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ARTICLE

Attenuating Growth in Children With Profound Developmental Disability

A New Approach to an Old Dilemma

Daniel F. Gunther, MD, MA; Douglas S. Diekema, MD, MPH

C aring for children with profound developmental disabilities can be difficult and de- manding. For nonambulatory children with severe, combined neurologic and cogni- tive impairment, all the necessities of life must be provided by caregivers, usually par- ents, and these tasks become more difficult as the child grows to adolescence and

adulthood. Many parents would like to continue caring for their child with special needs at home but find it difficult to do so as the child increases in size. If growth could be permanently arrested while the child was still small, both child and parent would likely benefit because this would facili- tate the option of continued care in the home. Treatment of the child with high-dose estrogen, ini- tiated at an early age, could provide this option. High-dose estrogen both inhibits growth and rapidly advances maturation of the epiphyseal growth plates, bringing about permanent attenuation in size after a relatively short period of treatment. We present a case report and discuss the medical and ethical considerations of such an intervention strategy. We suggest that after proper screening and informed consent, growth-attenuation therapy should be a therapeutic option available to these children should their parents request it. Arch Pediatr Adolesc Med. 2006;160:1013-1017

The American Academy of Pediatrics re- cently endorsed the goal of Healthy People 2010 to reduce the number of children and youth with disabilities in congregate care facilities to zero by the year 2010.1 The American Academy of Pediatrics Commit- tee/Section on Children With Disabilities notes that “most parents desire to raise their children with special health care needs at home”1(p507) and supports a shifting em- phasis away from placement strategies to permanency planning in the “belief that all children, regardless of the presence of a disability, belong in families.”1(p508)

However, caring for a nonambulatory child with severe, combined developmen- tal and cognitive disabilities can be a daunt- ing task for parents, especially as the child increases in size.2 The difficulties of car- ing for these children—dressing, bath- ing, diapering, transferring from bed to wheelchair, transporting—increase expo-

nentially as the children grow to adoles- cence and adulthood. Despite medical and technological advances, many parents who would like to continue caring for their child with special needs at home find it dif- ficult to do so given the physical limita- tions imposed by continued growth. Achieving permanent growth attenua- tion while the child is still young and of manageable size would remove one of the major obstacles to family care and might extend the time that parents with the abil- ity, resources, and inclination to care for their child at home might be able to do so.

Treatment with high-dose estrogen could accomplish this goal. In high doses, estrogen both arrests growth and rapidly ad- vances maturation of the epiphyseal growth plates. This combined effect should bring about permanent attenuation in size after a relatively short period of treatment.

For editorial comment see page 1077

Author Affiliations: Division of Pediatric Endocrinology (Dr Gunther) and Center for Pediatric Bioethics (Dr Diekema), Department of Pediatrics, Children’s Hospital and Regional Medical Center, University of Washington School of Medicine, Seattle.

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At our institution, we have begun such a treatment protocol in a child who meets the criteria for severe, ir- reversible neurologic and cognitive impairment. The treat- ment was requested by the parents and initiated after care- ful consultation and review by our institutional ethics committee. Other children are being considered for treat- ment as part of a comprehensive program that includes review by pediatric specialists in endocrinology, neurol- ogy, development, surgery, and ethics.

In this article, we present the child’s case, discuss the history of growth-attenuation therapy, and make an ar- gument for the careful application of such a treatment strat- egy in nonambulatory, profoundly impaired children. We believe that foreshortening growth in these children could result in a positive benefit in the quality of life for both child and caregiver, and we propose that in situations in which parents request such an intervention, it is both medi- cally feasible and ethically defensible.

CASE REPORT

The patient is a 6-year-7-month-old white female initially referred to the pediatric endocrine service for early puber- tal development. She had been the full-term product of an unremarkable pregnancy followed by an uncomplicated birth. After the first month of life, she began to display symp- toms of hypotonia, feeding difficulties, choreoathetoid movements, and developmental delay. Extensive subse- quent evaluation by specialists in neurology, medical ge- netics, and developmental pediatrics failed to uncover a spe- cific cause. Static encephalopathy with marked global developmental deficits eventually was diagnosed. In the en- suing years, her development never progressed beyond that of an infant. At the age of 6 years, she cannot sit up, am- bulate, or use language. She is gastrostomy-tube depen- dent for nutrition. However, she clearly responds to others— vocalizing and smiling in response to care and affection. The combined opinion of the specialists involved in her care is that there will be no significant future improve- ment in her cognitive or neurologic baseline.

