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Woodhouse-Sakati Syndrome

Synonym: Hypogonadism, Alopecia, Diabetes Mellitus, Intellectual Disability, and Extrapyramidal Syndrome

, MD, FRCPC, FAAN and , MD (Hons), ABP, ABMGG.

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Summary

Clinical characteristics.

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 post-lingual sensorineural hearing loss, and mild intellectual disability. To date 32 families (including 23 with a molecularly confirmed diagnosis) with a total of 76 affected individuals have been reported.

Diagnosis/testing.

The diagnosis is established in a proband with suggestive clinical findings and by identification of biallelic pathogenic variants in DCAF17 (formerly known as C2orf37) on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is symptomatic and should be managed by a multidisciplinary team. Hypogonadism requires hormone replacement therapy to induce secondary sex characteristics and promote bone health at the usual age of puberty. Alopecia is treated symptomatically for cosmetic reasons only. Treatment for dystonia is routine; oral medications are tried first and followed in some instances by botulinum toxin injection and/or deep-brain stimulation. Dysarthria often benefits from consultation with a speech therapist. Those with dysphagia often require measures to reduce oral secretions, use of thickened liquids and pureed foods to avoid aspiration, and eventually a gastrostomy to help maintain caloric intake. Hearing loss, intellectual disability, diabetes mellitus, and hypothyroidism are treated as per routine.

Surveillance: Monitoring for endocrine abnormalities is recommended at the following ages: hypogonadism (12-14 years), diabetes mellitus (in the 20s or later), hypothyroidism (in the 20s or later). Neurologic manifestations should be monitored by a neurologist as well as experts in rehabilitative medicine, speech, and swallowing. Hearing should be monitored annually.

Agents/circumstances to avoid: Persons with dystonia should avoid situations in which the risk of falling is increased.

Evaluation of relatives at risk: Molecular genetic testing for the DCAF17 pathogenic variants identified in the proband is appropriate for evaluation of apparently asymptomatic older and younger sibs to identify, as early as possible, those who would benefit from early identification and treatment of potential complications.

Genetic counseling.

WSS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic DCAF17 variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible options.

Diagnosis

Suggestive Findings

Woodhouse-Sakati syndrome (WSS) should be suspected in individuals with the following findings.

Endocrine

  • Hypogonadism (100% of individuals), hypogonadotropic in males and hypergonadotropic in females
    • Primary amenorrhea in females
    • Lack of development of secondary sexual characteristics in males and females
  • Low insulin-like growth factor 1 (IGF-1) (100%)
  • Adolescent- to young adult-onset diabetes mellitus (66%)
  • Hypothyroidism (30%)

Alopecia. Hair loss beginning in childhood or adolescence, resulting in partial to complete loss of scalp hair and eyelashes (100%) (Figure 1A, 1H)

Figure 1.

Figure 1.

Affected individuals from different families with WSS who have variable degrees of alopecia or hair loss and neurologic involvement A. Male age 23 with flat occiput; temporal and frontal alopecia

Neurologic

  • Adolescent to young adult onset of extrapyramidal findings (56%) including focal (later generalized) dystonia and chorea, dysarthria, and dysphagia
  • Sensorineural hearing loss (SNHL) with onset in childhood (62%)
  • Intellectual disability (58%)

Supportive Findings

Figure 2. . Brain MRI of individuals with WSS.

Figure 2.

