SUDANESE JOURNAL OF PAEDIATRICS

2021; Vol 21, Issue No. 1

ORIGINAL ARTICLE

Aetiologies and clinical patterns of hypopituitarism in Sudanese children

Samar S. Hassan (1), Renson Mukhwana (2), Salwa Musa (1), Areej A. B. Ibrahim (1), Omer Babiker (3), Mohamed A. Abdullah (4)

(1) Gafaar Ibn Auf Paediatric Tertiary Hospital, Khartoum, Sudan

(2) Gertrude’s Children Hospital, Nairobi, Kenya

(3) Sudan Childhood Diabetes Centre, Khartoum, Sudan

(4) Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan

Correspondence to:

Samar S. Hassan

Gafaar Ibn Auf Paediatric Tertiary Hospital, Khartoum, Sudan.

Email: dr.samar.hassan.80 [at] gmail.com

Received: 18 May 2020 | Accepted: 27 December 2020

How to cite this article:

Hassan SS, Mukhwana R, Abdul Bagi S, Ibrahim AAB, Babiker O, Abdullah MA. Etiologies and clinical patterns of hypopituitarism in Sudanese Children. Sudan J Paediatr. 2021;21(1):53–60.

https://doi.org/10.24911/SJP.106-1588448825

ABSTRACT

There is paucity of reported information regarding aetiology and clinical profile of hypopituitarism from resource-limited countries particularly in populations with high rates of consanguineous marriages. Here, we are reporting the first data on this aspect from Sudan. This is a descriptive, retrospective, hospital-based study, carried out in the two main paediatric endocrinology centres in Sudan (Gafaar Ibn Auf Paediatric Tertiary Hospital and Soba University Hospital, Khartoum) from January 2006 up to December 2014. Patients’ records were reviewed for relevant demographical, clinical, hormonal and radiological data using pretested study forms. The study included 156 patients. One hundred and one patients were males (M: F = 1.8:1). The commonest age groups were adolescents (57.7%). Consanguinity was found in 77.8% of patients overall and 91% of patients with congenital aetiologies. The commonest clinical presentation was short stature (93.5%). Congenital causes (86.5%) were more prevalent than acquired causes (13.5%). There were six family clusters with multiple pituitary hormone deficiencies (MPHD) and three families with isolated growth hormone (GH) deficiency (IGHD). Most of the congenital cases with MPHD were phenotypic for PROP1 gene mutation (77.5% of sporadic cases and 50% of familial cases). Craniopharyngioma was the commonest of the acquired causes (10.2%). GH was the most frequent hormone deficient (89.7%). Abnormal Magnetic resonance imaging brain findings were significantly seen more in MPHD in comparison to IGHD. The genetic forms of hypopituitarism in populations with high rates of consanguineous marriage like Sudan may be higher than those reported internationally. Molecular genetic studies are, therefore, highly recommended.

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KEYWORDS

Multiple pituitary hormone deficiency; Isolated growth hormone deficiency; Hypopituitarism; Children; Sudan.

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INTRODUCTION

Hypopituitarism is a rare condition where there is deficiency of one or more pituitary hormones. The clinical manifestations of hypopituitarism depend upon the cause as well as the type and degree of hormonal insufficiency [1]. Congenital causes can be due to developmental defects or genetic mutations. Acquired causes include brain tumours, head trauma, irradiation and various causes of brain insult such as inflammatory and infiltrative lesions [1-3]. Diagnosis and management could be very challenging and require professional endocrine and multidisciplinary care. Herby, we are reporting the first publication on hypopituitarism from Sudan.

