Hypothalamic Hamartoma and Multiple Pituitary Hormone Deficiency

Sir, Hypothalamic hamartoma (HH) is a rare intracranial lesion of childhood. According to the position of the lesion, hamartomas are divided into either parahypothalamic or intrahypothalamic variety. Parahypothalamic hamartomas are associated with central precocious puberty (CPP) and intrahypothalamic lesions usually present with gelastic epilepsy, often resistant to antiepileptics. The Delalande[1] classification divides HH into four subtypes (Type I–IV) based upon the position and lateral extension. The characteristic endocrine disorder in HH is CPP, which often occurs within the first 3 years of age.[2] Other rarely reported endocrinopathies include central diabetes insipidus (DI), growth hormone (GH) deficiency,[3] and hypogonadotropic hypogonadism. A combination of hypopituitarism and HH can also be found in Pallister–Hall syndrome (PHS). Here, we present an interesting case of HH who had multiple pituitary hormone deficiency. A 14-year-old boy was presented with short stature and delayed puberty. There was no history of consanguinity and similar illness in the family. The boy had a normal perinatal history and birth weight. He attained all the developmental milestones but in a delayed manner. His short stature was recognized in the last 2 years as he was falling short compared to peers in class. He had no headache or visual disturbances or polyuria/polydipsia. He did not have any behavioral abnormality. His height was 135 cm (<3rd centile and -2.75 standard deviation score), and bone age was 11.5 years (Tanner–Whitehouse III method). The mid-parental height was 168 cm. He had a stretched penile length of 3.5 cm, and both testicular volumes were less than 4 ml. He had absent pubic or axillary hair. There was no polydactyly. Detailed ophthalmologic examination including fundus and oto-rhino-laryngeal examination was normal. Routine biochemical examination was unremarkable, but he had central hypothyroidism [free T4 0.39 (0.89–1.76 ng/dL); thyroid-stimulating hormone1.41 (0.5-5.5 μIU/ml)]. He had a normal cortisol response following 1μg adrenocorticotropic hormone-stimulation test. GH and gonadotropin axis were evaluated after achieving euthyroidism. He had low insulin-like growth factor 1 (<25 ng/mL) [normal 57–241 ng/mL] and clonidine stimulation test (150 mcg/m2) revealed peaked GH level less than 1 ng/mL suggesting severe GH deficiency (GH response more than 7–10 ng/mL is normal[4]). Baseline luteinizing hormone (LH) and follicle-stimulating hormone (FSH) was 0.03 mIU/ml, and 0.09 mIU/ml respectively and testosterone was 3.35 ng/dl. Leuprolide stimulation test showed peak LH response as 0.42 mIU/mL confirming hypogonadotropic hypogonadism (LH level of >5–8 mIU/mL after leuprolide stimulation is considered normal[5]). MRI of the hypothalamic-pituitary area showed a nonenhancing, well-defined lesion measuring 10 × 8 × 9 mm, with the signal intensity of gray matter in all sequences suggestive of HH (T1, T1 post contrast and T2) [Figure 1a-c]. Moreover, MRI showed hypoplastic anterior pituitary and absent posterior pituitary bright spot (PPBS) with normal stalk [Figure 1a].Figure 1: T1W noncontrast (a), T1W postcontrast (b), and T2W noncontrast (c) sagittal images showing a well-defined lesion measuring 10 × 8 × 9 mm in the hypothalamus (white arrows), which follows the signal intensity of gray matter in all sequences. No enhancement of the lesion is noted in the contrast study. The hypoplastic anterior pituitary is seen (black arrow) along with the absent posterior pituitary bright spotThe child had recurrent nonprojectile vomiting after taking food. However, extensive workup including upper gastrointestinal endoscopy, ultrasonography of the abdomen, and awake electroencephalogram was normal. The boy had no features of raised intracranial tension. His vomiting was not controlled initially with domperidone and later, the frequency reduced with addition of ondansetron. Vomiting subsided after 6 months, and currently, he is fine without medication. The exact etiology of vomiting remains inconclusive in this case. A repeat MRI after 1 year showed no change in the HH. Currently, he is on levothyroxine supplementation awaiting GH therapy and pubertal induction with testosterone. HH presenting as short stature and delayed puberty is an exceedingly rare association in a non-PHS patient. PHS is an autosomal dominant disease caused by the pathogenic variation in the GLI3 gene,[6] where HH can be associated with pituitary hormonal deficiency. Other prominent features might include the bifid epiglottis, imperforate anus, postaxial polydactyly, genital, and renal abnormalities. The criteria for PHS index case include both HH and central polydactyly.[7] Several researchers have assessed the endocrine manifestations associated with HH recently. Taylor et al.[8] reported that, among 22 HH patients, 17 patients had CPP as the only endocrine manifestation. In a large series of 193 patients of HH, Harrison et al.[2] found that none had delayed puberty. Similarly, Doddamani et al.[9] found that no patient had pituitary deficiency preoperatively, though four patients had CPP including one PHS. Few reports of pituitary hormonal deficiency in HH had been described. A 17-year-old boy with deafness and behavioural abnormality reported by Martin et al.[10] had hypogonadotropic hypogonadism along with GH deficiency. Contrarily, our patient had no behavioral complications or deafness. Rousseau-Nepton et al. described a patient with HH and CPP, which was treated with gonadotrophic releasing hormone (GnRH) analogue in childhood. This patient was later found to have GH deficiency,[3] confirmed twice at 14 and 18 years of age. Another report[11] described a 14-year-old boy with delayed puberty as the first manifestation of HH. GH axis and pituitary imaging were normal in that case. However, we found hypoplastic pituitary and absent PPBS in MRI pituitary of our patient. Though absent PPBS can be seen in 3-5% of patients after 40 years, its absence in younger patients like ours is unusual.[12,13] Our patient did not have DI then, but a long-term follow up is nevertheless warranted. The development of CPP in HH is explained by several mechanisms: 1) HH acting as GnRH pulse generator or 2) secreting transforming growth factor-alpha[14] and 3) critical contact of HH with the tuber cinereum and the infundibulum.[15] However, the explanation for pituitary hormonal deficiency in HH is incompletely understood. The putative theories are: 1) nonpulsatile GnRH secretion suppressing LH release,[10] 2) anatomical compression at the level of arcuate nucleus decreasing GH releasing hormone (GHRH) secretion and thus causing GH deficiency[3] or 3) unrestrained somatostatin secretion inhibiting releasing hormone secretion from the hypothalamus.[3] In our case, due to its location, the hamartoma has the potential to block the transport of the hypothalamic releasing hormones (GHRH, GnRH, TRH) to the anterior pituitary and to disrupt the intrahypothalamic neuronal connections, resulting in decreased secretion of hypothalamic hormones. HH can be associated with multiple pituitary hormone deficiency without any features of PHS. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.