Woodhouse-Sakati Syndrome Research Articles

Woodhouse-sakati syndrome with no reportable MRI findings: a case report

BackgroundWoodhouse-Sakati Syndrome (WSS) is a rare autosomal recessive condition caused by biallelic pathogenic variants in the DCAF17 gene, with fewer than 200 cases reported in the literature. Symptoms first emerge in middle-late adolescence with a spectrum of hypogonadal and progressive neurological features.Case presentationWe present a case of WSS with no reportable T2-weighted, apparent diffusion coefficient mapping and susceptibility weighted MRI findings. This differs from cases reported in the current literature. Our patient developed abnormal movements in both legs, clumsiness of the hands, dysarthria, and swallowing difficulties. Moreover, she presented with alopecia manifesting as frontal and temporal balding, severe dystonia with painful dystonic spasms primarily in the left upper limb, as well as primary amenorrhea. She was not independently ambulatory on presentation, requiring wheelchair assistance. Genetic testing, the crucial test for a definitive diagnosis, was undertaken in Qatar and confirmed WSS. Treatment provided includes botulinum toxin injections and deep brain stimulation, providing better dystonia control, with progress in walking and strength exercises, and overall remarkable improvement. Intensive neurorehabilitation regimes were also deployed from admission, including physiotherapy, occupational therapy and speech and language therapy.ConclusionThis case adds to the current literature on WSS manifestations, with all previously reported cases having positive MRI findings, unlike our case.

Woodhouse-Sakati syndrome: genotype–phenotype review and case of intra-familial heterogeneity

Woodhouse-Sakati syndrome (WSS) is a rare eponymous disease described by Drs. Woodhouse and Sakati in 1983 as a syndrome of hypogonadism, alopecia, diabetes mellitus, intellectual disability, and ECG abnormalities. A couple of years later, a variant in the gene DCAF17 (DDB1 and CUL4-associated factor 17) was labeled as the founder mutation in most cases of WSS in the Arabian Peninsula and the Middle East. Reports around the world started to emerge on variable presentations of the syndrome, expanding its phenotypic spectrum. In addition, the discovery of new variants in the same gene grew our understanding of this multi-systemic syndrome. Genotype and phenotype expansion is increasing with the growing number of diagnosed cases owing to the availability and advances in clinical genetic testing. This review describes the current understanding of the DCAF17 gene with its molecular implication in WSS. We also provide an extensive analysis of the documented genetic changes associated with the syndrome, describing the geographical prevalence of these genetic variations. Additionally, we examine the disorder’s extensive manifestations and clinical presentations and describe a case of intra-familial phenotypic heterogeneity.

Nine Hereditary Movement Disorders First Described in Asia: Their History and Evolution.

Clinical case studies and reporting are important to the discovery of new disorders and the advancement of medical sciences. Both clinicians and basic scientists play equally important roles leading to treatment discoveries for both cures and symptoms. In the field of movement disorders, exceptional observation of patients from clinicians is imperative, not just for phenomenology but also for the variable occurrences of these disorders, along with other signs and symptoms, throughout the day and the disease course. The Movement Disorders in Asia Task Force (TF) was formed to help enhance and promote collaboration and research on movement disorders within the region. As a start, the TF has reviewed the original studies of the movement disorders that were preliminarily described in the region. These include nine disorders that were first described in Asia - Segawa disease, PARK-Parkin, X-linked dystonia-parkinsonism (XDP), dentatorubral-pallidoluysian atrophy (DRPLA), Woodhouse-Sakati syndrome, benign adult familial myoclonic epilepsy (BAFME), Kufor-Rakeb disease, tremulous dystonia associated with mutation of the calmodulin-binding transcription activator 2 (CAMTA2) gene, and paroxysmal kinesigenic dyskinesia (PKD). We hope that the information provided will honor the original researchers and help us learn and understand how earlier neurologists and basic scientists together discovered new disorders and made advances in the field, which impact us all to this day.