Brain MRI of individuals with WSS. Arrows indicate the following findings: A. Long TR sequence, showing increased signal intensities in the subcortical regions of the centrum semi-oval

Establishing the Diagnosis

The diagnosis of Woodhouse-Sakati syndrome is established in a proband with suggestive clinical findings and biallelic pathogenic variants in DCAF17 (formerly known as C2orf37) on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of DCAF17 identifies biallelic pathogenic variants in all individuals with typical findings of WSS. DCAF17 exon and whole-gene deletion/duplication variants have not been reported. However, gene-targeted deletion/duplication analysis may be useful to confirm homozygosity of a pathogenic variant detected by sequence analysis when parental DNA is not available (see Molecular Genetics, Pathogenic variants).
    For affected individuals who are ethnically Saudi Arabian or Qatari, targeted analysis for pathogenic variants may be performed first: to date, all affected individuals in these populations have been homozygous for the same founder pathogenic variant (c.436delC) [Alazami et al 2008, Ben-Omran et al 2011].
  • A multigene panel that includes DCAF17 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes DCAF17) fails to confirm a diagnosis in an individual with features of WSS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Woodhouse-Sakati Syndrome

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
DCAF17Sequence analysis 332/32 families
Gene-targeted deletion/duplication analysis 4None reported
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

Woodhouse-Sakati syndrome (WSS) is characterized by the endocrine findings of hypogonadism, diabetes mellitus, and hypothyroidism; and progressive childhood-onset alopecia along with neurologic findings of progressive extrapyramidal movements, sensorineural hearing loss, and intellectual disability.

WSS was first described in a few consanguineous Saudi families [Woodhouse & Sakati 1983]. Of note, a review of earlier literature revealed two families that appeared to have similar clinical manifestations – one from Lebanon [Slti & Salem 1979] and one from Italy [Bjornstad 1965, Crandall et al 1973].

As of July 2016, 32 families (including 23 families with a molecularly confirmed diagnosis) with a total of 76 affected individuals have been reported. While the majority are from the Middle East (i.e., Saudi Arabia, United Arab Emirates, Qatar, Kuwait, Palestine, Turkey), families from India, Belgium, the Roma population in France, Croatia, Pakistan, Tunisia, and Italy have been reported [Al-Awadi et al 1985, Mégarbané et al 2003, Medica et al 2007, Tatar et al 2009, Steindl et al 2010, Nanda et al 2014, Abdulla et al 2015, Hdiji et al 2016, and references cited below in this section].

Endocrine

Hypogonadism, present in all affected individuals, manifests as delayed puberty with lack of secondary sexual characteristics. The nature of hypogonadism has been difficult to characterize as both hypergonadotropic and hypogonadotropic hypogonadism have been described [Agopiantz et al 2014]; in about 30% of affected individuals the hormonal profile does not neatly fit either group. Sense of smell is normal.

Women typically have primary amenorrhea. Detailed endocrine investigation, available in 52 of the women described in the literature, typically revealed severely reduced or absent estradiol and high FSH and LH, consistent with hypergonadotropic hypogonadism. There appears to be decreased hypothalamic-pituitary responsiveness, as the FSH and LH are not as high as expected for the degree of ovarian failure [Woodhouse & Sakati 1983, Rachmiel et al 2011, Agopiantz et al 2014].

The ovaries are streak or underdeveloped [Al-Swailem et al 2006] and not visualized by laparotomy, laparoscopy, or autopsy [Gül et al 2000, Al-Semari & Bohlega 2007, Ben-Omran et al 2011, Rachmiel et al 2011]. Ovarian biopsy showed fibrous tissue with no identifiable oocysts [Woodhouse & Sakati 1983].

Men have moderately low testosterone and – in contrast to women – inappropriately low gonadotropins, consistent with hypogonadotropic hypogonadism which may be of central or central and peripheral etiology. Semen analysis may show azoospermia [Agopiantz et al 2014, Ali et al 2016]. One male had cryptorchidism [Rachmiel et al 2011].

Although the testes are of normal size, testicular biopsy reveals reduced spermatogenesis with predominance of Sertoli cells and few Leydig cells [Woodhouse & Sakati 1983].

Low insulin-like growth factor 1 (IGF-1). First described in 12 families [Al-Semari & Bohlega 2007], low IGF-1 was identified in all subsequently reported cases [Alazami et al 2010, Ben-Omran et al 2011, Habib et al 2011, Rachmiel et al 2011, Agopiantz et al 2014, Ali et al 2016]. Reduction of IGF1 is more pronounced in females [Al-Semari & Bohlega 2007, Ben-Omran et al 2011]. The low IGF-1 levels may reflect the low sex steroids resulting from hypogonadism.

