Editing Prader–Willi syndrome (section)

== Signs and symptoms ==
PWS symptoms can range from poor muscle tone during infancy to behavioral problems in early childhood. Some symptoms often found in infants, besides poor muscle tone, are a lack of eye coordination; almond-shaped eyes; thin upper lip; and, due to poor muscle tone, lack of a strong sucking reflex. Their cries are weak, and they have difficulty waking up.<ref>{{cite web |title=Mayo Clinic, Diseases and Conditions |url=https://www.mayoclinic.org/diseases-conditions/prader-willi-syndrome/symptoms-causes/syc-20355997 |website=Prader-Willi Syndrome, Symptoms and Causes |access-date=6 February 2019}}</ref>

More aspects seen in a clinical overview include hypotonia and abnormal neurologic function, hypogonadism, developmental and cognitive delays, hyperphagia and obesity, short stature, and behavioral and psychiatric disturbances.<ref name=Cas2008>{{cite journal|last1=Cassidy|first1=Suzanne B|last2=Driscoll|first2=Daniel J|title=Prader–Willi syndrome|journal=European Journal of Human Genetics|date=September 10, 2008|volume=17|issue=1|pages=3–13|doi=10.1038/ejhg.2008.165|pmid=18781185|pmc=2985966}}</ref>

The following features and signs are indicators of PWS, although not all will be present:<ref>{{Cite journal|last1=Holm|first1=V. A.|last2=Cassidy|first2=S. B.|last3=Butler|first3=M. G.|last4=Hanchett|first4=J. M.|last5=Greenswag|first5=L. R.|last6=Whitman|first6=B. Y.|last7=Greenberg|first7=F.|date=Feb 1993|title=Prader-Willi syndrome: consensus diagnostic criteria|journal=Pediatrics|volume=91|issue=2|pages=398–402|doi=10.1542/peds.91.2.398|issn=0031-4005|pmc=6714046|pmid=8424017}}</ref><ref>{{cite web |title=Prader-Willi syndrome - Symptoms |url=https://www.nhs.uk/conditions/prader-willi-syndrome/symptoms/ |website=NHS |language=en |date=23 October 2017}}</ref>

=== In-utero and birth ===
{{columns-list|colwidth=30em|
* Reduced fetal movement
* Frequent abnormal fetal position
* Occasional [[polyhydramnios]] (excessive amniotic fluid)
* Often [[Breech birth|breech]] or [[caesarean]] births
* [[Lethargy]]
* [[Hypotonia]]
* Feeding difficulties (due to poor muscle tone affecting [[sucking reflex]])
* Difficulties establishing respiration
* [[Hypogonadism]]
}}

=== Childhood ===
{{columns-list|colwidth=30em|
* Delayed milestones/intellectual delay
* [[Hypersomnia|Excessive sleeping]]
* [[Strabismus]] (crossed eyes)
* [[Scoliosis]] (often not detected at birth)
* [[Cryptorchidism]]
* [[Speech delay]]
* Poor physical coordination
* [[Polyphagia|Hyperphagia]] (excessive hunger) begins between the ages of 2 and 8, and continues throughout adulthood.
* [[Childhood obesity|Excessive weight gain]]
* [[Sleep disorders]]
* Delayed [[puberty]]
* Short stature
* [[Obesity]]
* Extreme flexibility
* Narrow forehead at the temples
* Narrow nose bridge
* Thin upper lip
* Downturned mouth
* Unusually fair hair, skin, and eyes
* Small hands and feet
* [[Tooth decay]] owing to the underproduction of saliva
* [[Constipation]] or swollen stomachs owing to poor muscle tone in the gut
* Low levels of [[HGH]]
}}

=== Adulthood ===
{{columns-list|colwidth=30em|
* Infertility (males and females)
* [[Hypogonadism]]
* Sparse pubic hair
* Obesity
* [[Hypotonia]] (low muscle tone)
* [[Intellectual disability|Learning disabilities/borderline intellectual functioning]] (but some cases of average intelligence)
* Prone to [[type 2 diabetes mellitus]]
* Extreme flexibility
}}