Three Siblings With Woodhouse-Sakati Syndrome: A Case Report of A New Saudi Family

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive multi-system genetic disease caused by loss of function mutations in the DCAF17gene on chromosome 2q31.1. The disease is characterized by gradual neurologic degeneration and polyendocrinopathy, particularly noteworthy for hypogonadism, beginning in early adolescence. Clinical features show wide variability with no clear genotype-phenotype correlation. The pathophysiology of WSS is unclear at present and no specific treatment is available other than hormone replacement which is administered in the course of individualized symptomatic multidisciplinary care. Genetic testing helps in confirming the diagnosis along with genetic counseling of the patient and family members. Here we report multiple cases of WSS in three siblings from a new SaudiArabia family who were diagnosed with WSS as a consequence of a common founder mutationin the DCAF17 gene with DNA analysis showing a homozygous single nucleotide frameshift deletion (c.436delC) in exon 4 of the gene.

Expanding on the phenotypic spectrum of Woodhouse-Sakati syndrome due to founder pathogenic variant in DCAF17: Report of 58 additional patients from Qatar and literature review.

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive neuroendocrine and ectodermal disorder caused by variants in the DCAF17 gene. In Qatar, the c.436delC variant has been reported as a possible founder pathogenic variant with striking phenotypic heterogeneity. In this retrospective study, we report on the clinical and molecular characteristics of additional 58 additional Qatari patients with WSS and compare them to international counterparts' findings. A total of 58 patients with WSS from 32 consanguineous families were identified. Ectodermal and endocrine (primary hypogonadism) manifestations were the most common presentations (100%), followed by diabetes mellitus (46%) and hypothyroidism (36%). Neurological manifestations were overlapping among patients with intellectual disability (ID) being the most common (75%), followed by sensorineural hearing loss (43%) and both ID and aggressive behavior (10%). Distinctive facial features were noted in all patients and extrapyramidal manifestations were uncommon (8.6%). This study is the largest to date on Qatari patients with WSS and highlights the high incidence and clinical heterogeneity of WSS in Qatar due to a founder variant c.436delC in the DCAF17 gene. Early suspicion of WSS among Qatari patients with hypogonadism and ID, even in the absence of other manifestations, would shorten the diagnostic odyssey, guide early and appropriate management, and avoid potential complications.

Movement Disorders Associated with Hypogonadism.

A variety of movement disorders can be associated with hypogonadism. Identification of this association may aid in guiding workup and reaching an accurate diagnosis. We conducted a comprehensive and structured search to identify the most common movement disorders associated with hypogonadism. Only Case Reports and Case Series articles were included. Ataxia was the most common movement disorder associated with hypogonadism, including entities such as Gordon-Holmes syndrome, Boucher-Neuhäuser, Marinesco-Sjögren and Perrault syndrome. Tremor was also commonly described, particularly with aneuploidies such as Klinefelter syndrome and Jacob's syndrome. Other rare conditions including mitochondrial disorders and Woodhouse-Sakati syndrome are associated with dystonia and parkinsonism and either hypo or hypergonadotropic hypogonadism. We also highlight those entities where a combination of movement disorders is present. Hypogonadism may be more commonly associated with movement disorders than previously appreciated. It is important for the clinician to be aware of this association, as well as accompanying symptoms in order to reach a precise diagnosis.

Woodhouse-Sakati Syndrome with Unique Unreported Previous Findings

We present here at 16 years old a Saudi girl with alopecia which noted since birth and delayed puberty and short stature, dyslipidemia, diabetes and hypothyroidism. Family history was positive for similar complaints. Genetic study shows a mutation at DCAF17 which is known a common founder mutation confirming diagnosis of Woodhouse-Sakati Syndrome. This patient has many unreported findings of hepatic hemangioma, with Hepatomegaly, high indirect bilirubin, high uric acid, focal segmental Glomerulonephritis and low growth hormone level. Presentation of this syndrome may overlap with other important differential diagnosis like autoimmune polyendocrine syndrome, Alopecia-progressive neurological defect (ANE syndrome), and Turner and Mitochondrial disease. In such presentation, the presence of dysmorphic features and low intelligence quotient (IQ) scores, should alert the physician to look for WSS as a possible diagnosis.

