The new england journal of medicine

circumstances was the reliance on inotropes or vas- the patients, trying to see the world through their
opressors to sustain life. But the other three factors
involved more subjective judgments by the ICU phy-
sicians: their predictions of survival and cognitive
function beyond the ICU and their perceptions of
the patient’s preferences. Thus, we influence the de-
cision-making process by virtue of how we forecast
the patient’s future, and the family influences us by
helping us to understand the patient’s desires.
Since these discussions carry such weight, many
of us who have the privilege of working in an inten-
sive care setting fear that our own biases about a
patient will color our interactions with the family,
which could, in turn, influence what family mem-
bers say about the patient’s preference — thus creat-
ing a self-fulfilling prophecy. Indeed, in interviews
conducted after the current report was accepted
for publication, some of the investigators noted the
near-impossibility of conveying their predictions
to patients’ families without, in part, influencing the
outcome. In the words of Gordon Guyatt, one of
the study’s investigators, “There’s no question that
the way the clinician presents information to the pa-
tient and family has a profound effect on the family’s
decision.”
But as we gain a better understanding of the im-
portance of the partnership between clinicians and
families in reaching one of the most heart-wrench-
ing decisions in medical practice or in a family’s life,
we are asking more questions. We are focusing on
eyes and to divine what they would do if they had the
cognitive ability to do it. As a result, when I am staff-
ing the ICU, I spend many hours in family meetings
that often involve not only the patient’s extended
family, but also close friends, members of the cler-
gy, and social workers. Peter Dodek, a coinvestiga-
tor in the current study, noted that ICU physicians
ask many more questions of family members than
they were trained to ask 20 years ago, and spend
more time listening to the answers. “I provide the
medical facts and then I ask questions. By that early
listening process, I’m not creating the outcome.
It’s not me telling them what to do. . . . My job is
to synthesize the medical facts with the patient’s
preference to come up with a plan. . . . Yes, I’m
creating the outcome because I’m stating the plan,
but I want to be sure that I’ve incorporated the pa-
tient’s preferences. I’m not trying to satisfy myself;
I’m trying to satisfy what the patient would want.”
In the struggle to understand what a patient in
the ICU would want if he or she could give us the
direction we desperately seek, this research shows
that we must be very careful as we speak with the
patient’s family and close friends. We must try to see
the problem through the patient’s eyes and make
decisions in the patient’s best interest. The words
of Francis Peabody still ring true: “. . . the secret
of the care of the patient is caring for the patient.”
I am indebted to Sandra Jacobs for research assistance.

New Revelations about the Role

of STATs in Stature
Erica A. Eugster, M.D., and Ora Hirsch Pescovitz, M.D.

In this issue of the Journal, Kofoed et al. (pages 1139–
1147) describe a novel mechanism for impaired
growth in the form of a mutation in the gene for the
intracytoplasmic protein signal transducer and acti-
vator of transcription 5b (STAT5b). The mutation
disrupts the intracellular signaling that promulgates
the physiologic effects of growth hormone. This
finding illuminates an important arena of molec-
ular genetic abnormalities involving the growth hor-
mone–insulin-like growth factor I (IGF-I) axis.
The most striking feature of the patient described
by Kofoed et al. is profound growth failure, mani-
fested by a height at a chronologic age of 16.5 years
that would be average for a child 6.5 years of age.
This phenotype could arise from several well-recog-
nized perturbations in the growth hormone system.
The growth pattern characteristic of early acquired
or congenital growth hormone deficiency owing to
a mutation in the gene for the growth hormone–
releasing hormone receptor, growth hormone, or a
pituitary transcription factor such as PIT-1 would
have been indistinguishable from that observed in
the patient. The finding of elevated serum growth
hormone levels in conjunction with a low level of

