A Clinical Guide to Pediatric Weight Management and Obesity, 1st Edition


Specific Genetic Causes of Obesity

More than 600 genes, gene markers, and chromosomal regions have been associated with human obesity (1).


Mechanisms of inheritance include the following:

  • Single gene mutations
  • Autosomal and recessive inheritance
  • Candidate genes with obesity as an associated feature
  • Linkages with obesity-related phenotypes

The following factors have all been associated with genetic markers (1):

  • Body weight
  • Body mass index (BMI)
  • Fat distribution
  • Body composition
  • Phenotypes related to energy expenditure
  • Waist circumference
  • Metabolic syndrome
  • Energy and macronutrient intake
  • Age at adiposity rebound (1)

The association of obesity with a wide array of genes is not surprising because obesity is intimately associated with energy regulation, a critical factor in survival. Also not surprising is the interaction of genetic susceptibility with the environment. This susceptibility manifests itself in populations who transition from energy-scarce to energy-dense environments either geographically or through successive generations as lifestyles change. The following sections describe a number of genetic syndromes and mutations associated with obesity and give a picture of some of the associated anomalies, which, if seen, should trigger genetic evaluation of the obese child.


Genetic Syndromes and Mutations

Melanocortin Receptor 4 Mutation

Single gene mutations are a rare cause of obesity. The melanocortin receptor 4 mutation is the most common of these. Leptin stimulates neurons in the arcuate nucleus of the hypothalamus, which express α-melanocyte-stimulating hormone (MSH), and agouti-related peptide, which binds to the MC4R receptor to produce a decrease in food intake (2). Heterozygous missense mutations of MC4R have been found in severely obese children (3).

In a study of obese adults, the prevalence of MC4R mutations was similar in patients who developed obesity in childhood (2.83%) and in those becoming obese in adulthood (2.35%) (4). In a family study with patients who had the onset of obesity before age 10 years, 5.8% had mutations of the MC4R gene. Both homozygous and heterozygous inheritance gave rise to early onset obesity and a pattern of codominance, with the homozygous individuals more obese than the heterozygous individuals. Mutation of MC4R is also associated with severe hyperinsulinemia, which precedes hyperphagia and obesity. Unexpectedly, 32% of the individuals in this study, who were heterozygous, were not obese (5).

Prader-Willi Syndrome


Prader-Willi syndrome (PWS) affects about 1 per 10,000 to 1 per 15,000 births. Seventy-three percent of cases result from a deletion of 15q11-q13 from the paternally derived chromosome, involving approximately 4 MB of DNA. The exact gene that causes this syndrome is unknown. Twenty-five percent of cases result from uniparental disomy, which involves inheriting two maternal alleles for chromosome 15 and is associated with advanced maternal age. Rarely, the paternally derived chromosome having maternal DNA methylation can cause Prader-Willi syndrome (4).

Clinical Manifestations

Decreased fetal movement and/or abnormal fetal position at delivery can be a prenatal manifestation of the hypotonia associated with PWS. In the neonate, hypogonadism may be present and can include a hypoplastic scrotum and bilateral or unilateral cryptorchidism. The newborn with PWS can also have poor suck and feeding problems and may present as an infant with failure to thrive. Hyperphagia and food-seeking behavior can become evident between 1 and 6 years of age and are characteristic of this syndrome. The hypothalamic abnormality in PWS results in lack of satiety, and this combined with decreased caloric requirement due to hypotonia, decreased lean body mass, and decreased activity results in obesity (6). Ghrelin, an enteric hunger-producing hormone, is elevated in patients with PWS independent of their BMI (7). Phenotypic features of PWS include a narrow bifrontal facial diameter, almond-shaped palpebral fissure, narrow nasal bridge, and microacria (small


hands and feet), with 50% of children reported to have hypopigmentation for the family skin tone. Short stature with growth hormone deficiency is also in the spectrum of findings. Manifestations of hypogonadism include small genitalia, incomplete or delayed pubertal development, and, not uncommonly, infertility. Delayed motor development is always present, with delay of early milestones, language and cognitive delay, and learning disabilities as part of the spectrum. Behavior difficulties are not unusual; temper tantrums, stubborn behavior, obsessive-compulsive tendencies, and difficulty with change are the most common (8). Five percent to 10% of patients may have significant mental illness, including psychosis, bipolar disorder, and obsessive-compulsive disorder. Some special characteristics of this syndrome include having a high threshold for pain, thick viscous saliva, skin picking, high threshold for vomiting, and unusual skill with puzzles (8).


Classical diagnostic criteria for PWS are listed in Table 14.1 (9). Recently, diagnostic criteria have been expanded to lead to a higher likelihood of diagnosis and earlier intervention. In a review of criteria for diagnosis, children between 2 and 6 years of age with global developmental delay and hypotonia and a history of being a “floppy baby” and having poor feeding with a weak suck would meet criteria for diagnostic testing. By 6 and 12 years of age, children with developmental delay, hyperphagia, and obesity with a similar history of hypotonia in infancy would be candidates for testing. By 13 years and older, evaluation of patients with a similar history, obesity, hyperphagia, and hypogonadotropic hypogonadism would include testing for PWS (6). Genetic testing is performed by DNA methylation test (6). Table 14.2lists features sufficient to prompt DNA testing.


