Premature Thelarche in an 8-Year-Old Girl Following Prolonged Use of Risperidone

Chief Complaint and Presenting Problem

L. is an 8 ½-year-old Caucasian girl who had been diagnosed with psychotic disorder-not otherwise specified (NOS) referred by her parents for psychiatric evaluation for premature breast development following prolonged use of risperidone.

History of Present Illness

According to parents, L. first reported hearing voices when she was around 5 years old. In the past L. reportedly said that the voices told her to disobey her parents or to not do her homework. Her mother reported that L. also complained of visual hallucinations, comprised of seeing faces of unknown children and adults. L.'s parents became concerned when the voices seemed to increase in frequency, and at the age of 7 ½ years she was evaluated by a child and adolescent psychiatrist who started her on risperidone at a dose of 0.5 mg twice daily.

Nine months after beginning risperidone and 5 months prior to referral, L. began treatment with a new child and adolescent psychiatrist. At that time, the child and adolescent psychiatrist recommended changing the medication in order to prevent side effects of long-term use of antipsychotics; however, L.'s parents were hesitant to make a change at that time since she had been doing well. L. continued on the risperidone until her parents made an emergency appointment with concerns that her breasts were developing prematurely; galactorrhea was notably absent. Re-evaluation was recommended, and L. was admitted for medication stabilization and evaluation of possible adverse effects.

L. had been on the risperidone for about one year at the time of referral. Total dose at the time of admission was 0.5 mg twice daily and 0.75 mg at bedtime. Parents reported at that time that L. had experienced recent symptoms of poor sleep and increased appetite. She also had poor concentration with varying energy levels throughout the day. Mother reported that L.'s mood had been irritable and grouchy; mother noted that the risperidone had previously helped to control her mood, but that effect seemed to be wearing off. At the time of admission she did not exhibit any acute symptoms of depression, mania or hypomania. L. had no history of suicidal or homicidal ideation during this time.

Past Psychiatric History

L. was being treated currently at an outpatient psychiatry facility. She was first evaluated for psychotic symptoms and started on medication at the age of 7 ½ years. Diagnoses included psychotic disorder NOS and generalized anxiety disorder (GAD). After further assessment, the current treatment team determined that L.'s anxiety symptoms were related to her psychosis, and so the diagnosis of GAD was disregarded. Past medication failures included methylphenidate; L. was on a dose of 5 mg twice daily, but the medication was discontinued as she showed an increase in aggressive behaviors as well as sleeplessness. There was no history of prior psychiatric hospitalization.

Developmental History

L. was in the product of a full-term, uncomplicated pregnancy with prolonged labor. According to parents most milestones were achieved at developmentally appropriate times; L. was talking at 8 months, but delayed in walking at 2 years.

Educational History

L. is in second grade in public school. She has never needed special classes or an individualized educational plan. Her school performance was described as good, although mother reports that L.'s grades had been falling in the month prior to admission.

Social History

L. lives with her mother and stepfather, two biological siblings and two step-siblings. L.'s biological father reportedly had drug and alcohol addictions and was absent from her life. L.'s parents denied any history of abuse or neglect. L. has a stable lifestyle with parents who are involved and concerned; her parents did note financial stressors and a somewhat limited support system.

Family History

L.'s family history is significant for bipolar disorder in a paternal aunt and paternal uncle and a maternal and paternal grandparent. Biological father reportedly had drug and alcohol addictions. There is also a family history of schizophrenia in a maternal grandparent.

Medical History

L. had no serious medical problems, hospitalizations, or surgery. Parents denied L. had any history of traumatic brain injury. She had no history of any major childhood illnesses and had received all her appropriate vaccinations.

Mother reported an unclear history of past seizures. L. was evaluated by a neurologist at the age of 7 ½ years, including an MRI and EEG; the workup was reported to be within normal limits. L.‘s growth curve appeared to reflect appropriate height and weight for her age. She was reported to be at Tanner Stage 3, with enlargement of the breasts and areolae but absent secondary mound formation. Pubic hair was reportedly absent. L. had not yet experienced menarche. Acne and other pubertal changes were not apparent. Her only known allergy was to penicillin.

Mental Status Exam

L. was well-developed, well-nourished, and well-groomed. Appearance was notable for breast development consistent with Tanner Stage 3; no other pubertal changes were observed. She was a fully alert cooperative child, oriented to person, place, time, and situation. Psychomotor activity was normal. Speech was normal in pace and clarity. L.'s mood in her own words was “mad,” her affect was restricted and inappropriate to content. Memory was intact. L. had normal thought processing. Thought content was notable for auditory hallucinations; she stated that she had been hearing the voices more often recently. L. described hearing voices inside her head that she did not recognize. She could not understand what the voices were saying, and that they seemed to mumble. L. denied visual hallucinations. L. denied homicidal or suicidal ideation. Assessment of attention and concentration revealed L. was easily distracted. She had limited insight and poor judgment.

Hospital Course

L.'s physical examination was unremarkable with the exception of her premature thelarche, presenting as enlargement of the breasts and areolae but without formation of secondary mounds. Her neurological examination was also within normal limits. Differential diagnosis of her premature breast development included pituitary tumor, precocious puberty, and hyperprolactinemia secondary to risperidone. L. underwent basic laboratory testing (including complete blood count with differential, complete metabolic panel, urinalysis, and urine toxicology screen) and all returned within normal limits. A prolactin level was found to be 16.7 ng/mL (normal range for age is 0–15 ng/mL). L. underwent an MRI of her brain with and without contrast to evaluate the possibility of a pituitary tumor; no micro- or macro- adenoma was identified.

