12 Psychosocial short stature: a syndrome with many variables

12 Psychosocial short stature: a syndrome with many variables ROBERT M. BLIZZARD ANAMARIA BULATOVIC

Psychosocial short stature (PSS) is a syndrome of short stature that occurs in childhood and adolescence in association with psychological harassment and/or emotional deprivation, and for which there is no other explanation (Talbot and Sobel, 1947; Powell et al, 1967a; 1967b; Money and Wolff, 1974). Delayed adolescence is frequently observed. Failure to thrive, which implies a poor nutritional state, may or may not be present. The introduction to modern medicine of the idea that the psyche might influence growth by way of hormonal imbalance was made by Talbot et al (1947), who published an article entitled 'Dwarfism in healthy children: its possible relation to emotional, nutritional and endocrine disturbances'. Several authors had previously written that lack of stimulation and attention in the home or in the hospital could lead to failure to thrive and even death (Bakwin, 1942; Spitz, 1945, 1946). However, the role through which psyche affected the endocrine system could not be demonstrated for some time because radioimmunoassays to measure growth hormone (GH) were not readily available until 1964 (Schalch and Parker, 1964). In 1962, Patton and Gardner published an article entitled 'Influence of family environment on growth: the syndrome of maternal deprivation'. The term 'maternal deprivation' used in association with dwarfism was first referred to in these papers, and it was from these descriptions that other names for the same entity evolved, including transient hypopituitarism, reversible hyposomatotrophism, emotional deprivation, psychosomatic dwarfism, abuse dwarfism, the 'garbage can' syndrome, and psychosocial short stature. The last term was chosen by most investigators because it is broader in concept and avoids using the term 'dwarfism'. Unlike the others, it does not imply presence or absence of growth hormone, presence or absence of overt psychological abuse, or emotional or maternal deprivation. With the development of methodology to measure GH in serum accurately, Powell et al (1967a, 1967b) clearly elucidated the interrelationship of emotional deprivation and hormonal production when they reported deficient G H in six of eight children tested, who had the syndrome. The role of nutrition and its interrelationship with hormone production in growth brought further challenges. Bailli~re' s Clinical Endocrinology and Metabolism--

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Confusion arose because the existence of at least two subtypes of PSS, one in children 2 years of age and under and one in children over 2 years of age, was not recognized. Most authors now have accepted the aetiology of growth failure in type II PSS to be related to underproduction of GH. Malnutrition without hormonal deficiency is the predominant aetiology in type I. The role of undernutrition in some cases of type II, however, cannot be ignored. The superimposed failure of exogenously administered G H to stimulate growth in individuals with type I! PSS suggests an end-organ defect which also may play an aetiological role in growth retardation. In this chapter we shall further report the variability of the syndrome, emphasizing the diversity of the clinical picture by using case presentations with various clinical manifestations, and discuss further the pathophysiology, including the possible roles of malnutrition and hormonal deficiencies. The frequency of the syndrome, the prognosis, and the diagnostic and therapeutic considerations also will be considered. CASE PRESENTATIONS Case 1 N.N., a 12-month-old male, was born weighing 3.2 kg and measuring 51 cm to a 20-year-old mother of two other children. The family received aid to dependent children and lived on limited income in a two room flat. The mother finished 10th grade age 16 years, and was the sole caretaker for her children. She qualified for food products through the government programme, but often 'did not have the time' or did not assume the responsibility to obtain the food. She loved her children but was disorganized and overburdened. The infant was provided 8 ounces (250 g) of formula five times per day and baby food twice per day between bottles. The mother had propped the bottle until N.N. was old enough to grasp it. In both situations the mother gave no supervision and did not hold the bottle or the infant. When the mother turned to the infant to recover the fallen bottle, she did not offer the remaining milk to the infant. Stimulation at all times was deficient, although the siblings were stimulated to some extent as they, as infants, had fewer siblings to occupy the mother's time. The weight was 7.4 kg and the length was 69.0 cm. Mental and motor delay and lack of stimulation were all evident when the public health nurse visited the home. In the manner of Krieger and Whitten (1969) and Whitten and Fischoff (1969) the infant was fed three times a day but not stimulated by a volunteer, who knew the goal was to determine if food alone would increase physical growth in this marginally malnourished short child. The prestudy laboratory data were nearly all within normal limits, including the G H levels obtained following clonidine and arginine stimulation given separately. The only abnormalities were low prealbumin, transferrin, haemoglobin and haematocrit concentrations in plasma. The last three reflected iron deficiency. After 44 days of special feeding during a 60-day period, the infant gained

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3 kg and grew 7.5 cm, although the developmental delay remained comparable to pretreatment. Utilizing a case manager over 12 months to educate the mother as a parent produced remarkable results in the physical, mental and social growth of the infant. Further follow-up with intermittent assistance from the case manager indicates that all parameters of growth continue within the normal percentiles. This infant has type I psychosocial short stature. Case 2

R.S., a 4.5-year-old boy, with a height age of 2.3 years and a bone age of 3.0 years was underweight for height (Figure 1). The mother gave a history

Figure 1. R.S., case 2, 4.5 years of age with a height age of 2.3 years and a bone age of 3.0 years. Type I PSS.

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compatible with steatorrhoea. It was initially believed, because of his protuberant abdomen and a history of steatorrhoea, that he had malabsorption, but this could not be documented while the patient was in hospital. Results of a metyrapone test indicated that the patient had limited corticotrophin (ACTH) reserve. An arginine insulin stimulation test (AITI') revealed that no GH was released with either stimulant. On the basis of these tests and the delayed height and bone ages, andin the absence of other cause for short stature, it was believed that this child had hypopituitarism, including GH deficiency (GHD). This child was placed in a foster home. Responsible parties were advised to have the patient return in 12 months for follow-up. Upon return, the child had grown 17.5 cm in 1 year to a height age of 4.4 years. Arginine and insulin stimulation produced significant and normal GH release. Initially the boy had been in a home environment where he was rejected by both mother and father. There was no evidence of physical abuse. The mother was pleased to relinquish his care to others. In retrospect, it was learned that he raided rubbish bins and drank water from the toilet bowl. These symptoms disappeared in the foster environment. He eventually reached the fiftieth percentile on the growth curve at the age of 12 years. R.S. was characteristic of a patient with type II PSS who manifested the symptomatology and had the laboratory studies of GHD. The history of steatorrhoea was not unexpected, although not adequately explained, as discussed in the subsequent section. Case 3

J.J., an 8.7-year-old white male was referred for failure to thrive, and recent death of his full sister resulting from an idiopathic wasting disease. He was the 2.7kg product of an incestuous relationship between a 13-year-old mildly retarded female and her brother. When first evaluated he had been living for 3 years in an adoptive home with his three biological sisters and two step-brothers. The foster mother professed to be very concerned about this boy's state of inanition and growth failure as she had been very much concerned about his sister's prior to the sister's death. The foster home was believed to be an ideal one. The foster parents kept all medical appointments and sought out consultative advice because of the wasting and failure to thrive. The foster home was strongly supported by a local church, and the foster parents were believed to be highly religious and caring. Upon admission at 8.7 years the HA was 4.5 years and the weight was 13.7 kg (weight age 2.5 years). J.J. reportedly wore the same size clothing as he wore at the time of adoption 3.5 years previously, having grown only 12 cm in that period. He was reported to eat dog food, garbage, faeces, and to drink water from the toilet bowl. He had intermittent swelling of his face, hands and feet and constant pruritus. The adoptive mother reported violent temper tantrums and self-abusive behaviour (head banging). She described him as a bright child with a Jekyll and Hyde personality. He underwent extensive evaluation which was remarkable for evidence of malnutrition and dehydration (Figure 2). The bone age was 4.5 years. Three

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random GH levels drawn during sleep were < 1 Ixg/l, the somatomedin-C (Sm-C) level was 0.14 units/ml, a very low value. An AITT 3 weeks after admission produced no GH levels above 1.0 txg/1despite adequate hypoglycaemia. An Sm-C done simultaneously was 0.61 units/ml. A repeat AITF 1 week later again showed all GH levels to be < 1 Ixg/1. Psychological testing demonstrated his intelligence quotient (IQ) to approach that of children with superior intelligence. He initially appeared

Figure 2. J.J., case 3, was admitted at 8.75 years with a height age of 4.5 years and bone age of 5.0 years; 14 days later his weight had increased by 5.6 kg (40% of initial body weight). Type II PSS.

