Ichthyosis prematurity syndrome: A well-defined congenital ichthyosis subtype

doi:10.1016/j.jaad.2008.06.014

Journal of the American Academy of Dermatology

Volume 59, Issue 5, Supplement, November 2008, Pages S71-S74

https://doi.org/10.1016/j.jaad.2008.06.014 Get rights and content

Ichthyosis prematurity syndrome is a rare syndrome characterized by the clinical triad of premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. We describe two siblings with ichthyosis prematurity syndrome. The index patient was born at gestational week 34. Immediately after birth he developed respiratory distress and needed intubation. Remarkable skin changes were noticed with universal red, edematous and desquamating, spongy skin giving an impression of excessive vernix caseosa. Marked regression of the edema and ichthyotic scaling was observed within a few weeks. The parents recalled that his elder sister had similar but milder skin changes and respiratory distress syndrome at birth. Ichthyosis prematurity syndrome was suggested and the diagnosis supported by electron microscopy of a skin biopsy specimen showing pathognomonic trilamellar membrane aggregations in the stratum corneum and stratum granulosum. Diagnosing this syndrome is important to reassure parents, obstetricians, and pediatricians about its benign course after complications in the perinatal period.

Section snippets

Case 1

The proband was a boy born at gestational week 34 with a birth weight of 2970 g, after an uneventful pregnancy and delivery. The parents were unrelated. Immediately after birth he developed respiratory distress and was intubated for a short time and later treated by continuous positive airway pressure in a neonatal care department for 1 week. Radiography showed bilateral pulmonary infiltrations, possibly a sign of aspiration pneumonia. He had a normal cord blood IgE less than 0.1 kU/L (<0.3)

Discussion

IPS was suspected in the boy because of the clinical triad: premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. The diagnosis was confirmed by ultrastructural analysis of a skin biopsy specimen. Furthermore, linkage to a locus on chromosome 9q34 was established in the affected children in a study of Scandinavian cases of IPS with identical linkage.¹ Haplotype analysis confirmed a strong founder effect for the disorder.¹ However, it has not been possible to trace the

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Recessive ichthyosis congenita type IV
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There are more references available in the full text version of this article.

Cited by (35)