The growth pattern is normal and growth hormone levels are usually normal; short stature is not a part of this syndrome [Agopiantz et al 2014].

Diabetes mellitus. Type 2 diabetes (either insulin dependent or non-insulin dependent) was reported in 66% of all individuals and 96% of those older than age 25 years [Al-Semari & Bohlega 2007, Agopiantz et al 2014].

Hypothyroidism of peripheral origin (primary but without evidence of autoimmunity) was found in 30% of individuals, typically around age 20 years [Al-Semari & Bohlega 2007].

Other. No abnormalities of the corticotropic axis or prolactin [Al-Semari & Bohlega 2007, Agopiantz et al 2014] have been reported.

Ectodermal

Alopecia. All affected individuals have predominantly frontotemporal alopecia with sparse thin scalp hair. Hair loss begins in childhood and often progresses to alopecia totalis in the third or fourth decade or earlier. Eyelashes and eyebrows are absent or sparse. In men, facial hair is absent or underdeveloped.

Scanning electron microscopy of the hair shows longitudinal grooves with no specific abnormalities [Devriendt et al 1996, Al-Semari & Bohlega 2007].

Facial skin is often wrinkled in advanced stages conferring a progeroid appearance [Woodhouse & Sakati 1983, Al-Semari & Bohlega 2007, Schneider & Bhatia 2008, Agopiantz et al 2014].

Anodontia. Total loss of teeth is rare; when it occurs, it is usually seen at later stage of the disease [Al-Semari & Bohlega 2007, Steindl et al 2010, Agopiantz et al 2014].

Nails appear to be normal.

Neurologic

Extrapyramidal abnormal movement was seen in more than 56% of reported individuals. In particular, dystonic spasms with dystonic posturing was seen in the majority, including segmental dystonia affecting the craniocervical region, oromandibular region, or one extremity. Often, the first neurologic manifestation is abnormal posturing movements that typically start insidiously in childhood or the early teens. Dysarthria (often with a high-pitched voice) and dysphagia are common.

In a majority of individuals, dystonia becomes generalized and disabling (Figure 1B, 1F, 1H). Progressive dystonia of the trunk may lead to severe dystonic scoliosis. As the dystonia progresses, gait difficulties ultimately lead to immobility.

Inter- and intrafamilial variability is common [Al-Semari & Bohlega 2007, Schneider & Bhatia 2008, Ben-Omran et al 2011, Ali et al 2016]. For example, families with the founder DCAF17 (c.436delC) pathogenic variant can have dystonia [Al-Semari & Bohlega 2007] or not [Alazami et al 2008]. Of note, although extrapyramidal features were not mentioned in the original report of Woodhouse and Sakati [1983], subsequent follow up in the originally reported families revealed progressive dystonia in a few family members (Figure 1H) [Al-Semari & Bohlega 2007].

Sensorineural hearing loss (SNHL). Moderate bilateral SNHL was noted in 62% of reports. When present, deafness is invariably postlingual, usually starting in adolescence [Woodhouse & Sakati 1983, Al-Semari & Bohlega 2007, Schneider & Bhatia 2008, Ben-Omran et al 2011].

Intellectual disability is described in 58% of individuals. It is typically mild and usually overshadowed by accompanying severe and disabling dystonia, dysarthria, and SNHL. The authors observed ten individuals who were able to complete their college education and hold permanent manual occupations [Author, personal observation].

Other. Seizures with onset in early childhood, tremors, and mild Parkinsonism features were rarely reported [Al-Semari & Bohlega 2007, Schneider & Bhatia 2008].

Polyneuropathy with stocking glove sensory loss and diminished deep tendon reflexes but normal strength has been reported [Schneider & Bhatia 2008].

