Paula and Bobby
Parents of Lillie
Prader-Willi syndrome (PWS)
What is Prader-Willi syndrome (PWS)?
Prader-Willi syndrome is a genetic disorder that is currently the most common cause of life-threatening childhood obesity. In childhood, individuals with the condition develop an insatiable appetite that triggers chronic overeating.
The syndrome occurs in 1 in 15,000 live births.
Prader-labhart-willi Syndrome, PWS
What gene changes cause Prader-Willi syndrome (PWS)?
In 70% of cases, a deletion on the paternal copy of chromosome 15 in each cell causes the syndrome. 25% of cases are caused by the duplication of chromosome 15 from the mother. The remainder of cases are caused by a translocation between both chromosomes 15 and subsequent deletion of a portion. The condition is most often the result of a random mutation or event.
Microdeletion inheritance occurs when there is a deletion of several genes on a chromosome. The specific chromosome on which the deletions occur will determine the syndrome they cause.
Normally we inherit one copy of each chromosome pair from each biological parent. In the case of disomy, both copies of the chromosome pair are received from one parent and none from the other. This is also often known as uniparental disomy. With most genes this is not an issue, and will not cause any medical or health issues. However when specific genes are concerned, issues with genomic imprinting, can cause specific genetic syndromes.
Genes, locations and inheritance modes:
SNORD115-1, 15q11.2 - Microdeletion, Disomy
SNORD116-1, 15q11.2 - Microdeletion, Disomy
NDN, 15q11.2 - Microdeletion, Disomy
PWAR1, 15q11.2 - Microdeletion, Disomy
HERC2, 15q13.1 - Microdeletion, Disomy
SNRPN, 15q11.2 - Microdeletion, Disomy
NPAP1, 15q11.2 - Microdeletion, Disomy
MKRN3, 15q11.2 - Microdeletion, Disomy
PWRN1, 15q11.2 - Microdeletion, Disomy
MAGEL2, 15q11.2 - Microdeletion, Disomy
IPW, 15q11.2 - Microdeletion, Disomy
OMIM Number - 176270 (please check the OMIM page for updated information)
What are the main symptoms of Prader-Willi syndrome (PWS)?
The main symptoms of Prader-Willi syndrome in infancy are hypotonia (low muscle tone), failure to thrive, and feeding difficulties. In childhood, these symptoms are replaced with an insatiable appetite, chronic overeating, obesity, and often the development of diabetes type 2.
Typical facial characteristics of the syndrome include a narrow forehead, almond-shaped eyes, and a triangular mouth. Short stature and small hands and feet are also common physical characteristics.
Other symptoms include underdeveloped genitals in both males and females and delayed or incomplete puberty that often results in infertility. Mild-moderate intellectual disability is common, as are issues with compulsive disorders and problem behavior related to a lack of impulse control.
Possible clinical traits/features:
Delayed speech and language development, Hypoventilation, Generalized hypotonia, Generalized hypopigmentation, Frontal upsweep of hair, Hypopigmentation of the skin, Hypopigmentation of hair, Hypogonadotropic hypogonadism, Hypoplastic labia minora, Short foot, Adrenal insufficiency, Hip dysplasia, Short stature, Global developmental delay, Growth hormone deficiency, Polyphagia, Hyperinsulinemia, Nasal speech, Hypermetropia, Kyphosis, Osteoporosis, Oligomenorrhea, Obesity, Primary amenorrhea, Precocious puberty, Psychosis, Syndactyly, Seizure, Cutaneous photosensitivity, Poor gross motor coordination, Poor fine motor coordination, Poor suck, Scrotal hypoplasia, Esotropia, Clitoral hypoplasia, Dolichocephaly, Ventriculomegaly, Motor delay, Delayed puberty, Impaired pain sensation, Decreased muscle mass, Failure to thrive in infancy, Cryptorchidism, Decreased fetal movement, Downturned corners of mouth, Infertility, Micropenis, Osteopenia, Intellectual disability, Myopia, Narrow nasal bridge, Narrow palm
How does someone get tested for Prader-Willi syndrome (PWS)?
