Clinical Endocrinology (2014) 81, 876–882

doi: 10.1111/cen.12510

ORIGINAL ARTICLE

The prevalence of isolated growth hormone deficiency among children of short stature in Jordan and its relationship with consanguinity Ayman A. Zayed*, Moaath K. Mustafa Ali*, Mohammad A. Al-Ani†, Munther S. Momani* and Al-Motassem F. Yousef‡ *Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Amman, Jordan, †Department of Internal Medicine, University of Florida Health, Gainesville, FL, USA and ‡Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman, Jordan

Summary Objective The prevalence of isolated growth hormone deficiency (IGHD) among short-statured children in Jordan, where consanguineous marriage (CM) is common, is unknown. No studies have investigated the relationship between degrees of consanguinity and IGHD. This study aimed to determine the prevalence of IGHD among short-statured children referred to a university hospital in Jordan and its relationship with different degrees of consanguinity. Design We conducted a 24-month cross-sectional observational trial at an outpatient tertiary care center in Amman, Jordan. Patients We obtained detailed family histories, medical evaluations and laboratory tests for 94 short-statured children (50 boys and 44 girls aged 6–16 years). Measurements Complete and partial GHD were defined as peak GH responses of 5 and 7 lg/l (15 and 21 mIU/l) [IRMA/ DiaSorinâ], respectively, in both exercise and insulin tolerance tests. Results GHD was diagnosed in 69
1% of the short children, including 86% (43/50) of the children of consanguineous parents (83
3%, 93
8% and 81
8% of children of first cousins, first cousins once removed and second cousins, respectively) and 50% (20/44) of the children of nonconsanguineous parents (P = 0
039, 0
002 and 0
013, respectively). However, there was no statistically significant difference in the prevalence of small pituitary MRI between GH-deficient children of consanguineous parents and those of nonconsanguineous parents (28
6% vs 13
6%, P = 0
3). Conclusions The prevalence of IGHD among referred short children in Jordan was exceptionally high and significantly higher in the children of CM. In countries where CM is com-

Correspondence: Ayman A. Zayed, who is now at the Division of Endocrinology and Metabolism, The University of Jordan/Jordan University Hospital-Amman, P.O. Box 13046, Amman 11942, Jordan. Tel.: 00962797224442; Fax: 0096265353388; E-mail: [email protected]

876

mon, preconception counselling and rigorous surveillance for GHD in short children may be indicated. (Received 9 January 2014; returned for revision 29 January 2014; finally revised 24 April 2014; accepted 16 May 2014)

Introduction Primary care physicians frequently encounter children with short stature (SS). Short stature is defined as a height that is at least two standard deviations below the average for that age and gender.1 SS is caused by several pathological and nonpathological aetiologies. One of the most important and treatable causes of SS is growth hormone deficiency (GHD), which is clinically defined as an inadequate GH peak after GH secretion is induced using a controlled stimulus.2 The prevalence of GHD in SS children ranges from 2
8% to 30%3–5; however, its prevalence in Jordan is unknown. Consanguinity is defined as a union of two people with a familial relationship of second cousins or closer. These couples include first cousins, first cousins once removed, second cousins and double first cousins.6 Consanguineous marriage (CM) has been practised widely throughout history and is common in Arab countries, representing 20–50% of all marriages. The high consanguinity rates in Arab countries can be attributed to many social and cultural factors, such as the desire to maintain the integrity of family structure and property, the ease of marital arrangements and better relations with in-laws.7 In Jordan, 32
03% of all marriages are between first cousins, 6
8% are between second cousins, 10
5% are between distant relatives, and 50% are between unrelated individuals.8 The practise of CM is associated with an increased risk of certain genetic diseases, especially autosomal recessive diseases and diseases caused by rare mutations.9Although most cases of GHD are sporadic, some have genetic causes, such as familial isolated growth hormone deficiency (IGHD). Familial IGHD is inherited in several Mendelian patterns, including autosomal recessive © 2014 John Wiley & Sons Ltd

