SUDANESE JOURNAL OF PAEDIATRICS

2023; Vol 23, Issue No. 2

ORIGINAL ARTICLE

Central precocious puberty in Sudan: 10 years’ experience of paediatric endocrinology centres

Olivia A. Al-Hassan (1), Mary S. Limbe (2), Justin Warner (3), Salwa A. Musa (4,5) , Mohamed A. Abdullah (5,6)

(1) Department of Paediatric Endocrinology and Diabetes, Aladan Hospital, Kuwait

(2) Department of Paediatric, Aga Khan University, Nairobi, Kenya

(3) Department of Paediatric Endocrinology, Noah’s Ark Children’s Hospital for Wales, Cardiff, United Kingdom

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

(5) Department of Paediatric Endocrinology and Diabetes, Gafaar Ibnauf Children’s Hospital, Khartoum, Sudan

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

Correspondence to:

Olivia A. Al-Hassan

Sudan Childhood Diabetes Center, Khartoum, Sudan.

Email: olivoniy [at] gmail.com

Received: 08 May 2022 | Accepted: 13 September 2023

How to cite this article:

Al-Hassan OA, Limbe MS, Warner J, Musa SA, Abdullah MA. Central precocious puberty in Sudan: 10 years’ experience of paediatric endocrinology centres. Sudan J Paediatr. 2023;23(2):145–152.

https://doi.org/10.24911/SJP.106-1652031727

ABSTRACT

Central precocious puberty (CPP) is frequently seen among cases presenting to our endocrine clinics. The purpose of this study was to have base line data on this condition with an attempt to point out any possible unique features of Sudan and to explore challenges faced in management and how that cultural and traditional practices may hamper care. Here, we are reporting the first data on this aspect from Sudanese subjects. Patients labelled as having CPP in Gafaar Ibnauf Children’s Hospital and Soba University Hospital Endocrinology Clinics from January 2006 to 2016 are included in a descriptive hospital-based study which was conducted over 10 years in these two main paediatric endocrinology centres. Records of all patients with CPP were reviewed and challenges in diagnosis and management were identified. Most of the children with CPP presented late. Organic causes were more frequent among girls than what has been reported in the literature; in most boys, it was idiopathic. Almost half of the patients with underlying pathology were older than 6 years of age. Most cases including girls have an organic cause, thus magnetic resonance image should be done in all patients. Management of precocious puberty in a resource-limited country is faced with various challenges (e.g., expensive investigations and medications). We suggest establishing a unified protocol for managing these cases and creating collaboration between governmental, nongovernmental organisations and health services.

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KEYWORDS

Central precocious puberty; Gonadotropin-dependent precocious puberty; Paediatrics; Sudan.

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INTRODUCTION

Precocious puberty (PP) has been defined as puberty that appears earlier than expected. This has traditionally been considered to be 8 years in girls, although USA guidelines have recommended that puberty could be considered precocious only with the appearance of breast development or pubic hair before the age of 7 years in white girls and 6 years in black girls. In boys, the onset of puberty before the age of 9 years is considered to be precocious [1,2].

PP can be classified into central precocious puberty (CPP), peripheral PP (PPP) and incomplete PP (IPP) which is considered a variation of normal puberty with only non-progressive isolated signs of puberty [2,3].

This study focused on CPP which is caused by early maturation of the hypothalamic-pituitary-gonadal axis. CPP usually starts with breast development in girls and testicular enlargement in boys. These occur in addition to elevated gonadotropin levels and accelerated linear growth in both sexes. It has an estimated incidence of 1:5,000–1:10,000 and it is 10 times more common in girls than boys [4–6]. It is either idiopathic or due to pathological conditions, most notably the central nervous system (CNS) related abnormalities [4].

CPP is an important condition with different frequencies and aetiologies among various racial and ethnic groups. There is a paucity of data on PP in developing countries and up to now, no research on this condition has been carried out in Sudan.

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MATERIALS AND METHODS

This retrospective study was carried out during the period from January 2006 to 2016, in two hospitals in Sudan (Gafaar Ibnauf Children’s Hospital and Soba University Hospital, Khartoum, Sudan). These are the only hospitals with established paediatric endocrinology services in Sudan. They serve children from the whole Sudan and receive patients from government and private hospitals, clinics and self-referrals. The average number of patients seen in both clinics/week is 40–50 endocrine patients. Both clinics are run by the same endocrinology team on different days. Medical records of all Sudanese children registered in the two endocrine clinics during the period of the study, with a diagnosis of CPP were revised. The diagnosis was made based on the unit’s protocol which is: breast enlargement in girls before 8 years or testicular enlargement in boys before 9 years. This was supported by either high basal serum luteinizing hormone (LH) >3 IU/l or 30–45 minutes post-stimulation LH level of >7 IU/l or 2–3 times the basal level or LH to follicular stimulating hormone (FSH) ratio >1, using a subcutaneous (SC) dose of 0.1 mg LH-releasing hormone (LHRH) stimulation test. On some occasions, we performed standard LHRH stimulation with basal FSH, and LH followed by intravenous (IV) LHRH 0.1 mg, then samples were taken at 0, 30, 60 and 120 minutes [7]. Patients not fitting those criteria, or with incomplete records were excluded.

