Pituitary adenomas are rare in childhood, with an approximate incidence of 0.1 cases per million children, of which around 50% are prolactinomas. The associated clinical signs and symptoms are associated with age, mass effect, hyperprolactinaemia and secondary hormone deficiency. Dopamine agonists are the medical treatment of choice.1 These usually achieve a significant reduction in tumour size, normalisation of prolactin blood levels and gonadal axis recovery in most patients.2
A retrospective review of patients under 21 years diagnosed with prolactin-producing adenoma (prolactinoma) in a tertiary hospital was conducted within the last six years. Patients' clinical, biochemical and radiological characteristics were collected, a genetic study performed and their clinical course assessed after the administration of medical treatment.
A total of nine patients (four males) took part, with a mean age of 15.3 years [11–20] and with mean resting prolactin levels at diagnosis of 1,205.2ng/mL [106.6−3,892]. Mean blood prolactin levels in male patients was 1,818.2ng/mL, while in female patients, it was 714.8ng/mL. MRI revealed a pituitary macroadenoma in all cases, with a mean greatest diameter of 17.6mm [22.5 in males and 13.8 in females]. Four patients (three male) had gonadotropic axis involvement at diagnosis. Two of these also manifested secondary hypothyroidism, requiring hormone replacement therapy.
Its clinical presentation was as follows: secondary amenorrhoea in three females, primary amenorrhoea in one female, short stature in three patients (two males), visual disturbance (inferior hemianopia with central involvement in the left eye) in one male patient, and delayed puberty in another (Table 1).
Clinical, biochemical and radiological characteristics of the sample.
| Case | Age at diagnosis (years) | Gender | Symptoms | PRL (ng/mL) | Lesion size (mm) | Visual disturbance | Involvement of other axes |
|---|---|---|---|---|---|---|---|
| 1 | 11 | F | Secondary amenorrhoea | 406 | 9×11 | Yes | No |
| 2 | 12 | M | Short stature | 875 | 14×11 | No | No |
| 3 | 13 | F | Short stature | 2,673 | 20×24 | No | Gonadotropic, thyroid |
| 4 | 16 | F | Secondary amenorrhoea | 253.1 | 10×9 | No | No |
| 5 | 17 | F | Secondary amenorrhoea | 241.3 | 14×13 | No | No |
| 6 | 15 | M | Short stature | 2,049 | 22×26 | No | Gonadotropic |
| 7 | 20 | M | Visual disturbance | 3,892 | 38×25 | Yes | Gonadotropic |
| 8 | 17 | M | Delayed puberty | 456.9 | 12×10 | No | Gonadotropic, thyroid |
| 9 | 17 | F | Primary amenorrhoea | 106.6 | 10×7 | No | No |
F, female; M, male; PRL, prolactin level.
Physical examination revealed delayed development of secondary sexual characteristics, all of which were in males.
Genetic testing was performed on seven of the subjects using a next-generation sequencing (NGS) panel (Ampliseq custom panel/Ion Torrent™ PGM) of the flanking exonic and intronic regions and 5'UTR regions of nine genes related to pituitary adenomas: MEN1, PRKAR1A, AIP, CDKN1B, GNAS, SDHB, SDHC, SDHD and DICER1. No pathogenic variants were found in five patients. In the other two, a variant of uncertain significance was found: c.34G>A; p.Gly12Ser in heterozygosis in exon 1 of the SDHD gene. Genetic testing of the parents and sister of one of the patients was performed, finding that the mother also had the same variant.3,4 In the other case, no genetic testing of family members was performed. No screening for other tumours was performed at diagnosis.
All patients were treated with cabergoline at a mean weekly dose of 1.44mg [0.5−3mg/week], achieving normal prolactin levels in six subjects. Prolactin levels partially decreased in the other three patients, so their cabergoline dose was progressively adjusted.
In terms of clinical response, all secondary and primary amenorrhoea cases were resolved a few months after starting treatment. At the time of writing, the menstrual cycle of all affected patients is regular. As for patients with short stature, one reached their target height after 4 years, while an adequate growth rate was observed in another after two years of treatment with cabergoline. In the case of the third patient, it is too soon to assess response, as treatment was only initiated six months ago at the time of writing. In the patient with visual disturbance, the normal field of vision was observed in the last eye examination performed three months after treatment was started.
Regarding radiological progression, MRI performed at least 6 months after the start of treatment revealed a progressive decrease in sellar mass in 6 patients. In the rest, diagnosis is recent and no imaging tests have yet been performed.
The finding of the same variant of uncertain significance of the SDHD gene in two patients (c.34G>A; p.Gly12Ser) is striking. Although this variant has been identified in 1% of the chromosomes of cancer patients (pheochromocytoma, paraganglioma), it has also been identified in 1.1% of European–American control chromosomes (in some homozygous individuals) at a frequency of 0.007268, which is approximately 4,652 times the maximum expected allele frequency of a pathogenic variant of SDHD (0.0000016), suggesting that this variant is probably a benign polymorphism. However, since there is insufficient evidence in this regard, these patients should be closely followed up.5–7 In summary, a similar prevalence of prolactinomas in both males and females of paediatric age was found. Prolactinomas should be clinically suspected in any paediatric patient with short stature and/or delayed puberty, and in girls with abnormal menstrual cycles. It seems important to conduct genetic testing in all young patients with pituitary adenomas, in order to identify the risk of developing other tumours and tailor specific follow-up.
FundingThis study did not receive funding of any kind.