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withdrawn and depressed. He gave the history that the parents withdrew food and drink from him as punishment for his behaviour and reported that he was locked into his bedroom at night to keep him from eating. An incident was recalled when he had gained weight after visiting family friends. Upon returning home he was whipped with a belt and placed on a restricted diet. He stated that he would starve himself to gain his mother's approval. During a month of hospitalization he became very outgoing and developed close relationships with the hospital staff; he ate ravenously, and gained 5.4 kg in 2 weeks (Figure 2) and 8 kg at 4 weeks, but there was no increase in height. Abnormal eating behaviours ceased. He was discharged into foster care. Two months later he showed additional weight gain and a 3.5 cm increase in height (annualized growth velocity = 20 cm/year) (Figure 3). His AITT was repeated and showed a normal peak response of 18.2 p~g/l. A 24h integrated growth hormone concentration (ICGH) with bloods drawn every 20 min was 4.9 p~g/1,with 13 secretory peaks. Repeat Sm-C was 0.38 units/ml. In respect to further follow-up there were two unsuccessful foster home placements, and he was subsequently placed in therapeutic foster care where he reportedly does well. His current chronological age is 11.9 years.

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Figure 3. T h e growth curves of cases 3, 4 and 5 demonstrate the effect of various variables on growth in these 3 boys. G H was relatively ineffective in treating A . M . Growth was m a n d a t e d in J.R. and he grew. J.J. grew rapidly w h e n r e m o v e d from the adverse environment.

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His height age is 10.4 years and he is on the tenth percentile (October 1991) for height and the fiftieth for weight. He is usually well behaved but intermittently demonstrates very aggressive verbal and physical traits. He has exhibited himself inappropriately. He continues to be seen on a regular basis for psychological counselling. The diagnosis is type II PSS, with atypical features including high IQ and lack of developmental delay. Although the home environment was considered ideal by the community, the boy suffered from severe emotional and physical abuse. Three years after being removed from the adoptive home he grew 30 cm, while remaining prepubertal. Case 4

J.R., a 10-year-old white male, was referred for evaluation of short stature, eating disorder and developmental delay (Figure 4). The neonatal course was complicated by feeding difficulties and colic-like symptoms. By i year of

Figure 4. J.R., case 4, 10.0 years of age with a height age of 5.0 years and a bone age of 7.5 years. H e was on the eightieth percentile, weight for height. Type II PSS but previously type I.

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age he was eating non-food items such as cigarette butts, garbage and dog faeces. At 2 years he was hospitalized for ethanol ingestion. At 4 years he was evaluated for failure to thrive and constipation, was diagnosed with Hirschsprung's disease and underwent rectal myomectomy. At 5 years of age he was seen with vomiting, diarrhoea, gastric distention and steatorrhoea. The diagnosis was anaemia, septicaemia and failure to thrive. He was sent home on parenteral feedings. He was referred to protective services on several occasions in different states, and had periods of improvement in growth, development and behaviour while under protective service supervision. When evaluated at chronological age 10 years, the height age was 5.0 years and his weight for height fell on the eightieth percentile. The bone age was 7.5 years. There was a history of gorging, eating from rubbish bins, drinking from toilet bowls, and pain agnosia since infancy. He reportedly had intermittent swelling and discoloration of the hands and feet, which were unexplained. He was a restless sleeper with frequent episodes of enuresis, had difficulty learning, and was unable to get along with his peers at school. An AITT with a blood sugar nadir of 2.3 nmol/1 gave a GH response of only 2.5 Ixg/1. The Sm-C was 0.61 units/ml. The baseline a.m. cortisol level was <83nmol/1, and 1 hour after administration of ACTH rose to 910 nmol/1. A repeat AITT 3 weeks later, while still in the hospital, showed a maximum GH level of 21.7 txg/1with a blood sugar nadir of 1.7 nmol/1. While in the hospital his behaviour improved and the abnormal feeding patterns ceased. At discharge he was told he would be placed in foster care if he did not grow in the following 3 months. Three months later he had grown 4.6 cm or at an annualized rate of 18.8 cm/year (see Figure 3). The patient and his parents, when asked separately, stated that he had grown in order to avoid placement in foster care. He remained in his original home and continued to be involved in counselling. On follow-up he had a drop-off in growth velocity to an annualized rate of 5.0 cm/year. In October 1991, at age 12.5 years, he and his father were seen. The father, who had responsibly accepted being the primary caretaker, reported that J.R. was a completely different boy. In school his grades were mostly Bs. He had no bizarre eating, drinking, or other habits. He remained a loner but allegedly socialized quite a bit more than 4 years previously. In response to the question, 'What is different now than 4 years ago?', the father replied: 'He was a total disaster and was dissatisfied and overreacted to everything. He had total disregard for safety. He ate everything--food and non-food. I undertook to educate him about life and change his behaviour, if possible. I slept in his room every night for 5 months and we talked. He is now a pretty normal boy, although he still occasionally reacts violently.' On physical examination his height age was 9.5 years and he had grown 23 cm in 30 months. His weight age was 11 years. He was sexually infantile, and the bone age was 10.3 years. This patient unequivocally has type II PSS, but probably had type I PSS as well, since his symptoms date to an early age. This is'an unusual but not unheard of association. More unusual is the fact that this boy grew 4.6 cm

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over a 3-month period after being told that he must grow or be placed in a foster home. Also most unusual was the resolution of the problem while he remained in the home. Cases 5-7