Control of the nutritional environment is crucial in the treatment of PWS. Restricting caloric intake and access to food is the only reliable therapeutic strategy to prevent or limit weight gain. Children with PWS are characterized by a constant drive to find and eat food; they may sneak and hide food, ask others for food, and eat beyond satiety. Parents, family members, and caregivers must be sensitive to these characteristics and work to create a nutritional and activity environment appropriate for these children. Supporting parents and caregivers, educating school regarding portion sizes and access to food, and planning for long-term care are all important aspects of ongoing care.


Initial Presentation

SA is a girl, 3 years and 8 months old, whose mother and aunt bring her to your office for a respiratory illness. As you begin to evaluate her, you note that her weight is 21.2 kg, which is greater than the 95th percentile, and her height is 91.3 cm, which


is less than the 5th percentile, giving her a BMI of 25.4. Her mother tells you that SA was a premature baby with a birth weight of 3 lb 4 oz at 35 weeks. The mother's pregnancy was complicated by gestational diabetes and premature rupture of membranes. The family history is positive for obesity, hypertension, diabetes, thyroid disease, and cardiovascular disease. SA had a complicated neonatal course, which involved respiratory distress syndrome. Mom also noted that a gastrostomy tube had to be placed for poor feeding and hypotonia, but now she is growing well and is “hungry all the time.” Over the next few years, SA had repeated episodes of respiratory illness. On physical examination you note that SA has thick saliva, central obesity, and small-appearing hands and feet. You discuss the possibility of a genetic etiology for SA's obesity and developmental delay with the mother and order a methylation study for PWS.

TABLE 14.1. Prader-Willi syndrome—diagnostic criteria

Major criteria (1 point each)

Neonatal and infantile central hypotonia with poor suck, gradually improving

Feeding problems in infancy with need for special feeding techniques and poor weight gain

Excessive or rapid weight gain after 12 months and before age 6, central obesity

Characteristic facial features: dolichocephaly, narrow face, almond-shaped eyes, small-appearing mouth, thin upper lip, downturned corner of the mouth (3 or more)


Genital hypoplasia

Delayed or incomplete gonadal maturation

Global developmental delay, moderate to mild mental retardation, learning disability

Hyperphagia, food foraging/obsession with food

Deletion of 15q11-13 or maternal disomy

Minor criteria (1/2 point each)

Decreased fetal movement, infantile lethargy, weak cry

Temper tantrums, violent outbursts, OCD, oppositional, rigid manipulative, possessive, stubborn, stealing, lying (5 or more)

Sleep disturbance or sleep apnea

Short stature for genetic background

Hypopigmentation for family

Small hands and/or feet

Narrow hands

Esotropia, myopia

Thick, viscous saliva

Speech difficulties

Skin picking

Total points for phenotypic diagnosis

Birth to age 3: 5 total points, including 4 major criteria; 3 to adult: 8 total points, including 5 major criteria (9)

OCD, obsessive-compulsive disorder.

Reprinted with permission from Holm VA, Cassidy SB, Butler MG, et al. Prader Willi syndrome; consensus diagnostic criteria. Pediatrics. 1993;91:398–402.

Three Weeks Later

Three weeks later when SA returns to your office, she is feeling much better. You have asked her mother and father to come in to discuss the results of testing. SA


does have PWS. You explain the results and describe the syndrome to the parents. You also arrange to have the parents tested for uniparental disomy. They have questions that revolve around SA's development and her eating behavior. You explain about hypothalamic control of eating and the fact that SA, by virtue of having PWS, needs environmental control of access to food to manage her weight. SA's parents are upset but somewhat relieved to find a reason for SA's developmental delay and her food-seeking behavior. You arrange to see the family again in 1 month.

TABLE 14.2. Features sufficient to prompt DNAtesting for Prader-Willi syndrome

Birth to 2 years

1. Hypotonia with poor suck

2–6 years

1. Hypotonia with history of poor suck

2. Global developmental delay

6–12 years

1. History of hypotonia with poor suck (hypotonia often persists)

2. Global developmental delay

3. Excessive eating (hyperphagia, obsession with food) with central obesity if uncontrolled

13 years through adulthood

1. Cognitive impairment, usually mild mental retardation

2. Excessive eating (hyperphagia, obsession with food) with central obesity if uncontrolled

3. Hypothalamic hypogonadism and/or typical behavior problems (including temper tantrums and obsessive-compulsive features)

Reprinted with permission from Gunay-Aygun M, Schwartz S, Heeger S, O'Riordan MA, Cassiday SB. The changing purpose of Prader-Willi syndrome (clinical diagnostic criteria and proposed revised criteria). Pediatrics. 2001;108(5):e92.

