|Year : 2019 | Volume
| Issue : 3 | Page : 150-153
Case report of two brothers with a novel homozygous mutation in ALOX12B leads to autosomal recessive congenital ichthyosis: Which type and which subtype? Two siblings with a novel homozygous mutation in ALOX12B
Department of Medical Genetics, Faculty of Medicine, University of Harran, Sanliurfa, Turkey
|Date of Submission||11-Jun-2018|
|Date of Acceptance||01-Dec-2018|
|Date of Web Publication||28-May-2019|
Dr. Evren Gumus
Department of Medical Genetics, Faculty of Medicine, University of Harran, 630 00 Sanliurfa
Source of Support: None, Conflict of Interest: None
Ichthyosis is a heterogeneous group of rare genetic skin disorders characterized by furfuraceous and dry skin. The classification of ichthyosis has always been a challenging process as genodermatoses. Here, we report a novel homozygous mutation in ALOX12B in two siblings with autosomal recessive congenital ichthyosis. We aimed to evaluate two brothers' genotype-phenotype association in the light of the last nomenclature information.
Keywords: ALOX12B, hearing aid, ichthyosis, nomenclature, novel mutation
|How to cite this article:|
Gumus E. Case report of two brothers with a novel homozygous mutation in ALOX12B leads to autosomal recessive congenital ichthyosis: Which type and which subtype? Two siblings with a novel homozygous mutation in ALOX12B. Dermatol Sin 2019;37:150-3
|How to cite this URL:|
Gumus E. Case report of two brothers with a novel homozygous mutation in ALOX12B leads to autosomal recessive congenital ichthyosis: Which type and which subtype? Two siblings with a novel homozygous mutation in ALOX12B. Dermatol Sin [serial online] 2019 [cited 2020 Mar 31];37:150-3. Available from: http://www.dermsinica.org/text.asp?2019/37/3/150/259209
| Introduction|| |
Ichthyosis is a heterogeneous group of rare genetic skin disorders characterized by furfuraceous and dry skin. According to the “First Ichthyosis Consensus Conference in Sorèze 2009,” ichthyosis has four major forms as follows: common ichthyoses, autosomal recessive congenital ichthyosis (ARCI), keratinopathic ichthyosis, and other forms. Histopathological signs observed in many forms of ichthyosis are same and nonspecific. The prevalence of ARCI is approximately 1/100,000. ARCI was divided into two groups: major types (harlequin ichthyosis [HI], lamellar ichthyosis [LI], and congenital ichthyosiform erythroderma [CIE]) and minor variants (self-healing collodion baby [SHCB], acral SHCB, and bathing suit ichthyosis)., Fourteen genes have been described until today for ARCI. Mutations in four genes (TGM1, ALOX12B, ABCA12, and ALOXE3) are responsible for more than 90% of cases with ARCI. Mutations in the TGM1 and ABCA12 gene were frequently associated with LI and HI, respectively. Mutations in the ALOX12B and ALOXE3 genes have been associated with all phenotypes outside HI, especially SHCB. The SHCB prevalence is <1/1000,000.
In the present paper, we report a novel homozygous mutation in ALOX12B in two siblings with ARCI.
| Case Report|| |
Two affected brothers are the product of healthy, consanguineous 26-year-old mother and 26-year-old father of Turkish origin. The couple referred to our clinic due to preconception genetic counseling. There is no significant family history other than affected siblings. This research was conducted in accordance with the Declaration of Helsinki Principles 2013. The siblings' parents gave their informed consent for the molecular genetic analysis of the brothers, the publication of patient data and photos.
