IFAP Syndrome (Ichthyosis Follicularis, Atrichia, Photophobia syndrome

Are You Confident of the Diagnosis?

What you should be alert for in the history

Characteristic findings on physical examination

IFAP is a syndrome characterized by follicular ichthyosis and alopecia from birth and accompanied by short stature, intellectual disabilities, and seizures that develop in the first few years of life. Photophobia may also be present in the first year of life or appear in infancy or early childhood. The most frequent features: developmental delay, short stature, seizures, generalized alopecia, follicular ichthyosis, hyperkeratosis, psoriasiform plaques, dystrophic nails, photophobia, atopic manifestations, inguinal hernia, renal and vertebral anomalies. The palms and soles are generally unaffected (Figure 1).

Figure 1.

Recurrent respiratory infections are characteristic of the IFAP syndrome. Affected or carrier females could present some features such as photophobia in the first year of life and cutaneous hyperkeratotic lesions that follow the lines of Blashko. Retinal vascular tortuosity may be another clinical sign of carrier status in females.

Expected results of diagnostic studies

Skin histopathology is non-specific and consists of deleted hair follicles with keratin plugs extending above the surface of the skin, decreased or absent sebaceous glands, and normal sweat glands. On electron microscopy moderate spongiotic changes, partial disruption of the intercellular bridges, decreased desmosomes, and some dyshesion of the cells could be seen.

Confirmation of the diagnosis is based on the presence of a mutation in the MBTPS2 gene.

Diagnosis confirmation

IFAP syndrome presents overlapping manifestations with the dermotrichic syndrome and the keratosis follicularis spinulosa decalvans syndrome (KFSD). Dermotrichic syndrome presents with megacolon and no respiratory complications; otherwise, both syndromes seem to be identical. KFSD differs from IFAP in that the alopecia is not congenital and is progressively scarring. Patients with KFSD have milder phenotype than those with IFAP. Recently, mutations in the MBTPS2 gene were found in KFSD patients, showing that both entities are within the spectrum of one genetic disorder.

Who is at Risk for Developing this Disease?

IFAP syndrome is an X-linked recessive disorder affecting mostly males. Affected or carrier females could display some of its clinical features.

What is the Cause of the Disease?

Etiology

Pathophysiology

IFAP syndrome is secondary to mutations in the MBTPS2 gene. Cholesterol homeostasis and ability to cope with endoplasmic reticulum stress is impaired because of a deficiency of MBT, an intramembrane zinc metalloprotease . Functional studies with the mutations showed that those resulting in the lowest residual MBTPS2 activity correspond with the most severe phenotype.

Systemic Implications and Complications

Life expectancy can vary from death in the neonatal period to a normal surviving age. Cardiopulmonary complications are the main cause of death.

Treatment Options

Follicular hyperkeratosis can be treated using topical keratolytics: ammonium lactate, urea preparations, and emollients. Topical retinoids are not suitable because of their irritation.

Corneal complications do not respond to topical corticosteroid therapy. Intensive lubrication of the ocular surface is essential.

Optimal Therapeutic Approach for this Disease

A moderate response to acitretin therapy at a dose of 0.3 to 1mg/kg/day with improvement in cutaneous features and corneal erosions, but no changes regarding alopecia and photophobia, have been noted in some patients.

Patient Management

General complications like seizures must be treated accordingly. Sunglasses may certainly help with the light sensitivity.

Unusual Clinical Scenarios to Consider in Patient Management

Candidal infections may complicate IFAP syndrome. Cutaneous candidiasis can be treated with Nystatin powder or topical azole lotions or creams once or twice daily, which is more effective. In candidal onychomycosis, topical antifungal preparations are not effective. Oral azoles such as fluconazole 150 to 300mg weekly for 6 months, or itraconazole 200mg once daily for at least 3 months or in pulse therapy 200mg twice daily for one week per month for at least 3 months is recommended .

What is the Evidence?

Mégarbané, H, Zablit, C, Waked, N, Lefranc, G, Tomb, R, Mégarban, A. “Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome: report of a new family with additional features and review”. Am J Med Genet. vol. 124A. 2004. pp. 323-7. (Two male sibs are reported. One of the sibs had bilateral absence of the fourth fingers and camptodactyly. This is a good review of the literature.)

Boente, MC, Bibas-Bonet, H, Coronel, AM, Asial, RA. “Atrichia, ichthyosis, follicular hyperkeratosis, chronic candidiasis, keratitis, seizures, mental retardation, and inguinal hernia: a severe manifestation of IFAP syndrome”. Eur J Dermatol. vol. 10. 2000. pp. 98-102. (Description of two related males with IFAP. One of the patients had a predisposition to cutaneous candidiasis.)

Keyvani, K, Paulus, W, Traupe, H, Kiesewetter, F, Cursiefen, C, Huk, W. “Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome: Clinical and neuropathological observations in a 33 year old man”. Am J Med Genet. vol. 78. 1998. pp. 371-7. (Description of the clinical and autopsy findings in the older patient with IFAP reported in the literature.)

Oeffner, F, Fisher, G, Happle, R, Konig, A, Betz, RC, Bornholdt, D. “IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response”. Am J Hum Genet. vol. 84. 2009. pp. 459-67. (By linkage analysis the authors mapped [Xp22.3-p22.11] and cloned the gene responsible of IFAP: MBTPS2. In addition new cases are described.)

Konig, A, Happle, R. “Linear lesions refelecting lyonisation in women heterozygous for IFAP syndrome (ichthyosis follicularis with atrichia and photophobia)”. Am J Med Genet. vol. 85. 1999. pp. 365-8. (Authors had the opportunity to delineate the IFAP phenotype in female carriers.)

Traboulsi, E, Waked, N, Mégarbané, H, Mégarbané, A. “Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome”. Ophthalmic Genet. vol. 25. 2004. pp. 153-6. (A nice review on eye problems encountered in patients with IFAP syndrome.)

Aten, E, Brasz, LC, Bornholdt, D, Hooijkaas, IB, Porteous, ME, Sybert, VP. “Keratosis follicularis spinulosa decalvans is caused by mutations in MBTPS2”. Hum Mutat. vol. 31. 2010. pp. 1125-33. (A paper demonstrating that IFAP and KFSD are allelic syndromes.)

Khandpur, S, Bhat, R, Ramam, M. “Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin”. J Eur Acad Dermatol Venereol. vol. 19. 2005. pp. 759-62. (The first paper showing a treatment with acitretin.)

Ming, A, Happle, R, Grzeschik, KH, Fisher, G. “Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome due to mutation of the gene MBTPS2 in a large Australian kindred”. Pediat Dermatol. vol. 26. 2009. pp. 427-31. (A second family treated by acitretin period)

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