Received: 05 September 2023 Revised: 21 October 2023 Accepted: 16 November 2023

DOI: 10.48309/jmpcr.2024.183574

FULL PAPER

A boy with short stature, be aware of multiple

pituitary hormone deficiency
N.M. Maya P. Wulandari | Nur Rochmah* | Yuni Hisbiyah | Rayi K. Perwitasari | Muhammad
Faizi

Department of Pediatrics, Faculty of Medicine

Universitas Airlangga, Dr. Soetomo General Multiple pituitary hormone deficiency (MPHD) is a disorder that
Academic Hospital, Surabaya, East Java,
Indonesia
can cause short stature and delayed puberty due to the deficiency
of several pituitary hormones. This case report aimed to deliver a
rare case of multiple pituitary hormone deficiencies, focusing on
the diagnosis approach and therapy. A thirteen-years-old boy
came with a main complaint of short stature with a height of only
101 cm. The growth chart showed that the patient was below the
third percentile. The Tanner stage was prepubertal. There was no
history of short stature, delayed puberty, and hormonal disorders
in his family. Hormonal tests showed deficiencies of GH, FT4, FSH,
LH, and testosterone, and normal serum levels of TSH. Those were
indicating growth hormone deficiency, central hypothyroidism,
and hypogonadotropic hypogonadism. Patients received
levothyroxine and recombinant human growth hormone as
hormone replacement therapy based on the etiology. The
evaluation of therapy is carried out every 3-6 months. MPHD may
be idiopathic or caused by hereditary disorders. The underlying
cause of MPHD remains unknown. Further screening and
diagnosis are required to evaluate risk factors and the best future
therapy.

KEYWORDS
*Corresponding Author:
Nur Rochmah Growth hormone; growth hormone deficiency; multiple pituitary
hormone deficiency; short stature; delayed puberty; central
Tel.: +62-817-0350-1118 hypothyroidism; hypogonadotropic hypogonadism.

Short stature itself is one of the most

Introduction
common reason children are taken to a
Multiple Pituitary Hormone Deficiency pediatrician, either because of the wishes of
(MPHD) is an endocrine disorder caused by a the parents or a referral from a family doctor.
deficiency of more than one pituitary hormone The main aim of evaluating short stature in
[1]. It may be caused by acquired children is to identify a number of children
hypothalamic-pituitary abnormalities such as with pathological causes, whether non-
a tumour, surgery, trauma, or irradiation. endocrine or endocrine causes. The cause of
They can also be idiopathic or the result of endocrine disorders is a small percentage, but
hereditary disorders. In 10% of cases, it is important because if diagnosed it can be
congenital MPHD is familial; however, it is treated. Considering that there are so many
frequently sporadic [2]. MPHD is a known differential diagnoses for short stature, an
cause of short stature and delayed puberty in appropriate history and physical examination
children. is needed to determine which supporting

J. Med. Pharm. Chem. Res. 6 (2024) 111-121 P a g e | 111

 P a g e | 112 N.M. M. P. Wulandari et al.

examination to choose, and to distinguish to deliver a rare case of multiple pituitary

