Brief Clinical Report

Rubinstein-Taybi Syndrome: A Girl With a History ofNeuroblastoma and Premature Thelarche

Kenji Ihara,* Ryuichi Kuromaru, Megumi Takemoto, and Toshiro HaraDepartment of Pediatrics, Faculty of Medicine, Kyushu University, Fukuoka, Japan

A 7-year-old girl with Rubinstein-Taybi syn-drome (RTS) who had a history of neuro-blastoma and premature thelarche is re-ported. The neuroblastoma was detected atage 6 months on a nation-wide neuroblas-toma screening program, surgically re-moved, and took a favorable clinical coursewith minimal therapy. She developed iso-lated breasts at age 6 years, had normalplasma levels of estradiol, follicular-stimulating hormone (FSH), and luteinizinghormone (LH), and showed a FSH-predom-inant pattern on the LH–releasing hormonestimulation test. In view of these findings,she was diagnosed to have premature the-larche. Premature thelarche may not be un-common in girls with RTS. Am. J. Med.Genet. 83:365–366, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: Rubinstein-Taybi syndrome;neuroblastoma; prematurethelarche

INTRODUCTIONRubinstein-Taybi syndrome (RTS) is a multiple con-

genital anomaly syndrome with a characteristic face,broad thumbs and great toes, short stature, and mentalretardation as the main clinical manifestations [Rubin-stein and Taybi, 1963]. Miller and Rubinstein [1995]reviewed 724 individuals with the syndrome, andfound 17 malignant tumors and 19 benign tumorsamong them. Twelve of the 17 malignancies were tu-mors of the nervous system, including two instances ofneuroblastoma. Precocious puberty and/or early devel-opment of breasts have not received much attention inreports of patients with RTS. There have been two re-ports on these associations: Stevens et al. [1990] re-ported on a girl with precocious puberty among 50 RTSpatients, and Kurosawa et al. [1993] described, in aseries of 16 RTS patients, a girl with precocious pu-

berty and two other girls with early breast develop-ment.

We report here on a 7-year-old girl with RTS and ahistory of neuroblastoma detected in infancy through anation-wide neuroblastoma-screening program, andpremature thelarche at age 6 years.

CLINICAL REPORT

The patient, a 7-year-old Japanese girl, is the secondchild of a nonconsanguineous couple. Her elder sister isnormal. The patient was born at term weighing 2,926g, and was tube fed during the neonatal period becauseof feeding difficulties. Developmental milestones weredelayed; she walked without support at age 2 1/2 years,and spoke meaningful words at 3 years.

At age 6 months, urinary assay of vanillylmandelicacid (VMA) and homovanillic acid (HVA), carried out incompliance with a nation-wide neuroblastoma-screen-ing program, was positive. VMA and HVA levels in theurine measured on three separate occasions increasedfrom 18.1 mg/mg to 24.3 mg/mg creatinine and 20.5 mg/mg to 25.0 mg/mg creatinine (normal levels, less than15 mg/mg creatinine), respectively. Serum catechol-amine levels were: adrenaline, 24 pg/ml (normal, lessthan 120 pg/ml); noradrenaline, 896 pg/ml (normal, 40to 550 pg/ml); and dopamine, less than 200 pg/ml (nor-mal, less than 700 pg/ml). Serum neuron-specific eno-lase was 15.0 ng/ml (normal, 6.5 to 16.0 ng/ml). Ab-dominal echogram and computed tomography demon-strated a 3 × 2.5 cm tumor in the left retroperitoneum.Then, stage I neuroblastoma was completely removed.N-myc was not amplified in the tumor tissues. Chro-mosomes in the tumor cells were not analyzed. A3-month course of chemotherapy (300 mg/m2 vincris-tine and 1.5 mg/m2 cyclophosphamide) was done andshe was followed-up for 6 years, during which no signsof relapse of the tumor were noted.

