The Curious Case Files: Harlequin Ichthyosis (HI)

Picture Hyperlink: https://en.wikipedia.org/wiki/Harlequin-type_ichthyosis

Dear prospective medical students,

Today, let's explore a rare medical condition that will leave you on the edge of your seat in intrigue. In this series of: The Curious Case Files, I’m going to explore the cases that made me want to pursue medicine in the first place, due to their unnatural, terrifying, curious nature. Let me know if this has sparked a lifelong intrigue in you, too.

It's time to scrub in...

Overview & Background

[Cleveland Clinic]

Harlequin Ichthyosis is an autosomal recessive disorder affecting the ABCA12 gene (essential for lipid transport to the skin), leading to an incomplete formation of the skin barrier. Can you comprehend taking your first breath and movements, riddled with pain, due to the cracking of hardened, armour-like plates of skin? The first case was reported in 1750 by Reverend Oliver Hart, and the overall incidence is 1 in 300,000 births [PubMed]. The disorder belongs to the group of ‘congenital ichthyosis’. Congenital ichthyosis is characterised by dry, thickened, scaly, or flaky skin, resembling fish scales (from the Greek word ichthys meaning fish) [GOSH]. Of this group, HI is considered the most severe as this rare form burdens its poor patients with armour-like plates of skin, outlined by deep red fissures that can lead to life-threatening complications [MedicalNewsToday].

Causation

The disorder is caused by another pesky mutation that causes the ABCA12 gene to be non-functioning or completely absent. ‘This gene provides instructions for making a protein known as an ATP-binding cassette (ABC) transporter.’. This protein transports lipids to the stratum corneum (outer surface of the epidermis) into the lamellar granules inside keratinocytes (skin cells). [MedlinePlus] Without it, the skin barrier remains lacking essential lipids. 

Context through dermatology:

To truly understand the detrimental effect of this disease, let us take a short whistle stop tour into the world of dermatology in order to explore the importance of lipids, and the implications of their absence. Cells called keratinocytes, in the basal layer (stratum basale) of the epidermis, mature to gain lamellar granules. These granules haul ceramides, cholesterol and fatty acids, basically all necessary goods that need to be transported up to the stratum corneum (outermost layer of epidermis). These lipids are transported by the ABCA12 protein. The stratum corneum resembles a brick house, the bricks being corneocytes (dead skin cells packed with keratin) and the mortar being the lipid matrix between the cells (received from the ABCA12 protein), as shown in the figure. [NIH Figure 1].

The lipids support the skin barrier by forming a protective, waterproofing layer, allowing the skin to block out infections and retain necessary moisture. 

 If the protein is absent or non functioning, then the lipids will not be delivered, and the lamellar granules will be defective. The stratum corneum cannot be formed fully. In unaffected bodies, the corneocytes are regularly shed due to the lipids ensuring hydration and regular exfoliation. Exfoliation is ensured due to the lipids containing enzymes that break the protein bonds holding corneocytes together. If the patient lacks the ABCA12 gene, lipids are not delivered from the lamellar granules therefore the body cannot shed the layers of corneocytes, causing a build up. The lack of lipids prevents retention of moisture so the corneocytes become dry and packed, creating the characteristic feature of dry, cracked scales or plates. Additionally, as previously mentioned, corneocytes are packed with keratin, a tough protein, and so their building thickens the stratum corneum making the plates truly hardened and armor-like. Any simple movement stretches this hard, dry skin over joints, causing the skin to crack and form  deep, red fissures.

[Italian Journal of Paediatrics]

Causation for facial abnormalities

Eclabium

This is where the lips are pulled outwards due to extreme tautness of the skin around the lips, flipping them inside out. This often makes it difficult for babies to close their lips, leading to feeding complications and further dehydration.

Nasal Constriction

The skin is extremely thick and mercilessly presses down on the nose, pushing it flat. These constricted nasal openings mean it can be difficult for the baby to breathe.

Ectropion

This is where the eyelid turns outward. This leaves the inner eyelid surface exposed and prone to irritation. The tight armor like plates pull the delicate eyelids away from the eyes causing it to puff outwards. [MayoClinic]

Symptoms & Diagnosis

As many of the symptoms and tell-tale signs have features in the introduction, I will keep this section brief.

Characteristic symptoms:

• Limited movement

• Cracked skin with deep red fissures.

• Armour like skin tissue

• Facial Abnormalities

  • Ectropion

  • Eclabium 

  • Flattened nose/absent nasal openings

• Breathing difficulties due to constricted skin around chest area

• Temperature regulation problems:

  • Fissures allow heat to escape

  • Sweat glands can be blocked and compressed so sweat cannot be secreted to prevent overheating

  • Rapid dehydration can affect temperature control as water cannot be retained due to missing lipid layer

[FirstSkinFoundation]

Management & Treatment

Children may need intensive support soon after birth as the scaly sore patches of skin can lead to rapid heat loss and infection. [GOSH] The broken skin means there is no protective barrier to pathogens entering the body so we have to manage opportunistic infection. They need to:

• Be admitted to Neonatal Intensive Care Unit (NICU) to ensure:

  • Sterile environments to avoid infections

  • Temperature-controlled incubators (since they can’t regulate their own temperature)

  • Careful fluid and electrolyte management to prevent dehydration

    
    

• Need to be given antibiotics and wound care to prevent bacteria entering through cracks

  
  

• ‘Oral retinoids such as acitretin have been instrumental in the treatment of severe inherited ichthyoses like Harlequin ichthyosis’. [PubMed] These retinoids can promote normal skin shedding and reduce thickness of the skin plates.

  
  

• Keratolytic creams can aid with gentle exfoliation.

  
  

• Regular bathing can help improve hydration.

  
  

• Manual removal of plates under strict medical and professional supervision can be extremely helpful for patients as well.

  
  

Management requires a multidisciplinary approach including neonatologists, dermatologists, nutritionists, geneticists, ophthalmologists etc. 

[Cleveland Clinic ]