Other Findings

Dysmorphic facial features include a long triangular face, prominent nasal bridge, widely spaced eyes, and sparse eyebrows, creating a characteristic facial appearance (Figure 1D, 1E, 1G).

Bilateral keratoconus was reported in four individuals [Al-Swailem et al 2006, Schneider & Bhatia 2008, Ben-Omran et al 2011].

Electrocardiographic (ECG) abnormalities (lengthening of the ST segments and T-wave flattening) were described in the original report [Woodhouse & Sakati 1983]; however, they were rarely reported subsequently [Koshy et al 2008, Schneider & Bhatia 2008]. Of note, these ECG abnormalities were asymptomatic and individuals with WSS have no major cardiac manifestations.

Genotype-Phenotype Correlations

There is no clear genotype-phenotype correlation. Even individuals with the same Saudi Arabian founder DCAF17 pathogenic variant (c.436delC) have displayed marked phenotypic variability.

Prevalence

From the time of the original description in 1983 to the present (July 2016), 32 families with 76 affected individuals have been reported. Of these, 44 individuals from 23 families have had the diagnosis confirmed molecularly (see Clinical Description).

The carrier frequency of the Saudi Arabian founder variant is 0.00243309 [Abouelhoda et al, submitted].

Differential Diagnosis

Table 2.

Disorders/Phenotypes to Consider in the Differential Diagnosis of Woodhouse-Sakati Syndrome

Disorder / PhenotypeGene(s)MOIDistinguishing Clinical Features
Gonadotropin-releasing hormone deficiencySee footnote 1XL
AD
AR
Idiopathic hypogonadotropic hypogonadism w/congenital olfactory deficit w/ataxia, epilepsy & congenital paresis of cranial nerves III, IV, VI
Gordon Holmes syndrome (OMIM 212840)RNF216
PNPLA6 2
ARHypogonadism, cerebellar ataxia, white matter lesions; no alopecia
Alopecia, neuropathy, endocrinopathy (ANE) syndrome (OMIM 6120793RBM28ARHypogonadotropic hypogonadism, alopecia, adrenal insufficiency and cognitive impairment
Hutchinson-Gilford progeria syndromeLMNAAD 4Alopecia, aged-looking skin, joint abnormalities, loss of subcutaneous fat
Cockayne syndromeERCC6
ERCC8
ARShort stature & appearance of premature aging
Deafness-dystonia-optic neuronopathy syndrome (Mohr-Tranebjaerg syndrome)TIMM8A 5XLEarly-onset hearing loss; movement disorder; impaired vision; behavior problems (almost exclusively in males)
Neurodegeneration with brain iron storage disordersPANK2
PLA2G6
C19orf12
FA2H
ATP13A2
WDR45
COASY
FTL
CP
AR
XL
AD 6
Variable phenotype: variable age of onset, dystonia w/postural instability
Brain iron accumulation on MRI
DystoniaSee footnote 7AD
AR
XL
Variable phenotype; hypogonadism & alopecia not observed
Deafness and hereditary hearing lossSee footnote 8AD
AR
XL
mtDNA
Variable phenotype w/variable age of onset; hypogonadism not a feature
Perrault syndrome (PRLTS)HSD17B4
HARS2
CLPP
LARS2
TWNK
ARHeterogeneous & variable; early deafness, premature ovarian failure, weakness, spasticity

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA; XL = X-linked

1.
2.
3.

Only one family reported to date as per OMIM

4.

Almost all individuals with Hutchinson-Gilford progeria syndrome have the disorder as the result of a de novo autosomal dominant pathogenic variant.

5.

Deafness-dystonia-optic neuronopathy syndrome occurs as either a single-gene disorder resulting from mutation of TIMM8A or a contiguous gene deletion syndrome at Xq22.

6.