L.'s risperidone was discontinued and she was started on aripiprazole 1 mg daily with no adverse effects. Family medicine was consulted over the phone, and her history, physical examination, and lab work were reviewed. The family physician recommended L. follow up with her primary care doctor on discharge for further investigation of the premature thelarche.

Brief Formulation

In summary, L. is an 8 ½-year-old Caucasian girl who meets diagnostic criteria for psychotic disorder NOS. Notable were reports of auditory hallucinations worsening over the past three years. Given some affective components to L.'s symptoms, an affective disorder, such as schizoaffective disorder, bipolar type, may be considered over time. L. had been taking risperidone for approximately one year prior to referral, and L.'s parents were concerned about premature breast development.

From a biopsychosocial perspective, biological factors were significant. L. had a clear and strong diathesis for a major mood disorder or psychotic illness, given the family history of bipolar disorder on both maternal and paternal pedigrees, substance abuse/addiction, and schizophrenia. There appeared to be no significant medical problems that might contribute to her present symptomatology; MRI, EEG and basic laboratory work was within normal limits. From a psychosocial perspective, L. was raised in a close family environment; although her biological father was absent from her life she appeared to have a healthy attachment to her stepfather. L. appeared to have some strengths, including good academic performance and a supportive family.

Multi-Axial Diagnoses

Discussion

This case represents an interesting finding of premature thelarche in an 8 ½-year-old girl with a diagnosis of psychotic disorder NOS treated with risperidone for approximately one year. At the time of admission L.'s prolactin level was mildly elevated at 16.7 ng/mL (normal range is 0–15 ng/mL). Risperidone is an atypical antipsychotic that demonstrates high affinity for the serotonin 5-HT2A and dopamine D2 receptors (Toren et al. 2004); it has been shown to significantly reduce psychotic symptoms in children (Sikich et al. 2004). Risperidone has several well-known adverse effects, including hyperprolactinemia. In a recent review Caccia (2013) reported an increase in prolactin in 82%–87% of pediatric patients taking risperidone, compared with 3%–7% on placebo; in studies of pediatric patients taking the drug for schizophrenia or autism, 71% of patients developed this effect within the first month, and 30% still had elevated levels after one year (Caccia 2013). In addition, another study reported that of medically healthy 7–17 year olds taking risperidone for an average of 2.9 years, 50% developed hyperprolactinemia (Caccia 2013).

Roke et al. (2012) reviewed the effects of antipsychotic medications on prolactin level and other associated adverse effects in the pediatric population; the study found that long-term use of risperidone (>16 months) in a population of adolescent males resulted in findings of hyperprolactinemia in about half, and may have contributed to sexual dysfunction. Interestingly, of those with risperidone-induced hyperprolactinemia, 46% did not have any prolactin-related adverse effects (Roke et al. 2012). Two long-term studies explored the association between risperidone use and the progression of puberty (Dunbar 2004; Reyes et al. 2006); no effect was noted on the progression of Tanner stages, although follow-up occurred after 1 year, which may not have been sufficient time to draw conclusions (Roke et al. 2009).

Hyperprolactinemia associated with prolactinoma is known to be linked with delayed puberty; however in patients with prolactinoma, prolactin levels are found to be markedly elevated, often in the range of 200 ng/mL or above (Patton and Wolf 1983; Sack et al. 1984; Greenspan et al. 1986; Howlett et al. 1989; Kawano et al. 2000). Roke et al. reported that adverse effects related to hyperprolactinemia, including gynecomastia, galactorrhea, irregular menses, and sexual side effects, were reported by 4.8% of patients included in the review (Roke et al. 2009).

A study by Szarfman et al. (2005) found that long-term use of antipsychotics, including risperidone, has been demonstrated to promote pituitary tumor growth in mice; in the pediatric population, risperidone was noted to have the highest adjusted reported ratio for presence of pituitary tumors.

A potential pituitary micro- or macro-adenoma was considered in L.'s case as part of her differential diagnosis, but L. denied symptoms of headache, double or blurry vision, and her neurological examination was normal. Brain MRI with and without contrast revealed no abnormality in the pituitary or otherwise. Given her only mildly elevated prolactin level, this made a pituitary tumor unlikely.

Another possibility in the differential was that L. was undergoing precocious puberty. A recent study by Cabrera et al. (2014) found the average age of thelarche in contemporary US females was 9.7 years, and the average age of menarche was 12.8 years for non-Hispanic Caucasian girls, with African Americans experiencing menarche 0.6 years earlier. Based on breast enlargement L. was staged at Tanner Stage 3. Mother denied pubic hair development or any other indications of puberty. L. had not undergone menarche. A family medicine practitioner was consulted and suggested that L. follow up with her primary care physician regarding her premature thelarche in lieu of consulting obstetrics and gynecology or endocrinology during her hospitalization.

Having ruled out other likely causes, the working diagnosis of premature thelarche was that it was secondary to risperidone. L. was subsequently started on aripiprazole, which resulted in stabilization of her psychotic symptoms, and discharged to home on aripiprazole 1 mg daily.

Roke et al. suggest that routine, systematic physical examination be performed in pediatric psychiatric patients taking antipsychotics to evaluate potential adverse effects related to hyperprolactinemia in those patients (Roke et al. 2009). In addition, they recommend that prolactin levels be followed in those patients experiencing sexual dysfunction, gynecomastia, galactorrhea, or hypogonadotrophic hypogonadism; if these adverse effects are related to antipsychotic-induced hyperprolactinemia, the dose of the medication may be lowered or the patient can switch to a prolactin-sparing antipsychotic. In the event that the symptoms persist, a dopamine agonist may be added (Correll 2008b). More long-term studies are indicated for antipsychotics in the pediatric population, as adverse effects and their implications are not presently well elucidated or understood.