The initial testing for Prader-Willi syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Prader-Willi syndrome (PWS)
* Based on London Medical Databases (LMD)
The cardinal features of this condition are well known. Severe hypotonia is usually present at birth, and feeding difficulties and failure to thrive may predominate in the first year of life. In the second year over-eating may begin, with subsequent obesity. Short stature, mental retardation, hypogonadism and small hands and feet complete the clinical picture. Average adult height in males is 155cm and in females 147cm (Holm et al., 1993). Nagai et al., (2000) provide growth curves for Prader-WIlli syndrome. Mental retardation is mild to moderate, although up to 10% of adults are said to have an IQ within the normal range (Greenswag, 1987). Excessive skin 'picking' and thick saliva have been noted as unusual signs. Fair hair and skin has been noted in many patients, especially those with a deletion of chromosome 15 (Lee et al., 1994, Spritz et al., 1997).
Growth hormone deficiency and precocious puberty have been reported (Crino et al., 2008) and repeated hypoglycemia with its consequences can add to the problem (Harrington et al., 2014).
Eiholzer et al., (2000) suggest that growth hormone improves motor development, but not speech development in Prader-Willi syndrome. Myers et al., (2000) studied 35 Prader-Willi children given growth hormone for 24 months and found that there was an increase in lean body mass, a decrease in percentage body fat and improvements in physical strength and agility. However, between 12 and 24 months the growth rate slowed. Eiholzer et al., (2003) suggested that a well-defined and easy-to-accomplish training program improves local body composition and has generalized effects on physical activity and capacity. A patient on growth hormone treatment who died suddenly was reported by van Vliet et al.,(2004). Unexpected death (hypothalamic dysfunction) must not be underestimated (Stevenson et al., 2004). Schrander-Stumpel et al., (2004), looked at the cause of death in 27 cases. In young children hypotonia and hypoventilation were risk factors. Rumination and aspiration, were contributary causes. No child was on growth hormone. Nagai et al., (2005) discussed the causes of sudden unexpected death and concluded that a respiratory dysregulation and hypothalamic dysunction may have been present in deceased PWS patients, and that growth hormone therapy may have led to obstructive respiratory disturbances. A patient reported by Wilson et al., (2006) developed respiratory distress whilst on growth hormone, and improved when therapy was stopped. Intractable metabolic acidosis resulting in death was reported by Zaglia et al., (2005). Nagai et al., (2006) mentioned that scoliosis was not induced by GH therapy, although a non-obese boy reported by Tokutomi et al., (2006), with severe scoliosis and respiratory distress, was on GH.
Ten patients over the age of 50 years were reported by Sinnema et al., (2012). Behavioral problems were common.
Vogels et al., (2003) studied 59 patients and found that six (15.7%) had experienced a psychotic episode. Five of these patients had uniparental disomy. Holm et al., (1993) present a good review of the consensus diagnostic criteria. Whittington et al., (2001) estimate the population prevalence to be 1 in 52,000, with a birth incidence of 1 in 29,000. The mean mortality rate was estimated to be 3% for all ages but about 7% above the age of 30. Smith et al., (2003) estimated the birth prevalence to be 1 in 25,000.
Fifty-five to seventy percent of patients can be shown to have a small, paternally-derived deletion of the proximal part of the long arm of chromosome 15 by cytogenetic analysis. Of cases without a cytogenetic deletion 40% have deletions detectable at the DNA level and 60% have maternal disomy for part or all of chromosome 15 (Mascari et al., 1992). Cassidy et al., (1997) provided evidence suggesting that cases with uniparental disomy were less likely to have a typical facial appearance or to show manifestations such as skin picking. Cases without evidence of 15q deletions or maternal disomy should be re-assessed clinically (Lai et al., 1993) (although Orstavik et al., (1992) reported a convincingly affected sib pair without 15q abnormalities). Smith-Magenis syndrome (17p-) should be considered where chromosome 15q studies are negative. Lammer et al., (2001) reported a child with features of Prader-Willi syndrome who was shown to have an Xq27.2->qter duplication.
