Middle East Journal of Medical Genetics:
A clinical and genetic study of childhood and adolescent obesity
El Gammal, Mona A.a; Mazen, Inas M.a; El Kotoury, Ahmed I.a; Amr, Khalda M.b; Abdel-Hamid, Mohamed S.b; Kholoussi, Naglaa M.c; Anwar, Ghada M.d; Ahmed, Gehan H.d; Tantawy, Sally M.a
aDepartment of Clinical Genetics
bDepartment of Medical Molecular Genetics
cDepartment of Immunogenetics, Division of Human Genetics and Genome Research, National Research Centre
dDepartment of Pediatric, Faculty of Medicine, Cairo University, Cairo, Egypt
Correspondence to Mona A. El Gammal, Department of Clinical genetics, NRC, El-Bohouth St., Dokki 12111, Egypt Tel: +20 235 857 986; fax: +20 122 488 996; e-mail: email@example.com
Received January 16, 2011
Accepted March 24, 2011
Purpose: Obesity is determined by genetic, environmental, and behavioral factors acting through the physiological mediators of energy intake and energy expenditure. The aim of this study was to define the most characteristic clinical, genetic, anthropometric, and laboratory findings in childhood obesity in an attempt to find the most efficient way to diagnose a genetic cause of obesity. An accurate diagnosis will provide proper genetic counseling concerning the nature, inheritance, recurrence risk, and implications of the disease on health status.
Patients and methods: All cases were subjected to full history taking, pedigree analysis, anthropometric measurements, and full clinical examination including dysmorphology and pubertal assessment. Endocrinal causes were excluded in this study. Serum leptin and insulin were estimated whenever a monogenic cause of obesity was suspected. Genetic investigations including molecular studies were performed in selected cases.
Results: This study included 30 obese children and adolescents. Their BMIs were above the 95th percentile for age, with a mean BMI of 35 and a mean BMI standard deviation of +7.26. Among the 30 studied cases, 17 had syndromic obesity (56.67%), seven had familial obesity (23.33%), and six had monogenic obesity (20%). In the six diagnosed cases with monogenic obesity, we detect one novel missense mutation in the leptin LEP gene (N103K) and another novel nonsense mutation in the leptin LEP gene (W121X) as well as missense mutation in the Leptin receptor gene LEPR (P316T).
Conclusion and recommendations: 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 monogenic and syndromic obesity. Early screening 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.
Obesity is a complex disorder that is caused by several genetic and nongenetic risk factors (Walley et al., 2009). The causes of obesity have been argued over the past 100 years; both biological and psychological explanations have emerged. Prader, Labhart, and Willi described the first syndromal form of obesity in 1956 (Hebebrand and Hinney, 2009). Milestone twin and adoption studies at the end of the 1980s and during the early 1990s provided evidence indicating that genetic factors play a considerable role in body weight regulation (Stunkard et al., 1986; Bouchard et al., 1990; Stunkard et al., 1990). Cloning of the leptin gene in 1994 (Zhang et al., 1994) led to a rapid expansion of biomedical research. Large-scale molecular genetic studies ensued (Rankinen et al., 2006). The successful treatment of children with leptin deficiency (Montague et al., 1997) with recombinant leptin (Montague et al., 1997; Clement et al., 1998; Farooqi et al., 1999; Farooqi et al., 2002; Gibson et al., 2004) showed for the first time that mutations in a single gene could lead to hyperphagia and obesity. Recent large-scale molecular genetic studies have substantiated that the genetic predisposition is in many cases due to the combined net effect of polygenic variants.
Environmental changes affecting both energy intake and expenditure are assumed to underlie the recent obesity epidemic as the gene pool of a population is unlikely to have changed substantially within the past generation (Taubes, 1998). Undoubtedly, gene–environment interactions will prove to play an important role in the etiology of obesity. Such interactions could for example be seen through changes in DNA methylation patterns (Andreasen and Andersen, 2009).
In this study, we aim to define the most characteristic clinical, genetic, anthropometric, and laboratory findings in childhood obesity in an attempt to find the most efficient way to diagnose a genetic cause of obesity. An accurate diagnosis will provide proper genetic counseling concerning nature, inheritance, recurrence risk, and implications of the disease on health status to help the affected families make proper medical and personal decisions.
Patients and methods
From 200 obese children and adolescents (age 2–18 years) attending at the clinical genetics clinic of the National Research Centre and Diabetic, Endocrine and Metabolic Pediatric Unit, Cairo University Children’s Hospital (Abo-Elrish), through a period of 1 year (June 2008–June 2009), we selected 30 obese children with suspected genetic causes for their BMI being above the 95th percentile for age according to the Egyptian Growth Charts (Ghalli, 2002).
Written informed consent was taken from all patients’ parents before enrollment in the study and after a full explanation of their role in the research. The study was approved by the ethical committee of the National Research Centre.
