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Prader-Willi syndrome(PWS)

MedGen UID:
46057
Concept ID:
C0032897
Congenital Abnormality
Synonyms: Obesity, muscular hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, and small hands and feet; Prader Labhart Willi syndrome; PWS
Modes of inheritance:
Sporadic
MedGen UID:
342827
Concept ID:
C1853237
Finding
Sources: HPO, OMIM
Cases of the disease in question occur without a previous family history, i.e., as isolated cases without being transmitted from a parent and without other siblings being affected.
not inherited
MedGen UID:
832438
Concept ID:
CN227390
Intellectual Product
Source: Orphanet
Describes a disorder that is not inherited.
Sporadic (HPO, OMIM)
not inherited (Orphanet)
SNOMED CT: Prader-Willi syndrome (89392001)
 
Genes (locations): HERC2 (15q13.1); IPW (15q11.2); MAGEL2 (15q11.2); MKRN3 (15q11.2); MKRN3-AS1 (15q11-q13); NDN (15q11.2); NPAP1 (15q11.2); PWAR1 (15q11.2); PWRN1 (15q11.2); SNORD115-1 (15q11.2); SNORD116-1 (15q11.2); SNRPN (15q11.2)
OMIM®: 176270
Orphanet: ORPHA739

Disease characteristics

Excerpted from the GeneReview: Prader-Willi Syndrome
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present. [from GeneReviews]
Authors:
Daniel J Driscoll  |  Jennifer L Miller  |  Stuart Schwartz, et. al.   view full author information

Additional descriptions

From OMIM
Prader-Willi syndrome is characterized by diminished fetal activity, obesity, muscular hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, and small hands and feet. It can be considered to be an autosomal dominant disorder and is caused by deletion or disruption of a gene or several genes on the proximal long arm of the paternal chromosome 15 or maternal uniparental disomy 15, because the gene(s) on the maternal chromosome(s) 15 are virtually inactive through imprinting. Horsthemke and Wagstaff (2008) provided a detailed review of the mechanisms of imprinting of the Prader-Willi/Angelman syndrome (105830) region. See also the chromosome 15q11-q13 duplication syndrome (608636), which shows overlapping clinical features.  http://www.omim.org/entry/176270
From GHR
Prader-Willi syndrome is a complex genetic condition that affects many parts of the body. In infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes mellitus (the most common form of diabetes).People with Prader-Willi syndrome typically have mild to moderate intellectual impairment and learning disabilities. Behavioral problems are common, including temper outbursts, stubbornness, and compulsive behavior such as picking at the skin. Sleep abnormalities can also occur. Additional features of this condition include distinctive facial features such as a narrow forehead, almond-shaped eyes, and a triangular mouth; short stature; and small hands and feet. Some people with Prader-Willi syndrome have unusually fair skin and light-colored hair. Both affected males and affected females have underdeveloped genitals. Puberty is delayed or incomplete, and most affected individuals are unable to have children (infertile).  https://ghr.nlm.nih.gov/condition/prader-willi-syndrome

