Hypothyroidism is usually associated with delayed puberty and occasionally may present with isosexual precocious puberty. In girls, this may present with breast development, multicystic ovaries and vaginal bleeding. This entity characterized by ovarian hyper stimulation leading to early puberty secondary to hypothyroidism is known as Van Wyke Grumbach syndrome. In contrast to the early puberty caused by other causes, precocious puberty of hypothyroidism is characterized by short stature and delayed bone age. Awareness about this condition and the treatment of this condition with levothyroxine will lead to avoidance of surgery and unnecessary intervention. We present the case of a six-year-old girl who presented with precocious puberty and pituitary hyperplasia. This case highlights the need for the professionals to familiarize themselves about uncommon complications of untreated hypothyroidism.

1. Van WykeGrumbach syndrome and pituitary
hyperplasia in a six-year-old girl

2. Case Report
Van WykeGrumbach syndrome and pituitary
hyperplasia in a six-year-old girl
Anjana Hulse*
Consultant Pediatric Endocrinologist, Apollo Hospitals, 154/11, Opp IIM, Bannerghatta Road, Bangalore 560076,
India
a r t i c l e i n f o
Article history:
Received 29 September 2013
Accepted 22 October 2013
Available online xxx
Keywords:
Primary hypothyroidism
Van WykeGrumbach syndrome
Pituitary hyperplasia
Early puberty
Levothyroxine
a b s t r a c t
Hypothyroidism is usually associated with delayed puberty and occasionally may pre-
sent with isosexual precocious puberty. In girls, this may present with breast develop-
ment, multicystic ovaries and vaginal bleeding. This entity characterized by ovarian
hyper stimulation leading to early puberty secondary to hypothyroidism is known as Van
WykeGrumbach syndrome. In contrast to the early puberty caused by other causes,
precocious puberty of hypothyroidism is characterized by short stature and delayed
bone age. Awareness about this condition and the treatment of this condition with
levothyroxine will lead to avoidance of surgery and unnecessary intervention. We pre-
sent the case of a six-year-old girl who presented with precocious puberty and pituitary
hyperplasia. This case highlights the need for the professionals to familiarize themselves
about uncommon complications of untreated hypothyroidism.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Untreated hypothyroidism usually is associated with delayed
puberty in children. But, occasionally it may be associated
with isosexual precocious puberty where it is known as Van
WykeGrumbach syndrome. In 1960, Van Wyk and Grumbach
described this association of hypothyroidism and precocious
puberty.1
This entity is characterized by untreated hypothy-
roidism, precocious puberty and ovarian hyper stimulation.
Treatment with levothyroxine leads to complete reversal of
pubertal signs.
Pituitary enlargement with untreated primary hypothy-
roidism is known to occur but is rare. Thyrotroph hyperplasia
can lead to expansion of sella turcica and enlargement of pi-
tuitary gland in long standing untreated hypothyroidism.2
Complete regression of pituitary hyperplasia occurs with
levothyroxine treatment.3,4
We report a case of a six-year-old
girl with Van WykeGrumbach syndrome with pituitary hy-
perplasia secondary to untreated hypothyroidism.
2. Case report
A six-year-old girl presented with bleeding per vagina and
intermittent abdominal pain since 4 days. She was referred
with a possible diagnosis of pituitary tumor based on her
magnetic resonance imaging (MRI) findings. On enquiry,
bleeding was scanty and the child was hemodynamically
stable. There was no history of urinary symptoms or bleeding
per rectum. There was no history of visual disturbances, gait
disturbances, headache or vomiting. There was history of long
standing constipation and poor appetite. But, there was no
* Tel.: þ91 (0)80 26304050, þ91 (0)9591382502 (mobile).
E-mail address: anmhulse@gmail.com.
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Please cite this article in press as: Hulse A, Van WykeGrumbach syndrome and pituitary hyperplasia in a six-year-old girl,
Apollo Medicine (2013), http://dx.doi.org/10.1016/j.apme.2013.10.009
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.10.009

