What Is Harlequin Ichthyosis?

Overview 

Harlequin ichthyosis (HI) is the most severe form type of ichthyosis. It is congenital, meaning it occurs in newborns. The disorder is caused by a mutation in the ABCA12 gene, which impairs lipid transport in the body which is necessary to prevent water loss and normal development of the skin.¹ HI is characterised by the thickening of the superficial layer of the skin, which is composed of keratin,  and deep fissures that distort physical features.¹ Hyper-keratinised skin becomes tighter than usual, pulling on regions such as the eyes and the mouth. This can lead to complications, such as difficulty feeding (due to eclabium), limited chest expansion that causes respiratory problems and deformation of the eyelids that causes them to face outwards (ectropion).¹ Malformation of the ears and nose, hypoplasia of the fingers, and alopecia are also seen. Neurological development is negatively impacted by HI and can lead to growth retardation, oedema, and microcephaly.² The highest risk of mortality is within the infant’s first three months of life, with the overall survival age ranging from 10 months to 25 years.

HI-affected neonates often do not survive past infancy, of which 75% of the mortality rate is attributed to respiratory failures or sepsis, followed by 33% caused by a systemic skin infection. A multidisciplinary group of physicians is necessary to provide the optimal treatment plan and interventions that can improve the survival rate. The administration of retinoids and vitamin D, as well as the application of emollients, are conventional management strategies to avoid the thick scaling of the skin and epidermal fissures.¹ More invasive, alternative options can also reduce skin fissures and prevent dehydration.  Early diagnosis can better prepare the patient’s family for the outcomes and allow management options for the disease to be initiated quickly, prolonging the life of the infant.¹

Causes of Harlequin ichthyosis 

HI is a result of a mutation in the ABCA12 gene, which encodes for a protein called the ATP-binding cassette transporter.⁵ The ABC transporter protein is responsible for transporting lipids and enzymes in cells of the epidermis, the outermost layer of the skin. In the absence of the lipid transporter, the skin barrier is disrupted due to the inability to transport lipids to the skin. This leads to abnormal development and dehydration of the skin.⁵

HI is an inherited autosomal recessive disease, which suggests that the causative mutation is located on one of the 22 autosomes and that both variations of the gene need to be mutated for the disease to occur. Recessive genetic disorders rely on the abnormal mutation being inherited from each parent. An individual who receives one normal, dominant gene from an unaffected parent and one abnormal, recessive gene from an affected parent will be a carrier of the disease; they will not present with symptoms of HI but will be able to pass on the mutated gene to their children. An individual’s risk of inheriting HI from two carrier parents is 25%. The child's risk of inheriting one recessive gene and becoming a carrier, similar to their parents, is 50%. The majority of individuals are unaware if they carry a recessive gene for a genetic disease until their child is born affected by the condition. Given the severe consequences of genetic diseases like HI, genetic screening and a consultation with a genetic counsellor is recommended before pregnancy.⁵

Signs and symptoms of Harlequin ichthyosis 

The main physical sign of Harlequin ichthyosis is the presence of thick, white, plate-like scales on the skin caused by excessive keratin, a protein responsible for making up the deep and superficial layer of the skin.¹ The separation of the scales on the skin can cause the formation of deep cracks. The skin plates pull around the mouth, eyes, eyelids and lips, forcing the eyelids and lips inside, resulting in ectropion and eclabium.⁵ The abdomen and chest of an affected infant can become restricted by the tightness of the scaly skin, resulting in eating and breathing difficulties.^2,5 Swelling of the hands and feet can be observed as well, with the tightness of the skin allowing the limbs to only partially flex.  A depressed nasal bridge, abnormal hearing, and decreased joint mobility are possible symptoms of infants affected with HI as the scaly skin can cause malformation of the organs and limbs. The physical disfigurement and delayed development can lead to impaired neurological development, which can go on to cause  growth retardation, oedema, eclabium, and microcephaly.^2,5 

Infants born prematurely are at an increased risk of developing further complications when affected by HI. It is common for premature infants to be below the normal weight range, which can cause the infant to suffer from lower body temperature, dehydration, hyperthermia, and hypernatremia(elevated sodium levels in the blood).^2,4 Infants with HI can experience constriction and swelling of the mouth, impairing the sucking response and making it difficult for the infant to feed. These infants require tube feeding. However, the early symptoms of HI can be difficult to detect, making it challenging to diagnose HI early. ^4,5 

