Abstract
Chief Complaint and Presenting Problem
L.
History of Present Illness
L. reported that she first experienced depressive symptoms following her fourteenth birthday. She described feeling slow, fatigued, and exhausted. Formerly an A student, her grades declined and her self-esteem dropped. She began working with her school counselor to improve homework completion with little success. She became unable to get out of bed in the morning and missed school. She ceased socializing with friends, became isolated from her parents, and experienced feeling out of control and unable to change the trajectory of her downward trend. She began to fail to maintain basic hygiene and hit herself out of frustration and exasperation.
Approximately 4 months after the onset of these symptoms L. developed suicidal ideation with a plan to jump in front of traffic. She reported this to her counselor who referred her for an emergency psychiatric evaluation. L. was subsequently admitted to a psychiatric inpatient unit where she was treated with fluoxetine and amphetamine salts, which were titrated up to 20 mg and 10 mg, respectively, prior to discharge. As a result, her energy and depressive symptoms improved. She was discharged after two weeks with a diagnosis of major depressive disorder (MDD), with a plan to initiate outpatient mental health services.
After about a month, L. stopped taking amphetamine salts, due to the development of gastrointestinal upset and a fine hand tremor. She continued to take fluoxetine, but often missed doses, and her depressive symptoms once again began to worsen. One day prior to a second admission, her father found her in her room attempting to choke herself by squeezing her throat with her hands. There was sufficient force to leave marks. She claimed that she felt she had no control over any decisions.
L. was admitted to a second inpatient unit where she was started on 5 mg of escitalopram and titrated to a maximum dose of 20 mg. This regimen resulted in moderate improvement in her symptoms. However, she continued to have persistently blunted affect, poor eye contact, delayed response latency, and severe psychomotor retardation. She slept long hours and often missed school and group activities. Her mentation was profoundly slowed to an extent that there was concern for thought blocking.
The inpatient treatment team was concerned that she had developed negative symptoms suggestive of a psychotic process, and augmentation of escitalopram with an antipsychotic was considered. However, L. had no positive signs of psychosis, no indication of paranoid thought content or disorganization of thought process. Additionally, it was noted that L. had persistent mild to moderate hypotension, with systolic blood pressures ranging from the 80 mm Hg to 110 mm Hg, and a mild but persistent tachycardia, with pulse ranging from 90 beats per minute to 120 beats per minute. L. had mild symptoms of hypotension, including lightheadedness on rising, and it was noted that this symptom often increased her tendency to stay in bed. In further exploration of symptoms, she revealed that for many months she had been constipated and defecated once every three days.
To address these symptoms, a full review of L.'s admission laboratory work was repeated. L. was found to have an isolated mild elevation of calcium of 11.3 mg/dL (normal range 8.4 mg/dL to 10.3 mg/dL) and rare calcium oxalate crystals in her urine. Repeat lab work confirmed persistent hypercalcemia (12.4 mg/dL). Phosphorus was in the low range of normal at 3.5 mg/dL (normal range 3.1–5.7 mg/dL). A parathyroid level subsequently returned at double the normal limit at 173 pg/ml (normal range 16—87 pg/ml). Vitamin D was decreased at 13.4 ng/mL (normal range 30—100 ng/mL). Further work-up included a neck ultrasound, which was normal, and a renal ultrasound (to rule out nephrocalcinosis), which showed a small lesion suggestive of calcification or angiomyolipoma, but was otherwise within normal limits. Random urine oxalate was calculated to be 186 mg/g of creatinine (normal 3–40 mg/g of creatinine). Urine calcium-to-creatinine ratio had remained consistently elevated at >0.2 (normal <0.14). Technetium-99m sestamibi scan was performed prior to discharge and showed a small parathyroid adenoma at the inferior pole of the right thyroid lobe.
L. was discharged on escitalopram 20 mg daily, with referral to a partial hospitalization program. She also continued to receive outpatient follow up in pediatric endocrinology and head and neck surgery clinics. She was scheduled for parathyroid exploration and removal of any abnormal glands within two months of discharge.
Past Psychiatric History
L. had no formal psychiatric history prior to her first inpatient admission at age 14 when she was diagnosed with MDD.
Developmental History
L. was the product of an uneventful pregnancy with full prenatal care and no maternal use of alcohol, tobacco, or narcotics. She was born full-term, weighing about 3 kg. Postnatal history was uneventful and she met all her milestones on time, including talking by 12 months and walking by 13 months. Temperament was reported to be shy.