Cassidy et al., (1992) reported a female infant with the clinical features of Prader-Willi syndrome where trisomy 15 had been demonstrated on a chorionic villus biopsy but cells from the infant showed a 46,XX karyotype with maternal disomy 15. Purvis-Smith et al., (1992) reported a similar case. Christian et al., (1996) studied three cases where mosaic trisomy 15 had been picked up at amniocentesis and four cases at CVS. One of the amniocentesis and one of the CVS cases was found to have uniparental disomy for chromosome 15. The authors recommend testing for uniparental disomy in all cases where mosaic trisomy 15 is encountered by CVS or amniocentesis. Olander et al., (2000) reported a boy with mosaic trisomy 15 associated with uniparental disomy 15. The phenotype was more severe than that usually seen in Prader-Willi syndrome.
Robinson et al., (1993) and Liehr et al., (2005) showed that in cases of Prader-Willi syndrome with an additional marker chromosome derived from 15, maternal uniparental disomy can be demonstrated. However Bettio et al., (1997) reported one case with a marker 15 not including the Prader-Willi region who had a 15q11-13 deletion and also a patient with a marker X chromosome and maternal uniparental disomy for chromosome 15. Mowery-Rushton et al., (1996) reported cases with mosaicism for deletions of 15q11-13. Hulten et al., (1991) reported a family where a balanced (15;22)(q13;q11) was segregating. Unbalanced paternal transmission of the derived 15 resulted in Prader-Willi syndrome, whereas maternal transmission resulted in Angelman syndrome. Toth-Fejel et al., (1996) reported two cases where cryptic translocations had apparently led to nondisjunction and secondary maternal disomy. The translocations involved heteromorphic satellite regions of chromosomes 14 and 15. High resolutions banding of chromosome 15 long arms was normal. The authors report that out of 50 PWS cases referred to the laboratory 3 (6%) had a translocation involving chromosome 15. Three families have been reported where normal individuals carrying a balanced chromosome 15 translocation involving 15q11-13 have had children with Prader-Willi or Angelman syndrome (Smeets et al., 1992; Horsthemke et al., 1996). The mechanism is a deletion, thought to be due to unequal crossing over involving the translocated chromosome with the 15 centromere. Devriendt et al., (1997) reported detailed molecular studies on a girl with mosaic trisomy 15 and mosaic XXX with features of Prader-Willi syndrome.
Ozcelik et al., (1992), Leff et al., (1992) and Glenn et al., (1993) showed that the small nuclear ribonuclear protein polypeptide N (SmN) gene (SNRPN) at 15q12 is imprinted in the mouse and Cattanach et al., (1992) showed that maternal disomy for the equivalent region on mouse chromosome 7 resulted in absence of SNRPN expression. Driscoll et al., (1992) identified parental differences in DNA methylation at the D15S9 locus, identified by the highly evolutionarily conserved cDNA, DN34. However, Buiting et al., (1993) demonstrated that the shortest region of deletion overlap in Prader-Willi syndrome does not include this locus, but does include the marker PW71 (D15S63) and the SNRPN gene. PW71 is subject to sex-specific methylation (Dittrich et al., 1993). Reed and Leff (1994) demonstrated maternal imprinting of the SNRPN gene in humans with Prader-Willi syndrome. Wevrick et al., (1994) identified a gene, IPW, from the Prader-Willi region. They suggested that this gene functions at the RNA level, similar to H19 and XIST. The gene was shown to be exclusively paternally expressed in fetal tissue and is located about 150 kb distal to SNRPN. Butler et al., (1996) reported a female case with a very small 100-200 kb deletion including the SNRPN gene but not the PW71 gene. She had clinical features of Prader-Willi syndrome but apparently no behaviour problems or hyperphagia, and borderline normal intelligence at the age of 6 years. Note Buiting et al., (1999) reported five families where there was a 28-kb deletion spanning the PW71 gene without pathological effect or abnormalities in imprinting. This appeared to be a neutral variant. Reis et al., (1994) reported abnormal maternal imprinting of paternal alleles at loci in the 15q11-q13 region in a small proportion of cases. Buiting et al., (1995) identified a putative imprinting centre proximal to the Prader-Willi syndrome critical region. Cases with deletion of this region on the paternal 15 had maternal-type imprinting. Ohta et al., (1999) studied further patients with imprinting mutations. Buiting et al., (1998) studied patients with Prader-Willi syndrome and Angelman syndrome with abnormalities of imprinting, but no evidence of a microdeletion of the imprinting centre. All cases were sporadic, and the authors suggested that these cases have a low recurrence risk. However note that Buiting et al., (2000) reported a normal male with two affected daughters with a microdeletion affecting the chromosome 15 imprinting centre.
