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Advances in dermatology and venereology Acta Dermato-Venereologica
Ichthyosis Prematurity Syndrome due to a Novel SLC27A4 Homozygous Mutation in an Italian Patient
Andrea DIOCIAIUTI 1 , Enrico ROSATI 2 , Maria Giovanna PAGLIETTI 3 , Paola VACCA 2 , Renata BOLDRINI 4 , Elisa PISANESCHI 5 , Daniele CASTIGLIA 6 , Antonio NOVELLI 5 and May EL HACHEM 1
1
Dermatology Unit , 3 Respiratory Unit , 4 Pathology Unit and 5 Laboratory of Medical Genetics , Bambino Gesù Children ’ s Hospital-IRCCS , Rome ,
2
Neonatology Unit , Perrino Hospital , Brindisi , and 6 Laboratory of Molecular and Cell Biology , Istituto Dermopatico dell ’ Immacolata , IRCCS , Rome , Italy . E-mail : andrea . diociaiuti @ opbg . net Accepted Apr 26 , 2018 ; Epub ahead of print Apr 27 , 2018
Ichthyosis prematurity syndrome ( IPS ) ( OMIM # 608649 ) is a rare autosomal recessively inherited syndromic ichthyosis characterized by prematurity and respiratory distress , a thick vernix caseosa-like material and transient eosinophilia . Ichthyosis manifestations rapidly improve , while the majority of patients develop atopy signs and increased levels of IgE ( 1 , 2 ). The disease gene , SLC27A4 , encodes the fatty acid transporter protein 4 ( FATP4 ), a member of the FATP family involved in fatty acid trafficking ( 2 ), expressed in the epidermis . IPS is observed mainly in Scandinavian countries , but isolated cases have been described worldwide ( 1 – 8 ). We report here the first molecular characterization of an Italian case of IPS .
CASE REPORT
The proband is a male , born at 29-week gestation weighing 1,744 g with healthy non-consanguineous parents . During pregnancy , polyhydramnios with hyperechogenic amniotic fluid had been detected on ultrasound examination . At birth , severe respiratory distress ( Apgar scores 1 , 4 , 7 at 1 , 5 and 10 min ) required intubation . Laboratory examination showed marked eosinophilia ( 38 %). The neonate was extubated on day 10 , and remained dependent on inhaled oxygen until day 40 . Chest X-ray repeatedly showed bilateral lung atelectasis . At birth , the skin appeared erythrodermic and oedematous ( Fig . 1a ) with a thick vernix caseosa-like desquamation , rapidly shed with hair loss . Erythroderma also disappeared , leaving a xerotic skin with cobblestone appearance and whitish scales ( Fig . 1b ). IPS was suspected , and molecular testing requested to our Medical Genetic Laboratory , following informed consent . Variant analysis , performed on genomic DNA from the infant and his parents using a next generation sequencing panel with inherited ichthyosis genes ( 9 ), revealed a novel homozygous missense variant c . 931C > T , p . Arg311Trp in the SLC27A4 gene ( NM _ 005094.3 ) in the proband . Sanger sequencing confirmed the mutation in homozygous and heterozygous status in the patient and his parents , respectively . Mutation p . Arg311Trp has not been previously reported , and is not annotated in any database of human genetic variations ; pathogenicity prediction software define it as deleterious and probably damaging ( SIFT : 0 ; PolyPhen-2 : 0.998 ) supporting its pathogenic role ( Fig . 2a ). Alignment of domains from orthologous and paralogous FATP proteins shows a strong predilection for a charged basic amino acid at position 311 , with arginine being the most conserved residue , attesting at mutation functional relevance ( Fig . S1 1 ).
At 2 months of age , the patient was transferred to our hospital to manage his respiratory distress . Physical examination showed diffuse hyperkeratosis , accentuated skin markings , mild palmoplantar keratoderma , and persistent alopecia ( Fig . 1c , d ). Eosinophilia was still present ( 16 %). He was dyspnoeic and tachypneic , and chest X-ray confirmed persistent lung atelectasis . A bronchoscopy did not reveal significant involvement of the upper airways . Nevertheless , ultrastructural examination of bronchoalveolar lavage ( BAL ) fluid showed the presence of remnants of shed stratum corneum composed of corneocytes containing the typical multilamellar structures in the cytoplasm ( Fig . 2b ). The same structures were also seen in the granular and horny layer in a skin biopsy ( Fig . 2c ). During hospitalization , the patient ’ s skin condition improved further ( Fig . S2 1 ), but the infant manifested severe itching , gastro-oesophageal reflux , and continued to experience episodes of polypnoea . Training for non-invasive mechanical ventilation to enhance alveolar recruitment improved the respiratory symptoms , allowing the infant to be discharged . However , recurrent infectious episodes required additional hospitalization . At 7 months of age , cow ’ s milk protein allergy was diagnosed . At present , the child , aged 10 months , presents dry skin with minimal scaling , and scalp hair regrowth , while itching remains severe .
DISCUSSION
IPS is a very rare syndromic ichthyosis ( 1 – 8 , 10 ). Pregnancy complications are polyhydramnios and a hyperechogenic amniotic fluid due to massive foetal epidermal cell shedding . Like most cases of IPS , our
1 https :// www . medicaljournals . se / acta / content / abstract / 10.2340 / 00015555-2957
Fig . 1 . Patient ’ s clinical features . ( a ) Erythroderma with oedema and trunk desquamation at birth . ( b ) Hyperkeratosis with accentuation of skin markings , and desquamation , the latter particularly marked on the partially alopecic scalp , at week 2 . Improved ichthyosis manifestations at 2 months of age : ( c ) forehead hyperkeratosis and scaling with scalp hair , eyelash and eyebrow loss ; ( d ) hyperkeratosis with accentuation of skin markings and mild desquamation of lower limb , and palmar hyperkeratosis ( inset ). Permission is given by the parents to publish these photos .
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2018 Acta Dermato-Venereologica . doi : 10.2340 / 00015555-2957 Acta Derm Venereol 2018 ; 98 : 803 – 804