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.
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).
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).
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.
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.
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.
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).
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.
There are no conflicts of interest.
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