Management and treatment for Harlequin ichthyosis 

Harlequin Ichthyosis (HI) requires personalised management and treatment, given the unique symptoms.³ A multidisciplinary team from the Neonatal Intensive Care Unit (NICU) is necessary for HI management to improve the survival rate of the affected individual. An early symptom of HI is dehydration of the infant’s skin, making immediate exposure to the incubator a significant step to maintain the integrity of the skin by controlling the humidity and temperature of the environment. Continuous lubrication with emollients is another option which keeps the skin hydrated. Oropharyngeal or nasogastric feeding tubes are utilised to provide adequate nutrition in the case where the infants do not meet their caloric intake due to impaired sucking and swallowing, which is a result of jaw constriction and eclabium.³ The constant monitoring of the kidneys and the liver is necessary to measure the urine output and serum electrolytes of the infant as those affected by HI will have difficulties maintaining a balance between water and electrolytes in the body. Following the infancy period, the hard skin plates can also shed and increase the skin turnover rate, which leads to a higher caloric need.³

The tightness of the epidermis around the eyes that causes ectropion, where the eyelids turn inside out, is managed with ointments and surgical intervention before complications like strabismus, conjunctivitis and keratitis arise. The use of topical and systemic retinoids, or an alternative like vitamin D, is adopted to manage the symptoms of HI before surgical intervention.³  However, retinoids can cause side effects, being associated with cardiovascular disease in HI patients. Surgical intervention in itself can pose a risk to the health of the patient. Infections acquired during the operation can be fatal in HI patients thus, antibiotics must be considered to prevent infection at the wound sites. It can be challenging to operate on HI patients as the condition of the skin can pose difficulties in immobilising it during surgery, potentially causing physical injuries.³ Therefore, initial sedation is needed before switching to local anaesthesia.  Although surgical intervention comes with its risks, necrosis of the fingers can be a consequence if surgery is not performed.³

FAQs

How is Harlequin ichthyosis diagnosed? 

HI is an autosomal recessive genetic disorder and thus, it can be diagnosed by genetic screening. This is done by blood test analysis to confirm the presence of a specific ABCA12 gene mutation. ABCA12 mutations result in the production of very few lipid transport proteins, with more severe mutations causing the complete absence of the protein .^4,5 Patients affected by the disease have a distinct skin phenotype. HI manifests as thick, scaly skin that has large diamond-shaped plates separated by deep fissures. The affected areas, such as the eyelids, nose, mouth, ears, and limbs, have restricted mobility, leading to impaired function, like difficulty eating and breathing. Normal skin function, such as water retention and regulation of body temperature, is disrupted in HI-affected patients, causing skin dehydration, sepsis and a higher risk of infections. Physical examination is significant to evaluate the severity of these skin abnormalities.^4,5

How can I prevent Harlequin ichthyosis?

Early diagnosis through genetic screening and genetic counselling can help manage HI effectively, preventing any severe complications. If HI runs in your family, you can receive guidance on family planning before conceiving so that you know how likely it is for your children to inherit this condition.^4,5

Who is at risk of Harlequin ichthyosis? 

HI is detected in newborns and infants during the first 28 days of their lives. Infants born to parents who are carriers of the ABCA12 mutation are more likely to develop HI than those born to completely unaffected individuals.^4,5

How common is Harlequin ichthyosis? 

HI is a rare genetic disease that affects every 1 in 3,000,000 infants.^1,5

When should I see a doctor? 

Since early symptoms of HI are difficult to observe before they become irreversible, there is a short time frame during which a physician needs to physically examine the infant and diagnose the disease. Discoloration and progressive firmness of the skin should be an indicator that the infant is developing HI.^4,5 

Summary

Harlequin ichthyosis is a rare disease caused by a mutation in the ABCA12 gene, which impairs the lipid transportation to the epidermal layer of the skin in newborns. HI is characterised by hyper-keratinised skin and deep fissures that contort the infant’s physical appearance. The consequences of the infant’s scaly skin and deep fissures include limited physical mobility, respiratory complications, ectropion and eclabium. Affected infant are at the highest risk of mortality in the first 3 months of their lives, with respiratory failure, recurring skin infection and sepsis often being the cause of death. Post-delivery, infants are managed and treated in the NICU to improve their chances of survival. The first-line treatments include retinoids, emollients, and vitamin D supplements. Surgical interventions are an alternative treatment option but are related to higher risks of mortality. The disease can be prevented through prenatal genetic screening and an evaluation of the family before pregnancy. Early detection and diagnosis of HI is very important as it prepares the patient’s family and physicians for the possible complications of the disease and allows treatment to be commenced before irreversible damage can occur.