Three siblings were born to an unstable couple with a history of frequent separations and changes in residence. The mother left the family when the children were 3.9 years (C.M., female) 2.3 years (P.M., female) and 2 months (A.M., male) of age. The father was sole caretaker for 18 months, and the oldest daughter (C.M.) took on a mothering role. The father abused alcohol and was frequently unemployed, and decided to place the children in foster care. They were placed in separate foster homes where they reportedly grew well except for P.M., the middle child, who was below the fifth percentile for height. The adoptive parents wanted only one child, but had to agree to take all three siblings into their home to obtain one. At the time of adoption into a home of two adults and two children, aged 11 and 14, the adopted children were 6.7, 5.2 and 3.0 years. They came to our attention when the youngest, A.M., was noted to be below the fifth percentile on a growth chart. At the time of initial evaluation, he was 4.9 years, and he had been in the adoptive home for almost 2 years (Figure 5). The HA was 3.3 years and weight for height was above the seventy-fifth percentile. There was a history of very little growth since adoption; in fact, none of the children had changed shoe sizes. There was also a history that he gorged himself and vomited frequently, ate non-food items, and drank from dog bowls and toilets. He had problems with constipation and rectal prolapse. Similar abnormal growth and eating patterns were reported for the two girls. The younger sister had sleep disturbances and the older was withdrawn and depressed. The initial examinations were normal except for short stature. The midparental heights were 179 cm for the boy and 166 cm for the girls. A.M.'s bone age was 2-2.5 years and the GH level post exercise was 3.4 ~g/l. The children were admitted for GH testing. All had low 24 h ICGH (q. 20 rain specimens) (A.M., 0.5 ~g/1; P.M., 0.6 ~g/1, and C.M., 0.9 ~g/1). A.M.'s basal Sm-C was 0.17 units/ml. He received GH (1.5 units q. 24 h x 6 days). The Sm-C rose to 1.3 units/m112 h after the last GH dose. P.M.'s basal Sm-C was 0.43 and 0.18 units/ml on sequential days. She received GH (2.0 units q. 24 h x 6 days) and had an Sm-C of 0.6 units/m112 h after the last GH dose. The basal Sm-C of the oldest girl (C.M.) was 0.5 units/ml. She received GH (2.5 units q. 24h x 6 days) and had a Sm-C of 2.7 units/ml 12h after the last GH dose. The diagnosis of PSS was strongly suspected. Family counselling was recommended. These children were well taken care of in their new home. They were well dressed and were regularly brought to appointments. The only obvious abnormality was the lack of bonding or tenderness between mother and children. Family counselling was not very successful, and the children returned 1 year later for repeat GH testing. In the previous 14 month period, A.M. grew only 3.6cm. The results of arginine and L-dopa showed a

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m a x i m u m G H level of 6.8 Ixg/1. H e r e s p o n d e d to growth h o r m o n e releasing factor (3.3 ~xg/kg) with a m a x i m u m G H of 25 ~xg/1. T h e S m - C w e n t f r o m 0.06 o n day 1 to 0.2 u n i t s / m l o n day 3. P . M . , h a v i n g g r o w n o n l y 4.6 c m over the p r e v i o u s y e a r , was also tested. T h e results of a r g i n i n e a n d L-dopa s h o w e d a

Figure 5. A.M. (case 5), on the right, was 4.9 years of age. His height age was 3.3 years and the bone age 2.5 years. P.M. (case 6), in the middle, was 7.1 years. The height age was 5.0 and the bone age 6.9 years. C.M. (case 7), on the left, was 8.6 years. The height age was 7.0 years and the bone age 5.7-6.8 years.

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maximum G H of 14.1 ~xg/1. She responded to GRF (3.3txg/kg) with a maximum G H of 20.5 txg/1. A.M. was started on a trial of GH which was continued over i year, during which he grew a modest 5.7 cm. This represented an increase in his growth velocity with no evidence of catch-up growth (see Figure 3). During the same interval, both sisters continued to fall off their respective growth curves. Continued attempts at family counselling were unsuccessful and many issues remained unresolved. The G H was stopped and the patients were lost to follow-up. In October 1991 contact was re-established with the family. By history, A.M. at age 14. l years was on the fifth percentile for height (height age 12.0 years), on the fiftieth percentile for weight, and sexually infantile. P.M. at age 16.2 years was on the first percentile for height (height age 12 years). C.M. left the home 3 years ago, and there is no follow-up regarding her auxological status. In respect to behaviour, A.M. lost his bizarre eating habits 3 or 4 years ago, as did P . M . A . M . remained a loner; his behaviour was often inappropriately aggressive. At school he was a management problem until placed in special education at age 13 years. P.M. was an extrovert, popular in school, and reportedly a delightful normal teenager. Menstruation occurred at 14 years. These siblings were all appropriately diagnosed as having type II PSS. Their histories are paradoxical. In the initial biological home the children were reported to be growing acceptably. When adopted into a new home, where physical care was good by apparently responsible parents, all three children stopped growing and manifested full blown symptomatology of PSS. The psychological counsellor determined that: 'The adoptive mother knew how to give care but not tender loving care.' Two of the three children remained in the adoptive home and the third was encouraged to leave for different placement. At 14.1 years A.M. had apparent constitutional delay in growth and puberty (CDGP). P.M. at 16.2 years had reached her ultimate height and had only modest CDGP. The growth of both improved over time. Also remarkable and paradoxical was the history regarding A.M., that he was markedly delayed in language development when adopted at age 3.0 years but language and social development advanced rapidly in the 1.9 years before presenting to us, although his growth had essentially stopped. Case 8

S.A. (Figure 6) was referred by the paediatric psychiatrists for consultation at age 15.3 years because of growth failure and sexual infantilism. The history revealed a disrupted and emotionally unstable home life for many years, and drinking from the toilet bowl and eating dog food from the dog's dish at 7-8 years of age. She hated her father and would not discourse or cooperate with male physicians. Academically she was delayed. At 15.3 years the height age was 9.5 years and the bone age was 10 years. An AITT produced insignificant G H release. A metyrapone test was abnormally low, indicating limited ACTH reserve. The thyroxine level was at the lower limit of normal and serum luteinizing hormone and follicle

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Figure 6. S.A., case 8, was seen at age 15.3 years (at left) with a height age of 9.5 years and a bone age of 10.0 years. At 16.0 years (middle) the height and bone ages were 11.0 and 13.0 years. At 16.9 years (right) the height age was 12.0 years. Simultaneously with rapid growth, sexual maturation occurred rapidly.

stimulating hormone were compatible with low prepubertal values or values found in gonadotrophin deficient individuals. One month after hospitalization she had grown 2.5 cm and breast buds were present. Out of the adverse home environment she grew rapidly and rapidly developed sexually (Figure 6). She remained emotionally unstable and was lost to follow-up at 17 years of age. This girl had type II PSS and presented at a relatively late adolescent age (15.3 years) with apparent hypopituitarism or severe CDGP by history, physical examination and laboratory testing. Except for the bizarre history and the rapid growth and sexual maturation while she was in the hospital, the diagnosis of PSS could easily have been missed. SUBTYPES OF PSS

At least two subtypes of PSS are recognizable: type I, the infantile form, and type II, the childhood variety (Blizzard, 1985). The first occurs in infants 2 years of age or younger. These infants usually have failure to thrive (nutritional deficiency) and short stature (Krieger and Whitten, 1969; Whitten and Fischoff, 1969; Chase and Martin, 1970;