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 perspective

IGF-I, however, clearly establishes the presence of

growth hormone resistance in this patient. Growth hormone
Typically referred to as the Laron syndrome, Growth hormone–
Growth hormone binding protein
growth hormone resistance is usually due to muta- receptor Cell
tions in the extracellular component of the growth membrane
hormone receptor, which has a sequence identical P
to that of the circulating growth hormone–binding P

protein (GHBP). Unlike patients with classic Laron P

Janus
P kinase 2
syndrome, this patient had normal levels of GHBP, –
P 13
indicating that the defect was distal to the extracel- kinase
lular growth hormone receptor domain. Mutations
in the transmembrane or intracytoplasmic regions Metabolism Insulin-receptor
Inhibition substrate
of the growth hormone receptor have been identi- Proliferation
Suppressors
fied in a subgroup of GHBP-positive patients with of cytokine SRC homology-2– Linear
the Laron syndrome but were not present in this pa- signaling Transcription containing growth
protein
tient. The constellation of elevated growth hor-
mone levels and low levels of IGF-I in this patient Mitogen-activated
protein kinase
would also be consistent with the presence of an Acid-labile subunit
abnormality in the IGF-I gene, which has been de- Insulin-like growth
scribed in one patient (but would not explain the factor–binding
STATs protein 3
low levels of acid-labile subunit and IGF-binding
protein 3). However, none of these aberrations were Insulin-like growth
factor 1
present. Rather, a homozygous missense mutation Extracellular signal-
in the STAT5b gene resulted in the loss of growth related kinases 1/2
hormone activity. The patient’s unaffected parents,
who were first cousins, were found to be carriers of
the same mutation.
STAT5b
STAT5b was first identified in mammary-gland
tissue from lactating sheep, where it was shown to P
be inducible by prolactin. Ubiquitously expressed P
P
in a wide variety of target tissues, the STATs serve Nucleus
DNA
essential functions in signal transduction in re-
sponse to multiple growth factors and cytokines, all
of which act through a related superfamily of re- Growth Hormone–Activated Intracellular Signaling.
ceptors. As shown in the Figure, the initial step in Phosphorylation of the growth hormone receptor is followed by the activation
growth hormone binding involves dimerization of of metabolic, proliferative, and transcriptional pathways. STAT5b stimulates
the growth hormone receptor. This is followed by the transcription of factors (shown in the box) that are critical for normal lin-
activation of the closely associated Janus kinase 2 ear growth. P denotes phosphorylation, and STAT signal transducer and acti-
vator of transcription.
(JAK2) molecules, which undergo rapid tyrosine
autophosphorylation while concurrently phospho-
rylating the intracellular portion of the growth hor-
mone receptor. Formation of the growth hormone
receptor–JAK2 complex activates several signaling the two isoforms have distinct and highly species-
pathways that ultimately subserve multiple growth specific roles. The crucial role of STAT5b in growth
hormone–related biologic functions. In one path- was first suggested by studies involving a knockout-
way, phosphorylated homodimers and heterodimers mouse model; knockout mice had a dramatic loss
of STAT1, STAT3, and STAT5 are translocated to the of sexually dimorphic growth patterns and hepatic
nucleus, where they bind to response elements on gene expression. In contrast to the teenage girl de-
DNA and stimulate the transcription of genes. scribed by Kofoed and colleagues, only male mice
Despite the existence of greater than 90 percent with STAT5b deficiency had growth failure. Addi-
sequence homology between STAT5a and STAT5b, tional consequences of a targeted loss of STAT5b
evidence from studies in animals has indicated that in mice include delayed onset of obesity, as well as

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 The new england journal of medicine

impairments in reproduction and lactation. It is
interesting that pubertal development was delayed
in the patient described by Kofoed et al., and it re-
mains to be seen whether abnormalities in body
composition or reproductive function will emerge
over time. It is clear that neither STAT5a nor the
other STATs can substitute for STAT5b in promot-
ing linear growth.
A fascinating aspect of this case report is the
long history of compromised immunologic func-
tion. This finding fits well with the proposed obli-
gate role of STAT5b in the activation of T cells and
the response to immune modulators such as inter-
feron, interleukin-2, and interleukin-3. Indeed, rec-
ognition of these seemingly disparate consequenc-
es of a single mutation will undoubtedly prompt
directed studies of patients with both growth fail-
ure and immune dysregulation. The demonstration
of precise molecular genetic defects paves the way
for the identification of innovative therapies tar-
geted to specific functional abnormalities within
cells, as has recently occurred in the case of chronic
myeloid leukemia. Irrefutably, what we currently
understand about the intricacies of the growth hor-
mone–signaling cascade is minuscule as compared
with what remains to be elucidated. Clearly, a new
era in the conceptualization of growth disorders
is upon us.
From the Section of Pediatric Endocrinology and Diabetology, De-
partment of Pediatrics, Riley Hospital for Children, Indiana Univer-
sity School of Medicine, Indianapolis.

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