Enlarged breasts were noted at age 6 years. Whenre-examined at age 6 11/12 years, she measured 108.2cm (−2.1 SD), weighed 20.3 kg (−0.5 SD), and had ahead circumference of 47 cm (−2.5 SD). She had broadthumbs and great toes, downward-slanted palpebralfissures, hypoplastic maxillae, and a beaked nose. Herbreasts were at Tanner stage 2 (Fig. 1). She had nei-ther pubic hair, axillary hair, nor any signs of estrogenstimulation of the vagina. Endocrinological examina-tion showed normal plasma levels of estradiol, follicu-

*Correspondence to: Kenji Ihara, M.D., Ph.D., Department ofPediatrics, Faculty of Medicine, Kyushu University, 3-1-1 Maida-shi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: k-ihara@mailserver.med.kyushu-u.ac.jp

Received 5 March 1998; Accepted 25 September 1998

American Journal of Medical Genetics 83:365–366 (1999)

© 1999 Wiley-Liss, Inc.

lar-stimulating hormone (FSH), luteinizing hormone(LH), and human chorionic gonadotropin-b subunit(HCG-b).

At age 7 1/2 years, she measured 112.8 cm (−1.8 SD),and weighed 22.8 kg (−0.2 SD). Tanner’s pubertal stagewas P1B3. Her bone age was 5 years. Magnetic reso-nance imaging examination of the brain and imagingstudies of the abdominal organs detected no neoplasiathat might have induced enlarged breasts. Bilateralovarian microcysts were noted. LH-releasing hormone(RH) loading test resulted in a marked increase of FSH(16.1 U) 120 min after loading, and a slight increase ofLH (1.14 U) 30 min after loading. Plasma levels of thy-roid hormones were normal. Various growth hormoneexcretion tests were normal. High-resolution–bandedchromosomes on her peripheral blood lymphocyteswere 46,XX.

DISCUSSION

The 7-year-old girl we describe here had clinicalmanifestations of RTS and a history of stage I neuro-blastoma that was detected at age 6 months through anational neuroblastoma-screening program, and surgi-cally removed without relapse. Miller and Rubinstein[1995] quoted two instances of neuroblastoma among724 RTS patients. The two patients were a 3-year-oldboy with neuroblastoma in the thorax [Siraganian etal., 1989] and a male infant with congenital, wide-spread (stage IV-S) neuroblastoma that regressedspontaneously [D’Cruz et al., 1993]. Neuroblastomarepresents at least two distinct clinical biologic entities[Brodeur and Castleberry, 1997]. One type, probablycongenital, is associated with young age and early

stage at diagnosis (with an exception of stage IV-S),more mature catecholamine synthesis and excretion,and excellent clinical outcome despite no or minimumtherapy. The second type, unfavorable neuroblastoma,presents at older age, generally with advanced stages,less mature catecholamine synthesis and excretion,and poor outcome. The girl we describe and the boyreported by D’Cruz et al. [1993] both belong to the fa-vorable category, whereas the other boy by Siraganianet al. [1989] belongs to the unfavorable group. In viewof these findings, it is of interest to look for malforma-tion syndromes that predispose to neoplasia amongindividuals who are found to have neuroblastomathrough a neuroblastoma screening, most of whom maybelong to the favorable category [Woods et al., 1996].

Our patient also had isolated breast development atage 6 years, normal plasma levels of estradiol, FSH,and LH, and an FSH-predominant response patternupon LH-RH stimulation [Stanhope and Brook, 1989],no estrogen effects on vaginal smears, retarded boneage, and accelerated linear growth. These findings in-dicate that she had premature thelarche, a conditionwith isolated development of the breast before 8 yearsof age without other evidence of precocious puberty.There was no sign of neoplasia that may have causedher breast development. Stevens et al. [1990] reportedthat one girl of 50 patients with RTS showed precociouspuberty. In a series of six boys and ten girls with RTS,Kurosawa et al. [1993] described a 16-year-old girl whohad precocious puberty at age 2 years, and two girlswho developed breasts at ages 1 year and 2 years, re-spectively. Therefore, early breast development maynot be uncommon in girls with RTS. Thus, furtherstudies are needed in RTS patients to learn of the fre-quency and clinical course of premature thelarche, aswell as related disorders.

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Fig. 1. The patient at age 6 1/2 years with early breast enlargementand broad thumbs.

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