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MATERIALS AND METHODS

This is a descriptive, retrospective, hospital-based study, carried out in the two main paediatric endocrinology centres in Sudan (Gafaar Ibn Auf Paediatric Tertiary Hospital and Soba University Hospital, Khartoum) from January 2006 up to December 2014. Medical records of all patients who were followed up in the above-mentioned centers were reviewed for age, sex, clinical presentation, family history and investigations. Investigations included:

1. Thyroid function test: Measuring thyroid stimulating hormone (TSH) and free T4 using radioimmune assay. A diagnosis of TSH deficiency was made if serum free thyroxine (T4) concentration is subnormal with a low or an inappropriately normal serum TSH concentration.
2. The plasma growth hormone (GH) response to at least two provocative tests in each patient (e.g., insulin tolerance test and clonidine stimulation test); GH levels <10 ng/ml were considered as GH deficiency (GHD). Facilities for measuring insulin-like growth factor-1 are not available in our setting.
3. Cortisol response was determined during an insulin tolerance test. In the presence of hypoglycaemia (<2.6 mmol/dl), failure of the cortisol levels to increase by two folds the baseline, or levels below 500 nmol/dl is considered hypocortisolism.
4. Gonadotroph axis was only investigated in those with delayed puberty. Follicular stimulating hormone (FSH) and luteinising hormone (LH) deficiency was diagnosed based on delayed or absent pubertal development with low serum testosterone or oestradiol levels , and blunted LH/FSH response to gonadotropin releasing hormone (GnRH) stimulation test when triptorelin (decapeptyl) was used in a subcutaneous dose of 0.1 mg. For patients within the period of minipuberty (from 2nd week till 6 months of life) random samples were taken.
5. Prolactin (PRL) function was not done for most of the patients.
6. Posterior pituitary function was tested in patients with polyuria. The diagnosis was made by measurement of an early morning urine sample for osmolality or specific gravity, and a serum sample for serum osmolality. Water deprivation test was carried out in patients with polyuria and equivocal results of their initial workup.
7. Magnetic resonance imaging (MRI) of the brain with pituitary views were reported by two neuro- radiologists.
8. Bone age was done and Greulich and Pyle’s method was used for assessment.
9. Molecular genetic testing, which is highly recommended, was not done due to logistic reasons.

Management included hormonal replacement therapy and follow up regarding the progress of growth and puberty.

Data were analysed using the Statistical Package for Social Sciences version 18. Frequencies and percentages were used as descriptive parameters for data analysis. The Chi square test was used to evaluate the relationship between variables. For all tests, p value < 0.05 was accepted as significant.

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RESULTS

A total of 156 patients were included in the study. One hundred and one patients (64.7%) were males (M: F = 1.8:1). The commonest age group was adolescents (11-18 years) which represented 73.3% of the patients. Out of a large number of tribes in Sudan, the origin of patients came from 31 tribes, with the highest frequency in the mixed tribes (Afro-Arabic) located in Northern Sudan. Consanguinity was found in 112 (71.8%) patients, in whom 143 (91%) had congenital aetiologies.

The commonest presenting symptoms were short stature (93.5%) and delayed puberty (35.3%). Fifteen patients (9.6%) had a history of prolonged neonatal jaundice, thirteen (8.3%) had micropenis and twelve (7.6%) had hypoglycaemia; but only four patients were diagnosed with these symptoms within the neonatal period. In addition to symptoms of pituitary hormonal deficiency, patients with craniopharyngioma presented with symptoms related to mass effect such as visual disturbance and headaches. Regarding height, 55.7% were between -2SD and -5SD, 37.2% of patients were more than -5 SD. There was no significant difference in height or length between patients with multiple pituitary hormone deficiencies (MPHD) and isolated growth hormone deficiency (IGHD). Delayed bone age was seen in 90.4% of patients.

With regards to aetiology, the acquired causes (21 patients, 13.4%) were outweighed by the congenital causes (Table 1). Brain tumours due to craniopharyngioma were the commonest cause. Three (14.3%) patients had nonfunctioning microadenomas, one patient had Langerhans cell histiocytosis and one with Hashimottos thyroiditis had lymphocytic hypophysitis. No patient had a significant history of surgery, radiation or head trauma (Table 1), seventeen (10.9%) patients had MPHD (Table 2) and only 4 patients isolated pituitary hormone deficiency (IPHD). The commonest hormonal deficiencies were GHD, LH and FSH deficiency.

