Published on March 11, 2014
Van WykeGrumbach syndrome and pituitary hyperplasia in a six-year-old girl
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: firstname.lastname@example.org. Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e x x x ( 2 0 1 3 ) 1 e3 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
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 Â 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 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. Primary hypothyroidism mimicking a pituitary macro adenoma: regression after thyroid hormone replacement therapy. Pediatr Radiol. 2009;39(2):164e167. 3. Young M, Kattner K, Gupta K. Pituitary hyperplasia resulting 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. 5. Khawaja NM, Taher BM, Barham ME, et al. Pituitary 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. a p o l l o m e d i c i n e x x x ( 2 0 1 3 ) 1 e3 3 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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