pathological forms from normal variants. hormone deficiencies, focusing on diagnosis
Therefore, it is very important to evaluate approach and therapy.
carefully when facing patient with short
stature. The objective of this case report is to Case Report
present a rare case of a child with short stature
Informed consent was obtained from the
due to multiple pituitary hormone deficiency,
patient's mother. A 13 years old boy came to
focusing on diagnostic approach and therapy.
the Pediatric Endocrinology outpatient clinic
The MPHD can be observed in a short
with a chief complaint of short. He looked
stature child, which is due to Growth Hormone
shorter than his peers since he was five years
(GH) deficiency as well as other pituitary
old. He was 101 cm in the first admission
hormone deficiency, especially thyroid
(Figure 1). When he was six years old, he was
hormone (TSH) [3]. The pituitary also
only 89 centimetres (cm) tall, and when he
produced Follicle-stimulating hormone (FSH)
was 11 years old, he was 98 cm tall. He had not
and Luteinizing hormone (LH). Therefore,
yet experienced wet dreams or any changes in
deficiency in any of those hormones can cause
his voice. No hair had grown either on his face
an absence of signs of sexual maturation. The
or body.
condition is called delayed puberty [4].
He was said to eat properly and drink milk
The prevalence of MPHD is estimated to be
on a daily basis. He never complained of
1 in 8000 individuals worldwide [5] while
recurrent vomiting and/or diarrhea. He never
congenital MPHD has an incidence of 2 in
complained of severe or prolonged headache.
100,000 live births [6]. Research conducted on
He also never complained of any visual
115,000 children in the United States reported
impairment. There were no history of
that of 555 children with a growth rate of less
consuming prolonged medication or
than 5 cm in 1 year, only 5% had endocrine
experiencing chronic diseases. There were no
disorders while the other 95% did not have
previous history of radiation, chemotherapy,
endocrine disorders. Research conducted in
or organ transplantation. There was no
Iran showed that the percentage of short
previous history of a head injury. He had
stature that was caused by Growth Hormone
completed all childhood immunization. His
Deficiency (GHD) was 6.1% [3] while delayed
developmental milestone was within normal
puberty itself occurs in 5% of the population.
limits. He also had a good school performance.
MPHD, which causes short stature and
He was born prematurely by caesarean
delayed puberty, can create various social
section at 34 weeks of gestation due to
issues. A study of children with growth
premature rupture of membranes. His birth
retardation have shown severe deficits in
weight was 1750 grams and his height was
emotional development, including a lack of
48cm. Based on Lubchenco's score, he
aggressive drive and abnormal object
belonged to appropriate for gestational age.
relationships. Children with short stature also
He was the second child in his family. His
showed shyness, impaired self-concept, and
sibling was a 17 years old girl with normal
social withdrawal [7].
weight and height.
Patients with pituitary hormone
There was no history of short stature,
deficiencies must be aware of other pituitary
delayed puberty, and hormonal defects in his
hormone abnormalities. It appears to be a
family. His mother had menstruation at the
dynamic condition in which new deficiencies
age of 12 years and his father experienced wet
might arise years after the initial diagnosis,
dreams at the age of 13 years.
and all hypopituitary patients should have
regular endocrine follow-ups. This case aimed
A boy with short stature, be aware of multiple … P a g e | 113

FIGURE 1 A patient with proportionally short stature. This patient had no dysmorphic features.
This was the situation prior to beginning hormone replacement therapy

The patient had a weight of 14 kg, a height From the history taking and physical
of 101 cm, and a head circumference of 48.5 examination, this patient assessment indicates
cm. Patients with an ideal body weight of 16 short stature and delayed puberty. To
kg, and the percentage of ideal body weight determine the etiology, we performed bone
was 87.5% indicating moderate malnutrition. age test, growth hormone stimulation test, and
Based on Centre for Disease Control (CDC) also thyroid and gonadotropine hormone test.
growth chart, his height was under the third
percentile (Figure 2). Based on the Nellhaus The first simple imaging examination was
chart, the head circumference was bone age (Figure 3). The bone age result was 2
microcephaly. His father's height was 160 cm years and 8 months. It meant that this patient
and his mother's height was 145 cm. His mid- had delayed bone age. These data
parental height was 159 cm and his genetic distinguished this patient from those with
potential height was 145.5 cm to 162.5 cm. familial short stature, in whom bone age
Physical examination showed that both corresponds approximately to chronological
testicles were palpable with volume 2 ml each. age. This patient with a chief complaint of
The upper per lower segment was proportionate short stature, delayed puberty,
proportionate with the ratio of 1.25 (upper no dysmorphic feature, and had delayed bone
segment was 56.3 cm and lower segment was age. This condition could be due to an
44.7 cm). His face and body did not show endocrine disorder. Therefore, we performed
characteristics of dysmorphic features. There some hormonal examinations to look for any
had not been any hair growth on his face, his hormonal defect.
armpit, and his genitals. There was no breast
enlargement. Tanner's stage was prepubertal
(G1P1A1).
P a g e | 114 N.M. M. P. Wulandari et al.

