Introduction

De Sanctis-Cacchione Syndrome (DCS) is an extremely rare disorder, affecting only 1 person per million.¹ It is an extremely rare autosomal recessive genetic disorder,² meaning that both parents need to carry the trait in order for it to be inherited by their child. Mostly, DCS affects children between two months and six years of age.⁵ The DNA within DCS sufferers’ cells isn’t able to be repaired as normal, causing the onset of this disorder. It is regarded as the most severe form of xeroderma pigmentosum (XP), where pigment in the skin is produced in patches (hyper/hypopigmentation), as well as sensitivity to light in the patient.² Alongside XP, DCS has many neurological clinical features, including intellectual disabilities, underdevelopment in the brain at birth or peripheral neuropathy.¹ This is a lifeline condition that needs to be managed with proper treatments and an intervention plan, in order to improve quality of life.

Motor dysfunction (MD) is caused by injury to both the central and peripheral nervous systems, affecting the brain/spinal cord and all other nerves too. This can cause symptoms like muscle spasms or tremors.³ Ataxia is also a muscle disorder, where coordination and movement are lost over time, diagnosed by clinical presentations like speech abnormalities and irregular eye movements.⁴ DCS has a major neurological component, specifically in the onset of peripheral neuropathy, which directly affects the functioning of the peripheral nervous system and muscles. As DCS progresses, MD and ataxia may also progress,² hence it is important to understand such links. Clarify DCS is the most severe form of xeroderma pigmentosum with neurological impairment.

DCS and its neurological features

DCS is a severe form of XP, where DNA is not able to be repaired if any mistakes are made in its synthesis within new cells. This is a genetic disorder defined as autosomal recessive inheritance. This means that for the DNA repair gene, two copies of the same allele (any variations of a gene) must be inherited for DCS to be manifested. There is only a 25% chance of a child having DCS if both parents are carriers of the recessive allele, but a 50% chance that the child may be a carrier of DCS.

DCS patients have a severe inability to repair their own DNA, which means that there is a range of neurological impairments affecting patients.² Common symptoms of DCS include:³

• Cutaneous photosensitivity (light sensitivity on the skin, causing variations in pigmentation)
• Microcephaly (a condition where children are born with a smaller head)
• Intellectual disabilities (sometimes referred to as intellectual disability, impacting intelligence in daily life)
• Shorter stature
• Hypogonadism (lower testosterone levels in men)
• Spasticity (contraction of a muscle all at once) 
• Peripheral neuropathy (nerves in the outer regions of the body become damaged)
• Sensorineural deafness (sound is not able to reach your inner ear)

Furthermore, reports have found that patients with DCS are much more at risk of developing skin cancers such as basal cell carcinoma or malignant melanoma, which have the possibility to spread to different areas.¹ Patients with DCS also showcase hyporeflexia, where patients’ reflex responses are absent or weakened depending on its severity.⁵

Patients with DCS are prone to having issues with movement as a result of these neurological features. Some cases have found patients with psychomotor retardation, meaning movement is slowed down significantly.² Symptoms like spasticity, ataxia and sexual immaturity are what differentiate the progression of DCS from just XP, making the condition more severe for sufferers.¹ Present inheritance more concisely: “Autosomal recessive with 25% risk if both parents are carriers.” Convert the symptom list into bullet points for readability.

Motor dysfunction and ataxia

MD can be presented in both the central nervous system (the brain and spinal cord only) and the peripheral nervous system (the rest of the nerves in the body). MD is characterised by spasticity, weakness, tremors and ataxia.³ All of these clinical presentations are also found in the progression of DCS, and become more prevalent the worse the condition gets. Most commonly, psychomotor retardation (also known as psychomotor impairment) is seen in most children with DCS. Typically associated with depression, psychomotor impairment makes it difficult to move, whether that be standing, walking or even affecting speech and visual movement.²