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Krieger and Mellinger, 1971; Krieger, 1973, 1974). They have not been observed to have GH deficiency and usually recover when sufficient calories are given. Rejection by the parents is usually not as blatant as is rejection exhibited by parents of children with the childhood type. Multiple children and responsibilities inundate the mothers of type I, who are usually disorganized, and the children do not receive the food or the attention they deserve, but the attention they receive is usually adequate for infants to grow again if they are given adequate calories (case 1). The second type is not characterized primarily by failure to thrive (cases 4-7), although it may be a significant component upon occasion (cases 2 and 3). Type II occurs characteristically in children 3 years of age or older, and there is a greater psychological component, both in respect to behaviour and interpersonal parent relations. The children in this group are usually abused psychologically by the parents who reject them. As reported by Powell et al (1967a) the parents are frequently chronic alcoholics. These children may or may not have G H demonstrable in their sera after stimulation with pharmacological agents that release GH from the pituitary into the serum (Powell et al, 1967b; Thompson et al, 1969; Sarr et al, 1987). Occasionally, type I patients are observed to advance into type II. Sarr et al (1987) observed 24 children with proven PSS and divided them into three groups by age. Those less than 5 years of age had language and motor delays. They were starved for affection and sought out human interaction. At times they were withdrawn or anxious and aggressive. Family circumstances were unfavourable and sibling rivalry was significant. In this group there was lack of mothering but without rejection, and the mothers were receptive to counselling. In the group 5-10 years of age, the authors observed parental rejection and pathological relationships between mother and child. The mother's image was perceived as enigmatic and dangerous. Punishment was frequent and often severe, and absence of stimulation was evident. The children were regressive, inhibited and anxious. Verbal skills were weak. Enuresis, hyperphagia and encopresis were common. Vacillations between gentle and aggressive moods were evident, similar to the Jekyll and Hyde personality described in case 3, J.J. In the group over 10 years of age, the parents were often separated. The relationship with the mother was exceedingly strained and the absence of the father was profoundly resented. They were usually anxious, introverted, immature and poor scholars. However, Sarr et al believe that the intellectual potential of this group is normal, as reflected by non-verbal testing. In some, sleeping difficulties were prominent. All of these children required psychological counselling and removal from the disruptive home. Sarr et al further stated that those children under 5 years of age corresponded to type I, as described by Blizzard (1985), with regard to clinical presentation. They emphasized the psychological component in the older groups where the children displayed the clinical symptoms described for type II. In our opinion, the division of patients, as made by Sarr, is useful to evaluate age-related psychological and emotional differences, but we propose that this categorization is not aetiologic, but represents a progressive

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variability of symptomatology. Sarr et al did not attempt to differentiate the groups according to G H release to pharmacological stimulation, which we believe is frequently a distinguishing characteristic between types I and II. For purposes of characterization by aetiology, we adhere to utilizing only two classifications, realizing the value of the observations presented by Sarr et al. Further observations and consideration of categorization are important, as PSS has provided us with an opportunity to make significant insights into some mechanisms through which the psychological environment may exert powerful influences on physical growth and psychological development via the central nervous system, and its regulation of psychoneural endocrine functioning (Green, 1990). INCIDENCE OF PSS

Infants with type I PSS are exceedingly common, and the diagnosis should be suspected in infants with failure to thrive. Failure to thrive is not necessarily present in all instances, as growth velocity will slow down before malnutrition is grossly obvious (Lifshitz and Moses, 1990). Every inner city and poor rural community has cases of nutritional failure leading to retardation in linear growth. Since it is difficult to assess how much nutritional deprivation is due to unavailability of food, and how much is due to neglect of feeding and supervision, it is not possible to state more than that 'there is a very high incidence' of type I PSS. The incidence of type II is not known either, but is much more common than is recognized. Thompson et al (1969) collected 25 cases in the city of Baltimore over a very short period of time. Sarr et al (1987) reported 34 children and adolescents in whom a severe growth deficiency had been considered as likely to be related to PSS. Drash et al (1968) diagnosed 14 children over a short period. The actual incidence is unknown because of the difficulty in detecting the emotional aberrations in short children when these are relatively moderate in degree. The frequency of the diagnosis is proportionate to the awareness and clinical acumen of the examiners. Rudolf and Hochberg (1990) surveyed 33 articles on the subject of PSS and non-organic failure to thrive. They reported that the number of boys affected was persistently greater than the number of girls. In the 17 articles in which the numbers of boys and girls were cited, only one contained more girls than boys, and in the larger studies there were approximately twice as many boys as girls. They postulate that boys may be more vulnerable than girls to negative factors that limit full expression of growth potential. This is in accord with our observation, as initially reported by Powell et al (1967a), in which there were ten boys out of the 13 studied. The frequency within a family with multiple children also is variable. It is not unusual for one or two of six or seven children to be affected. We have repeatedly observed that all children in a family do not respond similarly to rejection or lack of attention by parents. This syndrome occurs at all ages through adolescence, as exemplified by

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the case histories presented above. We suspect some patients with a diagnosis of CDGP have a psychological component as part or all of the aetiology. Bierich et al (1989) have reported that boys with CDGP secrete less GH than boys without CDGP. As stated by Mouridsen and Nielsen (1990) concerning a patient with classical PSS, 'even though our patient has been in regular contact with a large number of different health workers, the real nature of his condition was overlooked for four years'. This again emphasizes the difficulty in determining the incidence and frequency of the syndrome. However, its occurrence is much greater than reported or suspected. In respect to geographical distribution the majority of cases have been reported from the USA but all countries in the western hemisphere have also reported studies of such patients. SIGNS AND SYMPTOMS

These can be divided into those pertaining to behaviour or body structure and auxology. Many of those pertaining to behaviour have been included in the previous sections. In brief, there is an abnormal and disturbed relationship between the primary caretaker and child, which Green (1990) states is of primary aetiological importance. Mothers exhibit heterogeneous psychopathologies and fathers are usually absent or uninvolved. Child abuse and psychological neglect may occur together. Money et al (1985) and Money (1986) extended our understanding of the syndrome when they reported that PSS occurs in association with the Munchausen syndrome by proxy. In these instances the mothers reject and sacrifice their children by way of atonement for their own sins or guilt. Patients become addicted to abuse (Money et al, 1985) and frequently precipitate negative reactions as a way of gaining attention from their caretakers. In our experience the classical extreme behavioural characteristics listed in frequency of occurrence in 13 overt cases included polydipsia (13), polyphagia (13), stealing of food (12), eating from garbage cans (11), retarded speech (11), playing alone (nine), temper tantrums (nine), enuresis (nine), shyness (nine), steatorrhoea (eight), drinking from toilet bowls (six), prowling at night (seven), encopresis (six), and gorging to the point of vomiting (eight). These incidences were described in our early report in 1967a (Powell et al), and the incidence of each in that article is probably overstated as these patients were all severely affected. In the series by Sarr et al (1967), 100% of the children demanded affection, 79% were ignored by their mother, 54% manifested anxiety, 25% were aggressive, 46% had retarded language development, but only 17% had hyperphagia, enuresis, encopresis, and difficulty sleeping. It is unclear from Sarr et al's report whether it was the same 17% that had each of these manifestations. Nevertheless, it has been demonstrated that the signs and symptoms from child to child are variable and all of the above occur with significant frequency, although none may be present in the less overt cases. Green (1990) emphasized that the most typical behavioural disturbance