Eight of the ten genetically defined types of neurodegeneration with brain iron accumulation are inherited in an autosomal recessive manner. Exceptions are: beta-propeller protein-associated neurodegeneration, caused by de novo pathogenic variants in WDR45, which is inherited in an X-linked manner with suspected male lethality; and neuroferritinopathy, caused by pathogenic variants in FTL, which is inherited in an autosomal dominant manner.

7.

See Dystonia Overview for associated genes.

8.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Woodhouse-Sakati syndrome (WSS), the following evaluations are recommended:

  • Endocrine. Evaluation for possible endocrine findings (if not done at the time of diagnosis) relating to: hypogonadism, low IGF-1, diabetes mellitus, hypothyroidism
  • Ectodermal. Assessment of scalp hair
  • Neurologic
    • Neurologic examination for evidence of dystonia (if not done at the time of diagnosis) (see Dystonia Overview)
    • Speech and language assessment of dysarthria and dysphagia
    • Assessment of hearing (see Hereditary Hearing Loss and Deafness)
    • Assessment of psychomotor development (in young children) or intellectual ability in individuals older than age six years
  • Other. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No specific treatment exists for WSS. All treatment is symptomatic.

Endocrine

  • Hypogonadism. Sex hormone replacement therapy at the usual age of puberty to induce and maintain secondary sex characteristics and promote bone health
    Note: Standard replacement hormonal treatment will not promote fertility. It may be possible to stimulate testes with gonadotropins and harvest sperm with assisted reproductive technology.
  • Low IGF-1. Treatment with recombinant IGF-1 not recommended: no evidence shows that it improves the clinical features of WSS [Agopiantz et al 2014]. Of note, IGF-1 levels may increase with sex hormone replacement therapy.
  • Diabetes mellitus. Standard treatment
  • Hypothyroidism. L-thyroxine replacement therapy

Ectodermal

Treatment is symptomatic and cosmetic only.

Neurologic

Movement disorders

  • Dystonia. Treatment is aimed at relieving symptoms [Albanese et al 2015]:
    • Oral medications are usually tried first:
      • Anticholinergics such as trihexyphenidyl (moderately effective for ~40%-50% of individuals)
        Trihexyphenidyl can be titrated to high doses (~100 mg/day) in younger individuals.
        Anticholinergic side effects, particularly cognitive effects, must be monitored closely.
      • Baclofen (Lioresal®)
      • Benzodiazepines, especially clonazepam
      • Other medications tried alone or in combination with the above categories: levodopa, carbamazepine, and dopamine depleting agents (reserpine, tetrabenazine)
    • Botulinum toxin injections directly into dystonic muscles are generally the treatment of choice for adult-onset focal dystonias. For individuals with more widespread dystonia in whom specific muscle groups produce disabling symptoms, such injections may also be helpful, and are often used in combination with oral medications.
    • If medications fail, surgery to enable deep-brain stimulation (DBS) of the globus pallidus interna (GPi) has been shown to be an effective treatment for some forms of medically refractory primary generalized dystonia [Vidailhet et al 2007, Crowell & Shah 2016]. Its use in WSS has not been documented.
  • Dysarthria. Consultation with a speech therapist may be helpful.
  • Dysphagia. Oral secretions in individuals with bulbar symptoms can be reduced with tricylic antidepressants and anticholinergic agents, thus reducing the need for suctioning. Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food, as well as eventually using a gastrostomy tube to help maintain caloric intake and hydration. Nutritional management by a knowledgeable nutritionist is helpful.

Sensorineural hearing loss. See Hereditary Hearing Loss and Deafness.

Surveillance

Monitor for endocrine abnormalities:

  • Hypogonadism at age 12-14 years
  • Diabetes mellitus in the teens and later
  • Hypothyroidism in the teens and later

Neurologic manifestations should be monitored by experts in rehabilitative medicine, speech, and swallowing.

Dystonia may require monitoring by a neurologist.

Monitor hearing annually.