One hundred and thirty-five patients (86.5%) had congenital causes. Seventy-seven (57%) patients had IPHD (69 sporadic and 8 familial) and 58 patients had MPHD, sporadic in 40 patients and familial in 18 (Table 2). There were 6 families with MPHD and 3 with IGHD. Criteria for phenotype were based on the types of hormones deficient and the MRI features. HESX1, OTX2, and SOX2 mutations were considered in cases with septo-optic dysplasia (SOD) where there are two or more features of the classic triad which include hypopituitarism, optic nerve hypoplasia and midline brain defects, typically absence or hypoplasia of the septum pellucidum and/or corpus callosum. Hormonal deficiency ranges from isolated to multiple hormone deficits, with diabetes insipidus (DI) in a minority. PROP1 variance was considered in those with GH, PRL, TSH, LH, FSH and adrenocortical hormone (ACTH) deficiencies and a brain MRI showing small, normal, or enlarged anterior pituitary gland. POU1F1 mutations were considered in those with hormonal deficiency involving GH, PRL, TSH only with a brain MRI showing a normal or hypoplastic anterior pituitary gland. Most of the patients with MPHD (63.8%) were phenotypic for PROP1 mutation and only 3 (5%) were phenotypic for HESX1. Definitely, genotype-phenotype correlation requires genetic testing which was not feasible for this study.

Table 1. Acquired causes of hypopituitarism.

Cause	Frequency	Percent
Brain tumour	19	42.9
Infiltration	1	4.8
Inflammation	1	47.5
Others	0	0
Total	21	100

From a total of 156 patients in this study 46 (29.4%) patients had normal MRI brain images, 70 (44.8%) patients had abnormal MRI images and 40 (25%) patients had no MRI images done for financial reasons. As shown in Table 3, among the 74 patients with IGHD only 44 patients had brain MRI. Twenty-nine patients had normal MRI brain images, while in 15 patients significant MRI findings were found. Those with acquired causes included 2 patients with craniopharyngioma. Congenital causes included 4 (9%) with empty sella, 3 (6.9%) with hypoplastic anterior pituitary gland, 2 (4.5%) atrophied anterior gland, ectopic posterior gland and interrupted stalk; and one (2.3%) patient with agenesis of corpus callosum.

Among the 75 patients with MPHD only 65 patients had an MRI brain image. Twelve (18.5%) had normal brain MRI, while in 53 (1.5%) patients there were significant MRI findings. Those with acquired causes included 12 (18.5%) patients with cranopharyngioma and 3 (4.6%) with microadenoma. Congenital causes included 11 (17%) patients with empty sella, 9 (13.8%) hypoplastic pituitary gland, 3 (4.6%) with atrophied anterior gland, ectopic posterior gland and interrupted stalk; 3 (4.6%) patients with agenesis of corpus callosum, one patient (1.5%) with dermoid cyst, and 9 (13.8%) patients with other findings including brain atrophy, post meningeal infraction and hydrocephalus.

Table 2. Patterns of hormonal deficiency according to the aetiology.

Aetiology	Pattern of hormonal deficiency
	IPHD					MPHD
	GH	TSH	ACTH	FSH/LH	ADH
1/Congenital
Sporadic	64	0	0	2	3	40
Familial	8	0	0	0	0	18
2/Acquired
Craniopharyngioma	2	0	0	1	1	12
Others	0	0	0	0	0	5
Total	81					75

ACTH = Adrenocorticotrophic hormone; ADH = Antidiuretic hormone; FSH = Follicular stimulating hormone; GH = Growth hormone; IPHD = Isolated pituitary hormone deficiency; LH = luteinising hormone; MPHD = Multiple pituitary hormone deficiency; TSH = Thyrotropin stimulating hormone.

Table 3. Brain magnetic resonance image (MRI) findings in patients with multiple pituitary hormone deficiency versus isolated growth hormone deficiency.

MRI brain finings	MPHD		IGHD
1/Normal	12	18.5%	29	65.9%
2/Acquired
Craniopharyngioma	12	18.5%	2	4.5%
Microadenoma	3	4.6%	0	0%
Others	2	3.1%	0	0%
3/Congenital
Empty sella	11	17%	4	9%
hypoplastic pituitary gland	9	13.8%	3	6.9%
Ectopic posterior pituitary absent anterior and pituitary interrupted stalk	3	4.6%	2	4.5%
Agenesis of corpus collosum	3	4.6%	1	2.3%
Dermoid cyst	1	1.5%	0	0%
Others	9	13.8%	3	6.9%
Total	65	100%	44	100%
p value	0.001

MRI, magnetic resonance image; IGHD; isolated growth hormone deficiency; MPHD, multiple pituitary hormone deficiency.