=== Physical appearance ===
{{columns-list|colwidth=30em|
* Prominent nasal bridge
* Small hands and feet with tapering of fingers
* Soft skin, which is easily bruised
* Excess fat, especially in the central portion of the body
* High, narrow forehead
* Thin top lip
* Downturned mouth
* Almond-shaped eyes
* Light skin and hair relative to other family members
* Lack of complete sexual development
* Frequent [[skin picking]]
* [[Stretch marks]]
* Delayed motor development
}}

=== Neurocognitive ===
Individuals with PWS are at risk of learning and attention difficulties. Curfs and Fryns (1992) conducted research into the varying degrees of [[learning disability]] found in PWS.<ref name="pmid1340242">{{cite journal |vauthors=Curfs LM, Fryns JP | title = Prader-Willi syndrome: a review with special attention to the cognitive and behavioral profile | journal = Birth Defects Orig. Artic. Ser. | volume = 28 | issue = 1 | pages = 99–104 | year = 1992 | pmid = 1340242 }}</ref>

Cassidy found that 40% of individuals with PWS have borderline/low average intelligence,<ref name="pmid9391886">{{cite journal | author = Cassidy SB | title = Prader-Willi syndrome | journal = Journal of Medical Genetics | volume = 34 | issue = 11 | pages = 917–23 | year = 1997 | pmid = 9391886 | pmc = 1051120 | doi = 10.1136/jmg.34.11.917 }}</ref> a figure higher than the 32% found in Curfs and Fryns' study.<ref name="pmid1340242" /> However, both studies suggest that most individuals (50–65%) fall within the mild/borderline/low average intelligence range.{{citation needed|date=January 2023}}

Children with PWS show an unusual cognitive profile. They are often strong in visual organization and perception, including reading and vocabulary, but their spoken language (sometimes affected by [[hypernasality]]) is generally poorer than their comprehension. A marked skill in completing [[jigsaw puzzle]]s has been noted,<ref name="Udwin">{{cite web |author=Udwin O |title=Prader-Willi syndrome: Psychological and behavioural characteristics |date=November 1998 |publisher=Contact a Family |url=http://www.cafamily.org.uk/medicalinformation/conditions/azlistings/p33_3.html |url-status=dead |archive-url=https://web.archive.org/web/20110716085822/http://www.cafamily.org.uk/medicalinformation/conditions/azlistings/p33_3.html |archive-date=July 16, 2011  }}</ref><ref>{{cite journal |vauthors=Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, Greenberg F | title = Prader-Willi syndrome: consensus diagnostic criteria | journal = Pediatrics | volume = 91 | issue = 2 | pages = 398–402 | year = 1993 | doi = 10.1542/peds.91.2.398 | pmid = 8424017 | pmc = 6714046 }}</ref> but this may be an artifact of increased practice.<ref>{{cite journal |vauthors=Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H | title = Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome | journal = Journal of Intellectual Disability Research | volume = 48 | issue = Pt 2 | pages = 172–87 | date = February 2004 | pmid = 14723659 | doi = 10.1111/j.1365-2788.2004.00556.x }}</ref>

Auditory information processing and sequential processing are relatively poor, as are arithmetic and writing skills, visual and [[Working memory|auditory short-term memory]], and auditory [[attention span]]. These sometimes improve with age, but deficits in these areas remain throughout adulthood.<ref name="Udwin" />

PWS may be associated with psychosis.<ref>{{cite journal|last1=Boer|first1=H|last2=Holland|first2=A|last3=Whittington|first3=J|last4=Butler|first4=J|last5=Webb|first5=T|last6=Clarke|first6=D|s2cid=21083489|title=Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy.|journal=Lancet|date=January 12, 2002|volume=359|issue=9301|pages=135–6|doi=10.1016/S0140-6736(02)07340-3|pmid=11809260}}</ref>

