PWS look-alike disorders

(compiled by Linda Thornton)

In April 2001, Celanie K. Christensen, MS, and Bryan E. Hainline, MD, PhD from the Dept of Medical and Molecular Genetics and Pediatrics of Indiana University School of Medicine, wrote a comparative article on syndromes that have some similar characteristics as Prader-Willi Syndrome, namely other genetic syndromes which presented with obesity and intellectual disabilitiy.

This article was written in response to the paradigm shift in medical management of obesity which had, in the past, not been considered a true medical problem, but more of a sign of psychological weakness. It has been late in coming, and is still looked often upon by the person-in-the-street as a sign of weakness and greed, but obesity caused by genetic malfunctions is being taken seriously as not only life-threatening, but socially demoralising.

The article reinforces the need to consider many other possibilities as well as just obesity and goes on to group together some genetic syndromes which have the signal of obesity as part of their etiology. Although PWS can now be genetically tested within days of birth, this has only fairly recently become possible in most countries. There is still often confusion over the question from a lay-person as to whether someone they know might have PWS.

The paper goes on to list the syndromes:

"Genetic syndromes with obesity and delayed/altered intellectual development as major parts of the phenotype include Prader-Willi syndrome, Albright hereditary osteodystrophy, Alstrom syndrome, Bardet-Biedl syndrome, Borjeson-Forssman­Lehmann syndrome, Cohen syndrome, and fragile X syndrome. Chromosomal conditions including Down, Klinefelter, and Turner syndromes, also have an increased prevalence of obesity. In recent years, several single gene mutations have been linked to extreme obesity. Certain forms of brain damage can also be a cause of extreme obesity."

Albright hereditary osteodystrophy (AHO) is characterized by variable mental retardation, short stature, round face, short neck, short bones of the fingers and toes, calcifications or ossifications in subcutaneous tissues often near joints, delayed development of the adult teeth, enamel hypoplasia (incomplete or underdeveloped tooth enamel), and obesity. Individuals with AHO can have obesity of prenatal onset or develop it within the first year of life. AHO is also known as pseudohypoparathyroidism type 1a. AHO can be diagnosed by testing the amount of calcium and phosphorus in the blood and the level of cyclic AMP in urine. The gene for AHO has been mapped to chromosome 20 and it is inherited as a dominant condition.

 

 


 

Alstrom syndrome (AS) produces symptoms in children that include progressive loss of vision and hearing, an unusual rash (acanthosis nigricans) that is seen in people with some types of diabetes, short stature, renal (kidney) failure, dilated or enlarged heart, and obesity. Visual impairment typically begins with photophobia (abnormal sensitivity to light) in the first 6 months and advances to blindness by 30 years. Obesity is typically present before 5 years and increases with age. Deafness usually presents late in the first decade, and renal failure often occurs by the third decade. AS is inherited in an autosomal recessive pattern and one gene locus has been found on chromosome 2. Testing for AS is available on a research basis.

 


Bardet-Biedl syndrome (BBS) is characterized by more toes or fingers than normal at birth, progressive vision loss, renal abnormalities, developmental delay, hypogonadism (lack of sexual development), short to low normal stature, and obesity. Other findings include diabetes mellitus, endocrinological dysfunction, and behavioral abnormalities. In BBS, the onset of obesity is usually in early childhood. Visual impairment usually presents with color and or night blindness which progresses to blindness by 20 years. Renal abnormalities are varied with 60% of patients having hypertension with renal failure occurring infrequently. BBS is inherited in an autosomal recessive pattern, meaning that affected individuals have two copies of the altered gene and parents of an affected child have a 25% recurrence risk of having another such child together with each pregnancy. At least 6 gene loci (locations) have been found to be linked to BBS in different families. Other families have not been linked to any of these loci, leading researchers to continue to look for other Ioci responsible for BBS. Currently, genetic testing is available on a research basis to families with one or more affected children.


Borjeson-Forssman-Lehmann syndrome (BFLS) is characterized by epilepsy, severe mental retardation, hypotonia, poor sexual development, swelling of subcutaneous tissue in the face, narrow palpebral fissures (narrow opening between the upper and lower eyelids), large ears, height below the 50th percentile, and obesity. BLFS is inherited in an X-linked recessive pattern. An X chromosome gene, FGF13, has been hypothesized as the gene responsible for BLFS. Males with BLFS are severely affected, and female carriers can be mildly to severely affected.


Cohen syndrome is characterized by mental retardation with a sociable/cheerful personality, small head size, hypotonia (weak muscle tone), abnormal curvature or rounding of the spine, short stature, narrow hands1-progressive heart disease, near­sightedness, vision problems, prominent incisors (eye teeth), blood white cell problems, and obesity. In Cohen syndrome, obesity tends to develop by the school age years, and the mental handicap is non-progressive. :Cohen syndrome is inherited in an autosomal recessive pattern. The Cohen syndrome gene is designated COH1 and is located on chromosome 8.


Fragile X syndrome is characterized by mental retardation, increased growth in childhood, large head, large ears, dental crowding, and large testicles. In some cases, obesity is also seen in individuals with fragile X syndrome. Fragile X syndrome is an X­linked recessive condition involving the expansion of a repeated sequence of DNA in the FMR1 gene on the X chromosome. There are three levels of repeats: normal, premutation, and full mutation. Individuals with a premutation, especially females, have an increased risk of passing on a full mutation to offspring because of instability in the FMR1 gene.