Agents/Circumstances to Avoid

Persons with dystonia should avoid situations in which the risk of falling is increased.

Evaluation of Relatives at Risk

Molecular genetic testing for known familial DCAF17 pathogenic variants is appropriate for the evaluation of apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who will benefit from early identification and treatment of potential complications.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Woodhouse-Sakati syndrome (WSS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one DCAF17 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with WSS are obligate heterozygotes (carriers) for a pathogenic variant in DCAF17.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a DCAF17 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the DCAF17 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the DCAF17 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for WSS are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • NBIA Disorders Association
    2082 Monaco Court
    El Cajon CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
    Email: info@NBIAdisorders.org
  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 1730
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • Dystonia Society
    89 Albert Embankment
    3rd Floor
    London SE1 7TP
    United Kingdom
    Phone: 0845 458 6211; 0845 458 6322 (Helpline)
    Fax: 0845 458 6311
    Email: support@dystonia.org.uk
  • NBIA Disorders Association Research Registry and Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) Registry
    CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
    Email: pwood@nbiadisorders.org
  • NBIAcure
    Center of Excellence for NBIA Clinical Care and Research
    International Registry for NBIA and Related Disorders
    Oregon Health & Science University
    Phone: 503-494-4344
    Fax: 503-494-6886
    Email: gregorya@ohsu.edu
  • Treat Iron-Related Childhood Onset Neurodegeneration (TIRCON) Registry
    Germany
    Phone: 49-89-5160-7421
    Fax: 49-89-5160-7402
    Email: tircon@med.uni-muenchen.de

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Woodhouse-Sakati Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
DCAF172q31​.1DDB1- and CUL4-associated factor 17DCAF17 databaseDCAF17DCAF17

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Woodhouse-Sakati Syndrome (View All in OMIM)

241080WOODHOUSE-SAKATI SYNDROME; WDSKS
612515DDB1- AND CUL4-ASSOCIATED FACTOR 17; DCAF17

Gene structure. Alternate splicing of DCAF17 (formerly known as C2orf37) results in multiple transcript variants. The longest transcript variant, NM_025000.3, has 14 exons. In comparison another major variant, NM_001164821.1, lacks two exons in the coding region for a total of 12 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Eleven different DCAF17 pathogenic variants (4 small intragenic deletions, 3 nonsense and 3 splice site variants, and 1 small indel) have been described [Alazami et al 2010, Habib et al 2011, Abdulla et al 2015, Ali et al 2016]. Pathogenic DCAF17 missense variants have not been described.

Of the 23 families with molecularly confirmed WSS, only one with two compound heterozygous DCAF17 pathogenic variants has been reported [Ali et al 2016]. The remaining 22 families were homozygous for DCAF17 pathogenic variants. Gene-targeted deletion/duplication analysis may be useful to confirm apparent homozygosity of a pathogenic variant detected by sequence analysis when parental DNA samples are not available.

Table 3.

DCAF17 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.436delC 1p.Ala147HisfsTer9NM_025000​.3
NP_079276​.2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

This variant has the same nucleotide and protein change designations for either transcript variant NM_025000​.3 or NM_001164821​.1.

Normal gene product. The transcript variant NM_025000.3 encodes DDB1- and CUL4-associated factor 17, a 520 amino-acid protein known as the α isoform (NP_079276.2). This is a nucleolar protein of unknown function expressed in various tissues including brain, skin, and liver – which correlates to some extent with the multiorgan involvement in individuals with WSS. More than 30 DCAF17 isoforms have been described [Alazami et al 2008].

Abnormal gene product. The types of pathogenic variants known to result in WSS predict premature translation termination, missplicing, or nonsense-mediated decay, suggesting that WSS results from loss of DCAF17 function.