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involves bizarre acquisition of food and water, such as described above. Developmental or maturational lags in IQ scores most frequently occur in the mildly retarded or borderline ranges. Green also emphasized the characteristics of social immaturity, temper tantrums, poor peer relationships, social withdrawal, depression, apathy, elective mutism, sleep disorders, disturbances in sleep architecture on electroencephalogram (EEG) tracing recordings, and night roaming. Pain agnosia is a prominent sign, and short children who are unresponsive to injury or blood drawing are suspect for having PSS. The auxological parameters usually include significant short stature (below the third percentile) and slow growth velocity following normal growth at an early age. However, growth may fall behind at any age. Ferholt et al (1985) noted that growth failure began in three of ten children in the second year of life, for four in the third year, and for three of the ten in the sixth or seventh years. Growth failure may not occur until later childhood, as reported by Magner et al (1984). Delayed adolescence may be a prominent characteristic, as demonstrated in cases 5 and 8 (Figure 6). The short stature is proportionate. Skeletal maturation is usually significantly delayed and is usually commensurate with the height age rather than the chronological age (Powell et al, 1967a, 1967b). Birth weights are usually normal for gestational age. Weight for height may be increased, normal or decreased. The body structure in younger children often suggests malabsorption because of protuberant abdomens (see Figure 1). Coincident history of steatorrhoea in many children suggests malabsorption. Malnutrition is not typically present in classical PSS type II; however, it may coexist, as in case 3. LABORATORY FINDINGS

The laboratory findings vary markedly from patient to patient. Those concerning the endocrine system are most frequently found to be abnormal, but no abnormalities may be present, as was reported by Sills (1978) in his classic article dealing with the role of clinical and laboratory evaluation of failure to thrive. Normal laboratory values are usual in type I PSS, but these are also seen in some patients with type II PSS. The most typical and best studied endocrine abnormalities in PSS involve decreased G H production to pharmacological testing, as first reported by Powell et al (1967a) when six of eight patients tested did not make significant O H following insulin stimulation. Green et al (1989) summarized the literature and reported that serum O H levels following provocative stimulation with pharmacological agents is abnormally low in approximately 50% of patients tested soon after hospitalization. Sarr et al (1987) reported only three of 23 patients tested had complete OH deficiency, but 11 others were considered to have partial deficiency. Thompson et al (1969) reported that eight of 12 failed to respond normally to arginine and eight of 15 to insulin. Blizzard (1985) recorded that nine of 17 failed to respond normally to insulin, nine of 14 failed to respond normally to arginine, and six of 11

PSYCHOSOCIAL SHORT STATURE

703

receiving both tests failed to respond to either. Testing immediately or at least within 24 h of admission may be crucial to detecting low GH secretion, as recovery can be very quick in some patients (Powell et al, 1967a; Stanhope et al, 1988). Another possible reason for not observing GH deficiency in some patients may be related to using pharmacological agents (insulin, arginine, z-dopa, etc.) instead of physiological stimuli, such as ICGH, to test for GH production. The data acquired using ICGHs in these patients are very limited. Howse et al (1977) studied three children with PSS by drawing blood continuously over a 5 h period of sleep at night and correlated these levels with sleep EEGs. As compared with a group of normal short children, all three had low peak GH values, lower 5 h mean GH values, and subnormal GH responses to insulin induced hypoglycaemia. Stanhope et al (1988) demonstrated, using serial overnight GH profiles at 1, 6 and 18 days, that GH insufficiency was present on the first day of admission in a 6.4-year-oldpatient. During the hospitalization GH secretion progressively increased. During sleep the normal pattern of four major GH pulses was retained, but there was a progressive increase in the peak GH achieved: 8.2 p~g/1on day 1, 17.5 ~g/1 on day 6, and 25.0 ~g/1 on day 18. By day 6 of hospitalization the amount of GH secreted had increased significantly and by day 18 had tripled from the baseline determination. The three siblings reported above (cases 5-7) were tested at ages 4.5, 6.5, and 7.8 years. Their ICGHs over 24 h were < 0.5, 0.9, and 0.8 ~g/1, abnormally low values for their chronological ages. The majority of patients with PSS (Green, 1990) have subnormal Sm-C levels. In some children who resume normal growth the Sm-C levels will return to normal, while in others the levels stay below normal. The variation may be related to variations in IGF-I binding protein, which binds Sm-C. This has not been examined in PSS. Abnormalities in thyroid function have been reported but are not common. Thyroxine levels are normal in a large majority of cases. In type I PSS the values may be low because of low thyroxine binding globulin. The data reflecting ACTH deficiency and consequent cortisol deficiency is conflicting. Powell et al (1967b) emphasized that there was decreased ACTH reserve as tested by metyrapone stimulation in type II PSS patients. Thompson et al (1969) confirmed this defect when they reported that 18 of 22 patients had abnormally low 17-hydroxycorticosteroids following metyrapone administration. In six of these patients they demonstrated that compound S accounted for the 17-hydroxycorticosteroid levels post metyrapone administration, which confirmed normal absorption of the metyrapone and adequacy of dosage. In type I PSS increased cortisol production has been reported. Additional studies are desirable for conclusions regarding the limits of ACTH secretion. Insulin secretion is decreased, as it is in hypopituitary patients (Figure 7). The study referred to here is the only study known to us in which insulin function in children with PSS was evaluated. It is not known whether patients with PSS making adequate amounts of GH have decreased insulin secretion. In the patients reported in Figure 7, GH secretion following arginine stimulation was uniformly low.

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Gonadotrophin levels are compatible with the stage of sexual development. Those patients with associated delayed adolescence have suppression of their gonadotrophins, as in S.A. (case 8) and in the 19-year-old male reported by Magner et al (1984). ARGININE ::::::::::::::::::::::::: iiiii~i!fiiiiii~ii!!iiiii Z e=l Z

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Figure 7. Glucose levels and secretion of G H and insulin were studied in three groups (GH deficient, PSS and normals) of 11 patients, each following arginine administration over 30 min. The patients with PSS were more similar to the G H deficient patients than to normals. H G H , human growth hormone. From Blizzard et al (1990), with permission.

PSYCHOSOCIAL SHORT STATURE

705

Other laboratory tests performed on blood and urine have generally been normal. Because of the frequent history of steatorrhoea and the question of malabsorption, Parra (1973) reported that, of 19 patients with type II PSS and a history of steatorrhoea, the carotene levels were normal in 18, xylose absorption was normal in eight, faecal fat was normal in six of the seven tested, and when jejunal biopsy was done in five, all were normal by microscopic examination and by measurement of disaccharidase activity. EEGs have been evaluated by several groups, particularly in relation to GH secretion. In children, GH is released primarily during slow wave sleep (SWS), especially stage IV. Powell et al (1973) performed sleep EEGs on nights 5, 6, 26, 27, 28 and 40 following hospitalization of a patient with PSS and measured G H levels simultaneously with blood obtained from an indwelling catheter. The sleep EEGs were normal throughout; however, there was no significant GH secretion during SWS on the first two nights. On night 40 there was significant output of GH shortly after stage IV sleep began. Because there was no abnormality of EEG while there was decreased GH secretion on nights 5 and 6, the authors suggested that normalization of G H secretion associated with SWS occurs more slowly than normalization of GH secretion in response to arginine and insulin provoked hypoglycaemia. Howse et al (1977) studied both GH secretion by indwelling catheter and E E G monitored sleep in three patients with PSS (ages 4-13 years). These patients spent more time in stage IV sleep than did 14 normal but short children, but the patients had diminished and delayed GH secretion responses during stage III and IV sleep. Guilhaume et al (1982) studied the relationship between stage IV sleep deficit and G H secretion in four PSS patients (12-36 months of age). These patients probably had type ! PSS. Ten normal children of similar ages served as controls. The PSS patients had significantly more stage I sleep than controls, a tendency for paradoxical (rapid eye movement, REM), sleep to be of shorter duration than in controls, and an increased intervening wakefulness. Stage IV sleep was totally absent in three of the four and markedly less than that in the controls. The PSS patients also had shorter slow wave episodes than controls (t3.0 + 4.8 rain versus 31.1 _+4.5 min). In this study there were follow-up sleep recordings after 21-105 days in the new environment and during catch-up growth, during which time there was marked improvement in sleep. All four at that time had stage IV sleep which was no longer significantly different from controls. Stanhope et al (1988) studied a patient on days 1, 6 and 18 for correlation of E E G recordings with G H secetion and observed that the percentage of time spent in slow wave sleep and REM sleep was within 2 sD of the mean for normal children. During the first two profiles the onset of the first cycle of SWS was not associated with a large GH pulse. However, on day 18 the major peak of G H secretion of the night occurred at the onset of the first cycle of SWS. At this time one must conclude that the EEG tracings are variable, but there is a tendency for SWS pattern to be diminished or altered. One must also conclude that SWS (stage III, IV) may be present with PSS and yet G H secretion may not occur.

