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

Case Report

Van WykeGrumbach syndrome and pituitaryhyperplasia 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. Therewas 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

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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-

tuitarymay be enlarged andmay bemisdiagnosed 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 precociousmenstruation and galactorrhea in juvenile hypothyroidism. Anexample of hormonal overlap in pituitary feedback. J Pediatr.1960;57:416e435.Fig. 1 e Pituitary hyperplasia on MRI.

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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

2. Eom KS, See-Sung C, Kim JD, Kim JM, Kim TY. Primaryhypothyroidism mimicking a pituitary macro adenoma:regression after thyroid hormone replacement therapy. PediatrRadiol. 2009;39(2):164e167.

3. Young M, Kattner K, Gupta K. Pituitary hyperplasia resultingfrom primary hypothyroidism mimicking macro adenomas. BrJ Neurosurg. 1999;13:138e142.

4. Nicholas WC, Russell WF. Primary hypothyroidism presentingas a pituitary mass. J Miss State Med Assoc. 2000;41:511e514.

5. Khawaja NM, Taher BM, Barham ME, et al. Pituitaryenlargement in patients with primary hypothyroidism. EndocrPract. 2006;12(1):29e34.

6. Leener A, Montanelli L, Durme J, et al. Presence and absence offollicle-stimulating hormone receptor mutations provide someinsights into spontaneous ovarian hyper stimulationsyndrome physiopathology. J Clin Endocrinol Metab.2006;91(2):555e562.

7. Copmann TL, Adams WC. Relationship of polycystic ovaryinduction to prolactin secretion: prevention of cyst formationby bromocriptine in the rat. Endocrinology. 1981Mar;108(3):1095e1097.

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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

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