Multimodal Evoked Potential Profiles in Woodhouse-Sakati Syndrome.

Woodhouse-Sakati syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in the DCAF17 gene, characterized by marked neurologic and endocrine manifestations in the setting of brain iron accumulation and white matter lesions on neuroimaging. Here, we report electrophysiologic profiles in Woodhouse-Sakati syndrome and their possible value in understanding disease pathophysiology and phenotypic variability. Thirteen genetically confirmed Woodhouse-Sakati syndrome patients were evaluated via different evoked potential (EP) modalities, including brainstem auditory EPs, pattern reversal visual EPs, and somatosensory EPs to tibial and/or median nerves. All EP modalities showed variable abnormalities. Pattern reversal visual EPs were recorded in all patients, with nine patients exhibiting abnormal results. From those, seven patients showed prolonged P100 latencies after stimulation of right and left eyes for each in turn. Two patients showed P100 latency abnormality after single eye stimulation recorded from midoccipital electrode. Median somatosensory EPs were recorded in 10 patients, with 6 patients having a prolonged cortical N19 response. Tibial somatosensory EP was performed for 11 patients, and 8 patients showed abnormal results where P37 cortical response was absent or prolonged, whereas peripheral potentials at the popliteal fossa were normal. Brainstem auditory EPs were abnormal only in two patients, with prolonged wave III and V latencies. Five patients with hearing impairment presented with normal brainstem auditory EP results. Multiple EP abnormalities are observed in Woodhouse-Sakati syndrome patients, mainly in pattern reversal visual EPs and somatosensory EPs. These findings indicate potential myelin dysfunction that has a role in the underlying pathophysiology, disease course, and phenotypic variability.

Patterns of neurological manifestations in Woodhouse-Sakati Syndrome

BackgroundWoodhouse–Sakati syndrome (WSS) is a rare autosomal recessive disease with characteristic neuro-endocrine manifestations. WSS encompasses heterogeneous phenotypes and disease course. ObjectiveWe aimed to characterize neurological involvement of the disease through subgrouping of core neurological manifestations. MethodsA single-institution retrospective analysis of patients with clinically and genetically confirmed diagnosis of WSS. ResultsA total of 38 individuals belonging to 17 families were identified to have WSS. The mean age at enrollment was 30.1 years (range 16–53 years). Neurological involvement was noted in 31 patients (81.5%). Dystonia was the most common neurological manifestation (67%), followed by intellectual disability (45%) and sensorineural hearing loss (30%). Based on the Neurological Impairment Scale (NIS), the disease was recognized to have two distinct patterns. A disabling, rapidly progressive pattern (NIS of 3–4; Type 1) was noted in eighteen patients (12 males, 6 females; 47.4%) with severe disability that occurs within a mean duration of 7.4 ± 3.6 years. Type 2 WSS was identified in twenty patients (8 males, 12 females; 52.6%), and showed either absent or mild neurological involvement with preserved activities of daily living (NIS of 0–1). The mean age of onset for neurological manifestations was earlier in type 1 (12.6 ± 4.5 years) compared to type 2 (18.1 ± 4.3 years). Type 1 WSS has a significantly higher rate of intellectual disability (p= <0.001). ConclusionsIn this pleiotropic syndrome, we identified two distinct phenotypes with variable prognosis. A high Interfamilial and intrafamilial phenotypic variability despite having a similar gene mutation suggests a possible role of genetic or environmental modifying factor.