Clinical features

Adrenal insufficiency
MedGen UID:
1351
Concept ID:
C0001623
Disease or Syndrome
Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands as a result of a primary defect in the glands themselves.
Diabetes mellitus type 2
MedGen UID:
41523
Concept ID:
C0011860
Disease or Syndrome
Diabetes means your blood glucose, or blood sugar, levels are too high. With type 2 diabetes, the more common type, your body does not make or use insulin well. Insulin is a hormone that helps glucose get into your cells to give them energy. Without insulin, too much glucose stays in your blood. Over time, high blood glucose can lead to serious problems with your heart, eyes, kidneys, nerves, and gums and teeth. You have a higher risk of type 2 diabetes if you are older, obese, have a family history of diabetes, or do not exercise. Having prediabetes also increases your risk. Prediabetes means that your blood sugar is higher than normal but not high enough to be called diabetes. The symptoms of type 2 diabetes appear slowly. Some people do not notice symptoms at all. The symptoms can include. -Being very thirsty. -Urinating often. -Feeling very hungry or tired. -Losing weight without trying. -Having sores that heal slowly. -Having blurry eyesight. A blood test can show if you have diabetes. Many people can manage their diabetes through healthy eating, physical activity, and blood glucose testing. Some people also need to take diabetes medicines. NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Oligomenorrhea
MedGen UID:
18159
Concept ID:
C0028949
Pathologic Function
Infrequent menses (less than 6 per year or more than 35 days between cycles).
Precocious puberty
MedGen UID:
18752
Concept ID:
C0034013
Disease or Syndrome
The onset of secondary sexual characteristics before a normal age. Although it is difficult to define normal age ranges because of the marked variation with which puberty begins in normal children, precocious puberty can be defined as the onset of puberty before the age of 8 years in girls or 9 years in boys.
Primary amenorrhea
MedGen UID:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.(AE)
Delayed female puberty
MedGen UID:
543451
Concept ID:
C0271618
Disease or Syndrome
Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty.
Hypogonadotropic hypogonadism 7 with or without anosmia
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are revered to as \
Clinodactyly
MedGen UID:
120550
Concept ID:
C0265610
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Small hand
MedGen UID:
108279
Concept ID:
C0575802
Finding
Disproportionately small hand.
Radial deviation of finger
MedGen UID:
322852
Concept ID:
C1836189
Finding
Bending or curvature of a finger toward the radial side (i.e., towards the thumb). The deviation is at the metacarpal-phalangeal joint, and this finding is distinct from clinodactyly.
Short palm
MedGen UID:
334684
Concept ID:
C1843108
Finding
Short palm.
Short foot
MedGen UID:
376415
Concept ID:
C1848673
Finding
A measured foot length that is more than 2 SD below the mean for a newborn of 27 - 41 weeks gestation, or foot that is less than the 3rd centile for individuals from birth to 16 years of age (objective). Alternatively, a foot that appears disproportionately short (subjective).
Narrow palm
MedGen UID:
346628
Concept ID:
C1857632
Finding
For children from birth to 4 years of age, the palm width is more than 2 SD below the mean; for children from 4 to 16 years of age the palm width is below the 5th centile; or, the width of the palm appears disproportionately narrow for its length.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Obesity means having too much body fat. It is different from being overweight, which means weighing too much. The weight may come from muscle, bone, fat, and/or body water. Both terms mean that a person's weight is greater than what's considered healthy for his or her height. . Obesity occurs over time when you eat more calories than you use. The balance between calories-in and calories-out differs for each person. Factors that might affect your weight include your genetic makeup, overeating, eating high-fat foods, and not being physically active. . Being obese increases your risk of diabetes, heart disease, stroke, arthritis, and some cancers. If you are obese, losing even 5 to 10 percent of your weight can delay or prevent some of these diseases. For example, that means losing 10 to 20 pounds if you weigh 200 pounds. NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Truncal obesity
MedGen UID:
90229
Concept ID:
C0311277
Disease or Syndrome
A condition of having excess fat in the abdomen. Abdominal obesity is typically defined as waist circumferences of 40 inches or more in men and 35 inches or more in women. Abdominal obesity raises the risk of developing disorders, such as diabetes, hypertension and METABOLIC SYNDROME X.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
Height greater than two standard deviations below the mean of the appropriate reference population for the age and sex of the individual.
Poor suck
MedGen UID:
324693
Concept ID:
C1837142
Finding
An inadequate sucking reflex, resulting in the difficult of newborns to be breast-fed.
Sleep apnea
MedGen UID:
11458
Concept ID:
C0037315
Disease or Syndrome
Sleep apnea is a common disorder that causes your breathing to stop or get very shallow. Breathing pauses can last from a few seconds to minutes. They may occur 30 times or more an hour. The most common type is obstructive sleep apnea. It causes your airway to collapse or become blocked during sleep. Normal breathing starts again with a snort or choking sound. People with sleep apnea often snore loudly. However, not everyone who snores has sleep apnea. You are more at risk for sleep apnea if you are overweight, male, or have a family history or small airways. Children with enlarged tonsils may also get it. Doctors diagnose sleep apnea based on medical and family histories, a physical exam, and sleep study results. When your sleep is interrupted throughout the night, you can be drowsy during the day. People with sleep apnea are at higher risk for car crashes, work-related accidents, and other medical problems. If you have it, it is important to get treatment. Lifestyle changes, mouthpieces, surgery, and breathing devices can treat sleep apnea in many people. NIH: National Heart, Lung, and Blood Institute.
Hypoventilation
MedGen UID:
469022
Concept ID:
C3203358
Pathologic Function
A reduction in the amount of air transported into the pulmonary alveoli by breathing, leading to hypercapnia (increase in the partial pressure of carbon dioxide).
Decreased muscle mass
MedGen UID:
373256
Concept ID:
C1837108
Finding
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Diabetes mellitus type 2
MedGen UID:
41523
Concept ID:
C0011860
Disease or Syndrome
Diabetes means your blood glucose, or blood sugar, levels are too high. With type 2 diabetes, the more common type, your body does not make or use insulin well. Insulin is a hormone that helps glucose get into your cells to give them energy. Without insulin, too much glucose stays in your blood. Over time, high blood glucose can lead to serious problems with your heart, eyes, kidneys, nerves, and gums and teeth. You have a higher risk of type 2 diabetes if you are older, obese, have a family history of diabetes, or do not exercise. Having prediabetes also increases your risk. Prediabetes means that your blood sugar is higher than normal but not high enough to be called diabetes. The symptoms of type 2 diabetes appear slowly. Some people do not notice symptoms at all. The symptoms can include. -Being very thirsty. -Urinating often. -Feeling very hungry or tired. -Losing weight without trying. -Having sores that heal slowly. -Having blurry eyesight. A blood test can show if you have diabetes. Many people can manage their diabetes through healthy eating, physical activity, and blood glucose testing. Some people also need to take diabetes medicines. NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Hyperinsulinemia
MedGen UID:
43779
Concept ID:
C0020459
Disease or Syndrome
Abnormally high levels of insulin in the blood.(AE)
Temperature instability
MedGen UID:
329973
Concept ID:
C1820737
Finding
Disordered thermoregulation characterized by an impaired ability to maintain a balance between heat production and heat loss, with resulting instability of body temperature.
Nasal speech
MedGen UID:
107884
Concept ID:
C0566620
Finding
A type of speech characterized by the presence of an abnormally increased nasal airflow during speech.
Dysplasia of acetabulum
MedGen UID:
9258
Concept ID:
C0019555
Congenital Abnormality
The presence of developmental dysplasia of the hip.
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are revered to as \
Clinodactyly
MedGen UID:
120550
Concept ID:
C0265610
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Radial deviation of finger
MedGen UID:
322852
Concept ID:
C1836189
Finding
Bending or curvature of a finger toward the radial side (i.e., towards the thumb). The deviation is at the metacarpal-phalangeal joint, and this finding is distinct from clinodactyly.
Short foot
MedGen UID:
376415
Concept ID:
C1848673
Finding
A measured foot length that is more than 2 SD below the mean for a newborn of 27 - 41 weeks gestation, or foot that is less than the 3rd centile for individuals from birth to 16 years of age (objective). Alternatively, a foot that appears disproportionately short (subjective).
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Downturned corners of mouth
MedGen UID:
356471
Concept ID:
C1866195
Finding
A morphological abnormality of the mouth in which the angle of the mouth is downturned. The oral commissures are positioned inferior to the midline labial fissure.

