INTRODUCTION

Woodhouse-Sakati syndrome (WSS) (OMIM 241080) is a rare autosomal recessive neuroendocrine disorder first described in 1983 that is characterized by hypogonadotropic hypogonadism (HH), diabetes mellitus (DM), and alopecia. Over half of the patients show neurological involvement, including extrapyramidal symptoms, intellectual disability, and deafness. Dystonia and Parkinsonism are the primary extrapyramidal symptoms [1].

The DCAF17 gene, located on chromosome 2q22.3-q35 (C2orf37), underlies WSS, and numerous pathogenic variants have been identified. Variable clinical manifestations, even among relatives, complicate diagnosis [2].

Thirteen DCAF17 variants have been shown to be linked to WSS, with the c.436delC variant in exon 4 being the most common variant reported in Arab countries [3].

Approximately 200 cases have been documented, primarily in Saudi Arabia, with one case from Iran [1,4,5].

This report presents five WSS Iranian cases, including the first patient in Iran to undergo deep brain stimulation (DBS).

MATERIALS & METHODS

Patients and Methods

Patient 1

A 19-year-old man presented with progressive cervical retropulsion starting at 17 years of age. The patient subsequently developed abnormal posturing in both lower limbs, hand clumsiness, dysarthria, and swallowing difficulties. The parents were distant relatives of one another. Born prematurely at 28 weeks, he had normal motor development, but intellectual disabilities prevented him from finishing primary school. He was also diagnosed with DM. On examination, he had temporal baldness, a long triangular face, and hypertelorism, prominent speaking difficulty with oromandibular dystonia, and dystonic posturing of his neck (retrocollis) and upper and lower limbs. He had a dystonic and spastic gait, brisk deep tendon reflexes, and bilateral Babinski signs. Brain magnetic resonance imaging (MRI) scans revealed T2 hypointensity in the globus pallidus and substantia nigra (SN) (Figure 1A). Whole exome sequencing (WES) analysis using the SureSelect V6-Post Kit (Agilent Technologies) and the HiSeq 4000 system (Illumina) detected a known homozygous variant, c.580C>T, in exon 6 of DCAF17 (Table 1). The variants were verified in the proband through Sanger sequencing (BigDye Terminator v3.1 Cycle Sequencing Kit [Applied Biosystems] and ABI Prism 3130 Genetic Analyzer [Applied Biosystems]). Family members were not available for cosegregation analysis. He underwent globus pallidus internus (GPi) DBS, achieving significant improvement on the basis of the Burke-Fahn-Marsden Dystonia Rating Scale for severity of dystonia (the score of 32 was reduced to 14 post-DBS) (Supplementary Video 1 in the online-only Data Supplement). Before DBS, he needed botulinum toxin injections every 3 months for retrocollis and truncal dystonia, but post-DBS, these treatments were not necessary.

Patient 2

An 18-year-old girl with a normal birth history and normal development presented with initial symptoms of speech and swallowing impairment first appearing at age 11 years. At 16, she experienced gradual onset of cervical dystonia. She had delayed puberty, HH, impaired hearing, and temporal baldness. The patient’s parents are not related, and she has a brother and sister with similar symptoms. On examination, she had severe dysarthria, hypophonic speech, bitemporal baldness, hypertelorism, and retrocollis. Brain MRI scans revealed diffuse periventricular white matter changes, mainly in the posterior temporal horns, and iron accumulation in both putamens (Figure 1B, C, and D). Audiometry results revealed mild sensorineural hearing loss. WES results revealed a novel homozygous likely pathogenic variant, c.982-2A>G, in DCAF17. Sanger sequencing results revealed that her parents carried the variant in a heterozygous state. However, his affected brother, patient 3, had the variant in a homozygous state. Since the RNA of this case was not available, the effect of this splice site variant was evaluated using NNSplice 0.9 (Berkeley Drosophila Genome Project; http://www.fruitfly.org/seq_tools/splice.html) and Human Splicing Finder version 3.1 (HSF 3.1) (GENOMNIS). Both software programs predicted that this variant can disrupt normal splicing (Table 1). The patient received trihexyphenidyl (6 mg/day) and 300 units of abobotulinum toxin A for her neck muscles, which were partially effective in treating her dystonia.