References

Literature Cited

  • Abdulla MC, Alazami AM, Alungal J, Koya JM, Musambil M. Novel compound heterozygous frameshift mutations of C2orf37 in a familial Indian case of Woodhouse-Sakati syndrome. J Genet. 2015;94:489–92. [PubMed: 26440089]
  • Agopiantz M, Corbonnois P, Sorlin A, Bonnet C, Klein M, Hubert N, Pascal-Vigneron V, Jonveaux P, Cuny T, Leheup B, Weryha G. Endocrine disorders in Woodhouse-Sakati syndrome: a systematic review of the literature. J Endocrinol Invest. 2014;37:1–7. [PubMed: 24464444]
  • Al-Awadi SA, Farag TI, Teebi AS, Naguib K, el-Khalifa MY, Kelani Y, Al-Ansari A, Schimke RN. Primary hypogonadism and partial alopecia in three sibs with müllerian hypoplasia in the affected females. Am J Med Genet. 1985;22:619–22. [PubMed: 4061495]
  • Alazami AM, Al-Saif A, Al-Semari A, Bohlega S, Zlitni S, Alzahrani F, Bavi P, Kaya N, Colak D, Khalak H, Baltus A, Peterlin B, Danda S, Bhatia KP, Schneider SA, Sakati N, Walsh CA, Al-Mohanna F, Meyer B, Alkuraya FS. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet. 2008;83:684–91. [PMC free article: PMC2668059] [PubMed: 19026396]
  • 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. C2orf37 mutational spectrum in Woodhouse-Sakati syndrome patients. Clin Genet. 2010;78:585–90. [PubMed: 20507343]
  • Albanese A, Romito LM, Calandrella D. Therapeutic advances in dystonia. Mov Disord. 2015;30:1547–56. [PubMed: 26301801]
  • Ali RH, Shah K, Nasir A, Steyaert W, Coucke PJ, Ahmad W. Exome sequencing revealed a novel biallelic deletion in the DCAF17 gene underlying Woodhouse Sakati syndrome (WSS). Clin Genet. 2016;90:263–9. [PubMed: 26612766]
  • Al-Semari A, Bohlega S. Autosomal-recessive syndrome with alopecia, hypogonadism, progressive extra-pyramidal disorder, white matter disease, sensory neural deafness, diabetes mellitus, and low IGF1. Am J Med Genet A. 2007;143A:149–60. [PubMed: 17167799]
  • Al-Swailem SA, Al-Assiri AA, Al-Torbak AA. Woodhouse Sakati syndrome associated with bilateral keratoconus. Br J Ophthalmol. 2006;90:116–7. [PMC free article: PMC1856898] [PubMed: 16361682]
  • Ben-Omran T, Ali R, Almureikhi M, Alameer S, Al-Saffar M, Walsh CA, Felie JM, Teebi A. Phenotypic heterogeneity in Woodhouse-Sakati syndrome: two new families with a mutation in the C2orf37 gene. Am J Med Genet A. 2011;155A:2647–53. [PMC free article: PMC6905109] [PubMed: 21964978]
  • Bjornstad R. Pili torti and sensory-neural loss of hearing. Paper. Copenhagen, Denmark: 17th Combined Scandavian Dermatological Association Meeting. 1965.
  • Crandall BF, Samec L, Sparkes RS, Wright SW. A familial syndrome of deafness, alopecia, and hypogonadism. J Pediatr. 1973;82:461–5. [PubMed: 4698933]
  • Crowell JL, Shah BB. Surgery for dystonia and tremor. Curr Neurol Neurosci Rep. 2016;16:22. [PubMed: 26838349]
  • Devriendt K, Legius E, Fryns JP. Progressive extrapyramidal disorder with primary hypogonadism and alopecia in sibs: a new syndrome? Am J Med Genet. 1996;62:54–7. [PubMed: 8779325]
  • Gregory A, Hayflick SJ. Genetics of neurodegeneration with brain iron accumulation. Curr Neurol Neurosci Rep. 2011;11:254–61. [PMC free article: PMC5908240] [PubMed: 21286947]
