Linear growth in childhood posterior fossa tumor survivors may be negatively influenced by both endocrine and non-endocrine factors. Non-endocrine factors include radiation-induced direct damage to the vertebral growth plates. Spinal irradiation damages both the epiphyseal plates and the bony matrix. Patients treated with spinal irradiation often manifest stunted spinal growth, which becomes most apparent during puberty [10]. In the year after the diagnosis of medulloblastoma, poor growth may result from ill health and anorexia, though an associated transient GH deficiency is known to occur during or immediately after cranial irradiation. It has been shown that the major factor in poor growth is retardation of spinal growth particularly during periods of accelerated growth [11]. Brauner et al. [12] showed in a prospective study of 16 children, aged 1.7–15 years at the time of treatment, who received cranial (31–42 Gy) and spinal radiation for medulloblastoma or ependymoma. Their growth was compared to that of 11 children given similar doses of cranial radiation only. At the 2-year follow-up, children treated by cranial and spinal radiation had a mean height of −1.46 ± 0.40 SD below the normal mean. In contrast, the children given only cranial radiation had a mean height of −0.15 ± 0.18 SD further supports that poor growth in these children are mainly due to spinal irradiation.

Another cause for the poor growth is GH deficiency. GH is the most sensitive hormone to radiation injury; thus, GH deficiency is the most common endocrinopathy seen in childhood cancer survivors following cranial irradiation. GH deficiency occurs in a dose- and time-related fashion with risk increasing as doses exceed 18 Gy of radiation and the time interval increases from treatment [13]. Shalet has shown that doses as low as >2.9 Gy cause GH deficiency [14]. In survivors of medulloblastoma, young age at treatment was a determinant of GH deficiency in adulthood [15].

In order for a timely recognition of growth retardation in children with posterior fossa tumors, regular monitoring of height and sitting height is essential. After reviewing the child’s growth curves and treatment-related risk factors, GH stimulation testing is indicated in most cases based on documentation of poor growth. Failure of two GH stimulation tests, using two different pharmacologic agents known to increase GH secretion, is required for the diagnosis of GH deficiency. In patients who received irradiation, insulin-induced hypoglycemia may be the most sensitive and reliable pharmacologic test of GH status; however, it may cause serious hypoglycemia-related events and should only be done in experienced centers under close surveillance. IGF-1 and IGF-binding protein 3 (IGF-BP3), which are commonly used as surrogate markers of GH secretion in children assessed for short stature, are not reliable indicators of GH status following cranial irradiation or documented hypothalamo-pituitary injury due to tumoral expansion [16]. For children who prove to be GH deficient, a comprehensive consultation regarding the benefits and risks of GH therapy should be performed prior to the initiation of therapy. Although several studies have reported no evidence of increased risk of tumor recurrence associated with GH therapy [17], there are data showing a small risk of second neoplasms, particularly solid tumors, in childhood cancer survivors treated with GH [18].

Once the risks and benefits have been carefully discussed, GH therapy can be provided to patients with GH deficiency. In a report of 183 childhood cancer survivors treated with GH, higher final height was associated with a younger bone age at the time of initiation of GH and higher doses of GH, while a higher dose of spinal irradiation was negatively associated with final height [19].

Thyroid hormone is important for normal development and metabolism in children and young adults. Survivors of posterior fossa tumors develop hypothyroidism in varying frequency and the etiology depending on the exposure and the dose of radiation. Since both the neck and hypothalamo-pituitary area may have been exposed to radiation, they can develop primary hypothyroidism, central hypothyroidism, or a mixed form of hypothyroidism. The diagnosis of primary hypothyroidism is based on high serum TSH levels and low serum free T4 values, whereas in central and mixed hypothyroidism, low free T4 is accompanied by a normal or modestly elevated TSH. In a study investigating thyroid dysfunction in childhood posterior fossa tumors, hypothyroidism was found in 12/23 patients in the course of treatment, in two patients hormone deficits were diagnosed directly after irradiation, and in ten patients such condition was observed at the end of the whole therapy [20].

Primary hypothyroidism is seen more commonly than central hypothyroidism (38 % and 19 %) in medulloblastoma [21]. In that study, All seven children <5 years developed hypothyroidism, whereas the frequency of hypothyroidism was 60 % and 20 % in children of 5–10 years and >10 years respectively. Furthermore, hypothyroidism was documented in 83 % who had 23Gy + CT, 60 % who had 36Gy + CT, and 20 % who had 36Gy without CT. However, Ricardi et al. [22] have shown that the use of hyperfractionated craniospinal radiotherapy in the treatment of childhood posterior fossa primitive neuroectodermal tumors is associated with a lower risk of developing late thyroid dysfunction. Young age and the use of chemotherapy and conventional doses of radiotherapy are associated with a higher incidence of hypothyroidism. Levothyroxine is indicated for patients with TSH deficiency. Dose should be titrated to maintain normal free T4 levels. Serum TSH should be monitored to assess dosing adequacy and medication compliance.