A subset of patients with fragile X syndrome have physical characteristics (phenotype) that are different from those seen in the classic presentation. These individuals have a full, round face, small and broad hands/feet, areas of more darkly colored skin (hyperpigmentation), and obesity. The reported phenotype in these patients has been compared to the PWS phenotype with differences being lack of infantile floppiness and food seeking in childhood. In one study, individuals with these characteristics were found to have full fragile X syndrome mutations and no abnormalities in the PWS region. Fragile X analysis is widely available hand should be considered in cases of childhood obesity.


There are also several well-defined chromosomal abnormalities that are associated with increased risk for obesity. Individuals with Down, Klinefelter, and Turner syndromes have a high risk of becoming overweight and obese.

Down syndrome is caused by three copies of chromosome 21 and is a highly recognized genetic syndrome. Individuals with Down syndrome can develop obesity stemming from environmental causes such as overeating and lack of exercise. However, several features of Down syndrome can also explain a higher prevalence of obesity. Individuals with Down syndrome can have short stature, hypotonia, and hypothyroidism, all of which increase the likelihood of becoming obese.

Turner syndrome occurs in females and is the usual result of losing one X chromosome during fetal development. Short stature, broad chest, developmental abnormalities of the heart and large blood vessels, and neck webbing are common characteristics. Growth hormone replacement therapy is becoming common treatment for short stature individuals with Turner syndrome.

Role of Leptin

Leptin receptor mutations have also been associated with the characteristics of leptin deficiency plus initial growth retardation and hypothyroidism due to changes in the hypothalamus of the brain. Three sisters have been described with high serum leptin levels with mutations in the leptin receptor gene on chromosome 1. These individuals had normal birth weight, early growth deficiency and hyperphagia that led to obesity. Autosomal recessive inheritance was suggested.

MC4R Gene

Another gene with a possibly greater effect on the presence of obesity in the general population is MC4R, located on chromosome 19. MC4R, melanocortin receptor, is present in high levels in areas of the hypothalamus that are known to be involved in feeding behavior. Mutations in MC4R have been described in several families and have been found by screening populations of obese children and adults. Studies have found that 3-5% of individuals with a BMI greater than 40 have a mutation in the MC4R gene. Most individuals have one copy of the changed gene and one copy of the normal gene implying autosomal dominant inheritance for obesity associated with MC4R mutations. MC4R mutations appear to cause a "pure" obesity syndrome; no other endocrine abnormalities have been associated with mutations.

Head Trauma

A thorough evaluation of obesity in children should also include consideration of head trauma affecting the hypothalamus. This condition is termed hypothalamic obesity (Note: this is often called "Acquired Prader-Willi Syndrome") and is thought to arise from overeating due to poor regulation of satiety and hunger~-Besides obesity, hypothalamic insult can lead to other endocrine abnormalities including growth hormone deficiency and hypothyroidism, both of which exacerbate obesity. However, hormone replacement has not proven to be effective in treating obesity in these patients.

Hypothalamic obesity can be seen in children with brain tumors, those who have undergone surgery, or those who have had radiation. One study of patients with craniopharyngioma showed that these patients have increased serum leptin concentrations and severe obesity. This is contrary to expected effects of increased leptin, based on obese patients with leptin deficiency. A proposed explanation is hypothalamic insensitivity to endogenous leptin due to the underlying brain damage of study patients.

Obesity

Obesity, regardless of cause, has psychological impacts on affected individuals and families. In children that are mentally retarded, that impact may actually be greater on the parents and caregivers. Our society favors and holds individuals who are not overweight/obese in better esteem. This attitude is overtly expressed in the media, and a great amount of resources are aimed at persuading individuals that weight loss is not only desired, but also required for a successful life.

Many studies have shown that obese children demonstrate increased psychopathology and social problems when compared to non-obese peers. Data has also suggested that weight loss leads to improvement in psychological functioning. Many previous studies have used children seeking psychological or psychiatric treatment as a study population to observe differences between obese and non-obese children, It is very important that a correct diagnosis be made because of the varied treatment options available that are syndrome specific. Quality of life can be improved through treatments, and better psychological adjustment can be achieved through proper family education about a particular diagnosis."


Several genes have also been linked to severe childhood obesity without being associated with other congenital defects characteristic of traditional childhood obesity syndromes. The leptin gene, a gene having many similarities to the mouse obesity gene ob, has been mapped to chromosome 7. Leptin deficiency leading to morbid obesity has been recently described in two families. Leptin mutations have been associated with morbid obesity, increased appetite and hyperphagia, and poor or slow sexual development. Both of these families illustrated autosomal recessive inheritance. Leptin replacement therapy has been initiated with success in patients with congenital leptin deficiency. Weight reduction was sustained due to decreased appetite and food consumption. Gonadotropin (brain sex hormones) levels also increased after 12 months of leptin therapy. This treatment may help prevent the lack of sexual development seen in adults with leptin deficiency.

Klinefelter syndrome occurs in males and is also known as XXY syndrome. Characteristics of this syndrome include hypogonadism, infertility, long limbs, progressive enlargement of the breast tissue, truncal obesity, and increased risk for certain kinds of tumors. Testosterone therapy has proven useful in patients with XXY to normalize adolescent development and increase muscle mass.