Review: Pathogenesis, diagnosis, and management of harlequin ichthyosis

Harlequin ichthyosis (HI) is a rare, severe genetic skin disorder caused by ABCA12 mutations, leading to defective lipid transport and loss of skin barrier function. Infants present with thick, armor-like plates, deep fissures, ectropion, and eclabium, with high risks of dehydration, infection, and respiratory failure. Historically fatal, survival has improved with neonatal intensive care and systemic retinoids. This review covers pathophysiology, clinical features, diagnosis, management, genetic counseling, and emerging gene-based therapies.

Introduction

HI is the most severe form of congenital ichthyosis. Newborns are encased in rigid hyperkeratotic scales that compromise barrier function, leading to life-threatening complications. Recent advances in neonatal care and retinoid therapy have enabled long-term survival, and the genetic basis-ABCA12 mutations disrupting epidermal lipid transport-is now well established.

Pathophysiology

ABCA12 encodes a lipid transporter in keratinocyte lamellar granules. In HI, loss-of-function mutations prevent glucosylceramide transport, impairing formation of the stratum corneum lipid barrier. This triggers compensatory keratinocyte hyperproliferation, massive keratin accumulation, and retention of corneocytes. The resulting rigid plates restrict chest expansion, while fissures permit fluid loss and pathogen entry.

Signs and symptoms

Newborns display pathognomonic thick, yellow-white plates separated by deep erythematous fissures, severe ectropion, eclabium, flattened ears/nose, and joint contractures. Complications include respiratory distress, feeding failure, dehydration, temperature instability, and sepsis. Long-term, survivors face persistent hyperkeratosis, scarring, ocular issues, and psychosocial burden.

Diagnosis

Prenatal diagnosis via CVS or amniocentesis detects ABCA12 mutations in at-risk families. Postnatal diagnosis is clinical, confirmed by genetic testing to distinguish HI from other ichthyoses.

Management

Neonatal care focuses on fluid balance, infection prevention, respiratory support, and tube feeding. Systemic retinoids (oral acitretin) initiated early are disease-modifying, accelerating scale shedding and improving pliability. Daily emollients, keratolytics, and wound care are essential. Ophthalmologic lubrication and surgical correction address ectropion; physical therapy manages contractures. Psychosocial support is critical.

Prognosis

Historically fatal, survival now extends into adulthood with aggressive care. Quality of life varies; long-term retinoid use requires monitoring for hepatotoxicity and skeletal effects. Chronic skin fragility and social integration remain challenges.

Genetic counseling

HI is autosomal recessive; carrier parents have 25% recurrence risk. Reproductive options include prenatal diagnosis and preimplantation genetic testing. Counseling provides recurrence risk assessment and emotional support for informed decision-making.

Future directions

Gene therapy and CRISPR-Cas9 correction of ABCA12 in patient-derived cells are under investigation. Stem cell-based approaches using gene-corrected induced pluripotent stem cells for autologous skin equivalents show promise. Novel pharmacologies targeting alternative lipid pathways and nanotechnology-based topical delivery are early in development. International registries and standardized outcomes are urgently needed.

Conclusions

HI has transformed from a universally fatal neonatal condition to a chronic, manageable disease. Advances in neonatal care, retinoids, and multidisciplinary support have improved survival and quality of life. Genetic counseling empowers families, and emerging gene-based therapies offer hope for definitive correction. Continued research and equitable access to care remain essential.