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Woodhouse-Sakati syndrome(WDSKS)

MedGen UID:
83337
Concept ID:
C0342286
Disease or Syndrome
Synonyms: Autosomal-recessive syndrome with alopecia, hypogonadism, progressive extra-pyramidal disorder, white matter disease, sensory neural deafness, diabete; Extrapyramidal disorder, progressive, with primary hypogonadism, mental retardation, and alopecia; Hypogonadism, Alopecia, Diabetes Mellitus, Mental Retardation, and Extrapyramidal Syndrome; Hypogonadism, diabetes mellitus, alopecia, mental retardation and electrocardiographic abnormalities; Progressive extrapyramidal disorder with primary hypogonadism and alopecia; Woodhouse and Sakati syndrome
SNOMED CT: Diabetes, hypogonadism, deafness, intellectual disability syndrome (816067005); Woodhouse Sakati syndrome (816067005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): DCAF17 (2q31.1)
 
Monarch Initiative: MONDO:0009419
OMIM®: 241080
Orphanet: ORPHA3464

Definition

Virtually all individuals with Woodhouse-Sakati syndrome (WSS) have the endocrine findings of hypogonadism (evident at puberty) and progressive childhood-onset hair thinning that often progresses to alopecia totalis in adulthood. More than half of individuals have the neurologic findings of progressive extrapyramidal movements (dystonic spasms with dystonic posturing with dysarthria and dysphagia), moderate bilateral postlingual sensorineural hearing loss, and mild intellectual disability. To date, more than 40 families (including 33 with a molecularly confirmed diagnosis) with a total of 88 affected individuals have been reported in the literature. [from GeneReviews]

Additional descriptions

From OMIM
Woodhouse-Sakati syndrome (WDSKS) is a rare autosomal recessive disorder that encompasses hypogonadism, deafness, alopecia, impaired intellectual development, diabetes mellitus, and progressive extrapyramidal defects (summary by Alazami et al., 2010).  http://www.omim.org/entry/241080
From MedlinePlus Genetics
Woodhouse-Sakati syndrome is a disorder that primarily affects the body's network of hormone-producing glands (the endocrine system) and the nervous system. The signs and symptoms of this condition vary widely among affected individuals, even within the same family.

People with Woodhouse-Sakati syndrome produce abnormally low amounts of hormones that direct sexual development (hypogonadism), which typically becomes apparent during adolescence. Without hormone replacement therapy, affected individuals do not develop secondary sexual characteristics such as pubic hair, breast growth in women, or a deepening voice in men. Women with Woodhouse-Sakati syndrome do not have functional ovaries and may instead have undeveloped tissues called streak gonads. The uterus may also be small or absent. Men with this disorder have testes that produce little to no sperm. As a result, people with Woodhouse-Sakati syndrome have difficulty having biological children (a condition called infertility).

Some affected individuals have certain characteristic facial features, including a long, triangular face; widely spaced eyes (hypertelorism); and a prominent bridge of the nose. People with Woodhouse-Sakati syndrome also experience hair loss (alopecia) that begins in childhood and worsens over time. Eyelashes and eyebrows are sparse or absent, and affected men have little or no facial hair. By their mid-twenties, almost all affected individuals develop diabetes mellitus, and they may also have reduced production of thyroid hormones (hypothyroidism). 

Individuals with Woodhouse-Sakati syndrome may have neurological problems. A group of movement abnormalities called dystonias are common in affected individuals, and they generally begin in adolescence or young adulthood. These movement abnormalities can include involuntary tensing of the muscles (muscle contractions) or twisting of specific body parts such as an arm or a leg. Other neurological features can include difficulty with speech (dysarthria) or swallowing (dysphagia), and mild intellectual disabilities. 

Changes in the inner ears can lead to hearing loss (sensorineural hearing loss) in people with Woodhouse-Sakati syndrome. The hearing loss can range from mild to total. This loss usually occurs in adolescence.

In some affected individuals, abnormal deposits of iron in the brain have been detected with medical imaging. For this reason, Woodhouse-Sakati syndrome is sometimes classified as part of a group of disorders called neurodegeneration with brain iron accumulation (NBIA).