The following data were documented: age at onset and diagnosis, gender, presenting complaints, significant medical or family history, parents’ age at puberty, socioeconomic status and any treatment before referral. Others include anthropometric measurements, growth velocity and Tanner staging according to Tanner and Marshal. Investigations results of hormonal tests whether basal or post-stimulation, diagnostic imaging, the underlying cause if possible and management.

Data were analysed using the Statistical Package for Social Science (11.5). Data were used to calculate means, standard deviations, medians, ranges and percentiles. A one-tailed p-value of ≤0.05 was considered statistically significant.

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RESULTS

A total of 142 patients were presented to our centres for evaluation of PP between January 2006 and 2016. Seventy-four patients (52.1%) were diagnosed with IPP (56 as premature thelarche, 12 premature adrenarche and 6 cases as premature menarche). Six patients had PPP, and 62 patients had CPP. Of those who had CPP, nine cases were excluded (two patients with PP caused by long-standing primary hypothyroidism, and seven because of incomplete records). Fifty-three patients (37.3%) were enrolled in the study.

The majority of patients with CPP (73.6%) were girls and the female-to-male ratio was 2.8:1.

Most cases (30/53, 56.6%) were residing in Khartoum State. Twenty-eight patients (52.8%) were referred by medical practitioners to our services, two (3.8%) cases were under follow-up in our unit for congenital adrenal hyperplasia (CAH), and the rest were self-reported.

Three (5.7%) patients tried traditional and religious management before consultation as the cause was thought to be spiritual, caused by possession, or the evil eye. They used Rugya (reciting versis from the Quran to heal or alleviate the damage). There was no ethnic difference in case distribution. The mean age of onset was 4.92 ± 2.49 years, ranging between 0.08 and 8 years of age. It was noted that there was a long time lapse between the onset of signs of puberty and seeking medical help and diagnosis evident by a mean duration of 1.4 years (range 0.08–7.00 years). Ten boys (71%) and 16 girls (41%) started their puberty before 6 years of age. The commonest reasons for seeking medical help for girls were breast enlargement (100%); pubarche in 21 girls and menarche in 13 girls who represent (53.85%) and (33.33%) of cases, respectively (Table 1). For boys, they were pubarche in 13 of them (92.86%) and/or genital enlargement in 10 cases (71.43%).

Regarding patients’ past medical history, five cases (10%) were born small for a date, 10 children (20%) had developmental delay, 2 (4%) had epilepsy and another 2 (4%) had a history of convulsions with fever.

As an indicator of the pubertal degree of progression, Tanner staging according to Tanner and Marshal showed that 28 females (72%) were at B3, while 8 (57%) of males were at G3 at presentation. The mean bone age at diagnosis was 8.80 years.

Diagnosis of CPP was confirmed by assessing gonadotropin basal and post-stimulation levels. Basal LH was pubertal (>3 IU/l) in only 14 (28%) of patients, while 30–40 minutes poststimulation LH level was diagnostic (>7 IU/l) in all patients (100%) with a p-value of 0.003.

Ultrasound was done for 27 out of 39 girls (69.2%) and it revealed pubertal uterine features in 13 out of the 27 girls, enlarged ovaries in 3 and no ovarian cyst was found in any of the girls scanned. Ultrasound testis was done for a single boy with CAH and enlarged nodular testis to confirm testicular enlargement and to exclude adrenal rests and malignancies.

Brain magnetic resonance image (MRI) was requested for all patients except for five cases (9.4%) who developed CPP as a consequence of long-standing CAH. Thirty six (75%) out of 48 children for whom it was requested (25 girls and 11 boys) were able to do it while the rest could not afford the cost. It was normal in 21 patients (58.3%), and they were categorised as idiopathic CPP (ICPP), two boys had a history of epilepsy and one girl with a history of developmental delay.

Of those who underwent brain imaging, 3 (27%) of boys and 12 (48%) of girls had pathological findings on MRI. We noticed that almost 6 (50%) of girls with pathological CPP were 6 years of age or older. The details of the abnormal MRI findings in our cases are listed in Table 2.

Table 1. The main characteristics of the patients at presentation.

