Indian Journal of Pediatrics, Volume 77—June, 2010 693

Correspondence and Reprint requests : Dr Sriram Krishnamurthy,Assistant Professor, Department of Pediatric Medicine, LadyHardinge Medical College, New Delhi-110001, India.

[DOI-10.1007/s12098-010-0081-6][Received December 24, 2009; Accepted February 4, 2010]

Clinical Brief

Hypothyroidism is a frequently encountered endocrinedisorder. Long standing untreated hypothyroidism rarelyresults in the formation of enlarged multicystic ovaries. Thishas been referred to as the Van Wyk and GrumbachSyndrome.1 Sporadic case reports of this syndrome exist2-6 inliterature; however, due to lack of awareness, inadvertentsurgeries have been performed on the ovaries5, 7 when all theclinical features in this entity could be reversed just bythyroxine supplementation. Here is describe a young girlwith severe hypothyroidism, in whom promptsupplementation with thyroid hormone led to regression ofthe multicystic ovarian enlargement.

REPORT OF CASE

A 15-yr-old girl with a functioning diagnosis of ovariantumors was referred to us for evaluation of cardiomegaly.As a result of a suspicion of ovarian malignancy, she hadbeen advised oophorectomy few days ago. The surgeryhowever, had been deferred due to complaints of dyspneaon exertion and cardiomegaly. On probing, there was ahistory of poor height gain, lethargy, and recurrentinfraumbilical pain abdomen for 5 yr. Breast developmentwas noticed around 9 yr of age. For the last 5 yr, she hadbeen having cyclical bleeding per vaginum every 30 days,lasting 3 to 4 days, with normal flow. She was nowcomplaining of dyspnea on exertion for 2 months. She wasdevelopmentally normal.

Ovarian Tumors with Elevated CA-125 Levels and SevereJuvenile Hypothyroidism: A Need for IncreasedAwarenessSriram Krishnamurthy, Anju Seth, Archana Puri1, Rama Anand2 and Satinder Aneja

Departments of Pediatric Medicine, 1Pediatric Surgery and 2Radiodiagnosis, Lady Hardinge Medical College and associatedKalawati Saran Children’s Hospital, New Delhi, India

ABSTRACT

A 15-yr-old girl presented with bilateral gross ovarian tumors, clinical features of long-standing unrecognizedhypothyroidism and markedly elevated CA-125 levels. Ovarian resection was avoided, as the presentation was consistentwith the Van Wyk and Grumbach syndrome; and the patient was treated with replacement of thyroid hormone. Regressionof the ovarian tumors occurred 6 months after initiation of the treatment. The authors emphasise the need for increasedawareness and screening for hypothyroidism in patients with ovarian tumors, in order to prevent inadvertent operativeinterventions. [Indian J Pediatr 2010; 77 (6) : 693-694] E-mail: drsriramk@yahoo.com

Key words: Ovarian tumors; Hypothyroidism; Thyroid hormone

At admission, she weighed 30 kg; her height was 133cm(<3rd percentile). She had coarse puffy facies with somepallor, dry skin and non-pitting oedematous legs. Thethyroid gland was not enlarged. Tanner Stage was B5 P5.Heart sounds were muffled. Heart rate was 66 per min. Afirm, mobile, ill defined, non tender mass (approximately 7X 9 cm) could be palpated in the inguinal regions, extendingupto the umbilicus. On per rectal examination, the mass wasfelt in the pelvis.

Laboratory investigations showed: Hemoglobin 7.8 g/dL,free T3 0.58 ng/dL (normal value 2.87-4.55), free T4 0.26 ng/dL (0.9-1.4), thyroid stimulating hormone (TSH) 1582.33mIU/mL (0.7-6.4). Mid-cycle follicular stimulating hormone(FSH) was 6.9 IU/L (6-35), luteinizing hormone (LH) was38.7 IU/L (5-60); serum estradiol was markedly elevated[591.2 pg/mL (34-170)]. Thyroid peroxidase antibodies (anti-TPO) were 3205 IU/mL (normal value<40). The peripheralsmear showed macrocytic anaemia. The chestroentgenogram showed cardiomegaly. An echocardiogramdemonstrated global cardiac hypokinesia with a poorejection fraction of 45% and moderate pericardial effusion.Ultrasonogram of the abdomen revealed enlarged ovarieswith multiple cysts (Right ovary, largest cyst 104 × 83 mm,Left ovary, largest cyst 125 × 88 mm) and mild free fluid inthe peritoneal cavity (Fig. 1). Serum CA-125 levels were 186.3U/mL (normal <35 U/mL). Serum α-hCG and α-fetoproteinlevels were normal. The bone age (by Greulich Pyle atlas)was 15 yr. Blood glucose and anti-tissue transglutaminaselevels were normal.

In view of severe juvenile hypothyroidism due toautoimmune thyroiditis, she was prescribed levothyroxine25 µg per day which was gradually increased to 75 µg daily,which led to resolution of the pericardial effusion onechocardiogram after 2 months, while the ejection fractionimproved to 60%. Over the next 3 months, she became

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694 Indian Journal of Pediatrics, Volume 77—June, 2010

biochemically euthyroid; her abdominal pain, oedema anddyspnea settled; the abdominal lumps disappeared. She nowweighs 28 kg. A follow-up ultrasound after 6 months oftherapy showed regression of the ovarian tumors and cysts.The CA-125 levels normalized. She is currently underfollow-up at the pediatric endocrine clinic and doing well.

by the ovarian cysts, decreased clearance of serum CA-125,or stimulation of CA-125 production by pericardial effusion.6

The constellation of symptoms in patients with Van Wykand Grumbach syndrome responds well to thyroid hormonereplacement therapy.2-4, 6 Resolution of ovarian enlargementand cysts may occur, as early as 2 months,2 or even 12months, after treatment initiation.6 Surgery is recommendedonly for complications, such as ovarian torsion or rupture.