Some researchers classify Woodhouse-Sakati syndrome into two types, depending on the signs and symptoms. People with Woodhouse-Sakati syndrome type 1 tend to have more severe neurological problems, and those with type 2 have milder or no neurological problems.   https://medlineplus.gov/genetics/condition/woodhouse-sakati-syndrome

Clinical features

From HPO
Premature ovarian insufficiency
MedGen UID:
9963
Concept ID:
C0025322
Disease or Syndrome
Amenorrhea due to loss of ovarian function before the age of 40. Primary ovarian inssuficiency (POI) is a state of female hypergonadotropic hypogonadism. It can manifest as primary amenorrhea with onset before menarche or secondary amenorrhea.
Decreased testicular size
MedGen UID:
66027
Concept ID:
C0241355
Finding
Reduced volume of the testicle (the male gonad).
Uterine hypoplasia
MedGen UID:
120575
Concept ID:
C0266399
Congenital Abnormality
Underdevelopment of the uterus.
Hypoplasia of the fallopian tube
MedGen UID:
409653
Concept ID:
C1968706
Congenital Abnormality
Developmental hypoplasia of the fallopian tube.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Abnormal T-wave
MedGen UID:
326862
Concept ID:
C1839341
Finding
An abnormality of the T wave on the electrocardiogram, which mainly represents the repolarization of the ventricles.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Protruding ear
MedGen UID:
343309
Concept ID:
C1855285
Finding
Angle formed by the plane of the ear and the mastoid bone greater than the 97th centile for age (objective); or, outer edge of the helix more than 2 cm from the mastoid at the point of maximum distance (objective).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Hallucinations
MedGen UID:
6709
Concept ID:
C0018524
Mental or Behavioral Dysfunction
Perceptions in a conscious and awake state that, in the absence of external stimuli, have qualities of real perception. These perceptions are vivid, substantial, and located in external objective space.
Psychotic disorder
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A condition characterized by changes in personality and thought patterns, often accompanied by hallucinations and delusional beliefs, is known as psychosis.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Hyperlipidemia
MedGen UID:
5692
Concept ID:
C0020473
Disease or Syndrome
An elevated lipid concentration in the blood.
Anodontia
MedGen UID:
98313
Concept ID:
C0399352
Congenital Abnormality
The absence of all teeth from the normal series by a failure to develop.
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.
Fine hair
MedGen UID:
98401
Concept ID:
C0423867
Finding
Hair that is fine or thin to the touch.
Sparse hair
MedGen UID:
1790211
Concept ID:
C5551005
Finding
Reduced density of hairs.
Hypogonadotropic hypogonadism
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Hypogonadotropic hypogonadism is characterized by reduced function of the gonads (testes in males or ovaries in females) and results from the absence of the gonadal stimulating pituitary hormones
Elevated circulating thyroid-stimulating hormone concentration
MedGen UID:
108325
Concept ID:
C0586553
Finding
Increased concentration of thyroid-stimulating hormone (TSH) in the blood circulation.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Reduced function of the gonads (testes in males or ovaries in females) associated with excess pituitary gonadotropin secretion and resulting in delayed sexual development and growth delay.
Decreased serum insulin-like growth factor 1
MedGen UID:
892792
Concept ID:
C4072897
Finding
A reduced level of insulin-like growth factor 1 (IGF1) in the blood circulation.
Decreased serum testosterone concentration
MedGen UID:
892974
Concept ID:
C4073137
Finding

Recent clinical studies

Etiology

Ali R, Al-Dewik N, Mohammed S, Elfituri M, Agouba S, Musa S, Mahmoud L, Almulla M, El-Akouri K, Mohd H, Bux R, Almulla H, Othman A, Al-Mesaifri F, Shahbeck N, Al-Muriekhi M, Khalifa A, Al-Sulaiman R, Ben-Omran T
Am J Med Genet A 2022 Jan;188(1):116-129. Epub 2021 Sep 30 doi: 10.1002/ajmg.a.62501. PMID: 34590781
Alharbi MS
Saudi Med J 2021 Nov;42(11):1237-1242. doi: 10.15537/smj.2021.42.11.20210329. PMID: 34732557Free PMC Article
Bohlega S, Abusrair AH, Al-Ajlan FS, Alharbi N, Al-Semari A, Bohlega B, Abualsaud D, Alkuraya F
Parkinsonism Relat Disord 2019 Dec;69:99-103. Epub 2019 Oct 13 doi: 10.1016/j.parkreldis.2019.10.007. PMID: 31726291
Salomão RP, Pedroso JL, Gama MT, Dutra LA, Maciel RH, Godeiro-Junior C, Chien HF, Teive HA, Cardoso F, Barsottini OG
Arq Neuropsiquiatr 2016 Jul;74(7):587-96. doi: 10.1590/0004-282X20160080. PMID: 27487380
Alazami AM, Schneider SA, Bonneau D, Pasquier L, Carecchio M, Kojovic M, Steindl K, de Kerdanet M, Nezarati MM, Bhatia KP, Degos B, Goh E, Alkuraya FS
Clin Genet 2010 Dec;78(6):585-90. doi: 10.1111/j.1399-0004.2010.01441.x. PMID: 20507343