=== Behavioral ===
PWS is frequently associated with a constant insatiable appetite, which persists no matter how much the patient eats, often resulting in [[morbid obesity|severe obesity]]. Caregivers need to strictly limit the patients' access to food, usually by installing locks on refrigerators and on all closets and cabinets where food is stored.<ref name="treatments">{{cite web |url=https://www.nichd.nih.gov/health/topics/prader-willi/conditioninfo/Pages/treatments.aspx |title=What are the treatments for Prader-Willi syndrome (PWS)? |access-date=June 16, 2016 |url-status=live |archive-url=https://web.archive.org/web/20160706030852/https://www.nichd.nih.gov/health/topics/prader-willi/conditioninfo/Pages/treatments.aspx |archive-date=July 6, 2016  }}</ref> It is the most common genetic cause of morbid obesity in children.<ref name="Nordqvist" /> Currently, no consensus exists as to the cause for this symptom, although genetic abnormalities in chromosome 15 disrupt the normal functioning of the [[hypothalamus]].<ref name="pmid9391886" /> Given that the hypothalamic [[arcuate nucleus]] regulates many basic processes, including appetite, a link may well exist. In the hypothalamus, nerve cells that produce [[oxytocin]], a hormone thought to contribute to satiety, are believed to be abnormal in people with PWS.<ref>{{cite journal |last1= Fahrenholz |first1= Falk |last2= Gimpl |first2= Gerald |date= 2001 |title= The Oxytocin Receptor System: Structure, Function, and Regulation |url= https://journals.physiology.org/doi/full/10.1152/physrev.2001.81.2.629 |journal= [[Physiological Reviews]] |volume= 81 |issue= 2 |pages= 629–683 |doi= 10.1152/physrev.2001.81.2.629 |pmid= 11274341 |s2cid= 13265083 |accessdate= 2023-01-06}}</ref>

People with PWS have high [[ghrelin]] levels, which are thought to contribute directly to the increased appetite, hyperphagia, and obesity seen in this syndrome.<ref name="pmid12091883">{{cite journal | vauthors = Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, Schwartz MW, Basdevant A, Weigle DS | s2cid = 5253679 | title = Elevated plasma ghrelin levels in Prader Willi syndrome | journal = Nature Medicine | volume = 8 | issue = 7 | pages = 643–4 | date = July 2002 | pmid = 12091883 | doi = 10.1038/nm0702-643 | url = https://zenodo.org/record/1233443 }}</ref> Cassidy states the need for a clear delineation of behavioral expectations, the reinforcement of behavioural limits, and the establishment of regular routines.

The main mental health difficulties experienced by people with PWS include compulsive behaviour (usually manifested in skin picking) and anxiety.<ref name="Udwin" /><ref>{{cite journal |vauthors=Clark DJ, Boer H, Webb T |title=General and behavioural aspects of PWS: a review |journal=Mental Health Research |volume=8 |issue=195 |pages=38–49 |year=1995 }}</ref> Psychiatric symptoms, for example, hallucinations, paranoia and depression, have been described in some cases<ref name="Udwin" /> and affect about 5–10% of young adults.<ref name="pmid9391886" />  Patients are often extremely stubborn and prone to anger.<ref name="treatments" /> Psychiatric and behavioural problems are the most common cause of hospitalization.<ref>{{cite journal |vauthors=Cassidy SB, Devi A, Mukaida C |title=Aging in PWS: 232 patients over age 30 years |journal=Proc. Greenwood Genetic Centre |volume=13 |pages=102–3 |year=1994 }}</ref>

Typically, 70–90% of affected individuals develop behavioral patterns in early childhood.<ref name=Cas2008 /> Aspects of these patterns can include stubbornness, temper tantrums, controlling and manipulative behavior, difficulty with change in routine, and compulsive-like behaviors.<ref name=Cas2008 />

=== Endocrine ===
Several aspects of PWS support the concept of a growth hormone deficiency. Specifically, individuals with PWS are obese with short stature, abnormal body composition, reduced fat-free mass, reduced lean body mass and total energy expenditure, and decreased bone density. PWS is characterized by hypogonadism. This is manifested as undescended testes in males and benign premature [[adrenarche]] in females. Testes may descend with time or can be managed with surgery or testosterone replacement. Adrenarche may be treated with hormone replacement therapy.{{citation needed|date=May 2022}}

=== Ophthalmologic ===
PWS is commonly associated with the development of [[strabismus]]. In one study,<ref>{{cite journal |vauthors=Hered RW, Rogers S, Zang YF, Biglan AW | title = Ophthalmologic features of Prader-Willi syndrome | journal = J Pediatr Ophthalmol Strabismus | volume = 25 | issue = 3 | pages = 145–50 | year = 1988 | doi = 10.3928/0191-3913-19880501-10 | pmid = 3397859 }}</ref> over 50% of patients had strabismus, mainly [[esotropia]].

Some individuals (often those with deletions) may have hypopigmented fundi due to [[OCA2]] [[haploinsufficiency]].