Presenting complaint	Gender				Total
Female		Male
Breast enlargement	39	100%	-	-	39
Menarche	13	33.33%	-	-	13
Adrenarche	21	53.85%	13	92.86%	34
Genital enlargement	-	-	10	71.43%	10
Accelerated growth	27	69.23%	11	78.57%	38

Medical treatment was indicated in 50 (94.3%) of patients, except for 2 (3.8%) patients, as they were of borderline age, and did not show any underlying pathology, rapid progress in puberty, bone age advancement or psychological stress; but they were followed up closely. The child with craniopharyngioma was referred for surgery, but unfortunately, she died soon after surgery due to postoperative complications. In 7 (19%) of girls, there was pressure from parents for early treatment even if the bone age was not advanced because of sociocultural reasons.

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DISCUSSION

PP is not an uncommon disorder with a majority of cases due to CPP. It constitutes 6.2% of the 2,300 endocrine cases seen in our clinics, and almost 43.7% of these cases had CPP. Most of the patients were from the capital Khartoum due to the easier access to medical services. Thus, the numbers picked in this cohort might not be a true reflection of the prevalence of this condition. The frequency of various types of PP varies from one population to another, but generally, CPP is more common compared to PPP [8].

Few studies have looked at the sex distribution of CPP, with conflicting results. It is, however, estimated to affect 1 in 5,000–10,000 girls and to be less common in boys [9]. The female-to-male ratio is about 20:1 with debatable ranges from 3:1 to 23:1 [10,11]. Our study found that the numbers of girls outweigh those seen in boys with a ratio of 2.8:1.

Various studies highlighted that a tendency to an earlier age of pubertal onset should be considered. A Korean study concluded that CPP is seen more frequently in girls, especially those older than 6 years of age [12]. In the USA, it was well observed that African American girls tend to experience earlier pubertal onset, and as a consequence, American guidelines considered puberty which starts before age 7 in white girls and before age 6 in black girls as precocious [1,2]. A similar observation was noted in a study from Saudi Arabia where the mean age at attainment of puberty was earlier compared to some other populations which may support the secular trend [13,14].

Table 2. Abnormal MRI findings in our 15 cases with PCPP.

Category	Female 12	Male 3	Comments	Percentage
Space occupying lesion	Microadenoma	4	-	The hormonal evaluation was normal except for gonadotropin	26.6%
	Hamartoma	3	2	-	33.3%
	Craniopharyngioma	1	-	-	6.7%
	Neurofibromatosis	1	-	Pathology was not specified	6.7%
Hydrocephalus		1	1	One was shunted and the other was not	13.3%
Encephalitis		1	-	-	6.7%
Vasculitis		1	0	With residual neurological deficit	6.7%

In this study, 23 (59%) of girls were found to have puberty onset at an age equal to or more than 6 years. For those with no underlying pathology, it is not clear if this should be considered precocious or part of secular trends seen in different areas of the world.

There was a delay in seeking medical help by some parents as they believed the problem would vanish spontaneously or it was spiritual and therefore they tried traditional and spiritual management.

Sex incidence of idiopathic versus pathological CPP varies widely among studies. The ICPP outweighs the PCPP in females where it reached 80%–90% in some studies, while in ours, only 52% of girls were found to have ICPP. This could be explained by the fact that some families are less concerned about early puberty in their girls, especially if they are not extremely young, or there are no associated annoying symptoms such as headaches. Most studies documented the frequency of PCPP to ICPP of 1:10 after the age of 6 years. It was reported to be organic in 19.9% of girls aged 0–3.9 years, reducing to 7.4% in girls aged 7–7.9 years [1]. In this series, it was found that almost 50% of girls with neurogenic CPP were 6 years of age or older. This is contrary to the widely accepted concept that organic causes are more common in younger girls with CPP [1]. In boys, over 50% have an identifiable aetiology for CPP with the neurologic causes being twice as common as idiopathic [12,13]. This is contrary to our findings where ICPP was found to be the aetiology in eight (72.3%) of boys. The higher percentage of boys with ICPP might reflect either racial or geographical differences or indicate that the number of males with ICPP is increasing over time [15].

Diagnosis of CPP is complicated in areas with low facilities due to high-cost investigations. Gonadotrophin-releasing hormone (GnRH) stimulation test is considered the gold standard confirmatory test. It requires obtaining multiple blood samples at different intervals (0, 15, 30, 45, 60, 90 and 120 minutes). This makes the test time-consuming, uncomfortable for patients, and expensive (in Sudan patients have to pay 30–33 USD/sample in addition to the cost of the LHRH injection).

