A future therapeutic Harlequin Romance?

By Warren R. Heymann, MD
Sept. 17, 2018

My fiancé Ronnie, then a pediatric resident, called me excitedly, asking for my opinion about a remarkable neonate that was just delivered at Elmhurst Hospital. I was at our dermatology resident clinic in Van Etten Hospital, and recited her description of a newborn (large plates of creamy brown scale, fissures, everted lips [eclabium] and eyes [ectropion], a flat nose and abnormal ears) to my colleagues. Dr. Alan J. Halperin, our attending, suggested the diagnosis of a harlequin fetus. After clinic, my co-residents and I hightailed it from the Bronx to Queens to see the newborn baby. Nothing compares with the “shock and awe” of seeing a harlequin ichthyosis (HI) neonate for the first time. In 1981 it was essentially a guaranteed death sentence. (This was a pre-computer, cell phone, HIPAA, and retinoid era.)

HI is the most severe end of the spectrum of autosomal recessive congenital ichthyosis (ARCI); it is a rare, with an incidence of 1 in 300,000 births. HI is caused by mutations in the ABCA12 gene, which belongs to the superfamily of ATP binding cassettes. This performs transport of various biomolecules across cell membranes. (1) ABCA12 is associated with lipid transport in lamellar granules; ABCA12 mutations can lead to a defective lipid barrier in the stratum corneum which causes ARCI, including the HI phenotype. Most mutations associated with HI are deletion mutations resulting in truncation and a severe loss of function of ABCA12. (2)

Rajpopat et al reviewed 45 cases of HI with documented ABCA12 mutations. Of the 45 cases, the ages of the survivors ranged from 10 months to 25 years, with an overall survival rate of 56%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% of cases. Early introduction of oral retinoids improved survival, since 83% of those treated survived, whereas 76% who were not given retinoids died. Recurrent skin infections in infancy affected one-third of patients. Problems maintaining weight affected 44%. Three children developed an inflammatory arthritis, and developmental delay was reported in 32%. Mutation analysis revealed that 52% of survivors had compound heterozygous mutations, whereas all deaths were associated with homozygous mutations. The authors concluded that HI should be regarded as a severe chronic disease that is not invariably fatal because of improved neonatal care and the early introduction of oral retinoids. The number of survivors is increasing. Compound heterozygotes appear to have a survival advantage. (3)

There have been astounding advances in managing HI since my residency. I highly recommend that you read the outstanding article by Glick et al (4), detailing the coordinated, multidisciplinary, neonatal intensive care for patients with HI. The authors discuss skin care (including placing the neonate in a humidified isolette at 50-70% humidification, and utilizing bland emollients), neonatal monitoring (for infection, fluid and electrolyte balance), nutrition, pain control, ocular management (to avoid exposure keratitis), otologic management (removal of debris to prevent conductive hearing loss), maintenance of respiratory function, and prevention of infection. Most importantly, they discuss the ethical concerns of treatment, the need for family counseling “to cope with the initial shock of an affected child,” management suggestions for issues beyond the neonatal period as patients transition to an ichthyosiform erythroderma, and prenatal diagnostic options for parents considering having other children.

The use of systemic retinoids has become standard of care in managing HI. Most reports utilized acetretin (etretinate is no longer available; isotretinoin has been successfully prescribed). (5)

Administration of acetretin to a neonate requires extemporaneous preparation from the capsule. Damodaran et al precisely describe how to compound this formulation using Ora-Plus solution to 2mg/ml (administered doses vary from 0.5 mg/kg/day to 1 mg/kg/day). They also discuss the need for personal protection equipment (PPE) for nurses handling the drug, as many will be women during their child-bearing years. (6)

Prolonged therapy with acitretin for severe disorders of keratinization is often necessary to maintain quality of life for afflicted patients. Although usually not problematic, there is concern for skeletal changes (periosteal thickening, premature epiphyseal closure, and hyperostosis) with continuous therapy. Liang et al performed a retrospective study on 3 patients with Darier disease, bullous ichthyosiform erythroderma, and lamellar ichthyosis, respectively, who were continuously treated with acitretin for more than 12 years. The drug was effective in all three patients without any adverse skeletal findings. (7) Sitek et al reported the case of a premature 35-week-old infant with HI – treatment with acitretin 0.5 mg/kg/day was initiated on day 3 of life. On day 44, a skeletal survey revealed osteopenia and diaphyseal fractures of all extremities; acitretin was then discontinued. Although osteopenia may be appreciated in prematurity and with prolonged immobilization, in this case, acitretin administration may have been a contributing factor. The authors suggest that HI patients treated with retinoids be monitored carefully for skeletal problems. (8)
 
The future for HI is gene therapy. Akiyama et al reported the recovery of lamellar granule lipid secretion after corrective gene transfer of ABCA12 to HI keratinocytes. (9) At the start of my career, only comfort care could be offered to HI patients. Now they survive. It will not be long before they thrive — a true therapeutic harlequin romance.

Point to remember: Early therapy with oral retinoids (especially acetretin) is considered standard of care for neonates with harlequin ichthyosis.

1. Sheth JJ, et al. Harlequin ichthyosis due to novel splice sit mutation in the ABCA12 gene: Postnatal to prenatal diagnosis. Int J Dermatol 2018; 57: 428-33.
2. Loo BKG, et al. Compound heterozygous mutations with novel missense ABCA12 mutation in harlequin ichthyosis. BMJ Case Rep 2018; Jan 3; 2018.
3. Rajpopat S, et al. Harlequin ichthyosis: A review of clinical and molecular findings in 45 cases. Arch Dermatol 2011; 147: 681-686.
4. Glick JB, et al. Improved management of harlequin ichthyosis with advances in neonatal intensive care. Pediatrics 2017; 139.
5. Chang LM, Reyes. A case of harlequin ichthyosis treated with isotretinoin. Dermatol Online J 2014; 20: 7.
6. Damodaran K, et al. A unique preparation and delivery method for acetretin for neonatal harlequin ichthyosis. J Pediatr Pharmacol Ther 2018; 23: 164-7.
7. Liang J, et al. Long-term safety and efficacy of continuous acitretin monotherapy for three children with different severe hyperkeratotic disorders in China. J Dermatol 2018 May 145 [Epub ahead of print].
8. Sitek JC, et al. Osteopenia and multiple fractures in an infant with harlequin ichthyosis. JAMA Dermatol 2018; 154; 847-9.
9. Akiyama M, et al. Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. J Clin Invest 2005; 115: 1777-84.

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