Growth hormone deficiency/consanguinity 877 (IGHD type IA, IB), autosomal dominant (IGHD type II) and X-linked (IGHD III) inheritance.10 Accordingly, there may be a link between GHD and CM. Although there are numerous reports of IGHD due to different types of gene mutations reported in different countries,11–13 to the best of our knowledge, no studies have investigated the relationship between the different degrees of consanguinity and GHD. Magnetic resonance imaging (MRI) is commonly indicated in patients with GHD because the test aids in the determination of disease aetiology. It was reported that the most common autosomal recessive IGHD results in hypoplastic anterior pituitary.14 Nevertheless, other than hypoplastic anterior pituitary, it is unknown whether the pituitary MRI profiles of GHD children from consanguineous families are different from those of children of unrelated parents. This study aimed to determine the prevalence of IGHD among a referred sample of short-statured children to a university hospital in Jordan, with special consideration given to the impact of different degrees of consanguinity. In addition, we aimed to determine the relationship between pituitary MRI findings and the different degrees of consanguinity in children with IGHD. It is worth mentioning that this study was not a genetic study. Thus, determining the genetic basis of GHD and evaluating MRI on that basis are targets for future studies.

vertical board. Each child was drawn up to full height by placing upward pressure on the mandible. All participants underwent a comprehensive medical evaluation, including detailed history collection, physical examination, GH deficiency evaluation and laboratory testing that included complete blood count, complete blood chemistry, erythrocyte sedimentation rate (ESR) analysis, urine analysis, serum TSH assay, free T4 assay, tissue transglutaminase IgA and total serum IgA, bone age, serum IGF-1, serum IGFBP-3, EST for GH and karyotyping for females, even in the absence of physical features of Turner syndrome. Further evaluation of GH sufficiency was achieved by performing an ITT test to provoke GH secretion. A peak GH level of ≥7 lg/l (21 mIU/l) was applied as the physiological response cut-off for both exercise stimulation and ITTs. All participating

Short children presented for short stature evaluation (n = 121)

Parental consent for participation (n = 108) Exercise stimulation test (EST)

Subjects and methods This cross-sectional observational study was conducted from December 2010 to November 2012 at the Endocrine Division of Jordan University Hospital, a tertiary medical centre in Amman, Jordan. Notably, the data of the study were collected prospectively during the study period. The study design was approved by the Ethical and Research Committee and the institutional review board of the hospital. During the study period, 121 children presented to the Jordan University Hospital (JUH) outpatient endocrinology clinic for the evaluation of SS. The target population of our study was male and female children, aged 4– 17 years, with short stature and known biological parents. Children were excluded if: (i) their parents could not provide written consent for them; (ii) they were lost to follow up; (iii) they could not perform exercise stimulation tests (EST) for GH due to physical restrictions (e.g. asthma, heart disease. . .) or insulin stimulation test (ITT) due to a medical contraindication (e.g. seizure disorder); (iv) they had received GH therapy in the past or (v) they were known to have pituitary diseases or discovered to have panhypopituitarism. The mean age of the studied group (n = 94) was 11
2  4
8 years. Fifty children (53
2%) were males, and 44 children (46
7%) were females; their mean ages were 12
5  3
5 and 9
1  0
8 years, respectively. The parents of 108 participants provided written consent for their children’s participation in the study (Fig. 1). Short stature was defined as a standing body height lower than the third percentile for age and gender according to World Health Organization (WHO) standard growth charts.15 Each child’s height was measured with his or her head in a Frankfurt plane and the occiput, shoulder, buttocks and heels contacting a © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 876–882

Abnormal EST result (n = 92)

Normal EST result (n = 16)

Insulin tolerance test (ITT)

Lost to follow up (n = 14)*

Continued the study (n = 78)

Insulin tolerance test (ITT)

Normal ITT result (n = 16)

Normal ITT result (n = 13)

Abnormal ITT result (n = 65)

Fig. 1 Flowchart demonstrating how the patients were recruited and tested in this study, including the numbers of participants at each stage. EST, exercise stimulation test; ITT, insulin tolerance test; * 14 patients dropped out because they were lost to follow-up. : Shaded boxes represent the total number of patients included in the study.

878 A. A. Zayed et al. children underwent both an EST and ITT, and GHD was defined as an abnormal response to both the EST and ITT on two separate days. Patients with GHD were then subcategorized into two groups: complete deficiency was defined as a peak stimulated GH of