In summary, hypothyroidism should be considered in thedifferential diagnosis of all girls presenting with multicysticovarian enlargement. It is imperative that all health careproviders, including pediatric surgeons, gynecologists andpediatricians be aware of this entity, so as to avoidcatastrophic and unnecessary ovarian resections. Watchfulexpectancy is recommended to deal with any potentialcomplications, such as ovarian torsion or rupture.

Contributions: SK, AS, AP and RA; managed the patient. SK;reviewed the literature and drafted the manuscript. AS and SA;critically reviewed the manuscript. All authors approved the finalversion of the manuscript.

Conflict of Interest: None.

Role of Funding Source: None.

REFERENCES

1. Van Wyk JJ, Grumbach MM. Syndrome of precociousmenstruation and galactorrhea in juvenile hypothyroidism: anexample of hormonal overlap in pituitary feedback. J Pediatr1960; 57: 416.

2. Sharma Y, Bajpai A, Mittal S, Kabra M, Menon PS. Ovariancysts in young girls with hypothyroidism: follow-up andeffect of treatment. J Pediatr Endocrinol Metab 2006; 19: 895-900.

3. Campaner AB, Scapinelli A, Machado RO, Dos Santos RE,Beznos GW, Aoki T. Primary hypothyroidism presenting asovarian tumor and precocious puberty in a prepubertal girl.Gynecol Endocrinol 2006; 22: 395-398.

4. Panico A, Lupoli GA, Fonderico F et al. Multiple ovarian cystsin a young girl with severe hypothyroidism. Thyroid 2007; 17:1289-1293.

5. Browne LP, Boswell HB, Crotty EJ, O’Hara SM, BirkemeierKL, Guillerman RP. Van Wyk and Grumbach Syndromerevisited: Imaging and clinical findings in pre-andpostpubertal girls. Pediatr Radiol 2008; 38: 538-542.

6. Hunold A, Alzen G, Wudy SA et al. Ovarian tumor in a 12year old female with severe hypothyroidism: A case of VanWyk and Grumbach syndrome. Pediatr Blood Cancer 2009; 52:677-679.

7. Bhansali A, Shanmugasundar G, Walia R, Santosh R, Dutta P.Acute abdomen and hypothyroidism. BMJ Case Reports 2009[doi:10.1136/bcr.12.2008.1356].

8. Chattopadhyay A, Kumar V, Marulaiah M. Polycystic ovaries,precocious puberty and acquired hypothyroidism: the VanWyk and Grumbach syndrome. J Pediatr Surg 2003; 38: 1390-1392.

9. Anasti JN, Flack MR, Froehlich J, Nelson LM, Nisula BC. Apotential novel mechanism for precocious puberty in juvenilehypothyroidism. J Clin Endocrinol Metab 1995; 80: 276-279.

10. Dobozy O, Csaba G, Hetenyi G. Investigation ofgonadotropin thyrotropin overlapping and hormonalimprinting in the rat testis. Acta Physiol Hung 1985; 66: 169-175.

Fig. 1. Ultrasonogram of the abdomen showing enlarged ovarywith multiple large cystic lesions.

DISCUSSION

In 1960, Van Wyk and Grumbach1 first described asyndrome of enlarged multicystic ovaries and precociouspuberty in juvenile hypothyroidism, with reversion toprepubertal state following thyroxine administration. Sincethen, sporadic reports of juvenile hypothyroidism,precocious puberty and ovarian cysts have been published.2-

6, 8 In some of the reports, inadvertent surgery wasperformed because of the concern about probable malignantnature of the ovarian enlargement5, 7 due to elevated ovariantumor markers (CA-125), lack of recognition ofhypothyroidism as an etiology of multicystic ovarianenlargement, or failure to recognize salient features ofchronic thyroxine deficiency.7

The diagnostic features of the Van Wyk and GrumbachSyndrome are long standing hypothyroidism, elevated TSH(more than 100 mIU/mL) and enlarged multicystic ovaries2,

5-6 Usually, a delayed bone age is expected,3, 5, 7 especiallywith such severe hypothyroidism as in our patient.However, her bone age was normal for age. This could bedue to high serum estradiol levels which promote skeletaland sexual maturation; a phenomenon described earlier.6

While some authors have proposed that this syndromeresults from high levels of TSH affecting FSH receptors,causing gonadal stimulation,9 others have reported ovarianhyperstimulation due to high TSH levels by nuclear thyroidreceptors in the granulosa cells.10

The present case had markedly elevated CA-125 levels.This finding has been described earlier.4, 6 Benign ovarianneoplasms, adnexitis, several disorders of the uterus, liver,gall bladder, pancreas, gastrointestinal tract andhypothyroidism have been recognized as non-malignantcauses of elevated serum CA-125.4 Elevated CA-125 levels inhypothyroidism may be due to increased CA-125 secretion