A novel DCAF17 homozygous mutation in a girl with Woodhouse-Sakati syndrome and review of the current literature

Background Woodhouse-Sakati syndrome (WSS) (OMIM#241080) is an extremely rare multisystemic disease. Alopecia, hypogonadism, loss of hearing, hypothyroidism, diabetes mellitus (DM) and neurological disorders are the components of this syndrome. The syndrome is caused by homozygous or compound heterozygous mutations in DCAF17, and has recently been implicated in the development of both male and female gonads, thus resulting in hypogonadism. Case report A 16-year-old girl with consanguineous parents was admitted to our hospital with absence of breast development and amenorrhea. Hypogonadism was detected, in the form of hypergonadotropic hypogonadism. Whole-exome sequencing was used to identify the genetic etiology underlying the hypogonadism. A novel homozygous variant c.1091 + 1G > A was detected in DCAF17. Both parents were sequenced and identified as heterozygous for the same mutation. Conclusions We report a novel mutation detected in the DCAF17 gene and discuss the clinical findings in patients with previously reported mutations. Various manifestations of WSS, such as alopecia, endocrinological and neurological disorders, do not emerge until later in life, and therefore this situation can be challenging to diagnose particularly in pediatric cases, as in the present report. Careful attention should be paid to these additional findings, which may lead to early diagnosis and reduced genetic analysis costs, in patients with hypogonadism. In addition, there was no obvious genetic-phenotype correlation in reported cases.

Woodhouse-Sakati syndrome in a family is associated with a homozygous start loss mutation in the DCAF17 gene.

Woodhouse-Sakati syndrome (WSS) is a rare neuroendocrine and ectodermal disorder inherited in an autosomal recessive pattern. The syndrome presents prominent clinical features, including alopecia, neuroendocrine defects, neurological findings and progressive hearing loss. The condition results from mutations in the DCAF17 gene. To search for the underlying genetic defect in a Pakistani family with WSS phenotypes. Whole exome sequencing was used to search for the disease-causing variant. Analysis of the exome data revealed a start loss sequence variant (c.1A>G, p.M1?) in DCAF17. This variant is predicted to abolish translation of the DCAF17 polypeptide. To our knowledge, this is the first start loss variant identified in the DCAF17.

Woodhouse-Sakati Syndrome: A Case Report from Indonesia

Woodhouse-Sakati Syndrome: A Case Report from Indonesia

Brain MR Imaging Findings in Woodhouse-Sakati Syndrome

Woodhouse-Sakati syndrome is a rare autosomal recessive disorder characterized by hypogonadism, alopecia, diabetes mellitus, and progressive extrapyramidal signs. The disease is caused by biallelic pathogenic variants in the DCAF17 gene. The purpose of this study was to describe the spectrum of brain MR imaging abnormalities in Woodhouse-Sakati syndrome. We reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome (12 males, 14 females; age range, 16-45 years; mean age, 26.6 years). Follow-up studies were conducted for 6 patients. All patients had abnormal MR imaging findings. The most common abnormalities were a small pituitary gland (76.9%), pronounced basal ganglia iron deposition (73%), and white matter lesions in 69.2%. White matter lesions showed frontoparietal and periventricular predominance. All white matter lesions spared subcortical U-fibers and were nonenhanced. Prominent perivascular spaces (15.3%) and restricted diffusion in the splenium of the corpus callosum (7.6%) were less frequent findings. Follow-up studies showed expansion of white matter lesions with iron deposition further involving the red nucleus and substantia nigra. Older age was associated with a more severe degree of white matter lesions (P < .001). Small pituitary gland, accentuated iron deposition in the globus pallidus, and nonenhancing frontoparietal/periventricular white matter lesions were the most noted abnormalities seen in our cohort. The pattern and extent of these findings were observed to correlate with older age, reflecting a possible progressive myelin destruction and/or axonal loss. The presence of pituitary hypoplasia and white matter lesions can further distinguish Woodhouse-Sakati syndrome from other neurodegenerative diseases with brain iron accumulation subtypes.

Phenotypic Variability of c.436delC DCAF17 Gene Mutation in Woodhouse-Sakati Syndrome