Patient's height
was under the
3rd percentile

FIGURE 2 CDC growth chart showed height under third percentile [8]
A boy with short stature, be aware of multiple … P a g e | 115

FIGURE 3 Bone age of the patient was 2 years and 8 months

First, we identify if there is a growth cessation of bone maturation [3]. The Free T4
hormone deficiency, as growth hormone plays (FT4) level was 0.65 ng/dl (normal range 0.8
a role in all phases of growth, both prenatal to 1.9 ng/dl), and the TSH level was 2.87
and postnatal [3]. We performed a growth uIU/ml (normal range 0.4 to 4.2 uIU/ml). This
hormone stimulation test using Clonidine. was indicating central hypothyroidism. Then
Before starting the test, the patient was fasting we measured gonadotropine hormones, as it is
for 8 hours. Baseline growth hormone level important in the process of stimulating
was taken at minute 0 and the result was 0.05 growth and inducing secondary sexual growth
ng/mL, and then Clonidine 5 mcg/kg BW was [3]. Gonadotropine hormones were also low;
given orally. Growth hormone level was 0.05 the LH level was 0.5 mIu/mL (normal range 1
ng/mL, 0.124 ng/mL, 0.05 ng/mL, and 0.05 to 1.25 mIu/mL), the FSH level was 1.41
ng/mL at minute 30, 60, 90, and 120, mIu/mL (normal range 1.5 to 11.8 mIu/mL),
respectively. We could conclude that the and the testosterone level was 0.09 ng/mL
growth hormone stimulation test revealed a (normal range 2.2 to 10.5 ng/mL). Those data
low level of growth hormone with a peak value were indicating hypogonadotropic
of 0.124 ng/mL (normal level > 7ng/mL). This hypogonadism that was the cause of delayed
was indicating growth hormone deficiency. puberty. From the history taking, physical
We also measured thyroid hormone to identify examination, bone age, and hormonal
hypothyroidism, as thyroid hormone examination, we assessed this patient with
deficiency can cause growth retardation and short stature due to growth hormone
 P a g e | 116 N.M. M. P. Wulandari et al.

deficiency and central hypothyroidism, and The patient got hormone replacement therapy
also delayed puberty due to with recombinant human growth hormone
hypogonadotropic hypogonadism. This subcutaneous injection that was taken once a
condition was called multiple pituitary day at night with a dosage of 25 mcg/kg/day
hormone deficiency (MPHD) (Figure 4). To (0.3 mg per 24 hours) and levothyroxine that
identify the etiology of MPHD and to ensure was taken once a day with a dosage of (~100
there was no intracranial mass, we performed mg/m2). Evaluation of therapy is carried out
a head MRI. Fortunately, the head MRI every 3-6 months. The height was increase 2.5
revealed normal. This patient with MPHD cm during the first 3 months of treatment.
displayed a short stature and delayed puberty.

First admission day Next Next Next Diagnosed with

MPHD
• GH stimulation test
• First • Bone age revealed growth •MRI
admission results was 2 hormone deficiency
revealed
with chief years and 8 • Thyroid test
revealed central
complain months old hypothyroidism normal
(chronologica results
of short l age was 13
• Gonadotropine test
revealed
hypogonadotropic Started
years old) hypogonadism
Hormone
Replacement
Therapy

FIGURE 4 Timeline describing when each test was conducted and when the diagnosis was
made

Discussion further divided into familial short stature and

constitutional delay of growth and puberty
This patient came with a chief complaint of (CDGP) [3,9].
being shorter than his peers. The first thing to Familial short stature is caused by genetic
do when facing patient with short stature is to factors. It is almost always accompanied by
take measurements of height accurately and short stature on one or both of the parents. All
then do a proper plot based on the appropriate the laboratories examination in familial short
growth curve. For a 13-year-old kid, this stature is normal, bone age is normal, and
patient was only 101 cm tall. When we plotted there is no endocrine abnormality [3]. This
on the CDC growth chart, his height was under patient did not belong to familial short stature
the third percentile. Short stature is a term for because he had abnormal bone age and
height under the third percentile or - 2 SD hormonal level, and his parents was not short
according to age and sex on the growth chart stature.
which is used in the population [3]. The second type of nonpathological short
There are so many etiologies for short stature stature is a constitutional delay of growth and
(Figure 5), therefore proper history taking and puberty (CDGP), which has characteristics of
physical examination are needed. Therefore, delayed linear growth in the first three years
we have to do a thorough examinations to of life which is followed by normal growth. In
exclude the differential diagnosis. Short this type of short stature, there was no
stature is divided into two classification, abnormality of endocrine function [3]. In this
which are non-pathological short stature case, the patient did not belong to CDGP
(normal variant) and pathological short because he had an endocrine abnormality.
stature. Non-pathological short stature is
A boy with short stature, be aware of multiple … P a g e | 117

