Woodhouse-Sakati Syndrome

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Retrieved

2021-01-18

Source

Gene_reviews

Trials

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Genes

DCAF17, METTL8, TIMM8A, NF1, PLA2G1B, YWHAZ, ATP6V0A2, C19orf12, PLB1

Drugs

Deferiprone ( FERRIPROX, DEFERIPRONE LIPOMED ), Leuprolide acetate ( LUPRON INJECTION )

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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 testing 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.

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

On MRI:
- Variable abnormalities in periventricular white matter (Figure 2A, 2C, 2D) [Al-Semari & Bohlega 2007, Schneider & Bhatia 2008]
- Rarely, iron deposition in the globus pallidus (Figure 2B, 2D) [Al-Semari & Bohlega 2007, Gregory & Hayflick 2011, Hdiji et al 2016]
Parental consanguinity

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 ¹	Method	Proportion of Probands with Pathogenic Variants ² Detectable by Method
DCAF17	Sequence analysis ³	32/32 families
DCAF17	Gene-targeted deletion/duplication analysis ⁴	None reported

1.: See Table A. Genes and Databases for chromosome locus and protein.
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. 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 2016].

Differential Diagnosis

Table 2.

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

Disorder / Phenotype	Gene(s)	MOI	Distinguishing Clinical Features
Gonadotropin-releasing hormone deficiency	See footnote 1.	XL 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	AR	Hypogonadism, cerebellar ataxia, white matter lesions; no alopecia
Alopecia, neuropathy, endocrinopathy (ANE) syndrome (OMIM 612079) ³	RBM28	AR	Hypogonadotropic hypogonadism, alopecia, adrenal insufficiency and cognitive impairment
Hutchinson-Gilford progeria syndrome	LMNA	AD ⁴	Alopecia, aged-looking skin, joint abnormalities, loss of subcutaneous fat
Cockayne syndrome	ERCC6 ERCC8	AR	Short stature & appearance of premature aging
Deafness-dystonia-optic neuronopathy syndrome (Mohr-Tranebjaerg syndrome)	TIMM8A ⁵	XL	Early-onset hearing loss; movement disorder; impaired vision; behavior problems (almost exclusively in males)
Neurodegeneration with brain iron storage disorders	PANK2 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
Dystonia	See footnote 7.	AD AR XL	Variable phenotype; hypogonadism & alopecia not observed
Deafness and hereditary hearing loss	See footnote 8.	AD AR XL mtDNA	Variable phenotype w/variable age of onset; hypogonadism not a feature
Perrault syndrome (PRLTS)	HSD17B4 HARS2 CLPP LARS2 TWNK	AR	Heterogeneous & 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.: See Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency for associated genes.
2.: See PNPLA6-Related Disorders.
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.: See Deafness and Hereditary Hearing Loss Overview for associated genes.

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 EU Clinical Trials Register 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.