Educational History
L. entered day care at age four years. L. attended mainstream kindergarten and public school. She performed well academically and was consistently at the top of her class. Prior to the onset of symptoms, she had had no attendance difficulties. L. was currently in ninth grade at a highly selective high school. She did well in the first of the half of year, but after the onset of symptoms, her academic performance declined. She started having difficulty completing assignments and, as a result, failed multiple classes.
Social History
L. lived with her parents and an older sister, age 16, in an inner-city neighborhood. Father worked full time at a self-owned company. Mother also worked full-time in the service sector. According to the parents, L. had always been shy and had difficulty making and maintaining friendships. L. reported that she did not have any friends at school.
Pertinent Family History
L.'s sister had also been diagnosed with depression and was reported to have perfectionistic traits. There was no other reported history of psychiatric disorders in the family.
L.'s maternal uncle was noted to have had a history of recurrent kidney stones.
Medical History
L. had no prior history of major medical problems such as asthma, hearing or visual impairments. L. had not experienced any serious physical injuries. She had no allergies. Menarche was at age 12 and she had had regular menses. Growth and development were reported to be normal. On her second inpatient admission, she was at the 60th percentile for height and 19th percentile for weight.
Medication History
L.'s first trial of psychotropic medication began during her first inpatient hospitalization at age 14. She was discharged on 20 mg fluoxetine and 10 mg mixed amphetamine salts. L. took these medications intermittently for approximately two weeks following her discharge and then stopped taking the medication altogether due to the development of gastrointestinal upset and a fine hand tremor.
After her second hospitalization L. was started on escitalopram 5 mg daily, and gradually titrated to 20 mg daily in the morning. At one point her dose was lowered to 5 mg daily for three days for concern that it may have worsened her hypotension. When no effect on blood pressure was observed, the escitalopram was restored to 20 mg daily.
Mental Status Exam
L. was a disheveled-appearing 14-year-old girl. L. had difficulty getting out of bed and preferred to conduct her interview while laying down flat on her back and staring at the ceiling. Her eye contact was poor. She spoke in a soft monotone, and with increased speech latency. Her sentences were short, often monosyllabic “yes” or “no” responses. There was no spontaneous or conversational discourse. She was profoundly psychomotor retarded, with no spontaneous movements and minimal shifting of posture or position throughout the interview. There was minimal if any nonverbal communication.
L. described her mood as “okay,” yet her affect was nearly flat. She was without any reactivity or responsiveness to the interviewer. Her thought process seemed extremely slow, but was void of any evidence of disorganization. There was no evidence of paranoia or referential content. She denied suicidal ideation. Although she was able to intellectually recognize that she had significant symptoms, she appeared to have little understanding of their severity. Her insight and judgment were poor.
Brief Formulation
L. was a 14-year-old adolescent girl referred for treatment of major depressive symptoms. Despite a shy temperament, her early development was generally adaptive, until age 13 when she developed excessive fatigue, a decline in school performance, and low self-esteem.
From a biological perspective, L. may have been rendered vulnerable to mood symptoms by a convergence of a shy temperament, family history of depression, and hypercalcemia. However, it appears that the psychiatric manifestations of depression were of relatively acute onset in her early adolescent years. A family history of renal and affective disorders may imply a genetic contribution to the patient's symptomatology, including multiple endocrine neoplasia types 1 and 2a (MEN1, MEN2a), hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial hypocalciuric hypercalcemia andneonatal severe hyperparathyroidism (FHH/NSHPT), and familial isolated hyperparathyroidism (FIHPT).
From a psychosocial perspective, L. was raised in a household in which academic performance was highly valued. As a result of academic performance being a significant strength and of importance for maintenance of self-esteem, her academic decline left her vulnerable to depressive symptoms.
Multi-Axial Diagnoses
Discussion
The evolution of L.'s course of illness was important in understanding the etiology of her disorder, which represents the convergence of major medical and psychiatric symptomatology. L.'s unusual psychiatric presentation prompted a careful reassessment of her symptoms within a broader medical context, resulting in the discovery of primary hyperparathyroidism, a rare condition in children (prevalence 2–5 in 100,000), with only about 200 cases described in the world literature (Alagaratnam and Kurzawinski 2015).