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RADIOLOGICAL FINDINGS

The skeletal age is retarded, as in GHD, and is usually equal to or somewhat advanced as compared with the height age (Powell et al, 1967a; Sarr et al, 1987). Growth arrest lines are frequently observed, as reported by Hernandez et al (1978) who found that 20 of 23 children (87%) with PSS had such lines in the distal radii or knee films, while these were present in only two of 25 (8%) idiopathic GHD patients. A remarkable observation of widening of the cranial sutures during rapid growth during recovery was reported by several authors (Capitanio and Kirkpatrick, 1969; Afshani et al, 1973; Gloebl et al, 1976). This widening probably represents growth of the skull as it usually is associated with normal cerebrospinal fluid pressures, although pseudotumour cerebri was reported by Tibbles et al (1972) in four children 20-61 months of age with probable PSS. PATHOPHYSIOLOGY

For many years investigators disagreed, some contending that malnutrition accounted for the short stature and others contending that G H D accounted for the majority of cases. The consensus currently (1992) is that patients with type I PSS have short stature secondary to undernutrition. Patients with type II PSS are believed in most instances to have GHD. The observations of G H D by adequate testing in type II PSS patients who are malnourished supports this concept, as exemplified by the findings in case 3. Although markedly underweight (see Figure 2), J.J. had no measurable GH. Characteristically, starvation even for 24 h increases GH concentrations (Ho et al, 1988). The low Sm-C levels do not assist in differentiating the aetiology as these are low in both G H D and starvation. The explanation for short stature in the patients who make GH remains conjectural. In instances where delay has occurred in stimulation testing, the GH levels may be normal as the capability to secrete G H is restored. Possibly these patients secrete less GH than normal in the daily situation, even though they secrete significant G H with pharmacological stimulation (insulin, arginine, etc.). There are inadequate data regarding the ICGHs in these patients with type II PSS, but investigation in this field should be pursued. The frequent recording of possible malabsorption, as reflected by histories of steatorrhoea and large intake, but lack of excess weight gain, complicates the clinical picture with respect to explaining the pathophysiology. Documentation of steatorrhoea has not been possible in spite of these histories (Parra, 1973; Hopwood and Becker, 1979). It is possible that malabsorption abruptly disappears upon admission to the hospital, as lack of GH production quickly reverses itself upon admission. The biochemical control of the endocrine and gastrointestinal symptoms deserves further consideration in these patients. Absolute or relative excess of somatostatin could account for the decrease in GH secretion and for the steatorrhoea. These findings occur in the somatostatinoma syndrome (Krejs et al, 1979).

PSYCHOSOCIAL SHORT STATURE

707

The possible role of 13-endorphin in the pathophysiology of this syndrome must be mentioned. An excess of endorphins could account for the pain agnosia at any age and the suppression of gonadotrophins that occurs in teenagers with this syndrome. Interestingly, [3-endorphin administered intracisternally to 6-day-old rat pups markedly decreased brain, liver, heart and kidney ornithine decarboxylase (ODC). ODC is reported as a good index of the biological activity of GH (Green, 1990). The ODC changes were similar to those found in rat pups maternally deprived by removing them from the mother or by anaesthetizing the mother and continuing to allow the pups access to her (Schanberg et al, 1984; Schanberg and Field, 1987; Green, 1990). The deprived rat pup model is also an interesting one because serum G H levels were selectively depressed by 40 to 47% and were significantly lower than G H levels of control pups. Within 15 rain of their return to mothers, GH levels returned to normal and overshot those of control pups. In these studies there was another analogy between the deprived pups and children with PSS. There was relative loss of tissue responsivity to GH. The normal marked increase in ODC levels in liver and brain tissue following GH injections was negated in the maternally deprived pups. The resistance was reversed within 2 h after restoration of the pups to their mothers. The analogy encompasses the resistance to the action of GH in patients with PSS (Tanner et al, 1971; Frazier and Rallison, 1972; Tanner, 1973; Mouridsen and Nielsen, 1990), which appeared to be present in case 5, A.M. Another animal model that is of interest in studying PSS is that of Miller et al (1969), who demonstrated that socially isolated monkeys develop hyperphagia and polydipsia. Whether the results observed in animal models are those responsible for the signs and symptoms, including the growth failure, in PSS children remains tenuous, but these correlations should not be ignored as they may provide routes of investigation that will more clearly elucidate the pathophysiology of PSS in the human. Attention has recently been drawn to a possible human model to study the effect of tactile/kinesthetic stimulation on growth: the preterm infant (Green, 1990), After 12 days of tactile/kinesthetic stimulation, 20 preterm infants gained 47% more weight per day than control infants and gained more weight per calorie of intake per kilogram of body weight. The experimental group manifested greater motor activity, more alertness, and higher Brazelton Neonatal Behavior Assessment Scores. The infants in the experimental group reportedly were discharged, on average, 6 days earlier than those in the control group (Field et al, 1986; Schanberg and Field, 1987). PROGNOSIS

The prognosis for growth in both types of PSS is excellent if the environment can be altered. For most patients with failure to thrive, as in type I PSS, the administration of adequate calories usually enhances growth. For those patients with type II PSS, just the administration of more calories is almost uniformly inadequate to reverse the growth retardation. Removal from the