FIGURE 5 Etiology scheme of short stature [9]

(Source: https://blackbook.ucalgary.ca/schemes/endocrinology/short-stature/ )

This patient did not belong to both kind of medicine, and chronic disease. Therefore, the
nonpathological short stature, which is most possible etiology was due to endocrine
familial short stature and constitutional delay disorder [9]. In fact, after the growth hormone
of growth and puberty (CDGP). Therefore, the stimulation test and also thyroid and
next step was to look for the etiology of short gonadotropine hormone test were done, all
stature from the pathological one. Pathological the results were abnormal, showing an
short stature is subdivided into proportionate endorine disorder.
and disproportionate short stature [9]. This Growth hormone stimulation test revealed
patient with normal upper per lower body a low level of growth hormone with a peak
ratio belonged to the proportionate short value of 0.124 ng/ml (normal level>7 ng/ml).
stature. Pathological proportionate short It was indicating a growth hormone
stature is further subdivided based on deficiency. Growth hormone is a polypeptide
whether this patient has a dysmorphic feature hormone secreted by the anterior pituitary
or not [9]. This patient had no dysmorphic gland and is the chief driver of statural growth
feature so we could exclude the possibility of during childhood [10]. Therefore, deficiency of
syndromic disease in this patient. this hormone can result in short stature
Thereafter, we should further identify the condition.
etiology of pathological proportionate short In this patient, the laboratory results
stature in this patient. From history taking, we showed low FT4 and normal TSH level, which
could exclude the etiology of deprivation, belonged to central hypothyroidism.
P a g e | 118 N.M. M. P. Wulandari et al.

Hypothyroidism is majorly divided into two higher risk for developing additional hormone
categories, primary and secondary (central) deficiencies, as patients with MPHD have more
hypothyroidism. Central hypothyroidism is frequent anatomical abnormalities of the
when the thyroid gland itself is normal, and pituitary than those with isolated GHD [16]. A
the pathology is related to the pituitary gland study in Saudi Arabia in 2017 shows that most
or hypothalamus. It is caused by a defect in the of the children with MPHD (6/11) showed
hypothalamic-pituitary axis [11]. anterior pituitary hypoplasia or (3/11) aplasia
This patient had not yet experienced wet and 2/11 children with MPHD had normal MRI
dreams or any changes in his voice. No hair [17]. In addition, an MRI is performed to
had grown either on his face or body. The ensure the absence of an intracranial mass
volume of the testicle was still 2 ml each. His before giving growth hormone therapy [3].
Tanner's stage was prepubertal (G1P1A1). In Short stature due to MPHD is one of the
the male, delayed puberty is defined as a lack causes of short stature due to endocrine
of increase in testicular volume at 14 years of disorders, which although it has a small
age or a time-lapse of more than 5 years from percentage, is important because once
the start to completion of genital growth. This diagnosed it can be treated with hormone
patient has delayed puberty due to replacement therapy. Growth hormone plays a
hypogonadotropic hypogonadism, based on role in all phases of growth, both prenatal and
the low level of gonadotropine hormone. We postnatal. Children who experience growth
planned to give pubertal induction for this hormone deficiency will only experience a
patient after optimizing his potential height final height of around 130 cm. The goal of
with growth hormone therapy [12]. treatment with growth hormone is to improve
We did a bone age examination for this the prognosis for adult height. From various
patient and it turned out that his bone age was recent studies, it can be seen that the final
2 years and 8 months. Patients with growth height results of children who receive growth
hormone deficiency have a delay in bone hormone are much better than the predicted
maturation. The presence of hypogonadism height at the start of treatment [3].
with the consequent lack of circulating Treatment for short stature was given
estrogens, androgens, and other pubertal according to its etiology. Treatment with GH
hormones may also cause an important delay aimed to improve the prognosis of adult
in bone maturation during the pubertal period height. First, we gave recombinant human GH
[13]. as hormone replacement therapy for growth
We diagnosed this patient with multiple hormone deficiency. Treatment of growth
pituitary hormone deficiencies (MPHD) hormone could be started after confirming
because we found a growth hormone there was no intracranial mass by head CT
deficiency, central hypothyroidism, and Scan or MRI. Growth hormone (GH) was best
hypogonadotropic hypogonadism. MPHD may given at night subcutaneously to adapt with
be idiopathic or result from genetically endogen growth hormone production. The
defined conditions. Congenital MPHD may be dosage given was 25-50 mcg /kg/day for
familial in 10% of cases, but it is usually prepubertal age and 100 mcg/kg/day for
sporadic. MPHD is characterized by impaired pubertal age. Treatment was given 6 days per
production of GH and one or more of the other week. The evaluation was done every 3-6
pituitary hormones [14,15]. months. An increase in height and growth
We did a brain MRI on this patient and the velocity was the most important indicator for
result was normal. MRI is a useful modality for evaluation. The treatment for a GH was
delineating pituitary anatomy. MRI findings stopped if the final height was reached or the
have a role in identifying children who are at epiphyseal plate was closed. Therapy is also
A boy with short stature, be aware of multiple … P a g e | 119