Despite the rarity of the condition, the child and adolescent psychiatrist can apply the pharmacological decision-making lessons of this case to many. In this case, the initiation of a second-generation antipsychotic was initially considered to address a putative psychotic process. Whereas some of L.'s clinical picture could be understood as negative symptoms, there was a complete absence of positive signs and symptoms, and a significant component in her mental status of fatigue, psychomotor retardation, and slowed thought process in the setting of sustained organized thought that did not completely fit the pattern of negative symptoms. In conjunction with these findings were subtle vital sign abnormalities and, ultimately, the discovered electrolyte and hormonal abnormalities. Given that antipsychotics have particularly deleterious adverse effects in children and adolescence relative to adults (Maayan and Correll 2011; Correll 2005), the decision to review a full differential diagnosis before initiating new treatment was essential.
Primary hyperparathyroidism is exceedingly rare in children and adolescents (Alagaratnam and Kurzawinski 2015). Whereas genetic mutations in the calcium channel gene can precipitate a life-threatening onset of hypercalcemia in neonates, in older children and adolescents the etiology is more diverse. Approximately two thirds of cases are sporadic (65–70%), while the remaining third is familial (27–31%). Oncological processes are exceedingly rare in children, with only several cases reported in the literature (Hamill et al. 2002; Meier et al. 1999), and the usual cause is either an adenoma or hyperplasia of the parathyroid glands. Of the sporadic cases, the majority of causes (67–100%) are a solitary parathyroid adenoma (Alagaratnam and Kurzawinski 2015). In familial cases, multiple adenomas or hyperplasia involving all the parathyroid glands is most common. As noted, familial cases may include mutations in MEN1, MEN2, HPT-JT syndrome, and FIHPT (Alagaratnam and Kurzawinski 2015).
Exceedingly few youth present first with psychiatric manifestations of primary hyperparathyroidism. Whereas fatigue and hypotonia are common at the time of first diagnosis, usually gastrointenstinal complaints, renal stones, or musculoskeletal complaints are the most observed symptoms (Alagaratnam and Kurzawinski 2015). Published case series of these children and adolescents do include the presence of learning difficulties and depression, although these were not as common as the somatic presentations.
Workup includes measurement of serum calcium and parathyroid hormone (PTH), renal function tests, 1,25-hydroxyvitamin D and 25-hydroxyvitamin D levels, bone density scan, and ultrasound of the kidneys (Alagaratnam and Kurzawinski 2015). Imaging of the parathyroid glands via ultrasound and technetium-99 sestamibi parathyroid scan is required to evaluate morphology and guide workup: The presence of multiple adenomas or hyperplasia suggests a familial genetic cause and need for further genetic workup.
Management entails immediate stabilization through hydration, diuretics, and bisphosphonates to reduce serum calcium levels to nondangerous levels. There is currently no long-term conservative management, and surgery is recommended for all children. The surgical procedure, including the number of glands to be removed, depends on the underlying parathyroid pathology and imaging results. When all four glands must be removed, calcium and vitamin D3 supplementation or autotransplantation of parathyroid tissue should be considered, as there is currently no direct PTH replacement therapy available. Following surgery, nearly all patients (95%) will recover without complication.
The case calls to question whether calcium levels should be a part of routine screening in child and adolescent psychiatry: A basic metabolic profile does not always include this ion. It may be that for select individuals such as L. who present with symptoms suggestive of hypercalcemia, child and adolescent psychiatrists should have a lower threshold for ordering this study. The importance of vital sign instability as a signal that a general medical condition may be present should not be overlooked. It is lamented that, in the absence of universal calcium screening, the majority of these cases develop until symptoms, usually somatic, are pronounced: 80% of children and adolescents have symptoms and features of end-organ damage at the time of diagnosis (Alagaratnam and Kurzawinski 2015).
The decision to lower L.'s escitalopram to a quarter of the steady state dose in an evaluation of her hypotension may have been avoided had there be greater awareness of her hypercalcemia. With little association between the selective serotonin reuptake inhibitors and hypotension, this step may have been unnecessary. However, when an untoward sign or symptom occurs in the course of introduction of a new medication, it is reasonable to consider the possibility of an unusual adverse effect until proven otherwise.
Taken together, this interesting case illustrates the value of a nuanced and detailed psychiatric evaluation, which may bring these children and adolescents to curative care prior to the development of severe somatic illness burden.
Footnotes
Acknowledgments
We would like to acknowledge and thank Laura Ibanez Gomez, Mikayla Katz, and Natasha Toralba Kostek for their assistance in review and preparation of the manuscript.
Disclosures
Drs. Rice and Azova have no conflicts of interest or financial ties to disclose. Dr. Coffey has received research support from Eli Lily Pharmaceutical, NIMH, NINDS, Tourette Syndrome Association, Otsuka, Shire, Bristol-Myers, Pfizer, and Boehringer Ingelheim.