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home is usually necessary, although not always, as exemplified in cases 4 (see Figure 3) and 5. Many investigators believe that children who are not removed from their home are unlikely to reach their genetic potential. The hormonal abnormalities, when present, may change within 2 or 3 days of admission; however, some patients may require a few weeks for G H to increase, as in case 3, J.J., where normal GH release was demonstrable at 12 weeks, but not at 4 weeks after admission to the hospital (Powell et al, 1967b; Stanhope et al, 1988). The pain agnosia and the sleep aberrations also disappear quickly (Money et al, 1972). The prognosis for intelligence relates primarily to the age of correction of the adverse environment, assuming innate intelligence is intact (Money et al, 1983a 1983b). These authors demonstrated that children rescued before 5.5 years of age advanced their IQ from 71 _+21 to 104 + 11, whereas those rescued after 5.5 years advanced from 63 _+15 to only 78 +_ 16. Each group had the same amount of time for catch-up. One girl rescued at 3.8 years who initially tested with an IQ of 36, at 13.7 years had an IQ of 120 (Annecillo and Money, 1985). There are exceptions to the low iQ usually found in PSS, as exemplified by cases 3 and 5. The boys' mental capabilities were at least average before rescue and at the time of growth arrest. The prognosis for the emotional stability of these children as adults is poor, particularly for those diagnosed late in childhood. When they reach adulthood, these patients often abuse their children psychologically, probably as a result of poor bonding and the lack of adequate parenting they received as children. THERAPEUTIC CONSIDERATIONS The only effective treatment is to change the child's psychological environment. Often this means the geographic environment as well. Parents of type I PSS are usually more open to education than are parents of type II. Most of the latter do not have the emotional constitution to alter their attitudes towards their children. Consequently, removal from the home is frequently necessary. Occasionally, partial success can be attained, as in case 4, J.R., where the father is capable of and willing to assume the role of the primary parent. Wolff and Ehrich (1981) have had some success when the patients were treated in the home. However, a lengthy delay in transfer to a more stable home can cause significant detriment to the child's intellectual, physical and behavioural recovery. Unfortunately, many federal and regional laws do not make it easy to remove patients who are only psychologically and not physically abused from the home. Through the combined effort of social services, legal authorities and health professionals, efforts must be made prospectively to educate the judicial and legislative branches that transfer of such patients out of the adverse home environment is usually essential. The adage that the patient's home is better for the child than any other, as long as physical abuse is absent, is incorrect, as evidenced by the experiences of those who have studied the entity most extensively (Money et al, 1983a, 1983b, 1985; Money, 1986; Green, 1990).

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709

DISCUSSION The failure to identify an organic aetiology in any infant with failure to thrive or in any child with significant short stature makes a psychological cause probable. Psychosocial causes for short stature, with or without failure to thrive, occur in patients between birth and late adolescence. Short stature may be accompanied by remarkable delay in sexual development, as in the 17.5-year-old prepubertal boy whose height age was 11.5 years (147.5 cm) (Magner et al, 1984), who subsequently developed sexually and grew to 172 cm). All cases are not as blatant as the obvious cases reported in the literature. Therefore, all children with no other explainable cause for short stature or failure to thrive should have PSS considered in the differential diagnosis. CDGP is probably of multiple aetiologies; it occurs as a primary phenomenon most often in males and often in association with a family history. However, a variant occurs with chronic diseases such as regional enteritis, which may be subclinical, or isolated partial GHD which delays maturation of the hypothalamic-pituitary-gonadal axis. Therefore, the diagnosis of PSS needs to be included in the differential diagnosis of CDGP and GHD. Failure of an apparent G H D patient to have catch-up growth with G H treatment should also prompt the clinician to consider PSS. In our clinic an 8-year-old boy with apparent G H D responded only minimally with increased growth velocity over 2 years with GH treatment. The evaluation of the history and the home at that time made the diagnosis of PSS suspect, and in view of the poor response to GH, the correct diagnosis was made. The case histories in this text exemplify the variability of the syndrome and are presented to emphasize that variability. Case 1, N.N., has a classical case history of a patient with type I PSS. The history is distinctly different from the other case histories. Case 2, R.S., has a classical history of a patient with type II PSS. Case 3, J.J.'s history, was classical in respect to his bizarre eating, but was atypical in respect to his home setting where the adoptive parents were considered 'honorable Christian' citizens, but were apparently psychopathic personalities reminiscent of the parents, reported by Money (1986), who practised the Munchausen syndrome by proxy. The boy's high intelligence was atypical. Also remarkable was the absence of G H release while in a significant state of inanition, as G H elevation is expected in states of inanition. Case 4, J.R.'s case history, typifies that of a child who passes from type I PSS to type II. The therapeutic success (see Figure 3), although only partial while J.R. remained in his biological home, was atypical, but reflects and emphasizes the need for a responsible primary caretaker--in this instance the father. The case histories of patients 5, 6 and 7 (A.M., P.M. and C.M.) were atypical in that they apparently grew satisfactorily in the biological home in spite of separation from the mother, but failed to grow in the adoptive home where care was excellent but affection was inadequate. Also atypical was the rapid development of language and intellectual skills by A.M. while growth slowed. Case history 8, S.A., represents the effect at adolescent age of long-term psychological deprivation: the presence of short stature and sexual infantilism. The rapidity of recovery is also exemplified in

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this case history, as both GH and gonadotrophins were activated within 30 days of admission to the hospital. SUMMARY PSS is at least two syndromes of significant frequency, which often go unrecognized. It occurs in all socioeconomic groups. It is variable in its presentation and often masquerades in its subtle forms as other pathological causes of short stature such as G H D , CDGP, malabsorption and failure to thrive. It is an entity about which we understand little in respect to biochemical pathophysiology, and one which offers a challenge to both clinicians and basic scientists.

REFERENCES Afshani E, Osman M & Girdany BR (1973) Widening of cranial sutures in children with deprivation dwarfism. Radiology 109: 141-144. Annecillo C & Money J (1985) Abuse of psychosocial dwarfism: an update. Growth, Genetics and Hormones 1:4: 1-4. Bakwin H (1942) Loneliness in infants. American Journal of Diseases in Children 62: 30-40. Bierich JR, Brugmann G & Kiessling E (1989) Spontaneous secretion of GH during nocturnal deep sleep. Investigation in pituitary dwarfism and in constitutional delay of growth and adolescence. Monatsschrift Kinderheilkunde 137: 80-85. Blizzard RM (1990) Psychosocial short stature. In F. Lifsnitz (e&) Pediatric Endocrinology, A Clinical Guide, pp 87-107. New York: Marcel Dekker. Capitanio MA & Kirkpatrick JA (1969) Widening of the cranial sutures. Radiology 92: 53-59. Chase HP & Martin H (1970) Undernutrition and child development. New England Journal of Medicine 282: 933-939. Drash PW, Greenberg NE & Money J (1968) Intelligence and personality in four syndromes of dwarfism. In Cheek DB (ed.) Human Growth: Body Composition, Cell Growth, Energy, and Intelligence, pp 568-581. Philadelphia: Lea & Febiger. Ferholt JB, Rotem DL, Genel M e t al (1985) A psychodynamic study of psychosomatic dwarfism: a syndrome of depression, personality disorder and impaired growth. Journal of the American Academy of Child Psychiatry 24: 49-57. Field TM, Schanberg SM, Scafidi F et al (1986) Tactile/kinesthetic stimulation effects on preterm neonates. Pediatrics 77: 654-658. Frazier SD & Rallison O (1972) Growth retardation and emotional deprivation: relative resistance to treatment with human growth hormone. Journal of Pediatrics 80: 603-609. Gloebl HJ, Capitanio MA & Kirkpatrick JA (1976) Radiographic findings in children with psychosocial dwarfism. Pediatric Radiology 4: 83-86. Green WH (1990) A theoretical model for classical psychosocial dwarfism (psychologically determined short stature). In Holmes CS (ed.) Psychoneuroendocrinology: Brain, Behavior and Hormonal Interaction, pp 92-112. New York: Springer-Verlag. Guilhaume A, Benoit O, Gourmelen M & Richardet JM (1982) Relationship between sleep stage IV deficit and reversible HGH deficiency in psychosocial dwarfism. Pediatric Research 16: 299-303. Hernandez RJ, Poznanski SK, Hopwood NJ & Kelch RP (1978) Incidence of growth lines in psychosocial dwarfs and idiopathic hypopituitarism. American Journal of Roentgenology 131: 477-479. Ho KY, Veldhuis JD, Johnson ML et al (1988) Fasting enhances growth hormone secretion and amplifies the complex rhythm of growth hormone secretion in man. Journal of Clinical Investigation 81: 968-975.

