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Ali Grant

Harlequin Ichthyosis

Presented by Checobia Hugie

A CASE OF HARLEQUIN ICHTHYOSIS

H.I. Inheritance

References

Model Organism

H.I Treatment

Family History

H.I. Genetics

H.I. in Ali

Global H.I.

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

What's wrong with Ali?

Ali resting in the NICU

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.

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

What's wrong with Ali?

Harlequin Ichthyosis (H.I. Statistics)

H.I. patient

image of how H.I. is shown on infant

What is HI?

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.

What causes it?

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.

Harlequin Ichthyosis

Chromosome 2

Two genetic mechanisms that can result in harlequin icthyosis.

  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).

The Genetics Behind Harlequin Icthyosis

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.

  • Affects the shape of the eyelids, nose, mouth, and ears.
  • Limits movement of the arms and legs.

Mutation affects

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

Normal functions of ABCA12

The Genetics Behind Harlequin Icthyosis (ABCA12)

Why did Ali have H.I.?

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

  • Autosomal recessive pattern

Inheritance of H.I.

Ali's Family History

(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

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.

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.

H.I. & The Z9Pigs

infant receiving care from nurses

  • 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

Treatments may include:

Treatment for Ali

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

References