  • Gül D, Ozata M, Mergen H, Odabaşi Z, Mergen M. Woodhouse and Sakati syndrome (MIM 241080): report of a new patient. Clin Dysmorphol. 2000;9:123–5. [PubMed: 10826625]
  • Habib R, Basit S, Khan S, Khan MN, Ahmad W. A novel splice site mutation in gene C2orf37 underlying Woodhouse-Sakati syndrome (WSS) in a consanguineous family of Pakistani origin. Gene. 2011;490:26–31. [PubMed: 21963443]
  • Hdiji O, Turki E, Bouzidi N, Bouchhima I, Damak M, Bohlega S, Mhiri C. Woodhouse-Sakati syndrome: report of the first Tunisian family with C2orf37 gene mutation. J Mov Disord. 2016;9:120–3. [PMC free article: PMC4886203] [PubMed: 27240811]
  • Koshy G, Danda S, Thomas N, Mathews V, Viswanathan V. Three siblings with Woodhouse-Sakati syndrome in an Indian family. Clin Dysmorphol. 2008;17:57–60. [PubMed: 18049083]
  • Medica I, Sepcić J, Peterlin B. Woodhouse-Sakati syndrome: case report and symptoms review. Genet Couns. 2007;18:227–31. [PubMed: 17710875]
  • Mégarbané A, Gannagé-Yared MH, Khalifé AA, Fabre M. Primary hypergonadotropic hypogonadism, partial alopecia, and Müllerian hypoplasia: report of a second family with additional findings. Am J Med Genet A. 2003;119A:214–7. [PubMed: 12749067]
  • Nanda A, Pasternack SM, Mahmoudi H, Ishorst N, Grimalt R, Betz RC. Alopecia and hypotrichosis as characteristic findings in Woodhouse-Sakati syndrome: report of a family with mutation in the C2orf37 gene. Pediatr Dermatol. 2014;31:83–7. [PubMed: 24015686]
  • Rachmiel M, Bistritzer T, Hershkoviz E, Khahil A, Epstein O, Parvari R. Woodhouse-Sakati syndrome in an Israeli-Arab family presenting with youth-onset diabetes mellitus and delayed puberty. Horm Res Paediatr. 2011;75:362–6. [PubMed: 21304230]
  • Schneider SA, Bhatia KP. Dystonia in the Woodhouse Sakati syndrome: A new family and literature review. Mov Disord. 2008;23:592–6. [PubMed: 18175354]
  • Slti IS, Salem Z. Familial hypogonadotropic hypogonadism with alopecia. Can Med Assoc J. 1979;121:428–30. [PMC free article: PMC1704396] [PubMed: 466617]
  • Steindl K, Alazami AM, Bhatia KP, Wuerfel JT, Petersen D, Cartolari R, Neri G, Klein C, Mongiardo B, Alkuraya FS, Schneider SA. A novel C2orf37 mutation causes the first Italian cases of Woodhouse Sakati syndrome. Clin Genet. 2010;78:594–7. [PubMed: 21044051]
  • Tatar A, Ocak Z, Tatar A, Yesilyurt A, Borekci B, Oztas S. Primary hypogonadism, partial alopecia, and Mullerian hypoplasia: report of a third family and review. Am J Med Genet A. 2009;149A:501–4. [PubMed: 19213036]
  • Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Lagrange C, Yelnik J, Bardinet E, Benabid AL, Navarro S, Dormont D, Grand S, Blond S, Ardouin C, Pillon B, Dujardin K, Hahn-Barma V, Agid Y, Destée A, Pollak P., French SPIDY Study Group. Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol. 2007;6:223–9. [PubMed: 17303528]
  • Woodhouse NJ, Sakati NA. A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and ECG abnormalities. J Med Genet. 1983;20:216–9. [PMC free article: PMC1049050] [PubMed: 6876115]

Chapter Notes

Revision History

  • 4 August 2016 (bp) Review posted live
  • 2 February 2016 (sab) Original submission
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