Patient 3

This 11-year-old male was the brother of patient 2. Symptoms started with abnormal posturing in his right hand, gradually preventing his writing activities at school. He had an uncomplicated birth history and normal development and later displayed characteristics of attention deficit hyperactivity disorder.

On examination, he had dystonic posturing in his right hand. Brain MRI scans revealed a small pituitary gland and iron accumulation in the bilateral basal ganglia. His genotype was similar to that of his sister (Table 1). Treatment with trihexyphenidyl (4 mg/day), methylphenidate (10 mg once a day), and risperidone (1 mg/day) had some beneficial effects.

Patient 4

This 28-year-old male from a consanguineous marriage with a normal birth history and psychomotor development began to show abnormal limb posturing at the age of 11. Initially, a dystonic posture manifested in the left upper limb and progressively affected the contralateral side and neck. He developed speech and swallowing difficulties over time. He exhibited alopecia with temporal balding and insulin-dependent DM. He also presented with intellectual disability. On examination, he had a triangular face, and flat occiput, slurred speech, and severe dystonia in the neck, face and upper extremities (Supplementary Video 2 in the online-only Data Supplement). Brain MRI scans revealed T2 hypointensity in the GPi and SN (Figure 1E), and an electrodiagnostic study revealed sensorimotor polyneuropathy.

WES results revealed a homozygous pathogenic variant, c.436delC, in the DCAF17 gene (Table 1). Sanger sequencing showed that his parents presented the candidate variant in a heterozygous state. Injections of 500 units of abobotulinum toxin A every 3 months for neck dystonia showed some effectiveness. His symptoms progressively worsened, and the patient needed assistance for mobility (Supplementary Video 2 in the online-only Data Supplement).

Patient 5

This 22-year-old woman had a normal birth history and normal developmental milestones. Her symptoms started with progressive jaw dystonia at age seven. She slowly developed abnormal posturing of her left arm and neck, causing difficulties in daily activities. She had primary amenorrhea and normal cognition.

On examination, she had a triangular face and hypertelorism. She was anarthric with tongue protrusion and severe jaw-opening dystonia. Eye movements were normal. She had cervical dystonia, dystonic posturing in her left arm, spasticity in both her lower limbs, and downward plantar reflexes. A brain MRI scan revealed T2 hypointensity in the GPi and SN (Figure 1F). WES detected a novel homozygous variant, c.838+1G>A, in DCAF17 (Table 1). Her family members did not consent to engage in this study, and cosegregation analysis was not performed in this family. The impact of this splice site variant was assessed by NNSplice 0.9 and HSF 3.1. Both computational tools predicted that this variant had the potential to disrupt normal splicing. Treatment included trihexyphenidyl (12 mg/day) and tetrabenazine (75 mg/day) without benefit, and the patient was given 60 units of abobotulinum toxin in each lateral pterygoid muscle for jaw opening dystonia.

RESULTS

We described five cases with syndromic presentations consistent with WSS, matching previous reports, and genetic analysis confirmed this condition.

WES using the SureSelect V6-Post Kit and the Illumina HiSeq 4000 system (Illumina) identified four homozygous variants, c.436delC, c.982-2A>G, c.580C>T, and c.838+1G>A, within the DCAF17 gene (NM_025000.4; NP_079276.2) in our probands (Table 1). These variants were subsequently verified in the corresponding probands through Sanger sequencing (Big-Dye Terminator v3.1 Cycle Sequencing Kit and ABI Prism 3130 Genetic Analyzer), and then screened in their available family members.

DISCUSSION

Few heredodegenerative diseases cause childhood-onset extrapyramidal syndromes (notably dystonia) and endocrine disturbances [1]. WSS, although rare, is a significant hereditary disease causing these symptoms.