Since birth, the patient has been cared for in the home by her parents, both of whom are college-educated pro- fessionals. She has 2 healthy siblings. Despite her severe disability, she clearly is an integral, and much loved, mem- ber of the family.

The patient presented for endocrine evaluation with a 1-year history of pubic hair development and 3-month his- tory of breast budding. The parents were particularly con- cerned about accelerated growth, the patient having ad- vanced from the 50th to the 75th percentile for length during the previous 6 months. After some probing, it was clear that the onset of puberty had awakened parental fears for their daughter’s long-term future. The parents particu- larly feared that continued growth eventually would make it untenable for them to care for their daughter at home, despite their strong desire to do so. They were concerned that care might eventually have to be “put in the hands of strangers.” There were also concerns about the compli- cations of puberty, particularly the onset of menses.

After extensive consultation between parents and phy- sician, a plan was devised to attenuate growth by using high-

dose estrogen and to reduce the long-term complications of puberty in general, and treatment adverse effects in par- ticular, by performing pretreatment hysterectomy. Be- cause a growth-attenuating treatment regimen is uncon- ventional, and bound to be controversial, the case was referred to our institutional ethics committee. The com- mittee met with the family, the patient, and the patient’s physicians and carefully explored the family’s reasons for their request. After a lengthy discussion, the committee reached consensus that both the requests for growth at- tenuation and hysterectomy were ethically appropriate in this case. The committee also recognized that, although jus- tified in this patient, growth attenuation should be con- sidered in future patients only after careful evaluation of the risks and benefits on a case-by-case basis. Toward that end, plans were instituted to convene an interdisciplinary review panel that includes pediatric specialists in endocri- nology, neurology, development, surgery, and ethics.

After uneventful surgery, the patient began a course of 400 µg of transdermal estradiol daily. She is followed up every 3 months and carefully monitored for growth, bone age, insulin-like growth factor I, estrogen and prolactin lev- els, and thrombotic factors. She is now a little more than a year into therapy and approaching the end of her growth. As of yet, there have been no treatment complications.

THE HISTORY OF GROWTH-ATTENUATION THERAPY

Physicians long have appreciated that one consequence of early puberty is its deleterious effect on growth. In chil- dren who are exposed to sex steroids prematurely, final adult height is seriously attenuated because of accelera- tion in epiphyseal (growth plate) maturation.3 The ear- lier the onset of puberty, the greater the reduction in final height.4 Although both estrogens and androgens acceler- ate growth, it is now appreciated that estrogen is the domi- nant hormone in the advancement of skeletal maturation in both boys and girls and seems exclusively responsible for bringing about epiphyseal fusion and an end to growth.5

The effect of estrogen on growth appears to be bipha- sic. Although physiologic levels of estrogen accelerate growth (the pubertal growth spurt), supraphysiologic doses paradoxically tend to inhibit growth.4,6,7 The mechanism by which high levels of estrogen interfere with growth is not completely understood but may be caused, at least in part, by estrogen’s suppression of insulin-like growth fac- tor I (or somatomedin C), the peptide that mediates the growth-promoting effects of growth hormone.8-10

It is not surprising that this biphasic effect of estro- gen eventually would be exploited therapeutically in situ- ations in which attenuating growth was thought to be de- sirable. Tall adolescent girls wishing to minimize any further gain in height represented one such population. The first use of high-dose estrogen in girls with consti- tutional tall stature was reported by Goldzieher in 1956.11

In the ensuing years, this practice became an estab- lished, if somewhat controversial, strategy for attenuat- ing growth in these girls, and many reports have ap- peared in the literature.12-15 The practice continues to this day, although less commonly, no doubt because of a de- creasing sense of stigma associated with tall stature in

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women.16 Most of what is known about the effective- ness and potential adverse effects of high-dose estrogen treatment comes from these reports in this population.