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DISCUSSION

The number of patients diagnosed with hypopituitarism in 8 years’ time, was relatively large, with only a few other similar studies surpassing it [4]. A considerable number of cases in the community are possibly missed or have no access to endocrine services in a large country like Sudan. No population analysis could be conducted to indicate the incidence of hypopituitarism during the same period, but the incidence is expected to be high The immediate explanation is the high rates of consanguineous marriages in the Sudanese population reflected in the percentage of cases with parents of 1st or 2nd degree cousinship (77.8%). Supporting this are the similar results seen in a study conducted in Sauda Arabia; a country with a high rate of consanguinity [5].

Hypopituitarism may present at any age. The commonest age group in our study was the adolescents, mirrored by short stature and delayed puberty being the commonest clinical presentation. Although growth failure in almost all patients started between ages 2-4 years, yet patients presented late to our endocrine services [6]. The small number of patients presenting in the neonatal period, in addition to the small percentage of patients with neonatal hypoglycemia and micropenis, maybe under estimated [7]. This could be explained by the number of patients who die in the neonatal period with an uncertain diagnosis.

The lack of accurate data on the socio-economic status of patients’ families in the records, as well as deficient information on the psychological, social, and educational impact of the disease on each patient and his/her family should be an incentive to conduct a future study on these aspects, taking into account the high rates of poverty and the lack of health insurance to cover the expenses of investigations and treatment. There was no information in patients’ records regarding the mode of delivery and if any patient was breech delivery. In the present study birth weights for patients with GHD were normal as known in the literature [8]. This is similar to the findings of a retrospective study that compared the weight, length and BMI of 44 GHD (M: F= 26:18) children, where GH per se had a minimal effect on intrauterine growth but a significant effect during the infancy period [9].

The incidence of congenital hypopituitarism is estimated between 1/4,000 and 1/10,000 live births [10]. To date, only a few studies investigated the aetiologies of hypopituitarism in children and adolescents. It is reported that the incidence of pituitary tumours is lower in children [11]. Therefore, children and adolescents have completely different aetiologies of hypopituitarism. In the present study, the number of patients with congenital causes outweighed those with acquired causes. Familial cases represented almost 20% of the congenital cases. Again, the high rates of consanguineous marriage may explain the larger magnitude of congenital causes. However, brain masses may be underrepresented because they might have been managed by neurosurgery or adult endocrinology services.

Family clusters with MPHD phenotypic for PROP1mutations were more frequent than other gene mutations such as POU1F1 and HESX1. Most sporadic cases of congenital MPHD were also phenotypic for PROP1 mutations, yet it is expected to find low rates of gene mutations among sporadic cases. A multicenere study screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 MPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1 [12]. The prevalence of PROP1 mutations in unselected sporadic cases of hypopituitarism was lower (1.1%) than in familial cases (29.5%) [12]. PROP1 mutations can be associated with a highly variable phenotype, and both pituitary hypoplasia and pituitary hyperplasia [12]. Taking into consideration the high rates of consanguineous marriage, genotyping will be highly beneficial in a population like Sudan. A multicenter study in both national and international paediatric and adult endocrinology centers (France, Tunisia, Egypt, Argentina, Turkey, Belgium, Lebanon, and Switzerland) screened pituitary transcription factor genes in 195 patients with MPHD. The total prevalence of mutations was 13.3% and 52.4% in 20 patients with familial MPHD history. No mutation of HESX1 was observed in 16 patients harbouring SOD. In 109 patients without extra pituitary abnormalities, 20 had PROP1 mutations, including 8 patients with a family history of MPHD. One POU1F1 gene defect was found in one patient presenting the rare post pubertal association of thyrotroph (TSH deficiency) and somatotroph (GH deficiency) deficits [13].