Professional guidelines

PubMed

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Recent clinical studies

Etiology

Bennett JA, Hodgetts S, Mackenzie ML, Haqq AM, Zwaigenbaum L
Int J Mol Sci 2017 Feb 28;18(3) doi: 10.3390/ijms18030517. PMID: 28264487Free PMC Article
Salles J, Strelnikov K, Carine M, Denise T, Laurier V, Molinas C, Tauber M, Barone P
Neuropsychologia 2016 May;85:137-47. Epub 2016 Mar 16 doi: 10.1016/j.neuropsychologia.2016.03.015. PMID: 26994593
Shivers CM, Leonczyk CL, Dykens EM
J Autism Dev Disord 2016 Jun;46(6):2126-37. doi: 10.1007/s10803-016-2741-5. PMID: 26883647
Bravo GL, Poje AB, Perissinotti I, Marcondes BF, Villamar MF, Manzardo AM, Luque L, LePage JF, Stafford D, Fregni F, Butler MG
Am J Med Genet B Neuropsychiatr Genet 2016 Mar;171B(2):266-75. Epub 2015 Nov 21 doi: 10.1002/ajmg.b.32401. PMID: 26590516
Griggs JL, Sinnayah P, Mathai ML
Neurosci Biobehav Rev 2015 Dec;59:155-72. Epub 2015 Oct 22 doi: 10.1016/j.neubiorev.2015.10.003. PMID: 26475993