Diagnosis

Kohil A, Abdallah AM, Hussain K, Al-Shafai M
Orphanet J Rare Dis 2023 Jan 31;18(1):22. doi: 10.1186/s13023-023-02614-8. PMID: 36721231Free PMC Article
Ali R, Al-Dewik N, Mohammed S, Elfituri M, Agouba S, Musa S, Mahmoud L, Almulla M, El-Akouri K, Mohd H, Bux R, Almulla H, Othman A, Al-Mesaifri F, Shahbeck N, Al-Muriekhi M, Khalifa A, Al-Sulaiman R, Ben-Omran T
Am J Med Genet A 2022 Jan;188(1):116-129. Epub 2021 Sep 30 doi: 10.1002/ajmg.a.62501. PMID: 34590781
Kurnaz E, Türkyılmaz A, Yaralı O, Demir B, Çayır A
J Pediatr Endocrinol Metab 2019 Nov 26;32(11):1287-1293. doi: 10.1515/jpem-2019-0173. PMID: 31472064
Abusrair AH, Bohlega S, Al-Semari A, Al-Ajlan FS, Al-Ahmadi K, Mohamed B, AlDakheel A
AJNR Am J Neuroradiol 2018 Dec;39(12):2256-2262. Epub 2018 Nov 8 doi: 10.3174/ajnr.A5879. PMID: 30409855Free PMC Article
Rachmiel M, Bistritzer T, Hershkoviz E, Khahil A, Epstein O, Parvari R
Horm Res Paediatr 2011;75(5):362-6. Epub 2011 Feb 8 doi: 10.1159/000323441. PMID: 21304230

Prognosis

Abusrair A, AlHamoud I, Bohlega S
J Clin Neurophysiol 2022 Sep 1;39(6):504-509. Epub 2020 Dec 30 doi: 10.1097/WNP.0000000000000811. PMID: 33417382
Shah K, Jan A, Ahmad F, Basit S, Ramzan K, Ahmad W
Clin Exp Dermatol 2020 Mar;45(2):159-164. Epub 2019 Aug 28 doi: 10.1111/ced.14046. PMID: 31323129
Bohlega S, Abusrair AH, Al-Ajlan FS, Alharbi N, Al-Semari A, Bohlega B, Abualsaud D, Alkuraya F
Parkinsonism Relat Disord 2019 Dec;69:99-103. Epub 2019 Oct 13 doi: 10.1016/j.parkreldis.2019.10.007. PMID: 31726291
Kurnaz E, Türkyılmaz A, Yaralı O, Demir B, Çayır A
J Pediatr Endocrinol Metab 2019 Nov 26;32(11):1287-1293. doi: 10.1515/jpem-2019-0173. PMID: 31472064
Louro P, Durães J, Oliveira D, Paiva S, Ramos L, Macário MC
Am J Med Genet A 2019 Nov;179(11):2237-2240. Epub 2019 Jul 26 doi: 10.1002/ajmg.a.61303. PMID: 31347785

Clinical prediction guides

Kohil A, Abdallah AM, Hussain K, Al-Shafai M
Orphanet J Rare Dis 2023 Jan 31;18(1):22. doi: 10.1186/s13023-023-02614-8. PMID: 36721231Free PMC Article
Abusrair A, AlHamoud I, Bohlega S
J Clin Neurophysiol 2022 Sep 1;39(6):504-509. Epub 2020 Dec 30 doi: 10.1097/WNP.0000000000000811. PMID: 33417382
Shah K, Jan A, Ahmad F, Basit S, Ramzan K, Ahmad W
Clin Exp Dermatol 2020 Mar;45(2):159-164. Epub 2019 Aug 28 doi: 10.1111/ced.14046. PMID: 31323129
Abusrair AH, Bohlega S, Al-Semari A, Al-Ajlan FS, Al-Ahmadi K, Mohamed B, AlDakheel A
AJNR Am J Neuroradiol 2018 Dec;39(12):2256-2262. Epub 2018 Nov 8 doi: 10.3174/ajnr.A5879. PMID: 30409855Free PMC Article
Nanda A, Pasternack SM, Mahmoudi H, Ishorst N, Grimalt R, Betz RC
Pediatr Dermatol 2014 Jan-Feb;31(1):83-7. Epub 2013 Sep 9 doi: 10.1111/pde.12219. PMID: 24015686

Recent systematic reviews

Kohil A, Abdallah AM, Hussain K, Al-Shafai M
Orphanet J Rare Dis 2023 Jan 31;18(1):22. doi: 10.1186/s13023-023-02614-8. PMID: 36721231Free PMC Article
Agopiantz M, Corbonnois P, Sorlin A, Bonnet C, Klein M, Hubert N, Pascal-Vigneron V, Jonveaux P, Cuny T, Leheup B, Weryha G
J Endocrinol Invest 2014 Jan;37(1):1-7. Epub 2014 Jan 8 doi: 10.1007/s40618-013-0001-5. PMID: 24464444

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