The estrogen compounds used for growth attenua- tion, and the dosages used, have evolved across time and varied by region. In western and northern Europe, in- jectable estrogen compounds initially were used before being replaced by oral stilbestrol and eventually oral ethi- nyl estradiol (the estrogen most commonly used in oral contraceptives today). In the United States, the conju- gated estrogen Premarin (Wyeth Pharmaceuticals Inc, Philadelphia, Pa; a combination of different estrogenic compounds derived from the urine of pregnant horses) was used predominantly.12,13 Initially, doses greater than 10 to 15 times physiologic (or what was thought to be so at the time) were used, but eventually more modest doses were found to be as effective.15 In most cases, severe uter- ine breakthrough bleeding occurred in girls taking es- trogen alone, and a progestin was added at the end of the monthly cycle to induce normal menstrual periods.12

Although all reports claimed varying degrees of suc- cess in reducing adult stature, the amount of success var- ied. Most reported decreases in adult height were be- tween 2 and 10 cm.12-14 In most cases, treatment was not initiated until the girls were in early adolescence, and many had already had their first menses (a point at which girls will, on average, have already achieved 93% of their final adult height). Not surprisingly, the greatest reductions in height were seen when treatment was started earliest.12

How much reduction in height could we expect to achieve in young children using high-dose estrogen? With- out prior experience, we can only reasonably speculate, and it would obviously depend on the child’s age at the start of treatment. The younger the child at the beginning of treatment, the greater the reduction in height. We be- lieve it a reasonable prediction, for example, that treat- ment beginning in a 5-year-old boy of average height and weight might result in a reduction in final length of as much as 24 inches (60 cm) and in weight of more than 100 pounds (45 kg). Older, larger children will see less of an effect.

THE RISKS OF TREATMENT

Because we have no direct experience with high-dose es- trogen treatment in young children, the possible adverse effects and risks are difficult to assess with certainty. In adolescent girls treated for constitutional tall stature, re- ported adverse effects included nausea, headache, and weight gain, but these were generally mild and virtually never a reason for discontinuing treatment. Hyperprolac- tinemia has been reported but is generally of no clinical significance and resolves after treatment.17 There is one report of a girl with a prolactinoma after high-dose estro- gen treatment, but it is unclear whether this was a preex- isting condition.18 Recently, concerns about long-term ef- fects on fertility in treated girls have been raised,19 but clearly this is not relevant to our population.

The consequence of introducing high-dose estrogen in young prepubertal children will be significant. In boys, the only likely outward manifestation of estrogen exposure would be the development of gynecomastia. In girls, there will be rapid advancement of isosexual secondary sexual

characteristics—most notably breast development and uter- ine bleeding. Uterine bleeding might be controlled by a combination of concurrent estrogen/progesterone treat- ment, but breakthrough bleeding is likely.20 Although monthly or quarterly injections of depot medroxyproges- terone acetate are often used to control menses in some patients with severe developmental disabilities,21,22 an al- ternative for these children is pretreatment hysterectomy, as was performed in our patient.

A word here about hysterectomy is probably appro- priate. Hysterectomy in children, particularly in the dis- abled, is controversial and invariably associated with the negative connotations and history of forced “steriliza- tion.” But in these profoundly impaired children, with no realistic reproductive aspirations, prophylactic hys- terectomy has several advantages as an adjunct to high- dose estrogen treatment. This onetime procedure elimi- nates the complications of menses, and in many cases, will spare the individual and her caregivers the expense, pain, and inconvenience of a lifetime of hormone injec- tions. Hysterectomy also eliminates the need to give con- current progesterone during the treatment phase, poten- tially reducing the risks of thrombosis.23,24 It also eliminates the possibility of future uterine and cervical cancer. With the ovaries left in situ, hormones continue to be pro- duced, providing some protection from osteoporosis. The risks of this surgical procedure in prepubertal girls, and the risks of long-term complications, are minimal— certainly they do not exceed the risk of similar proce- dures many of these children will experience as part of their medical care. The decision to perform hysterec- tomy should be made carefully, and the ethical (and le- gal) considerations important in making this decision have been discussed elsewhere.25

