Woodhouse-Sakati
Woodhouse-Sakati Syndrome (WSS) is caused by a mutation in the DCAF17 gene, which causes malformations in the body and deficiencies in the endocrine system. The endocrine system normally has feedback loops of hormones released by the body’s internal glands, but when that loop is disrupted, a variety of body functions can be affected.
WSS is ultrarare, with fewer than 100 affected individuals reported in the medical literature. Two types of WSS have been described with varying prognoses, and both can occur within the same family:
- Type 1: Severe and progressive neurologic disability at a younger age, which causes significant impairment to the individual’s quality of life
- Type 2: Absent or mild neurological involvements that do not have a profound impact on the individual’s quality of life
Clinical Features
Woodhouse-Sakati Syndrome is a multisystem disorder featuring such symptoms as hypogonadism (too little hormone for normal sex gland functioning), alopecia (hair loss), diabetes, intellectual deficits and dystonia, a movement disorder common in NBIA. Individuals with WSS present endocrine findings of hypogonadism during puberty. These affected individuals also have progressive childhood-onset hair thinning that will oftentimes develop into alopecia in adulthood. Patients may also experience slurred or slowed speech because of weakness in mouth muscles, known as dysarthria; difficulty swallowing, called dysphagia; seizures; and sensory polyneuropathy, the simultaneous breakdown of many peripheral nerves, making it difficult for individuals to move or feel physical sensations.
People with WSS may experience sensorineural deafness — hearing loss caused by dysfunction of the vestibulocochlear (auditory) nerve, inner ear, or central processing center of the brain. Hearing loss can range from mild to total.
Craniofacial abnormalities also may be present, including a high forehead, triangular face, prominent nasal root, an increased distance between the eyes and a flattened occiput (back of the head). Also possible are scoliosis, a sideways curvature of the spine; hyperreflexia, or overactive reflexes, and camptodactyly, a condition in which the finger(s) stay in a bent position.
Clinical Diagnosis
T2 weighted imaging, which is a basic pulse sequence on an MRI, can indicate iron accumulation in the brain. When that coincides with hair loss, diabetes, hearing loss, gonadal dysfunction and intellectual disabilities Woodhouse-Sakati Syndrome is indicated. Onset is typically in adolescence. An ECG may also pick up flattened T waves in WSS individuals.
Neuroimaging findings on an MRI include:
- Partially empty sella, the compartment that houses the pituitary gland. The space is often filled with cerebrospinal fluid, and the pituitary gland is smaller than normal.
- Progressive white matter lesions in the brain’s frontoparietal region.
- Iron deposits in the brain’s globus pallidus as well as in the substantia nigra (the part of the basal ganglia that controls movement) and, to a less extent, the red nucleus, part of the ventral midbrain that controls limb movements, especially when reaching.
Symptom Management
Various treatments can help manage different symptoms, and oversight by a multidisciplinary team is needed.
Hypogonadism requires hormone replacement therapy to develop secondary sex characteristics and aid bone health during puberty. Alopecia is treated on a symptomatic basis and is done only for cosmetic reasons. Speech therapy can be beneficial to dysarthria. Dysphagia typically requires extra measures to lower oral secretions, such as pureed food and thick liquids to avoid aspiration, and, potentially, a gastrostomy (direct access to stomach for a feeding tube). Standard treatments also are available for symptoms such as diabetes, hypothyroidism, hearing loss and intellectual disabilities.
Options for managing dystonia include oral medications, botox injections to help relieve involuntary contractions and deep-brain stimulation.
Please see our Medical Information section for more in-depth information on these therapies.
Monitoring symptoms is recommended as follows:
- Hypogonadism: beginning at ages 12-14
- Diabetes/hypothyroidism: starting at age 20
- Insulin-like growth factor (IGF-1): every three to five years after diagnosis
- Dystonia: annual neurological assessments
- Dysarthria/dysphagia: assessments as needed
- Intellectual development: annual assessments throughout childhood
- Hearing loss: annual audiology evaluations
Genetics
Woodhouse-Sakati Syndrome is an autosomal recessive disorder, meaning it is passed to the offspring when both parents are carriers. Statistically, there is a one in four chance that two carriers will have a child with WSS; a two in four chance that their child will be a carrier; and a one in four chance that their child will not receive the gene mutation.
Carrier testing for at-risk relatives and prenatal testing for pregnancies are suggested if there is an affected family member.
Prenatal Testing
If the disease-causing genetic mutation has been identified within the family, prenatal diagnosis for at-risk pregnancies can be done. DNA can be extracted from fetal cells and then analyzed around 15 to 18 weeks gestation. Alternatively, sampling of the chorionic villus, the tiny projections on the edge of the placenta, can be done around 10 to 12 weeks gestation.
Embryo screening, also known as preimplantation genetic diagnosis, may be an option for some families.
Note
The main resource for this clinical information is Woodhouse-Sakati Syndrome - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult for the general public to understand.
Natural History Studies
TIRCON International NBIA Registry
The TIRCON International NBIA Registry was created under a European Union grant called Treat Iron-Related Childhood-Onset Neurodegeneration to act as a clearinghouse for data on NBIA disorders. Grant funding ran from 2011 to 2015, and the project is housed at Ludwig Maximilian University of Munich, Germany. The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 12 countries take part in the registry by entering their patient data. As of September 2021, over 750 entries were in the registry consisting of NBIA patients and controls. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA. For more information on the registry, contact Anna Baur-Ulatowska Anna.Baur@med.uni-muenchen.de.
Research Publications and Articles
Following is a list of some recent research articles. Others can be found at PubMed Central.
2019 - Patterns of neurological manifestations in Woodhouse-Sakati Syndrome
2018 - Brain MR Imaging Findings in Woodhouse-Sakati Syndrome
2017 - Endocrine manifestations of Woodhouse-Sakati Syndrome – a Portuguese case