He was delivered by C/S at 35 weeks of gestation due to a decrease of fetal movements and parameters at birth were; weight 3400 g (25–50 percentile), length 51 cm (50–75 percentile), and occipitofrontal circumference (OFC) 33.5 cm (10–25 percentile). At birth, the patient presented a shiny glue-like membrane that covered all the body surface. He was followed up in intensive care unit for a week after birth. He did not pass the hearing test. One week after birth, the membranes were separated into large pieces and shedded. At the end of the 1st month, the membrane was completely peeled out. He could not pass the repeated hearing test. A hearing aid is fitted to the patient receiving a conductive hearing loss diagnosis. At the time of presentation (5-year-old), his weight is 18 kg (10–25 percentile) and his length is 110 cm (25–50 percentile). Clinical examination showed peeling only in the corners of mouth [Figure 1]. Based on the clinical information provided, first we planned the panel test include 3 genes with the most frequent mutations in the SHCB patients. Blood sample was taken from the antecubital vein via vacutainer tubes containing ethylenediaminetetraacetic acid (BD, Franklin Lakes, NJ, USA). DNA was isolated from white blood cells using Magpurix Blood DNA Extraction Kit 200 (Zinexts LSC, New Taipei City, Taiwan [R.O.C.]). Quantitative-purity determinations and fluorimetric analysis were performed. Next-generation sequencing was performed using Agilent HaloPlex (Agilent, CA, USA) with a custom designed multi-gene panel containing ALOX12B, ALOXE3 and TGM1. The sequencing was performed on an Illumina Miseq sequencer (Illumina, CA, USA) using MiSeq Reagent Kit v3 (2 bp × 300 bp). The fraction of target bases with at least 20 reads was approximate 99%. The analysis showed homozygous variant c. 1798C >T p.(Arg600Trp) in ALOX12B [Figure 2]. To date, this variant is not described in the exome aggregation consortium, Genome Aggregation Database, 1000 genomes or the NHLBI GO Exome Sequencing Project. For the in silico prediction tools, this variant is a disease-causing (SIFT: deleterious, Provean: deleterious, Mutation Taster: Disease-causing, Human Splicing Finder 3.1: Potential alteration of splicing). Furthermore, arginin is a preserved amino acid between species; therefore, any change in this amino acid can create modifications of the protein structure. This variant confirmed by conventional Sanger sequencing method. Parents were heterozygous for this change [Figure 3]. In our study with 25 local participants, we did not observe any changes in homozygous or heterozygous form at the same position [Figure 4]. In the hearing test after the diagnosis, conductive hearing loss was shown again [Figure 5].
|Figure 2: The Integrative Genomics Viewer images of P, M, and F. P: Patient, M: Mother. F: Father|
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|Figure 3: Sanger confirmation images of P1, P2, M, and F. P: Patient, M: Mother. F: Father|
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The younger brother of the index patient was 8-month-old; he presented with same clinical manifestation as his brother, namely, red cheeks and peeling on the face [Figure 1]. His perinatal story is similar to his brother. In the postnatal period, although he could not pass the hearing test during the first application, he passed after cleaning the external acoustic canal. His weight, length, and OFC are 50%–75% percentile at the time of presentation. Sanger sequencing performed and the homozygous change in ALOX12B c. 1798C>T was shown [Figure 3].
| Discussion|| |
The classification of genodermatoses has always been a challenging process. The most important factor in this situation is variable phenotypes besides the excess of groups and subgroups. Undoubtedly, the identification of the ARCI subtypes is also a difficult process. Although the first classification of major groups did not change, for the naming of minor groups over time; non-LI/non-CIE, congenital ichthyosis with fine or focal scaling and congenital ichthyosis with mild scaling are used. Since 2010, the definition of pleomorphic ichthyosis (PI), which we think is a more accurate locution, has started to be used as an umbrella term. Severe signs of ichthyosis and colloidal membranes at birth show dramatic improvement within a short time in patients with PI group and only minor findings remain. It is one of the most prominent characteristics of this group that the findings of this minor findings are exacerbated by environmental influences such as exercise, heat, and irritation. Because of this “dynamic and labile” situation, we also think that the term “pleomorphic” is more appropriate. The result of the dynamic situation observed also in SHCB patients, this term has been changed to self-improving collodion ichthyosis (SICI) because of the observation of periodic minor ichthyosis findings in SHCB. The reason for the dramatic improvement of ichthyosis in SICI patients is not clear. It is thought that this change, which occurred shortly after birth, is due to enzyme activity affected by the uterine hydrostatic pressure., SICI has been associated with variations in ALOX12B, ALOXE3, and TGM1. Disease-causing variants in ALOX12B were detected in 10 of 38 (26%) patients in the PI group and in 9 of 18 (50%) patients in the SICI group. Disease-causing variants in ALOX12B and ALOXE3 are associated with the CIE group at a second frequency. In the CIE group, nail dystrophy, cardiac malformations, erythema, and palmoplantar hyperkeratosis are expected. Our patients did not show any of these findings. Thus, our patients were diagnosed with SICI.
The most important complications in all phenotypes with the colloidal membrane; temperature instability, dehydration, infections, hypothermia, obstruction of the external meatus of ear and skin cancers.,,, The pilot study in 2014 showed that 16% of the patients with ichthyosis need hearing aids. Although it cannot be proven that it is a definite relationship, we also highlight the importance of early cleanliness in the external acoustic canal for normal hearing.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We cordially thank parents contributed to the study. We would like to thank Zafer Yuksel, MD for his contribution and critical review.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]