Several studies were conducted to evaluate the best suitable method for performing GnRH stimulation by comparing peak LH levels at different times during the test. A Korean study suggested that a single LH assessment at 30 minutes was reliable [16]. Another study concluded that LH values >5 IU/l at both 40 and 45 minutes post-GnRH stimulation have shown 98% sensitivity and 100% specificity which seems to be more cost-effective in our setting [17]. Basal or GnRH-stimulated FSH is not useful in the diagnosis of CPP or in differentiating it from premature thelarche, especially in the grey zone of puberty, as it can be high in both conditions [17,18]. In our study, we found that basal gonadotropin level was elevated in only 15 (28%) of cases, while pubertal LH level was detected in almost all cases 30–40 minutes post-GnRH stimulation. Given the limited resources, supportive literature, and our results, we proposed skipping the basal LH level and taking only a blood sample 40 minutes poststimulation as this would be adequate for diagnosis, save time, and alleviate the cost.

Brain MRI is usually indicated to exclude neurological pathology in patients who meet the following criteria; girls younger than 6 years at onset, all boys and any child with associated neurological features [1,19]. Performing CNS imaging in girls 6 years of age or older with CPP remains dialectical due to the low prevalence of CNS lesions, yet an appreciated proportion of CNS lesions in girls 6–8 years of age with CPP was reported in some studies and should not be ignored [1].

As we have more cases of PCPP in girls in this series with considerable numbers in those 6 years of age and older, we recommended performing an MRI on all girls with CPP regardless of their age.

In this study, microadenomas were detected in four girls, two of them aged >6 years. Its clinical significance is controversial; however, pituitary FSH-secreting adenomas were reportedly associated with CPP [9,20]. Thus, the Endocrine Society guidelines recommended hormonal evaluation and periodic follow-up for all patients with pituitary micro-adenoma as data on long-term outcomes are lacking in paediatric population [21].

The management of CPP is challenging, several types of depot GnRH agonists (GnRH-a) are available worldwide, but our choice of formulation depends on local availability and affordability. We generally use monthly SC Gozerelin (Zoladex) 3.6 mg, or recently monthly IM Triptorelin (decapeptyl) 7.35 mg. Recent studies have shown that the three monthly leuprolide injections give similar results to the monthly one. Though it is not available locally, this alternative is prescribed to patients who can outsource it. This option was noticed to improve the patient’s compliance and quality of life in different series including ours [22].

Investigations and treatment cost poses a major challenge in the diagnosis and management of patients with CPP in Sudan. Most families have no health insurance and were found to be of low-moderate socioeconomic status (monthly income < 30$ or 100–500$, respectively, based on World Bank criteria 2015). The medications were not fully covered by the government as only 10 patients (19%) received Gozerelin (Zoladex) injections provided by the Khartoum Oncology Hospital with great interruption of the supply while 20 patients (38%) received donations. At the time of study conduction, the cost of a monthly injection was 233$, in contrast to 400$ for the three-monthly formula. The duration of GnRH-a management is usually individualised and it is proposed to be discontinued by the age of 10.6–12 years, with a mean bone age ranging from 12.1 to 13.9 years [23]. The need for this expensive drug for a long duration has resulted in interruption or discontinuation of treatment by some of our patients. Consequently, 7 patients never started treatment, 6 patients discontinued treatment, and out of 11 patients who completed treatment, 3 received the medication interruptedly, due to unaffordable medication costs. At the time of the study, 25 patients were still on treatment, with 3 of them receiving medication irregularly. Currently, the Sudan Society for Paediatric Endocrinology helped these patients by raising funds and has successfully convinced the government to secure these injections free of charge.

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CONCLUSION

CPP is not an uncommon endocrine problem in Sudan. Most cases including girls have an organic cause, thus MRI should be done in all patients. LHRH stimulation test with a collection of one sample after 40 minutes of SC or IV injection is a cost-effective method. The three monthly LHRH analogue injections are cheaper and more convenient and, therefore, should be secured. Investigations and treatment of these cases are expensive and beyond the capability of most patients and therefore should be supported by the government. Further studies with larger numbers and from other parts of Sudan are needed.

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ACKNOWLEDGEMENTS

The authors would like to thank the managers and the medical records staff in all paediatric endocrinology clinics for their patience and help, and we acknowledge the help of the parents.

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CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest regarding this article’s publication.

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FUNDING

This research was funded by the European Society of Paediatric Endocrinology (ESPE).

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ETHICS APPROVAL

This study was approved and ethics clearance was issued by the Endocrine Institutional Board Committee and Gafaar Ibnauf Children’s Hospital Research Committee in 2015. Informed consent was obtained from parents. This is a retrospective record-based study; permission to access patients’ records was obtained from hospital authorities, ensuring the confidentiality of all participants’ information at all levels.

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