Case seriesPatients: 38, female • 28, female • 41, female • 18, female • 23, maleFinal Diagnosis: Woodhouse-Sakati syndromeSymptoms: Hypogonadism • dystonia • alopecia • hearing loss • diabetesMedication: —Clinical Procedure: —Specialty: Endocrinology and MetabolicObjective:Rare diseaseBackground:Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive genetic condition that was first described in 1983. Since its original description, approximately 50 cases have been reported with various clinical signs and symptoms. Characteristics include progressive neurologic deterioration with extrapyramidal involvement and polyendocrinopathy most notable for hypogonadism starting in early adolescence. Clinical presentation is variable, and a subset of patients may have additional features, such as premature aging, alopecia, distinctive facial features, cognitive impairment, or deafness.Case Report:We illustrate the phenotypic variability of 5 patients with WSS due to the previously reported homozygous single nucleotide deletion c.436delC in the DCAF17 gene, identified in 2008. Despite identical genetic alteration, our 5 patients had various clinical features among them and compared with previously reported cases with the same pathogenic mutation.Conclusions:The phenotypic variability of WSS due to c.436delC founder mutation may have a wider range than previously recognized.

Woodhouse-Sakati Syndrome With Psychosis and Basal Ganglia Calcification: A Case Report

Woodhouse Sakati syndrome is a rare autosomal recessive multisystem disorder characterized by neuropsychological, endocrinal, and ectodermal symptoms. We report a 52-year-old Saudi female with psychosis, extrapyramidal signs, sensorineural hearing loss, diabetes, hypothyroidism, amenorrhea, hypergonadotropic hypogonadism, absence of secondary sexual characters, and alopecia totalis. Her brain computed tomography (CT) showed bilateral basal ganglia calcification and her genetic testing confirmed homozygous single nucleotide deletion (C.436delC) of frameshift mutation (p.A147HfsX9) in exon 4 of the gene DCAF17 gene. Woodhouse Sakati syndrome seems to be more prevalent, and probably underdiagnosed, in the Middle East and Arab countries, and should be considered in patients with a combination of neurological and endocrinal dysfunction. To our knowledge, this is the first case reported to have psychotic symptoms. J Med Cases. 2018;9(2):73-75 doi: https://doi.org/10.14740/jmc2996w

Woodhouse-Sakati Syndrome With Psychosis and Basal Ganglia Calcification: A Case Report

Woodhouse-Sakati Syndrome With Psychosis and Basal Ganglia Calcification: A Case Report

Japanese siblings with woodhouse-sakati syndrome: The first family in East Asia

Background: Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive neurodegenerative disorder caused by mutation in the DCAF17 gene and characterized by endocrinopathy, deafness, alopecia, intellectual disability, and extrapyramidal symptoms. Seventy-six patients with WSS were reported mainly from Middle East Asia; however, no patient was found in East Asia.

Endocrine manifestations of Woodhouse-Sakati Syndrome - a Portuguese case

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Deep Brain Stimulation in Rare Inherited Dystonias.

Rare causes of inherited movement disorders often present with a debilitating phenotype of dystonia, sometimes combined with parkinsonism and other neurological signs. Since these disorders are often resistant to medications, DBS may be considered as a possible treatment. Patients with identified genetic diseases (ataxia-telangiectasia, chorea-achantocytosis, dopa-responsive dystonia, congenital nemaline myopathy, methylmalonic aciduria, neuronal ceroid lipofuscinosis, spinocerebellar ataxia types 2 and 3, Wilson's disease, Woodhouse-Sakati syndrome, methylmalonic aciduria, and X trisomy) and disabling dystonia underwent bilateral GPi DBS (bilateral thalamic Vim nucleus in 1 case). The primary outcome was the difference in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) between baseline, 1 year and last available follow-up. Preoperative factors such as age at surgery, disease duration at surgery, proportion of life lived with dystonia and severity of dystonia were correlated to the primary outcome. Eleven patients were operated between February 2003 and December 2013. Age and duration of disease at time of surgery were 30 ± 19 and 12.5 ± 15.7 years, respectively. DBS effects on dystonia severity were variable but overall marginally effective, with a mean improvement of 7.9% (p = 0.39) at 1-year follow-up and 16.7% (p = 0.46) at last follow-up (mean 47.3 ± 19.9 months after surgery). No preoperative factors were identified to predict the surgical outcome. Our findings support the current knowledge that DBS is modestly effective in treating rare inherited dystonias with a combined phenotype. However, the BFMDRS might not be the best tool to measure outcome in these severely affected patients.

A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging.

Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology.