The diagnosis of BBS cases was made according to the modified diagnostic criteria of BBS (Beales et al., 1999). The diagnosis of PWS cases was made according to the consensus diagnostic criteria of PWS (Holm et al., 1993).
According to their history, all cases had learning disabilities and developmental delay. IQ evaluation was carried out for 10 selected cases, and seven had mild mental retardation and three had borderline mental retardation.
Seven cases were diagnosed with familial obesity. They were diagnosed after exclusion of endocrinal causes of obesity including Cushing syndrome. None of the cases had mental retardation or additional clinical features suggestive of any recognized syndromic obesity. Six cases had a positive family history of simple obesity (86%). One case had delayed walking due to rachitic bone changes one case had delayed speech.
Among the six diagnosed cases with monogenic obesity, four had congenital leptin deficiency whereas the other two had congenital leptin receptor deficiency. They all had severe early-onset obesity (<3 months of age), consanguineous parents (first cousins), severe hyperphagia, and repeated infections. Two cases had hypogonadism in the form of undescended testis (case numbers 2 and 5) and delayed puberty in case number 3. Three females were still too young to assess pubertal features. Molecular study detected one novel missense mutation in the leptin LEP gene (N103K) in family 1 and another novel nonsense mutation in the leptin LEP gene (W121X) in family2 (Fig. 3), as well as a new missense mutation in the Leptin receptor gene LEPR (P316T) in family 3. Figure 4 shows a comparison of leptin levels in leptin-deficient versus leptin receptor-deficient cases. Table 4 shows the laboratory data of each case.
The relatively rapid increase in the prevalence of obesity in the last 30 years has led some to question the importance of genetics in the etiology of obesity.
Appreciating the importance of genetic variation helps to dispel the notion that obesity represents an individual defect in behavior with no biological basis, and provides a starting point for efforts to identify the genes involved (Farooqi and O’Rahilly, 2006).
Childhood obesity is a common and complex problem that may persist in adulthood. It may present as a component of genetic syndromes associated with dysmorphic features, developmental abnormalities, mental retardation and/or learning disabilities, and often neuroendocrine dysfunction. New exciting genetic pathways contributing to syndrome phenotype and leading to obesity have recently been identified by Kousta et al. (2009).
The 30 obese children and adolescents participating in the study were selected according to their BMI percentile with respect to the Egyptian Growth Curves as the BMI growth charts show ethnic differences (Speiser et al., 2005).
Among the 30 studied cases, 17 had syndromic obesity (56.67%), seven had familial obesity (23.33%), and six had monogenic obesity (20%).
A significant difference was found between parental consanguinity of the three groups, 64% of the syndromic group (100% in BBS), 0% of the familial group, and 100% of the monogenic group. The high prevalence of parental consanguinity among those two groups (apart from PWS) can be attributed to the autosomal recessive nature of inheritance of the diseases in contrast to the familial obesity group. Aldahmesh et al. (2009) emphasized the strong effect of the consanguinity factor on the increased frequency of rare autosomal recessive conditions in genetically isolated populations and referred to it as ‘a well-established phenomenon’ in their recent study in Saudi Arabia.
Pleiotropic syndromes were found in 56.67% of the cases, namely, BBS, PWS, and AS There are rare instances of single gene/locus syndromes that result in human obesity (e.g. PWS, BBS, AS, Cohen syndrome) in association with other often dysmorphic phenotypes (Leibel and Chua, 2001). The pivotal role of genetics in the control of body weight is confirmed by the existence of single gene mutations capable of producing profound increases in body fat content. The fact that mutations in different genes can produce obesity suggests that these genes may be part of a control system for the regulation of body weight.
Eight patients met the modified diagnostic criteria of BBS by Beales et al. (1999). All BBS cases were the offspring of consanguineous marriages compared with the 8% of Beales et al. (1999). This huge difference may be attributed to the popularity of consanguineous marriages among Egyptians and the Arab world due to various sociocultural aspects. Cherian and Al Sanna’a (2009) reported 11 Saudi Arabian BBS patients from four consanguineous marriages.
Polydactyly was found in five out of the eight BBS patients (62.5%) which coincides with the 58% of Green et al. (1989) and 69% frequency of Beales et al. (1999) but lower than the 72.7% of Cherian and Al Sanna’a (2009) in Saudi Arabia. Retinal affection or rod cone dystrophy was diagnosed by an ophthalmologist in 87.5% of our cases, which coincides with the high frequency of 93% found by Beales et al. (1999) and with the 100% found by Cherian and Al Sanna’a (2009) in Saudi Arabia. Learning disabilities were found in 100% of our studied cases, which is a much higher frequency than the 62% found by Beales et al. (1999). Hypogonadism was found in 50% of our cases in both males and females. The frequency calculated among males was 57%, which is lower than that reported by Beales et al. (1999), which was 87% among studied males. The lower frequency of male hypogonadism in our study may be attributed to the limited number of cases studied (seven males). Renal abnormalities, which are known to be frequent in BBS, were not detected in any of our studied cases (0%); this could be attributed to the limited number of patients and the nature of the selected cases, all having been selected from outpatient departments for genetic diseases or endocrinal disorders, whereas those patients with renal affection usually have chronic renal impairment, and are either on regular dialysis or hospitalized and have their follow-up in the nephrology outpatient and inpatient departments. High and also variable frequency of renal abnormalities has been reported in the literature (Hurley et al., 1975; Linne et al., 1986; Harnett et al., 1988 and Garber and de Bruyn, 1991; Cherian and Al Sanna'a, 2009). To date, mutations in 15 BBS genes as well as in MKS1 and CEP290 have been identified as causing BBS. The vast genetic heterogeneity of BBS renders molecular genetic diagnosis difficult in terms of both the time and the cost required to screen all 204 coding exons (Harville et al., 2010). The cost, time, and unavailability of molecular diagnosis of BBS were the main factors that did not allow us to perform genetic laboratory testing of our BBS patients.
Eight of our studied cases met the consensus diagnostic criteria of PWS by Holm et al. (1993). Neonatal and infantile hypotonia was reported in six of our eight PWS children (75%), which almost coincides with the 87.9% found by Holm et al. (1993) and Oiglane Shlik et al., 2006. Increased weight gain after 12 months but before 6 years of age was reported in 100% of our PWS patients, which is more than the 66.7% reported in the patients of Holm et al. (1993).
Hyperphagia was found in all of our eight PWS patients (100%) whereas Holm et al., 1993 found hyperphagia, food foraging, or obsession with food in 84.4% of their patients, which is as high as our percentage. A recent study focused on genetic and behavioral aspects of one important component of the motivation to eat – how appetitive arousal is elicited through the presentation of food-associated stimuli. Individuals with PWS completed a computerized response task in the presence of motivational stimuli. In the controls, appetitive arousal was specific to particular stimuli. In contrast, individuals with PWS showed a nonspecific pattern of arousal and overactivation of the anticipatory motivation system when shown food stimuli (Hinton et al., 2010).
Characteristic facial features were found in 100% of our PWS cases, which is in agreement with Oiglane Shlik et al. (2006). Our frequency is higher than that obtained by Holm et al. (1993), which was 88.4%. Mild to moderate mental retardation and global developmental delay were seen in 100% of our PWS cases, which coincides with the 98.9% frequency seen by Holm et al. (1993).
Hypogonadism was found in 87.5% of the PWS patients in our study, which is higher than the 51.5% in Holm et al. (1993)’s study. Variable hypogonadism in PWS has generally been attributed to hypothalamic dysfunction. Recent studies have documented primary testicular dysfunction in PWS males. A cross-sectional study was performed on 45 PWS females (ages 6 weeks–32 years). Age of onset and progression of puberty varied; most adults had incomplete sexual development. Spontaneous menarche was reported in four (ages 15–30 years) but all had subsequently developed secondary amenorrhea or oligomennorrhea Eldar Geva et al., (2010).
We identified one female with AS, who had some of the key features of the syndrome, which are obesity, visual impairment due to rod-cone dystrophy detected by electroretinogram, and sensorineural hearing loss. She was born to positive consanguineous parents. She also had acanthosis nigricans, which is a common finding in this syndrome. The diagnosis was confirmed with the Winter–Baraitser Dysmorphology Database, London Medical Databases, 2005. The diagnosis of AS is usually made clinically as the molecular detection of mutations of the ALMS1 gene is very costly and, in our case, was not available.
