HEALTH PRESENTATION

A CASE OF HARLEQUIN ICHTHYOSIS

Presented by Checobia Hugie

H.I. Genetics

Ali Grant

H.I. Inheritance

H.I. in Ali

Family History

Global H.I.

H.I Treatment

Harlequin Ichthyosis

Model Organism

References

Ali Grant

• Ali Grant is the son (3 months XY) of Olivia (25 XX) & Calvin (27 XX).

• Olivia is white, born in New Orleans, while Calvin is also white, he was born in Virginia and later on moved to New Orleans, where he met Olivia.

• After 2 years of being together, Olivia & Calvin had a set of twin girls .

• 6 years later, Ali Grant was born.

3-month-old Ali

What's wrong with Ali?

• Ali's story began during Olivia's third trimester (about 27 weeks pregnant).

• Ali's diagnosis was determined based off his appreance during a ultrasound where the sonographer noticed he had a flat nose, short feet, and his mouth was largely opened.

• Olivia had to prepare for an early induction.

Ali's ultrasound showing his flat nose and his mouth being opened wide

What's wrong with Ali?

After Ali was born he required intensive NICU care where he needed tube feeding to support nutrition and prevent dehydration.

Ali's prognosis was very poor, and although most affected babies do not survive after their first week of being born, he passed away at 3 months old.

Ali resting in the NICU

Harlequin Ichthyosis (H.I. Statistics)

Harlequin Ichthyosis

What is HI?

Harlequin ichthyosis (H.I.) is a rare severe form of congenital ichthyosis, which may be fatal. The neonate is encased in an 'armor' of thick scale plates separated by deep fissures.

What causes it?

H.I. is caused by a change or variant in a gene called ABCA12. This gene usually provides instructions for making a protein that’s needed for normal skin development. Without this protein, the epidermis, or outer layer of the skin, doesn’t develop normally. People with H.I. inherit two copies of the altered gene, one from each parent.

image of how H.I. is shown on infant

H.I. patient

The Genetics Behind Harlequin Icthyosis

Chromosome 2

1. The location of the HI gene is 2q35.

2. The type of gene infected by HI is ABCA12 which provides intructions for making a protein known as an Adenosine triphosphate (ATP).

Two genetic mechanisms that can result in harlequin icthyosis.

The Genetics Behind Harlequin Icthyosis (ABCA12)

Normal functions of ABCA12

Mutation affects

• Affects the shape of the eyelids, nose, mouth, and ears.

• Limits movement of the arms and legs.

ABCA12 is considered to transport lipids, including ceramides to form extracellular lipid layers in the stratum corneum of the epidermis.

A. The facial skin of a patient wth tight and thick scales and mild ectropion and eclabium beingevident. B. The entire body surface being mildly erythrodermic and covered diffusely with large whitish scales. C. Haematoxylin and eosin staining. D. Ultrastructure of the skin. E. Immunofluorescence of ABCA12. F. Glucosylceramide (GlcCer) in the skin.

Why did Ali have H.I.?

Inheritance of H.I.

• Autosomal recessive pattern

- a genetic condition occurs when the child inherits one mutated copy of a gene from each parent.

Ali's Family History

H.I. & The Z9Pigs

Researchers created a novel ENU-induced deepintronic mutation IVS49-727 A>G in the ABCA12 gene that results in abnormal mRNA splicing and truncated protein production, causing hyperkeratotic skin in Bama miniature pigs.

These pigs provide a remarkable model of human H.I. to better understand the pathological mechanisms of this disease and develop novel prevention and treatment strategies.

(A) Newborn Z9 pigs displayed a phenotype of sclerosis, dry and chappedskin, and neonatal death. (B) Histological sections of epidermis of neonatal Z9 pigs exhibited hyperkeratotic SC, lack of normal skin folds,and disordered SS. (C) Ultrastructural defects in the epidermis of Z9 pigs were observed by TEM, including massive hyperkeratotic structure in the SC (top) andnumerous multivesicular bodies in the SG (middle and bottom). Scale bar, 1 µm (top and middle) and 200 nm (bottom). The bottom panelsshow the magnified images of the selected region (red frames) of middle panels. (D) Cornified envelopes isolated from newborn Z9 pigs wereirregular and fragile compared with WT controls. Scale bar, 100 µm. (E) Toluidine blue staining of euthanized neonatal Z9 pigs shows defectsin epidermal barrier function. (F) The TEWL assay shows a defect in barrier formation of the dorsal and abdominal skin from Z9 pigs

Treatment for Ali

Treatments may include:

• Infants with H.I. are cared for in high-humidity incubators and fed frequently

• Nurses/ Guardians moisturizes the babies skin

• A drug called etretinate may be given to help remove the thick, plate-like scales covering the skin

• Bathing frequently using a mild, soap-free cleanser to soften the skin and loosen skin scales

• Rubbing the skin lightly with a loofah, rough-textured sponge, or pumice stone to remove scales

infant receiving care from nurses

References

• Akiyama, M., Dale, B. A., Smith, L. T., Shimizu, H., Holbrook, K. A. Regional difference in expression of characteristic abnormality of harlequin ichthyosis in affected fetuses. Prenatal Diag. 18: 425-436, 1998. https://www.omim.org/entry/242500?search=%22harlequin%20ichthyosis%22&highlight=%22harlequin%20ichthyosi%22

• Elias, S., Mazur, M., Sabbagha, R., Esterly, N. B., Simpson, J. L. Prenatal diagnosis of harlequin ichthyosis. Clin. Genet. 17: 275-280, 1980. https://pubmed.ncbi.nlm.nih.gov/7371219/

• Kelsell, D. P., Norgett, E. E., Unsworth, H., Teh, M.-T., Cullup, T., Mein, C. A., Dopping-Hepenstal, P. J., Dale, B. A., Tadini, G., Fleckman, P., Stephens, K. G., Sybert, V. P., and 15 others. Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am. J. Hum. Genet. 76: 794-803, 2005. https://www.omim.org/entry/607800?search=%22harlequin%20ichthyosis%22&highlight=%22harlequin%20ichthyosi%22#references

• Stewart, H., Smith, P. T., Gaunt, L., Moore, L., Tarpey, P., Andrew, S., Dady, I., Rifkin, R., Clayton-Smith, J. De novo deletion of chromosome 18q in a baby with harlequin ichthyosis. Am. J. Med. Genet. 102: 342-345, 2001. https://www.omim.org/entry/242500?search=%22harlequin%20ichthyosis%22&highlight=%22harlequin%20ichthyosi%22#references

• Lattuada, H. P., Parker, M. S. Congenital ichthyosis. Am. J. Surg. 82: 236-239, 1951. https://pubmed.ncbi.nlm.nih.gov/14847077/

• Dean, M., and Allikmets, R. (2001). Complete characterization of the humanABC gene family. J. Bioenerg. Biomembr. 33, 475–479. https://www.researchgate.net/publication/338215644_A_harlequin_ichthyosis_pig_model_with_a_novel_ABCA12_mutation_can_be_rescued_by_acitretin_treatment