stopped if the response to therapy is responders and revisit the diagnosis, adjust
inadequate, namely if the increase in growth the GH dose, or discontinue treatment [18].
rate is less than 2 cm per year. In cases of Thyroid hormone plays an important role
growth hormone deficiency, growth hormone in bone maturation in the prenatal and
therapy should continue until adulthood, to postnatal periods. Deficiency of thyroid
optimize the metabolic effects of growth hormone in childhood will cause slowed
hormone and achieve normal peak bone mass. growth and retarded bone maturation. With
Children receiving growth hormone therapy levothyroxine treatment, growth will be seen
require periodic monitoring. Usually done to catch up so that they can reach normal
every 3 months to monitor growth with height. Medication can be given in the morning
meaningful measurements. During the or evening as long as it is given at the same
treatment evaluation, height, weight, pubertal time every day [3].
status, examination of the injection site, and a Short stature has so many differential
comprehensive physical examination are diagnosis and etiologies, one of them is MPHD.
carried out. The objective result of growth Although MPHD was rare, we still have to be
hormone therapy is an increase in growth rate aware of the possibility of MPHD in a child
and final height. Treatment is considered to with short-stature. Studying a case of children
provide a good response if linear growth with MPHD can provide valuable insights into
increases > 2 cm per year. Increase in height as the diagnosis approach and management
well as increase in growth rate are important patient with MPHD, especially when facing
evaluation indicators. Research on the safety patient with short stature.
of using growth hormone has been conducted
by the Growth Hormone Research Society. In Conclusion
general, the side effects are minimal and only
occur in less than 3% of cases. Side effects of We report a 13 years old boy who presented
growth hormone therapy include intracranial with short stature and delayed puberty. His
hypertension (pseudotumor cerebri), edema, height was under the third percentile for age.
slipped capital femoral epiphysis, worsening Tanner stage was prepubertal. Growth
scoliosis, gynecomastia, hyperglycemia, and hormone stimulation test revealed a low level
malignancy. During the period of growth with a peak value of 0.124 ng/ml (normal level
hormone therapy, it is necessary to >7 ng/ml), thyroid hormone test showed low
periodically check bone age every 12 months FT4 and normal TSH level, and gonadotropine
and thyroid function every 6 months as well as hormone test showed low level of FSH, LH, and
evaluate the side effects of treatment [3]. testosterone level. Working diagnosis was
Growth hormone deficiency in children is growth hormone deficiency, central
mostly idiopathic and is treated with daily GH hypothyroidism, and hypogonadotropic
injections for a mean duration of 4 to 11 years. hypogonadism. This patient treated with
As a result, GH treatment is not only growth hormone and thyroid hormone. The
demanding on patients and their families, but height increase 2.5 cm during 3 months of
it is also expensive. Furthermore, not all hormone replacement therapy. This article
children benefit from GH treatment, and the presents a rare case of a boy with short stature
poor response rate in GHD has been estimated that turned out to be a multiple pituitary
to be between 10 and 30%. To minimize hormone deficiency (MPHD). MPHD has a
unnecessary daily injections and expenses, it small percentage, but it is important because if
is customary to monitor the response to GH diagnosed it can be treated. Appropriate
therapy after one year to discover poor clinical examination and evaluation is very
necessary so that an early diagnosis can be
P a g e | 120 N.M. M. P. Wulandari et al.

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