The most significant safety concern regarding high- dose estrogen treatment is the risk of thrombosis, most com- monly deep vein thrombosis. The increased risk for devel- oping deep vein thrombosis among women taking oral contraceptives is somewhere between 2- and 5-fold, in- creasing with age, although it is still relatively uncom- mon.26,27 The risk of thrombosis also is increased among postmenopausal women receiving hormone therapy.28 The mechanism through which estrogen increases thrombo- genesis is not completely clear but probably is related to its direct effects on thrombotic factors.29-32 Although con- cerns about the risk of thrombosis have been raised in the treatment of adolescent girls of tall stature,33 few actual events have been reported. In combined reports of more than 700 girls with tall stature treated at 2 different centers, there was only 1 report of a mild deep vein thrombosis in a girl with a strong family history.14,15 Weimann and Brack34 also reported a case of deep vein thrombosis in a girl who had undergone arthroscopy during her treatment.

The actual risk of thrombosis in developmentally de- layed children is difficult to assess. On the one hand, the risk of thrombosis seems decreased in the young; on the other, the risk is greater in those who are nonambula- tory. Some evidence suggests that spasticity, a not un- common finding in this population, might provide a mea- sure of protection against thrombosis.35 The risk might also be reduced by using transdermal estrogen, which we elected to do in our patient, and by performing pretreat-

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ment hysterectomy, thus eliminating the need for pro- gesterone. The risk in boys taking estrogen is probably similar to the risk in girls.36

THE ETHICAL DEBATE

There is not much doubt that growth can be attenuated sig- nificantly by using high-dose estrogen, particularly if un- dertaken in patients at an early age. But should it be? Is such an intervention in the best interest of these children?

There are good historical reasons to proceed cau- tiously when considering any intervention directed at per- sons with developmental disabilities. Past abuses against this population are well documented. During the late 19th and early 20th centuries, for example, many persons who had mental retardation (or who were thought to have men- tal retardation) were subject to involuntary sterilization because of the belief that they were genetically “unfit” and would pass their “defects” on to future genera- tions.37,38 In many cases, these individuals were capable of living independently, marrying, and raising children. These decisions were based not on the best interest of the patient but rather on the perceived interest of society and, in some cases, the interests of parents or caretakers.

The lessons of these and other abuses must be remem- bered, but past abuses should not dissuade us from ex- ploring novel therapies that offer the potential for benefit. The population we propose to treat—children like our pa- tient with profound cognitive and neurologic impair- ment, who are nonambulatory and wholly dependent on others for every need—is different from the mildly to mod- erately impaired. Nevertheless, we recognize the concern about inappropriate application of these procedures in chil- dren who are less severely disabled. To guard against the arbitrary application of growth-limiting therapy, it seems appropriate, even perhaps necessary, that a formal mecha- nism exists to ensure proper application of treatment. At our institution, we are convening an interdisciplinary group consisting of pediatric specialists in endocrinology, neu- rology, development, surgery, and ethics to consider each case on its merits. This same group will also carefully con- sider whether any additional procedures, such as hyster- ectomy, are appropriate and serve the interests of the child. Ideally, this approach might be combined with a research protocol approved by an institutional review board. Growth attenuation should be considered only after careful con- sideration of the risks and benefits to each patient on an individual basis.

When deciding whether it is ethically appropriate to attenuate growth in these children, there are 2 primary considerations. First, does growth attenuation offer the patient benefit? And second, does growth attenuation do any harm to the patient? The question here, then, is whether there is a reasonable expectation of improved quality of life for a nonambulatory child with profound developmental disability, and at what risk?