Follow-up Visits

One month later, SA returns, having lost 3 lb. Her parents say they have spoken to other relatives and the daycare she attends and have asked everyone to limit her access to food. They have also eliminated sugar-containing beverages, as you have requested. You urge the parents to keep SA active and ask them to use her stroller as little as possible, encouraging walking and supervised free play. You also ask them to contact SA's school about early developmental programs. You arrange to follow up with her monthly.

Other Single Gene Mutations

Other single gene mutations are listed in Table 14.3.

Albright Hereditary Osteodystrophy


Albright hereditary osteodystrophy is a sex-influenced autosomal dominant syndrome with a female-to-male ratio of 2:1.



TABLE 14.3. Single gene mutations

·   Leptin receptor gene 1p31
Early-onset morbid obesity; homozygous patients have no pubertal development and decreased secretion of growth hormone and thyrotropin (10)

·   PCSKI (protein convertase subtilisin/kexin type I) gene 5q15-q21
Extreme childhood obesity, abnormal glucose homeostasis, hypogonadotropic hypogonadism, hypercortisolism, elevated plasma proinsulin and POMC concentrations but very low insulin levels, suggestive of defective prohormone processing (11)

·   17q22-q24 growth hormone deficiency
Delayed skeletal maturation and height retardation, truncal obesity, delayed secondary dentition, high-pitched voice, and delayed puberty (12)

·   MC4R (melanocortin 4 receptor) 18q21.3 (see text)

·   Prader-Willi syndrome 15q11-q13 (see text)

·   Ulnar mammary syndrome 12q24.1
Ulnar finger and fibular toe ray defects; delayed growth and onset of puberty, obesity, and hypogenitalism and diminished sexual activity; and hypoplasia of nipples and apocrine glands with subsequent diminished ability to perspire (13)

POMC, pro-opiomelanocortin.

Clinical Manifestations

One of the earliest identifiable features of the syndrome is early onset of hypocalcemia, with 80% of affected children having hypocalcemia in the first or second year of life. Other features in addition to obesity and hypocalcemia include the following:

  • Short stature
  • Brachydactyly
  • Ectopic calcifications
  • Mental retardation
  • Pseudohypoparathyroidism

Short stature is characterized by generalized shortening of the extremities and cone-shaped, absent, or prematurely closed epiphysis (14).

Autosomal Recessive Disorders

Bardet-Biedl Syndrome


Bardet-Biedl syndrome is a heterogeneous autosomal recessive disorder associated with five separate genetic loci: 11q13 (BBS1), 16q21 (BBS2), 3p12-13 (BBS3), 15q22.22-q23 (BBS4), and 2q31 (BBS5).



Clinical Manifestations

Characteristics of this syndrome include the following:

  • Obesity
  • Mild mental retardation
  • Pigmentary retinopathy with loss of visual acuity and dark adaptation
  • Polydactyly
  • Hypogonadism
  • Renal dysfunction

Symptoms are variable among subgroups: 90% of adults in all groups are above the 90th percentile for weight, children younger than 10 years may be below the 90th percentile in some subtypes, and obligate heterozygotes are reported to have increased incidence of obesity, diabetes, hypertension, and renal disease. Pigmentary retinopathy in this syndrome is associated with abnormal electroretinograms in infancy, degeneration of retinal photoreceptors affecting cones and rods, and progressive loss of visual acuity and dark-adapted sensitivity. Visual acuity decreases to the 20/100 range by about 11 to 12 years, and 93% of patients older than 30 years are legally blind. There is universal infertility in males with hypogonadism, poorly developed secondary sexual characteristics, and primary testicular pathology. Hypothalamic-pituitary and ovarian dysfunction is present in females; secondary sexual characteristics are normal, but there is an increased rate of structural genitourinary abnormalities. Ninety percent of patients have renal involvement, which is characterized by heterogeneous parenchymal lesions, distal tubular dysfunction, and glomerular disease (15).

Other Autosomal Recessive Disorders

Other autosomal recessive disorders are listed in Table 14.4.

X-Linked Disorders

Obesity has also been associated with X-linked disorders (Table 14.5).

TABLE 14.4. Autosomal recessive disorders

·   Alstrom's syndrome 2p14-p13
Early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans (16)

·   Bardet-Biedl syndrome 1 11q13 (see text)

·   Bardet-Biedl syndrome 2 16q21 (see text)

·   Bardet-Biedl syndrome 3 3p13-p12 (see text)

·   Bardet-Biedl syndrome 4 15q22.3-q23 9 (see text)

·   Cohen's syndrome 8q22-q23
Developmental delay, microcephaly, truncal obesity with slender extremities, sociable behavior, joint hypermobility, high myopia and/or retinal dystrophy, and neutropenia. Patients fulfilling 6 or more criteria likely to have true Cohen's syndrome (17)



TABLE 14.5. X-linked disorders

·   Mehmo's syndrome Xp22.13-p21.1
Mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity with death in childhood (18)

·   Wilson-Turner syndrome Xp21.1q22
Mental retardation, obesity, gynecomastia, speech difficulties, emotional lability, tapering fingers, and small feet (19)


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