Fatty acid transport protein 1 can compensate for fatty acid transport protein 4 in the developing mouse epidermis
2015, Journal of Investigative Dermatology
Citation Excerpt :
Suprabasal keratinocyte expression of a Fatp4 transgene in Fatp4 mutant skin rescues the neonatal lethality and ameliorates the skin phenotype, underscoring the crucial, skin-intrinsic roles of FATP4 in skin development and function (Moulson et al., 2007). Mutations affecting human FATP4 occur in patients with the ichthyosis prematurity syndrome (IPS), characterized by premature birth, respiratory distress, peripheral blood eosinophilia, and edematous skin with severe caseous scaling (Bygum et al., 2008; Klar et al., 2009; Sobol et al., 2011). Symptoms of surviving patients become mild during childhood and manifest mainly as dry and pruritic skin, although respiratory and/or food allergies are common (Khnykin et al., 2012).
Fatty acid transport protein (FATP) 4 is one of a family of six FATPs that facilitate long- and very-long-chain fatty acid uptake. Mice lacking FATP4 are born with tight, thick skin and a defective barrier; they die neonatally because of dehydration and restricted movements. Mutations in SLC27A4, the gene encoding FATP4, cause ichthyosis prematurity syndrome (IPS), characterized by premature birth, respiratory distress, and edematous skin with severe ichthyotic scaling. Symptoms of surviving patients become mild, although atopic manifestations are common. We previously showed that suprabasal keratinocyte expression of a Fatp4 transgene in Fatp4 mutant skin rescues the lethality and ameliorates the skin phenotype. Here we tested the hypothesis that FATP1, the closest FATP4 homolog, can compensate for the lack of FATP4 in our mouse model of IPS, as it might do postnatally in IPS patients. Transgenic expression of FATP1 in suprabasal keratinocytes rescued the phenotype of Fatp4 mutants, and FATP1 sorted to the same intracellular organelles as endogenous FATP4. Thus, FATP1 and FATP4 likely have overlapping substrate specificities, enzymatic activities, and biological functions. These results suggest that increasing expression of FATP1 in suprabasal keratinocytes could normalize the skin of IPS patients and perhaps prevent the atopic manifestations.
Fatty acid transporters in skin development, function and disease
2014, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Citation Excerpt :
Prenatal sonographic signs of IPS are separation of the amniotic and chorionic membranes, echogenic amniotic fluid and echo-free chorionic fluid occurring between 28 and 32 weeks of gestation [63]. IPS is characterized by premature birth, often with respiratory complications, peripheral blood eosinophilia, and edematous skin with severe caseous scaling [64–66]. Symptoms of surviving IPS patients become mild during childhood and manifest mainly as dry and pruritic skin, though respiratory and/or food allergy are common [67].
Fatty acids in the epidermis can be incorporated into complex lipids or exist in a free form, and they are crucial to proper functions of the epidermis and its appendages, such as sebaceous glands. Epidermal fatty acids can be synthesized de novo by keratinocytes or taken up from extracutaneous sources in a process that likely involves protein transporters. Several proteins that are expressed in the epidermis have been proposed to facilitate the uptake of long-chain fatty acids (LCFA) in mammalian cells, including fatty acid translocase/CD36, fatty acid binding protein, and fatty acid transport protein (FATP)/very long-chain acyl-CoA synthetase. In this review, we will discuss the mechanisms by which these candidate transporters facilitate the uptake of fatty acids. We will then discuss the clinical implications of defects in these transporters and relevant animal models, including the FATP4 animal models and ichthyosis prematurity syndrome, a congenital ichthyosis caused by FATP4 deficiency. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.
Interactions between FATP4 and ichthyin in epidermal lipid processing may provide clues to the pathogenesis of autosomal recessive congenital ichthyosis
2013, Journal of Dermatological Science
Citation Excerpt :
Ichthyosis prematurity syndrome (IPS) is a rare type of autosomal recessive congenital ichthyosis (ARCI) characterized by premature birth, usually at gestational weeks 30–32, thick desquamating epidermis, respiratory complications, and transient eosinophilia [1–5].
Autosomal recessive congenital ichthyosis (ARCI) is caused by mutations in ≥10 different genes, of which transglutaminase-1 (TGM1) predominates. A rare form is ichthyosis prematurity syndrome (IPS) caused by mutations in SLC27A4 encoding fatty acid transporter protein 4 (FATP4), believed to be an acyl-CoA synthetase activating long- and very-long-chain FA. Another ARCI is caused by mutations in NIPAL4, coding for ichthyin, which is proposed to be a magnesium transporter or a trans-membrane receptor. A possible interaction between FATP4 and ichthyin has not been studied before.
To find common denominators in the pathogenesis of ARCI.
FATP4 and ichthyin were analyzed by immunofluorescence and proximity ligation assay (PLA) in healthy and ARCI patient skin and in in vitro models of ARCI epidermis.
Both proteins were expressed in the upper stratum granulosum of normal epidermis and PLA confirmed a close interaction between FATP4 and ichthyin. In IPS skin lacking FATP4 we found reduced ichthyin expression and this finding could be reproduced in organotypic epidermis with siRNA silenced SLC27A4. In contrast, increased FATP4 staining was found in patients with ichthyin (NIPAL4) mutations and in organotypic epidermis with silenced NIPAL4. In patients with TGM1 mutations, the expression of both FATP4 and ichthyin was increased, but the PLA signal was low probably indicating a malfunctioning protein interaction.
Our study suggests that FATP4, ichthyin and TGM1 interact in lipid processing essential for maintaining the epidermal barrier function. It is also hypothesized that ichthyin serves as Mg²⁺-transporter for FATP4 in this process.
Collodion baby: An update with a focus on practical management
2012, Journal of the American Academy of Dermatology
Collodion baby is an uncommon clinical presentation of several genetic conditions, primarily disorders of cornification. The severely compromised epidermal barrier presents the greatest challenge during the newborn period and advances in neonatal care have significantly improved the prognosis. This review summarizes the clinical characteristics, complications, outcomes, and differential diagnosis of the collodion baby. A practical approach to management based on the literature and clinical experience is presented.
Clinical and molecular classification of ichthyosis
2012, Piel
Ichthyosis prematurity syndrome: Clinical evaluation of 17 families with a rare disorder of lipid metabolism
2012, Journal of the American Academy of Dermatology
Ichthyosis prematurity syndrome (IPS) is classified as a syndromic congenital ichthyosis based on the presence of skin changes at birth, ultrastructural abnormalities in the epidermis, and extracutaneous manifestations. Recently, mutations in the fatty acid transporter protein 4 gene have been identified in patients with IPS.
We sought to perform a detailed clinical evaluation of patients with IPS identified in Norway.
Clinical examination and follow-up of all patients (n = 23) and light and electron microscopic examination of skin biopsy specimens were performed.
IPS was characterized prenatally by ultrasound findings of polyhydramnios, separation of membranes, echogenic amniotic fluid, and clear chorionic fluid. All patients were born prematurely with sometimes life-threatening neonatal asphyxia; this was likely caused by aspiration of corneocyte-containing amniotic fluid as postmortem examination of lung tissue in two patients revealed keratin debris filling the bronchial tree and alveoli. The skin appeared erythrodermic, swollen, and covered by a greasy, thick vernix caseosa-like “scale” at birth, and evolved rapidly to a mild chronic ichthyosis. Many patients subsequently had chronic, severe pruritus. Histopathologic and ultrastructural examination of skin biopsy specimens showed hyperkeratosis, acanthosis, dermal inflammation, and characteristic aggregates of curved lamellar structures in the upper epidermis. Peripheral blood eosinophilia was invariably present and most patients had increased serum immunoglobulin E levels. Over 70% of the patients had a history of respiratory allergy and/or food allergy.
The study included only 23 patients because of the rarity of the disease.
IPS is characterized by defined genetic mutations, typical ultrastructural skin abnormalities, and distinct prenatal and postnatal clinical features.

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Case reportIchthyosis prematurity syndrome: A well-defined congenital ichthyosis subtype

Section snippets

Case 1

Discussion

A founder mutation for ichthyosis prematurity syndrome restricted to 76 kb by haplotype association

J Hum Genet

Pränatale Diagnostik von Genodermatosen

Hautarzt

The skin

Recessive ichthyosis congenita type IV

Am J Dermatopathol

Case report
Ichthyosis prematurity syndrome: A well-defined congenital ichthyosis subtype