Diagnosis

Bennett JA, Hodgetts S, Mackenzie ML, Haqq AM, Zwaigenbaum L
Int J Mol Sci 2017 Feb 28;18(3) doi: 10.3390/ijms18030517. PMID: 28264487Free PMC Article
Even-Zohar Gross N, Geva-Eldar T, Pollak Y, Hirsch HJ, Gross I, Gross-Tsur V
Eur J Med Genet 2017 Apr;60(4):205-211. Epub 2017 Jan 22 doi: 10.1016/j.ejmg.2017.01.003. PMID: 28119110
Hassan M, Butler MG
Eur J Med Genet 2016 Nov;59(11):584-589. Epub 2016 Sep 19 doi: 10.1016/j.ejmg.2016.09.017. PMID: 27659713
Shivers CM, Leonczyk CL, Dykens EM
J Autism Dev Disord 2016 Jun;46(6):2126-37. doi: 10.1007/s10803-016-2741-5. PMID: 26883647
Hurren BJ, Flack NA
Clin Anat 2016 Jul;29(5):590-605. Epub 2016 Jan 29 doi: 10.1002/ca.22686. PMID: 26749552

Therapy

Bravo GL, Poje AB, Perissinotti I, Marcondes BF, Villamar MF, Manzardo AM, Luque L, LePage JF, Stafford D, Fregni F, Butler MG
Am J Med Genet B Neuropsychiatr Genet 2016 Mar;171B(2):266-75. Epub 2015 Nov 21 doi: 10.1002/ajmg.b.32401. PMID: 26590516
Bonnot O, Cohen D, Thuilleaux D, Consoli A, Cabal S, Tauber M
Eur J Pediatr 2016 Jan;175(1):9-18. Epub 2015 Nov 19 doi: 10.1007/s00431-015-2670-x. PMID: 26584571
Botezatu A, Puiu M, Cucu N, Diaconu CC, Badiu C, Arsene C, Iancu IV, Plesa A, Anton G
Gene 2016 Jan 10;575(2 Pt 1):353-8. Epub 2015 Sep 1 doi: 10.1016/j.gene.2015.08.058. PMID: 26335514
Manning KE, McAllister CJ, Ring HA, Finer N, Kelly CL, Sylvester KP, Fletcher PC, Morrell NW, Garnett MR, Manford MR, Holland AJ
J Intellect Disabil Res 2016 Feb;60(2):149-55. Epub 2015 May 27 doi: 10.1111/jir.12203. PMID: 26018613Free PMC Article
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Am J Intellect Dev Disabil 2015 Jul;120(4):315-27. doi: 10.1352/1944-7558-120.4.315. PMID: 26161469

Prognosis

Shivers CM, Leonczyk CL, Dykens EM
J Autism Dev Disord 2016 Jun;46(6):2126-37. doi: 10.1007/s10803-016-2741-5. PMID: 26883647
Hurren BJ, Flack NA
Clin Anat 2016 Jul;29(5):590-605. Epub 2016 Jan 29 doi: 10.1002/ca.22686. PMID: 26749552
Johnson L, Manzardo AM, Miller JL, Driscoll DJ, Butler MG
Am J Med Genet A 2016 Mar;170(3):594-601. Epub 2015 Nov 30 doi: 10.1002/ajmg.a.37488. PMID: 26615966
Alqahtani AR, Elahmedi MO, Al Qahtani AR, Lee J, Butler MG
Surg Obes Relat Dis 2016 Jan;12(1):100-10. Epub 2015 Jul 22 doi: 10.1016/j.soard.2015.07.014. PMID: 26431633
Hirsch HJ, Eldar-Geva T, Bennaroch F, Pollak Y, Gross-Tsur V
Hum Reprod 2015 Nov;30(11):2587-96. Epub 2015 Sep 6 doi: 10.1093/humrep/dev213. PMID: 26345685

Clinical prediction guides

Bennett JA, Hodgetts S, Mackenzie ML, Haqq AM, Zwaigenbaum L
Int J Mol Sci 2017 Feb 28;18(3) doi: 10.3390/ijms18030517. PMID: 28264487Free PMC Article
Saeves R, Klinge RF, Risnes S
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Shivers CM, Leonczyk CL, Dykens EM
J Autism Dev Disord 2016 Jun;46(6):2126-37. doi: 10.1007/s10803-016-2741-5. PMID: 26883647
Hurren BJ, Flack NA
Clin Anat 2016 Jul;29(5):590-605. Epub 2016 Jan 29 doi: 10.1002/ca.22686. PMID: 26749552
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Am J Med Genet A 2016 May;170A(5):1181-6. Epub 2016 Jan 6 doi: 10.1002/ajmg.a.37542. PMID: 26738920

Recent systematic reviews

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J Clin Endocrinol Metab 2013 Jun;98(6):E1072-87. Epub 2013 Mar 29 doi: 10.1210/jc.2012-3888. PMID: 23543664Free PMC Article

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