Dittrich et al., (1996) identified novel transcripts of the SNRPN gene, lacking protein coding potential. Deletions in the SNRPN gene were found in three Prader-Willi cases. The authors suggest that deletion of exon 1 of the SNRPN gene are associated with a block of the maternal to paternal imprint switch. Bielinska et al., (2000) studied a male with a mosaic deletion of exon 1 of the SNRPN gene and showed that the deletion chromosome acquired a maternal methylation imprint in his somatic cells. Similar findings were also shown in chimeric mice. The studies demonstrated that the imprinting sensor element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance. Kubota et al., (1996) provided data showing that SNRPN methylation analysis may be useful for prenatal diagnosis using CVS samples, but not PW71, in families known to carry imprinting centre defects. Glenn et al., (2000) confirm this from 24 cases of prenatal diagnosis of Prader-Willi and Angelman syndromes. Rogan et al., (1998) reported two cases with relaxation of imprinting. Although the SNRPN gene appeared to be imprinted, other imprinted genes in the region were normally expressed. The patients had a partial Prader-Willi phenotype. Wevrick and Francke (1996) reported a diagnostic test by looking at SNRPN expression by PCR analysis of reverse transcribed mRNA in leukocytes. MacDonald and Wevrick (1997) identified a gene necdin, which is deleted in Prader-Willi syndrome and is expressed exclusively from the paternally inherited allele. This makes it a good candidate for some of the features of Prader-Willi syndrome. Necdin codes for a nuclear protein expressed exclusively in differentiated neurons in the brain in the mouse. Grard et al., (1999) knocked out the necdin gene and showed that mice inheriting a paternal deletion had early post-natal lethality, whereas those inheriting a maternal deletion were normal.
de los Santos et al., (2000) identified a novel imprinted gene, PWCR1, mapping to the Prader-Willi deletion region. This gene was expressed only from the paternal allele and required the imprinting-centre regulatory element for expression. The gene was intronless and did not appear to encode a protein product. PWCR1 was highly expressed in the brain.
LaSalle and Lalande (1996) demonstrated association between maternal and paternal chromosome 15s during late S phase of mitosis. This was not present in cells from Angelman or Prader-Willi patients.
Schulze et al., (1996) reported a case with a translocation through the SNRPN gene with features of Prader-Willi syndrome. Methylation and expression studies suggested that the paternal SNRPN gene was unaffected and that sequences distal to the gene may be critical for the Prader-Willi phenotype. Sun et al., (1996) reported a patient with a de novo translocation through the SNRPN gene with features of Prader-Willi syndrome. The translocation was paternal in origin. Kuslich et al., (1999) reported a boy with a balanced translocation interrupting the second and third exons of the SNRPN gene. Wirth et al., (2001) studied another patient with a de novo balanced reciprocal translocation with one breakpoint in proximal 15q. They demonstrated a translocation breakpoint cluster between SNURF-SNRPN and IPW. Ishikawa et al., (1996) reported affected sibs with Prader-Willi syndrome who were apparently just deleted for SNRPN by FISH, but not GABRB3, or other probes in the Prader-Willi critical region. Surprisingly, no comment is made about FISH studies on the parents.
Coppes et al., (1993) reported a case with a paternal deletion of 15q11-q13 and associated Wilms' tumour. No deletion or disomy for 11p was found. Cassidy et al., (2000) provides a good review of the clinical and molecular features up to 2000.
Hassan et al. (2016) described a female with a rare atypical submicroscopic deletion involving imprinting center and encompassing the SNURF-SNRPN gene complex and adjacent non-coding RNA SNORD116. The authors compared her clinical findings to the findings of other individuals in the literature with similar atypically sized deletions without involvement of the imprinting center. Individuals with involvement of the minimal critical region had better growth and fewer cognitive problems.
Cao et al. (2017) described a female patient with a de novo 6.4 kb deletion in 15q11.2 region, encompassing SNURF/SNRPN genes and being the shortest deletion reported up to date associated with PWS phenotype.
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