Because of the exposure of the neck to radiation during craniospinal irradiation, children with posterior fossa tumors are at risk for both benign and malignant thyroid neoplasms [23]. The raised TSH values in association with the radiation damage to the thyroid may be an important factor in carcinogenesis [24]. Thus, treatment with thyroxine to suppress elevated TSH may be appropriate in these patients. Treatment prior to 10 years of age and/or total doses of radiation between 20 and 29 Gy appear to confer the greatest risk for the development of thyroid cancer [23]. The association between radiation dose and thyroid cancer is curvilinear, with risk increasing at low to moderate doses and decreasing at doses >30 Gy due to cell-killing effect [25]. Among patients treated with radiation doses to the thyroid of ≤20 Gy, treatment with alkylating agents appears to increase thyroid cancer risk [26]. The risk of thyroid cancer persists throughout the adult life of at-risk survivors. There are case reports of thyroid carcinoma that developed 7–12 years after irradiation for medulloblastoma [27, 28]. The Children’s Oncology Group (COG) currently recommends annual exam of the thyroid gland via careful palpation. Routine use of screening thyroid ultrasonography in childhood cancer survivors increases detection of small nodules of uncertain clinical significance and may result in unnecessary and excessive invasive procedures. This was illustrated in a study of pediatric Hodgkin lymphoma survivors who underwent routine screening thyroid ultrasonography. Although thyroid nodules were a common finding, only one case of malignant thyroid cancer was detected by ultrasound screening. Another six cases of thyroid cancer developed in the cohort, which were detected after clinical findings prompted further evaluation. All seven patients with thyroid cancer were alive at the time of data analysis [29]. Thus, in survivors of posterior fossa tumors, careful palpation and/or thyroid US annually is recommended. In patients who have suspicious nodules (based on ultrasonographic and clinical features), a fine needle aspiration is required to rule out malignancy. Continuous follow-up with US is needed in those with benign cytology.

Survivors of childhood posterior fossa tumors may have delayed or arrested puberty depending on their age due to hypogonadotropic hypogonadism or gonadal insufficiency. Those who have reached sexual maturity can also develop treatment-related LH/FSH deficiency. Presentation in adult females includes secondary amenorrhea, and in males, loss of libido, erectile dysfunction, and reduced energy or stamina.

Delayed puberty is defined by lack of breast development in girls by 13 years of age and lack of testicular enlargement in boys by 14 years of age. Arrested puberty is nonprogression or lack of completion of puberty that has started. Those who are treated with doses of radiation >30–40 Gy to the hypothalamo-pituitary axis are at risk for deficits of LH and FSH called hypogonadotropic hypogonadism (low serum FSH and LH levels) [30]. In addition, survivors are at risk for primary gonadal dysfunction due to direct damage to the ovaries or testes (in which case serum FSH and LH are elevated and is called hypergonadotropic hypogonadism). Similar to those in hypothyroidism, some patients with gonadal failure may also have partial gonadotropin deficiency which prevents the elevation of gonadotropins and masks gonadal damage. Measurement of inhibin B and antimüllerian hormone (AMH) may be helpful in these circumstances. Cuny et al. [31] measured plasma inhibin B in 34 boys and 22 girls to evaluate the roles of hypothalamo-pituitary and spinal irradiations and chemotherapy in gonadal deficiency after treatment for medulloblastoma or posterior fossa ependymoma. Two boys had partial gonadotropin deficiency, combined with testicular deficiency in one boy. Six boys had increased levels of FSH, indicating tubular deficiency, combined with Leydig cell deficiency in five boys. The seven boys with inhibin B levels <100 ng/mL included the one with combined deficiencies and the six with testicular deficiency. Puberty did not progress in seven girls; three had gonadotropin deficiency, combined with ovarian deficiency in one, and four had increased FSH levels, indicating ovarian deficiency. Inhibin B and AMH levels were low in the girl with combined deficiencies, in the four girls with ovarian deficiency, and in four girls with normal clinical-biological ovarian function, including two who underwent ovarian transposition before irradiation. Thus, it appears that plasma concentrations of inhibin B and AMH are useful means of detecting primary gonad deficiency in patients with no increase in their plasma gonadotropin levels because of radiation-induced gonadotropin deficiency.

The etiology of hypogonadotropic hypogonadism is clearly radiation exposure of brain. However, gonadal failure may result from radiation exposure to gonads and/or damage due to chemotherapy. Ovarian [32] and testicular [33] damage after abdominal irradiation in childhood is known for a long time. This is influenced not only by the total radiation dose but also by the fractionation and time sequence of treatment and the sex and age of the patient. Single doses of 6 Gy are probably 100 % effective in inducing permanent sterility in women of all ages [34]. Brown et al. [35] have shown that after spinal irradiation of 35 Gy, the scattered dose to the ovaries may be as high as 10 Gy, and by the use of skin dose meters, they calculated a cumulative dose of approximately 2.4 Gy to the testes. It has been shown that patients who had had CCNU but no spinal radiotherapy had evidence of primary gonadal damage [35].