2015/10/16 by Kana Tanahashi, Kazumitsu Sugiura, Tomoe Sato +1 · 1 citation
Biochemistry, Genetics and Molecular Biology · #Skin and Cellular Biology Research #Genetic and rare skin diseases. #Dermatological and Skeletal Disorders
paper · doi:10.1111/bjd.14228
openalex publication_date 2015/10/16 · openalex created_date 2016/06/24 · openalex updated_date 2026/07/29
Dear Editor, Harlequin ichthyosis (HI) (OMIM 242500) is the most severe form of autosomal recessive congenital ichthyosis caused by mutations in the ATP‐binding cassette, sub‐family A (ABCA), member 12 (ABCA12) gene (ABCA12). The clinical features at birth include ectropion, eclabium, flattened ears and large, thick plate‐like scales over the entire body.1 Although HI is occasionally fatal even today, the survival rate has improved due to the early introduction of oral retinoids and intensive neonatal care.2 Long‐term HI survivors report improvement of the dermatological symptoms. It is important to prevent irreversible after‐effects associated with HI in order to improve long‐term quality of life in affected patients. Here, we report a case of HI survival with digital autoamputation caused by cutaneous constriction bands. We also describe novel ABCA12 mutations detected in the case. A girl was born by scheduled Caesarean section because of breech presentation. She is the first child of healthy, unrelated Japanese parents. There was no remarkable family history of any related disorders. Apgar scores were 4 and 8. The skin revealed hard, thick plate‐like scales with deep fissuring overlying erythrodermic skin. Severe eclabium and ectropion were observed. These clinical features are typical of HI. She was brought to the neonatal intensive care unit due to the skin abnormality. She was treated with local application of emollient ointment and systemic retinoids (1 mg kg−1) from postnatal day 6 under respiratory management, nutrition management and infection control. The digital necrosis caused by cutaneous constriction bands appeared from postnatal day 2 to day 3, and resulted in the autoamputation of all the fingers and toes at the distal middle phalanx, except the left forefinger, the thumbs and the first toes (Fig. 1a,b). Now at the age of 2·5 years, she shows generalized erythroderma with desquamative scaling, persistent mild ectropion and flattened ears. She has normal mental and physical development. Clinical features of the patient's foot and hand. The toes (a) and the fingers (b) were autoamputated at the distal middle phalanx, except the thumbs and the first toes. The ethics committee of the Nagoya University Graduate School of Medicine approved the present studies, which were conducted according to the principles of the Declaration of Helsinki. The participants provided written informed consent. We searched for mutations in the ABCA12 gene in the patient and both parents. Direct sequencing of the patient's polymerase chain reaction (PCR) amplification products revealed that the patient had the following compound heterozygous ABCA12 gene mutations: c.11941221del28 (p.Ile398Metfs15X) in exon 11 and c.5985G>A (p.Gly1996Asp) in exon 41 (Fig. 2a,b). The patient's father was heterozygous for c.11941221del28 and her mother heterozygous for c.5985G>A. To the best of our knowledge, both mutations are novel. The c.5985G>A mutation was not detected in 100 control alleles (50 individuals; data not shown), and the resulting mutation occurs at the amino acid residue Gly1996, which is highly conserved across different species (Fig. 2c). p.Gly1996Asp was analysed using SIFT (http://sift.jcvi.org/) and PolyPhen‐2 (http://genetics.bwh.harvard.edu/pph2/). The SIFT score was 0·002 and the PolyPhen‐2 score was 1·000; both scores predicted that the p.Gly1996Asp substitution was a damaging aberration. The p.Ile398Metfs15X mutation is located in the N‐terminal domain of the protein, while the p.Gly1996Asp mutation is located within the second cluster of the transmembrane domains (Fig. 2d). Because the two mutations are considered to lead to severe loss‐of‐function, we predicted that these mutations were causative mutations for HI. Mutational analysis and localization of the ABCA12 gene mutations. (a) Direct sequencing revealed a heterozygous c.11941221del28 (p.Ile398Metfs15X) mutation in exon 11 of the ABCA12 gene in the patient and her father, but not in normal control samples. (b) A heterozygous c.5985G>A (p.Gly1996Asp) mutation was identified in exon 41 of the ABCA12 gene in the patient and her mother, but was absent in normal control samples. (c) Partial ABCA12 amino acid sequence alignment of diverse species shows a high conservation of the Gly1996 residue (red characters). (d) The p.Ile398Metfs15X and p.Gly1996Asp mutations (red arrows) identified in the patient with harlequin ichthyosis. In the literature, seven cases of HI with digital autoamputation or necrosis due to cutaneous constriction bands have been reported previously.3 4 5 Of these, both cases with an established outcome died of sepsis within 15 days after birth. Our case survived thanks to thorough treatment, even though her fingers and toes were necrotic just after birth. Resolution of digital ischaemia by relaxation incision was reported in one HI case.6 Relaxation incision is thought to be a conceivable therapy for digital ischaemia. Even the incision of a superficial, thick stratum corneum may be effective for treatment of digital necrosis in HI cases. In conclusion, we report a digital autoamputation caused by cutaneous constriction bands in a long‐term survivor of HI due to two novel ABCA12 mutations. The present case suggests that the digital necrosis observed could occur despite the application of appropriate general treatments. It is important to inform family members of patients affected by HI about the possibility of digital necrosis. The authors thank Ms Haruka Ozeki and Ms Yuka Terashita for their technical help in analysing mutations of ABCA12. This study was supported in part by a Grant‐in‐Aid for Scientific Research (B) to M.A. (15H04887), a Grant‐in‐Aid for Challenging Exploratory Research to M.A. (15K15415), a Grant‐in‐Aid for Scientific Research (B) to K.S. (15H04886) and a Grant‐in‐Aid for Challenging Exploratory Research to K.S. (15K15414) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the grant H26‐itaku (nan)‐ippan‐027 to K.S. from the Japan Agency for Medical Research and Development (Research on Measures for Intractable Disease), Japan. Funding sources: no external funding. Conflicts of interest: none declared.