All cases were subjected to full history taking, pedigree analysis, anthropometric measurements according to Tanner et al., 1969, full clinical examination including dysmorphology and pubertal assessment according to Tanner et al. (1969). Intelligence quotient (IQ) and assessment of cognitive functions was performed using the standardized Wechsler IQ test (WISC and WPPSI). In cases suspected to have monogenic obesity, fasting serum leptin was estimated using an immunoenzymometric assay for the quantitative measurement of human leptin in serum and plasma ‘the biosource leptin EASIA assay.’ The kit was supplied by BioSource Europe S.A., Nivelles Belgium. Also, insulin was quantified using a microparticle immunoassay (IMx system Insulin; Abbott Laboratories, Chicago, Illinois, USA) in an IMx automatic analyser (Abbott Laboratories) (German et al., 2009).
Genomic DNA was extracted from blood samples using the QIAamp DNA Mini Kit (QIAGEN, Frankfurt, Germany). The whole coding regions of the LEP and LEPR genes were amplified as previously described (Montague et al., 1997; Farooqi et al., 2007). PCR was performed under the following conditions: denaturation at 96°C for 5 min, followed by 30 cycles of denaturation at 96°C for 50 s, annealing at 58.5°C for 50 s, and elongation at 72°C for 50 s, followed by a final elongation of 5 min. The PCR products were purified using the QIAquick PCR purification kit (QIAGEN, Germany), sequenced in both directions using the Bigdye Termination Kit (Applied Biosystem, Foster City, California, USA), and analyzed on an ABI Prism 3100 automated sequencer (Applied Biosystem).
This study included 30 obese children and adolescents from 23 families, 21 of whom were males (70%) and nine were females (30%). Their BMIs were above the 95th percentile for age, with a mean BMI of 35 and a mean BMI standard deviation of +7.26. Their ages ranged from 2 to 18 years, with a mean age at presentation of 10 years for females and 6.8 years for males. A positive family history of a similar condition was seen in 20 cases (66.7%), whereas a positive family history of simple obesity (not a part of genetic syndrome or an endocrinal disorder or drug induced) was seen in 11 cases (36.7%).
Among the 30 studied cases, 17 had syndromic obesity (56.67%), seven had familial obesity (23.33%), and six had monogenic obesity (20%). Table 1 shows a summary of positive data among the three groups.
The 17 cases with syndromic obesity included eight cases with Bardet–Biedl syndrome (BBS) (26.6% of all cases, 47% of syndromic cases). Figure 1 shows two siblings with BBS. Table 2 shows descriptive statistics for the clinical presentation of patients with BBS and eight with Prader–Willi syndrome (PWS) (26.6% of all cases, 47% of syndromic cases). Figure 2 shows selected cases with PWS. Table 3 shows descriptive statistics for the clinical presentation of cases with PWS and one with Alström syndrome (AS) (3.3% of all cases, 5.8% of syndromic cases).
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.
Aldahmesh MA, Abu Safieh L, Khan AO, Al Hassnan ZN, Shaheen R, Rajab M, et al. Allelic heterogeneity in inbred populations: the Saudi experience with Alstrom syndrome as an illustrative example. Am J Med Genet. 2009;A149A:662–665
Andreasen CH, Andersen G. Gene-environment interactions and obesity – further aspects of genomewide association studies. Nutrition. 2009;25:998–1003
Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey. J Med Genet. 1999;36:437–446
Bouchard C, Tremblay A, Despres JP, Nadeau A, Lupien PJ, Theriault G, et al. The response to long-term overfeeding in identical twins. N Engl J Med. 1990;322:1477–1482
Brophy S, Cooksey R, Gravenor MB, Mistry R, Thomas N, Lyons RA, et al. Risk factors for childhood obesity at age 5: analysis of the millennium cohort study. BMC Public Health. 2009;9 :467–473
Cherian MP, Al Sanna’a NA. Clinical spectrum of Bardet–Biedl syndrome among four Saudi Arabian families. Clin Dysmorphol. 2009;18:188–194
Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401
Eldar Geva T, Hirsch HJ, Benarroch F, Rubinstein O, Gross Tsur V. Hypogonadism in females with Prader–Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction. Eur J Endocrinol. 2010;162:377–384
Farooqi IS, O’Rahilly S. Genetics of obesity in humans. Endocr Rev. 2006;27:710–718
Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341:879–884
Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110:1093–1103
Farooqi IS, Wangensteen T, Collins S , Kimber W, Matarese G, Keogh JM, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237–247
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889–894
Garber SJ, de Bruyn R. Laurence–Moon–Biedl syndrome: renal ultrasound appearances in the neonate. Br J Radiol. 1991;64:631–633
German J, Kim F, Schwartz GJ, Havel PJ, Rhodes CJ, Schwartz MW, et al. Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology. 2009;150:4502–4511