3. concern about excess sleep or recent weight gain. There was
no history of developmental delay and according to the par-
ents, her scholastic performance was excellent. The child was
treated with oral iron supplements for anemia in the past. On
examination, she was short with a height of 98 cm (<3rd
centile) and weight 16 kg (<3rd centile). The patient had puffy
face and was very quiet during examination. Skin was
moderately dry. She was in Tanner stage 3 breast develop-
ment. There was no pubic or axillary hair. Examination of the
perineum and external genital examination were normal.
Other systems as well as fundoscopy were normal.
Investigations revealed hemoglobin of 11.2 g%, serum TSH
>100 mIU/ml (range 0.27e4.2), free T4 0.3 ng/dl (range 0.8e1.8),
E2 <20 pg/ml, basal FSH 2.3 mIU/ml, LH 0.02 mIU/ml and
prolactin 20 mg/ml (range 1.2e13.5). Anti TPO (thyroid peroxi-
dase) antibodies level was 68 IU/L and anti-thyroglobulin an-
tibodies level was 7 IU/L. Bone age was delayed by 3 years.
Ultrasound of the pelvis showed prepubertal uterus, bilateral
multicystic ovaries with the largest cyst measuring
5 cm  6 cm on the left side. Imaging of the pituitary which
was done prior to referral to our hospital showed an enlarged
pituitary gland (Fig. 1). This was done as a part of evaluation of
early puberty, prior to the referral to pediatric endocrine
department. A diagnosis of precocious puberty and pituitary
enlargement secondary to untreated hypothyroidism of
autoimmune etiology was made and the patient was started
on levothyroxine 50 mg per day. Vaginal bleeding stopped one
week after starting levothyroxine. Recent follow up 3 months
after starting treatment showed an improvement in her
growth (height 102 cm, weight 16 kg). Breast development
regressed significantly. Repeat imaging of the pituitary was
not done as the pituitary enlargement associated with hypo-
thyroidism is known to regress with levothyroxine
treatment.2e6
3. Discussion
Van WykeGrumbach syndrome is an unusual syndrome of
isosexual precocity with juvenile hypothyroidism.1
This syn-
drome is characterized by one or more of the following signs
and symptoms in girls: breast enlargement, galactorrhea,
irregular vaginal bleeding and multicystic ovaries on ultraso-
nography but very little or no sexual hair development. Boys
may present with macro-orchidism but with no signs of viri-
lization. Other features of hypothyroidism are usually pre-
sent. Sexual precocity of hypothyroidism is the only form of
precocious puberty where there is growth arrest rather than
growth advancement. There may be other consistent findings
such as autoimmune thyroiditis, increased prolactin and FSH
levels but low or normal LH levels and delayed bone age. Pi-
tuitary may be enlarged and may be misdiagnosed as pituitary
tumor as in this case.
Etiology of Van WykeGrumbach syndrome has been
considerably clarified over the recent years. Van Wyk and
Grumbach postulated that this syndrome resulted from hor-
monal overlap in the negative feedback regulation of pituitary
hormone secretion with over production of TSH and gonado-
tropins (gonadotropins share a common alpha subunit with
TSH).1
Recently, the syndrome has been postulated to arise
from the weak intrinsic FSH activity of extreme TSH eleva-
tion.6
Hyperprolactinemia also may sensitize the ovaries to
the trace amounts of gonadotropins present in the prepuber-
tal children.7
Pituitary hyperplasia may be associated with long standing
hypothyroidism and it is known to regress with treatment.2e6
In the present patient, prior to obtaining thyroid profile, im-
aging was carried out and this case was thought to be macro
adenoma of the pituitary leading to precocious puberty. This
case highlights the importance of detailed history taking and
clinical examination which if omitted may lead to misdiag-
nosis and compel the professionals to go for unnecessary in-
vestigations creating anxiety to the patients and their family.
History of long standing constipation and short stature on
examination were the clues to the diagnosis of hypothyroid-
ism in this case.
Precocious puberty associated with hypothyroidism can be
treated simply with thyroxin replacement. In a child with
precocious puberty, simple investigations such as thyroid
function test and bone age assessment should be considered
before going in for expensive investigations such as cranial
imaging. This is utmost important especially when there is
growth retardation as most of the other causes of precocious
puberty lead to growth acceleration. This will not only cut the
cost of evaluation but also helps in avoiding undue anxiety for
the parents and the children. Awareness about this condition
will aid the professionals to avoid unnecessary investigations
or surgery.
Conflicts of interest
The author has none to declare.
r e f e r e n c e s
1. Van Wyk JJ, Grumbach MM. Syndrome of precocious
menstruation and galactorrhea in juvenile hypothyroidism. An
example of hormonal overlap in pituitary feedback. J Pediatr.
1960;57:416e435.Fig. 1 e Pituitary hyperplasia on MRI.
a p o l l o m e d i c i n e x x x ( 2 0 1 3 ) 1 e32
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Apollo Medicine (2013), http://dx.doi.org/10.1016/j.apme.2013.10.009

4. 2. Eom KS, See-Sung C, Kim JD, Kim JM, Kim TY. Primary
hypothyroidism mimicking a pituitary macro adenoma:
regression after thyroid hormone replacement therapy. Pediatr
Radiol. 2009;39(2):164e167.
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from primary hypothyroidism mimicking macro adenomas. Br
J Neurosurg. 1999;13:138e142.
4. Nicholas WC, Russell WF. Primary hypothyroidism presenting
as a pituitary mass. J Miss State Med Assoc. 2000;41:511e514.
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enlargement in patients with primary hypothyroidism. Endocr
Pract. 2006;12(1):29e34.
6. Leener A, Montanelli L, Durme J, et al. Presence and absence of
follicle-stimulating hormone receptor mutations provide some
insights into spontaneous ovarian hyper stimulation
syndrome physiopathology. J Clin Endocrinol Metab.
2006;91(2):555e562.
7. Copmann TL, Adams WC. Relationship of polycystic ovary
induction to prolactin secretion: prevention of cyst formation
by bromocriptine in the rat. Endocrinology. 1981
Mar;108(3):1095e1097.
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