Craniopharyngioma was the commonest cause of acquired hypopituitarism. Hormonal patterns in almost all patients with craniopharyngioma were MPHD with results fairly similar to a study done by Jenkins et al. [14], where 95% of patients with craniopharyngioma had at least one anterior pituitary hormone deficiency at diagnosis. Among 20 patients with craniopharyngioma 19 had GH and gonadotropin deficiencies at diagnosis, 13 patients had secondary or tertiary hypothyroidism and 10 had ACTH deficiency [14]. Diabetes insipidus (DI) does not usually occur preoperatively [15]. On the other hand, nearly all patients with surgical resection will have at least temporary vasopressin deficiency. The development of further pituitary deficiency depends upon degree of tumour resection. In the present study, finding no patient with history of head trauma, surgery or radiation may be attributed to the deficient information in patients’ records. Another explanation could be that our study did not include patients’ records in radiation and neurosurgery centers. This remains an area of interest for further research.

In the literature, MPHD is more prevalent than IGHD. The estimated prevalence of MPHD and IGHD by the National Institute of Health) is 1 in 8,000 and 1 in 10,000, respectively In our study in total IGHD and MPHD were almost equal, yet there was a slightly higher number of cases with congenital IGHD than congenital MPHD. It is well known that many patients with IGHD may progress to MPHD over years [16], as described in a long term observational study with a mean follow up of more than 15 years [17]. The loss of follow up of some patients in addition to the deficient information in patients’ records were limitations in our study and for these reasons the progression of patients with isolated forms to combined forms of deficiency and the sequencing of hormonal deficiency in our patients was beyond the scope of this study.

In our study, GHD was the commonest hormone deficient followed by TSH, LH, FSH and ACTH deficiencies. A multicenter study done by the GENHYPOPIT network found that among the 748 patients (325 females), 172 had isolated deficiency (n = 139 index cases) and 576 had MPHD (from 472 unrelated families) [18]. Of the 694 pedigrees, 104 were observed as familial cases, 590 were sporadic, and 65 index cases were born from a consanguineous union. Among the 748 patients studied the phenotypes included different combinations of hormonal deficiency affecting GH (70.4% of the whole cohort), TSH (55%), LH/FSH (50.4%) or ACTH (50.5%). Isolated deficiency included 91 GH (IGHD), 64 ACTH, 12 FSH/LH and 5 TSH deficiencies [18]

Significant findings on brain imaging were seen in patients with MPHD more than those with IGHD. Normal MRI brain was found in a number of patients but this doesn’t exclude genetic mutations. It has been reported that structural pituitary abnormalities occur in approximately 50%-70% of patients with congenital forms of GHD [13,19-22]. These abnormalities are more prevalent in patients with MPHD (90%) than in IGHD (20%-50%) [18]. Contrary findings were found in a study by Dutta et al. [23] that described the clinico-radiological correlation in 31 children (23 boys), aged 1-17 year. The patients were divided into two groups those with IGHD and those with MPHD, they measured the degree of severity of GHD in each patient and a value of < 3 ng ml was defined as severe GHD. In conclusion, they observed an almost similar prevalence of imaging abnormalities in IGHD and MPHD groups but they attributed this to the more number of patients with severe GHD (< 3 ngLml) in the IGHD group.

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CONCLUSION

Congenital causes are more common than acquired causes in our region due to high rates of consanguineous marriage. Genetic studies are valuable in congenital hypopituitarism in such areas with a higher probability of detecting novel gene mutations Larger studies are required, and from this point, we call out for the support of genetic testing from centers with interest in MPHD.

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ACKNOWLEDGEMENT

The Authors would like to thank Mr. Hassan for handling statistical analysis.

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CONFLICT OF INTEREST

The authors declare that there is no conflict of interest regarding the publication of this article.

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FUNDING

None.

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ETHICAL APPROVAL

The study was approved, and an ethical clearance was given by the Endocrine Institutional Board Committee and Gafaar Ibn Auf Childrens’ Hospital Research Committee. The study is a retrospective (record-based) study. No names were used for data collection. Participants’ consent is not required according to the approved research guidelines of the committees, and confidentiality was ensured at all levels.

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