Wilson’s disease presents with dystonia and liver dysfunction leading to endocrinopathies. Low ceruloplasmin and Kayser-Fleischer rings are differentiators [6]. Mitochondrial dysfunction has been recognized as a pathophysiological factor in dystonia, with many mitochondrial disorders having endocrinopathies as part of their complex phenotype [7]. Niemann–Pick disease type C, with abnormal cholesterol metabolism and genetics, may present with dystonia, vertical gaze palsy, and hepatosplenomegaly, causing secondary endocrinopathies [8].

The DCAF17 c.436delC variant, the most common variant among inhabitants of Middle Eastern countries, was observed in one of our families (patient 4) living in an Iranian province with many Arab people that neighbors Saudi Arabia. This observation supports the possibility of a founder mutation [2,3,9]. Therefore, prioritizing screening of c.436delC is suggested for patients from this region.

Nonetheless, the identification of three more variants in this study and one more variant in our earlier work [1] indicates more allelic heterogeneity in Iran, perhaps due to ethnic diversity. Notably, clinical heterogeneity was apparent not only among distinct families carrying the same variant (for example, in patients with the c.436delC founder mutation) but also within a single family with the identical variant (patients 2 and 3). Such heterogeneities are not exclusive to WSS and have been documented in other neurodegenerative disorders. Other genetic, epigenetic, and environmental determinants may be involved in these heterogeneities.

With no specific medications for WSS, treatment should be managed by a multidisciplinary team. Dystonia is initially managed with oral medications, potentially followed by botulinum toxin injections or DBS [10]. DBS is a standard treatment for medication-resistant movement disorders. Strong evidence supports GPi DBS in managing generalized and segmental isolated dystonias, but its effects on rare genetic dystonias remain unclear. An analysis of patients with inherited progressive combined dystonia undergoing GPi DBS results revealed poorer outcomes, with some experiencing functional benefits [11]. In earlier studies, patients with WSS undergoing GPi DBS had variable outcomes, with some achieving less favorable results and others showing significant improvements in mobility and dystonia management [11,12].

Here we highlight that, although rare, WSS should be considered in patients with both neurological and endocrine symptoms and suggest that DBS may yield potential benefits for these patients. This study had several limitations, including a small sample size, lack of functional validation, retrospective design, and absence of longitudinal follow-up. The lack of evidence-based guidelines complicates the diagnosis and treatment of this condition.

Supplementary Materials

Video 1.

Patient 1 presented with cervical and upper limb dystonia and a dystonic and spastic gait before treatment, with improvement in symptoms after DBS.

Video 2.

Patient 4 presented with severe dystonia in the face, neck, and upper extremities.

Notes

Ethics Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all the patients included in the study.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Acknowledgments

None

Author Contributions

Conceptualization: Mohammad Rohani, Sepehr Khosravi. Data curation: Sepehr Khosravi, Afagh Alavi. Formal analysis: all authors. Investigation: all authors. Methodology: Mohammad Rohani. Resources: all authors. Software: Sepehr Khosravi. Supervision: Mohammad Rohani. Validation: all authors. Visualization: Sepehr Khosravi, Mohammad Rohani. Writing—original draft: Sepehr Khosravi. Writing—review & editing: Mohammad Rohani, Afagh Alavi.

Figure 1.

Brain MR images of patients with Woodhouse-Sakati syndrome. The axial T2 sequence of patient 1 shows hypointensity of the bilateral globus pallidus (A), SWI (B) and T2 sequences (C) of patient 2 with bilateral hypointensity of the globus pallidus; sagittal T2 sequence of patient 2. Red arrow shows the small pituitary gland (D), axial T2 sequence of patient 4 showing bilateral hypointensity of the globus pallidus (E), and SWI sequence of patient 5 with bilateral iron deposition in the pallidi (F). MR, magnetic resonance; SWI, susceptibility weighted.

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