Simple obesity in children is an indication of their state of nutrition, method of nutrition and eating habits, and the impact of other environmental factors such as physical activity (Weker, 2006). We identified seven children with simple familial obesity. Six of them had normal birth weights and one had high birth weight (4.5 kg). Brophy et al. (2009) demonstrated that large at birth children were more likely to be obese regardless of ethnicity. They all had poor eating habits and did not incorporate sports in their daily activity. Okeyo et al. (2009) reported a significant inverse association between BMI and minutes spent in moderate-intensity physical activity per day (P<0.01). Physical activity also predicted BMI (P<0.01). In conclusion, physical activity was a significant predictor to BMI.
Six of them had obese parents. The parental obesity was not due to any endocrinological disorder, or a genetic syndromes of obesity, and they did not take any drug inducing obesity. The parents had the same poor dietary habits as their kids and the same sedentary lifestyle. A positive correlation was demonstrated between the BMI (BMI z-score) and the parents’ BMI (father’s BMI, mother’s BMI). Simple obesity in children aged 3–15 years is linked to familial and environmental factors such as parents’ level of education, familial predisposition to obesity, and health habits including incorrect eating habits. A significant correlation was found between children’s obesity and mothers’ level of education (Weker, 2006). Our findings from the familial obesity group agreed with most of the previous studies (Weker, 2006; Brophy et al., 2009; Nasreddine et al., 2010).
Our familial cases with simple obesity showed no parental consanguinity; recent studies have suggested genetic variants with obesity and genome-wide association studies have shown that variations in the upstream region of the insulin-induced gene 2 (Herbert et al., 2006) and in the fat-mass and obesity-associated gene (Frayling et al., 2007; Hinney et al., 2007; Scuteri et al., 2007) are associated with the obesity phenotype.
Up to December 2009, polygenic variants have been confirmed in a total of 17 independent genomic regions. Further study of genetic effects on human body weight regulation should detect variants that will explain a larger proportion of the heritability. The development of new strategies for the diagnosis, treatment, and prevention of obesity can be anticipated (Hinney et al., 2010).
Although monogenic obesity syndromes are rare autosomal recessive disorders, the high consanguinity rate in our society will lead to the discovery of a high number of patients.
In this study, we identified six cases from three families with severe early-onset obesity (<3 months of age), severe hyperphagia, and impaired immunity in the form of recurrent infections. Our studied cases shared all the characteristics of the disease reported by Farooqi et al. (2007) and Clement et al (1998). They all exhibited rapid weight gain in the first few months of life, with severe hyperphagia and aggressive behavior when denied food. Cortisol levels were in the normal range as were Clement et al. (1998)’s patients. Our patients had normal plasma insulin levels in contrast to mildly elevated plasma insulin in Clement et al., (1998) patients and hyperinsulinism in Farooqi et al. (2007) patients.
Direct nucleotide sequencing of the LEP gene was carried out for four cases and revealed homozygosity for a novel missense mutation (N103K) in the two siblings of the first family (family 1) (Mazen et al., 2009) and homozygosity for a novel nonsense mutation (W121X) in the other two siblings of the second family (family 2).
However, sequence analysis of the leptin receptor gene (LEPR) in the two cases from family three with elevated serum leptin levels identified a new homozygous missense mutation (P316T) (Mazen et al., 2011).
Finding these families implies that monogenic obesity syndromes might be common in Egypt and emphasize the importance of investigating patients with early hyperphagia and a positive family history of obesity for diagnosing monogenic patients. In suspected monogenic obesity, it is necessary to perform molecular genetic studies to confirm an accurate diagnosis.
In conclusion, although genetic causes of obesity are rare autosomal recessive disorders, the high consanguinity rate in our society will lead to the discovery of a high incidence of syndromic and monogenic obesity. Early screening, accurate diagnosis, and regular follow-up for obesity and its complications are particularly indicated for patients with syndromic forms of obesity, together with genetic counseling of the parents.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2012 Middle East Journal of Medical Genetics
Egyptian; genetics; leptin; monogenic; mutation; obesity; syndromic