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Hopwood NJ & Becker DJ (1979) Psychosocial dwarfism: detection, evaluation and management. In Franklin AW (ed.) Child Abuse and Neglect vol. 3, pp 439--447. London: Pergamon. Howse PM, Rayner PHW, Williams JM et al (1977) Nyctohemeral secretion of growth hormone in normal children of short stature and in children with hypopituitarism and intrauterine growth retardation. Clinical Endocrinology 6: 347-359. Krejs G J, Orci L, Conon JM et al (1979) Somatostatinoma syndrome. New England Journal of Medicine 301: 285-292. Krieger I (1973) Endocrine and nutrition in psychosocial deprivation in the USA: comparison with growth failure due to malnutrition on an organic basis. In Gardner LI & Amacher P (eds) Endocrine Aspects of Malnutrition: Marasmus, Kwashiorkor and Psychosocial Deprivation, pp 129-162. Santa Ynez, CA: Kroc Foundation. Krieger I (1974) Food restriction as a form of child abuse in 10 cases of psychosocial deprivation dwarfism. Clinical Pediatrics 13: 127-133. Krieger I & Mellinger RC (1971) Pituitary function in the deprivation syndrome. Journal of Pediatrics 79: 216--225. Krieger I & Whitten CF (1969) Energy metabolism in infants with growth failure due to maternal deprivation, under-nutrition, or causes unknown. Journal of Pediatrics 75: 374-379. Lifshitz F & Moses N (1990) Nutritional growth retardation. In Lifshitz F (ed.) Pediatric Endocrinology 3rd edn, pp 111-132. New York: Marcel Dekker. Magner JA, Rogol AD & Gorden P (1984) Reversible growth hormone deficiency and delayed puberty triggered by a stressful experience in a young adult. American Journal of Medicine 76: 737-742. Miller JA, Mirsky IA, Caul WF & Sakata T (1969) Hyperphagia and polydypsia in socially isolated rhesus monkeys. Science Sept: 1027-1028. Money J (1986) Munchausen's syndrome by proxy: update. Journal of Pediatric Psychology 11: 583-584. Money J & Wolff G (1974) Late puberty, retarded growth and reversible hyposomatotropinism (psyehosocial dwarfism). Adolescence 9: 121-134. Money J, Wolff G & Annecillo C (1972) Pain agnosia and self-injury in the syndrome of reversible somatotropin deficiency (psychosocial dwarfism). Journal of A utism and Child Schizophrenia 2: 12%139. Money J, Annecillo C & Kelley JF (1983a) Growth of intelligence: failure and catch-up associated respectively with abuse and rescue in the syndrome of abuse dwarfism. Psychoneuroendocrinology 8: 309-319. Money J, Annecillo C & Kelley JF (1983b) Abuse-dwarfism syndrome: after rescue, statural and intellectual catch-up growth correlate. Journal of Clinical Child Psychology 12: 279-283. Money J, Annecillo C & Hutchinson JW (1985) Forensic and family psychiatry in abuse dwarfism: Munchausen's syndrome by proxy, atonement, and addition to abuse. Journal of Sex and Marital Therapy 11: 30-40. Mouridsen SE & Nielsen S (1990) Reversible somatotropin deficiency (psychosocial dwarfism) presenting as conduct disorder and growth hormone deficiency. Developmental Medicine and Child Neurology 32: 108%1104. Parra A (1973) Discussion of psychosocial dwarfism. In Gardner LI & Amacher P (eds)

Endocrine Aspects of Malnutrition: Marasmus, Kwashiorkor and Psychosocial Deprivation, p 155. Santa Ynez, CA: Kroc Foundation. Patton RG & Gardner LI (1962) Influence of family environment on growth: the syndrome of maternal deprivation. Pediatrics 30: 957-962. Powell GF, Brasel JA & Blizzard RM (1967a) Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. I. Clinical evaluation of the syndrome. New England Journal of Medicine 276: 1271-1278. Powell GF, Brasel JA, Raiti S & Blizzard RM (1967b) Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. II. Endocrinologic evaluation of the syndrome. New England Journal of Medicine 276: 1279-1283. Powell GF, Hopwood NJ & Barratt ES (1973) Growth hormone studies before and during catch-up growth in a child with emotional deprivation and short stature. Journal of Clinical Endocrinology and Metabolism 37: 674-679.

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Rudolf MCJ & Hochberg Z (1990) Are boys more vulnerable to psychosocial growth retardation? Developmental Medicine and Child Neurology 32: 11)22-1025, Sarr M, Job JC, Chaussain JL & Golse B (1987) Les retards de croissance psychogenes. Etude critique des 616ments de diagnostic. Archives Frangaises de Pediatrie 44: 331-338. Schalch DS & Parker ML (1964) Sensitive double antibody immunoassay for human growth hormone in plasma. Nature 203: 1141. Schanberg SM & Field TM (1987) Sensory deprivation stress and supplemental stimulation in the rat pup and preterm human neonate. Child Development 58: 1431-1447. Schanberg SM, Evoniuk G & Kuhn CM (1984) Tactile and nutritional aspects of maternal care: specific regulators of neuroendocrine function and cellular development. Proceedings of the Society for Experimental Biology and Medicine 175: 135-146. Sills RH (1978) Failure to thrive. The role of clinical and laboratory evaluation. American Journal of Diseases in Children 132: 967-969. Spitz R (1945) Hospitalism, an inquiry into the genesis of psychiatric conditions in early childhood. Psychoanalytical Study of Children 1: 53-74. Spitz R (1946) Hospitalism, a follow-up report. Psychoanalytical Study of Children 2: 113-117. Stanhope R, Adlard P, Hamill G e t at (1988) Physiological growth hormone (GH) secretion during the recovery from psychosocial dwarfism: a case report. Clinical Endocrinology 28: 335-339. Talbot NB & Sobel EH (1947) Endocrine and other factors determining the growth of children. Advances in Pediatrics, vol 2. New York: Interscience. Talbot NB, Sobel EH, Burke BS, Lindemann E & Kaufman SB (1947) Dwarfism in healthy children: its possible relation to elaotional, nutritional, and endocrine disturbances. New England Journal of Medicine 236: 783-793. Tanner JM, Whitehouse RH, Hughes PCR & Vince FP (1971) Effect of human growth hormone treatment for 1 to 7 years on growth of 100 children, with growth hormone deficiency, low birth weight, inherited smallness, Turner's syndrome, and other complaints. Archives of Disease in Childhood 46: 745-782. Thompson RG, Parra A, Schultz RB & Blizzard RM (1969) Endocrine evaluation in patients with psychosocial dwarfism. American Federation of Clinical Research 17:592 (abstract). Tibbles JAR, Vallet HL, Brown BSJ & Goldbloom RB (1972) Pseudotumor cerebri and deprivation dwarfism. Developmental Medicine and Child Neurology 14: 322-331. Whitten C & Fischoff J (1969) Evidence that growth failure from maternal deprivation is secondary to undereating. Journal of the American Medical Association 209: 1675-1682. Wolff G & Ehrich JHH (1981) Psychosomatische Storungen und Krankheiten bei Kindern und Jugendlichen. In Steinhause HC (ed.) Psychosozialer Minderwuchs. Kohlhammer.