminoacid). No other subtype has as yet been used for therapy, probably because of the costs needed for regulatory approvals. However, in a small phase I study, rIFN-alpha1 (then termed rIFN-
Vol 348 • August 10, 1996