The primary benefit offered by growth attenuation is the potential to make caring for the child less burden- some and therefore more accessible. A smaller person is not as difficult to move and transfer from place to place. Although this may seem to be an advantage that accrues to the caretakers rather than the child, it offers several

distinct benefits to the child as well. A child who is easier to move will in all likelihood be moved more fre- quently. Being easier to move means more stimulation, fewer medical complications, and more social interac- tion. Physical contact between parent and child is likely to be more direct and personal without the need for hoist- ing apparatus or other devices. Being easier to move and transfer also makes it more likely that the child will be included in family activities and family outings.

Finally, as we have already argued, parents often wish to continue caring for an older child but find them- selves unable to manage the physical demands as their child grows to adult size. Although size may not be the only consideration, and not all parents will choose this option, growth attenuation may offer some parents at least the opportunity to extend the time they can care for their child at home, whereas otherwise institutionalization, or foster care, might be the only alternative.

For all of these reasons, growth attenuation in the non- ambulatory child with severe developmental disability seems mutually beneficial to caretakers and patient. There does not appear to be a conflict between the interests of the parents and the interests of the child.

Having established a probable benefit to small stature, the second consideration derives from the ethical prin- ciple of nonmaleficence, primum non nocere, to “do no harm.” Could growth attenuation cause harm to these children?

Several potential harms should be considered. Already mentioned are the possible medical adverse effects of high- dose estrogen, the most significant of which is the risk of thrombosis. Although these are real risks, they do not ap- pear to be excessive and probably do not significantly ex- ceed the risks of similar therapies used in this population to control menstruation or prevent pregnancy.

Can one imagine harm to this population from sim- ply being small? Height and normal stature clearly have social value for most individuals. Being taller has been associated with enhanced social stature, greater pay, greater success in attracting a mate, and other social ben- efits.39 However, a nonambulatory, severely impaired child is not someone who will experience these benefits of tall stature and therefore will not suffer their loss if kept short. For an individual who will never be capable of holding a job, establishing a romantic relationship, or interact- ing as an adult, it is hard to imagine how being smaller would be socially disadvantageous.

One might argue that being smaller might alter the way others interact with an older disabled person, perhaps tending to treat that person as a child instead of an adult. Whereas this might be an important issue for a short- statured adult who is capable of normal adult interac- tions, it is unlikely that such “infantilization” harms a person whose mental capacity will always remain that of a young child. In fact, for a person with a developmen- tal age of an infant, smaller stature may actually consti- tute an advantage because others probably would be more likely to interact in ways that are more appropriate to that person’s developmental age.

In summary, the harms associated with growth at- tenuation for persons with severe developmental disabil- ity are primarily those associated with the medical risks of treatment. These risks do not appear to be unreason-

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able and are not out of line with the risks of other medi- cal interventions these children undergo.

CONCLUSIONS

A parent’s desire to seek growth attenuation for a per- manently nonambulatory child with profound develop- mental, neurologic, and cognitive impairment would seem reasonable and understandable. We have argued that a compelling case can be made that the child will benefit from such treatment, that the risks of harm are limited to the adverse effects of the therapy, and that such risks do not significantly exceed those of other standard medi- cal interventions.

To prevent the possibility of abuse and to ensure the safe administration and follow-up of therapy, we sug- gest that treatment should proceed only after evaluation by a pediatric neurodevelopmental specialist and with the supervision of a pediatric endocrinologist, preferably af- ter review by the institution’s ethics committee or in the context of a study reviewed by an institutional review board. Parents should be made aware of the risks and un- certainties of a novel, untested medical intervention. In the presence of those safeguards, we suggest that such treatment is both ethical and feasible and should be an option available to parents.

Accepted for Publication: March 2, 2006. Correspondence: Daniel F. Gunther, MD, MA, Division of Pediatric Endocrinology, Department of Pediatrics, Children’s Hospital and Regional Medical Center, 4800 Sand Point Way NE M1-3, Seattle, WA 98105 (Dan .Gunther@seattlechildrens.org). Author Contributions: Study concept and design: Gun- ther and Diekema. Acquisition of data: Gunther and Diekema. Drafting of the manuscript: Gunther and Diekema. Critical revision of the manuscript for impor- tant intellectual content: Gunther and Diekema. Admin- istrative, technical, and material support: Gunther and Diekema. Study supervision: Gunther and Diekema.

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