Furthermore, damage to the peripheral nervous system has also been seen in cases of DCS. One case shows damage to the nerves in the calf area, with the nerve reaching toward the back of your ankle. The more damage there was to the structure and function of the nerve, the worse the symptoms became.³ Some patients also could experience quadriparesis, a pattern where the muscles in all four limbs become much weaker.⁶ Patients have also shown difficulties in standing, due to the diminished function of the Achilles tendon.¹

Ataxia is defined as the inability to coordinate muscle movements. This is shown through presentation of symptoms such as having a unique limb coordination pattern (abnormal gait), unique eye movements or changes in speech patterns too.⁴ In a child with DCS, this could mean that from a young age, language difficulties are common, and issues with vision can also present themselves. There are three types of ataxia: vestibular, cerebellar and sensory, all of which relate to the parts of the brain which are dysfunctioning in this pattern.⁴ Cerebellar ataxia is the most common, and has been seen in a few cases of DCS as well.⁵ The cerebellum is the region of the brain responsible for fine movements, balance and coordination of incoming information. Consequently, any dysfunction within this area for DCS sufferers will accelerate the onset of its symptoms, particularly affecting the child’s ability to move as expected. Shortened definition of MD: “Motor dysfunction involves impaired control of voluntary movement, with features such as spasticity, tremors, weakness, and ataxia.”

Diagnosis and treatment

In order to diagnose DCS, there needs to be a clear clinical presentation of the mentioned neurological motor symptoms.³ The motor dysfunction and involvement of abnormal neurological development are important to recognise, to differentiate from a simple case of XP. Initially, a dermatology consultant may be useful for diagnosing XP.¹ Neuroimaging techniques have been incredibly useful in diagnosing DCS, particularly in diagnosing its clinical features, such as atrophies or ataxia in different areas of the brain, found to be consistent with DCS progression5. Atrophy is when a region of an organ or tissue withers away as a result of excessive cell death. Patterns of atrophy in areas like the optic nerve or the cortex of your brain can be detected by MRI or CT scans.³ Furthermore, genetic testing methods can support these findings in diagnosis.7 Methods, like gene sequencing or chromosomal breakage studies, are commonly used as a confirmation.⁷

Treating DCS is a difficult task, as it is a genetic disorder. Gene therapies are in their early stages of research and may take a while longer to develop properly. The primary route is to prevent UV damage to the skin by sun protection and preventing skin tumours, as directed by a dermatologist.⁷ As for the motor dysfunction and ataxia, there are no straightforward treatments due to the hereditary nature of DCS.⁴ However, some prescription drugs may be prescribed, and even lifestyle changes like increased exercise may be suggested to help the severe progression in some cases.⁴ Highlight that there is currently no curative treatment; management is preventative and supportive.

Summary

DCS is a hereditary genetic disorder where the gene for DNA repair is damaged, leading to defective DNA synthesis in the patients’ cells. DCS is the most severe form of XP, a condition where the skin is extremely sensitive to light and UV rays, with a higher likelihood of developing skin tumours. It is classified as DCS when neurological symptoms such as ataxia, intellectual disability and microcephaly are presented.¹ In DCS, motor dysfunction and ataxia are common in many cases. This will have consequences such as not being able to coordinate muscle movement, particularly difficulty in standing and involvement of the peripheral nervous system. Diagnosing DCS may require the help of neurologists and dermatologists, who may employ techniques such as genetic testing or neuroimaging to accurately determine the best course of treatment for the progression of the disease.⁵ Treatment mainly focuses on the XP symptoms of UV sensitivity, as treating the neurological dysfunction is incredibly complex.¹ However, symptoms like tremors or spasticity from ataxia may be managed through medication or exercise as directed by professionals.⁴ Rewrite as “DCS is the most severe form of XP, combining photosensitivity with neurological deficits such as microcephaly, intellectual disability, motor dysfunction, and ataxia. Diagnosis requires clinical, imaging, and genetic evaluation. Management is supportive, focusing on UV protection, prevention of malignancies, and symptomatic relief of neurological dysfunctions.”