Ghalli I (2002). Egyptian growth curves 2002 for infants, children and adolescents. Proceedings of the 1st
National Congress for. Egyptian Growth Curves. Department of Bio-anthropology, National Research Centre, Cairo
Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, et al. Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab. 2004;89:4821–4826
Green JS, Parfrey PS, Harnett JD, Farid NR, Cramer BC, Johnson G, et al. The cardinal manifestations of Bardet–Biedl syndrome, a form of Laurence–Moon–Biedl syndrome. N Engl J Med. 1989;321:1002–1009
Harnett JD, Green JS, Cramer BC, Johnson G, Chafe L, McManamon P, et al. The spectrum of renal disease in Laurence–Moon–Biedl syndrome. N Engl J Med. 1988;319:615–618
Harville HM, Held S, Diaz Font A, Davis EE, Diplas BH, Lewis RA, et al. Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. J Med Genet. 2010;47:262–267
Hebebrand J, Hinney A. Environmental and genetic risk factors in obesity. Child Adolesc Psychiatr Clin N Am. 2009;18:83–94
Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, et al. A common genetic variant is associated with adult and childhood obesity. Science. 2006;312:279–283
Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G, Müller TD, et al. Genome Wide Association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS ONE. 2007;2 Art. no. e1361
Hinney A, Vogel CI, Hebebrand J. From monogenic to polygenic obesity: recent advances. Eur Child Adolesc Psychiatr. 2010;19:297–310
Hinton EC, Isles AR, Williams NM, Parkinson JA. Excessive appetitive arousal in Prader–Willi syndrome. Appetite. 2010;54:225–228
Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, et al. Prader–Willi syndrome: consensus diagnostic criteria. Pediatrics. 1993;91:398–402
Hurley RM, Dery P, Norady MB, Drummond KN. The renal lesion of the Laurence—Moon—Biedl syndrome. J Pediatri. 1975;87:206–209
Kousta E, Hadjiathanasiou CG, Tolis G, Papathanasiou A. Pleiotropic genetic syndromes with developmental abnormalities associated with obesity. J Pediatr Endocrinol Metab. 2009;22:581–592
Leibel RL, Chua SCR,MScriver CR, Beaudel AL, Slu WS, Valle D. Obesity: The molecular physiology of weight regulation The metabolic and molecular bases of inherited disease. 20018th ed New York McGraw-Hill
Linne T, Wikstad I, Zetterstrom R. Renal involvement in the Laurence–Moon–Biedl syndrome. Functional and radiological studies. Acta Paediatr. 1986;75:240–244
Mazen I, El Gammal M, Abdel Hamid M, Amr K. A novel homozygous missense mutation of the leptin gene (N103K) in an obese Egyptian patient. Mol Genet Metab. 2009;97:305–308
Mazen I, El Gammal M, Abdel Hamid M, Farooqi IS, Amr K. Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity. Mol Genet Metab. 2011;102:461–464
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387:903–908
Nasreddine L, Mehio Sibai A, Mrayati M, Adra N, Hwalla N. Adolescent obesity in Syria: prevalence and associated factors. Child Care Health Dev. 2010;36:404–413
Oiglane Shlik E, Zordania R, Varendi H, Antson A, Magi ML, Tasa G, et al. The neonatal phenotype of Prader–Willi syndrome. Am J Med Genet. 2006;140:1241–1244
Okeyo OD, Ayado OL, Mbagaya GM. Physical activity and dietary fat as determinants of body mass index in a cross-sectional corelational design. East Afr J Public Health. 2009;6:32–36
Pinkel D, Gray JW, Trask B, van den Engh G, Fuscoe J, van Dekken H. Cytogenetic analysis by in situ hybridization with fluorescently labeled nucleic acid probes. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):151–157
Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, et al. The human obesity gene map: the 2005 update. Obesity (Silver Spring). 2006;14:529–644
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genetics. 2007;3:e115
Speiser PW, Rudolf MC, Anhalt H, Camacho Hubner C, Chiarelli F, Eliakim A, et al. Childhood obesity. J Clin Endocrinol Metab. 2005;90:1871–1887
Stunkard AJ, Sorensen TI, Hanis C, Teasdale TW, Chakraborty R, S chull WJ, et al. An adoption study of human obesity. N Engl J Med. 1986;314:193–198
Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med. 1990;322:1483–1487
Tanner JM, Hiernaux J, Jarman SWeiner JS, Lourie JA. Growth and physical studies Human biology A guide to field methods.. 1969;45 Oxford: Blackwell Scientific Publication:13–23
Taubes G. As obesity rates rise, experts struggle to explain why. Science. 1998;280:1367–1368
Verma RS, Babu A Human chromosomes: principal and techniques. 19952nd ed New York, San Francisco Mc Graw-Hill Inc
Walley AJ, Asher JE, Froguel P. The genetic contribution to non-syndromic human obesity. Nat Rev Genet. 2009;10:431–442
Weker H. Simple obesity in children. A study on the role of nutritional factors. [Polish]. Med Wieku Rozwoj. 2006;10:3–191
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432
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