王若光教授专题之［出生缺陷］（18）鱼鳞病

病例来源

2016-5-20，2016-6-9

湖南生殖内分泌与产前诊断（一）群、（二）群及广州及泛珠三角胎儿医学群

王若光 湖南省第二人民医院：

以上病例均为鱼鳞病，涉及基因较多，华大基因专门做过相关研究。

司书斌 华大基因：

板层鱼鳞病是一类罕见的皮肤病，出生时即发病并且终身受累。发病率约为1:200,000～300,000，在挪威较为常见，发病率约为1:90,000。

患者出生时皮肤上包裹一层紧而透明的鞘状火棉胶膜，这层膜常在出生后数周脱落，但仍有鳞状皮肤和嘴唇、眼睑外翻的症状。患者皮肤表面被典型的大片深色的鳞状物覆盖，其他临床症状包括毛发脱落（秃头症）、少汗和手掌及脚底皮肤增厚，另有部分患者可能会出现红斑和关节挛缩。

患病婴儿可能会出现感染、脱水和呼吸困难。使用含有尿素、乳酸铵或其他α-羟基酸等药物的保湿剂，对死皮层脱落有帮助。另外，类维生素A类药物，如他扎罗汀也可用于改善症状。

研究表明，TGM1、ALOX12B、ALOXE3、ABCA12、CYP4F22、NIPAL4、PNPLA1、STS、FLG、SLC27A4、CLDN1、SPINK5、ST14、SNAP29、MBTPS2 与鱼鳞病致病相关，其中ABCA12、ALOX12B、ALOXE3、TGM1等基因导致的鱼鳞病会更为严重。

贾蓓 南方医科大学南方医院产前诊断与遗传病诊断中心：

ABCA12基因突变，可以宫内超声诊断（诊断孕周偏大），或早孕基因诊断，为常染色体隐性遗传。

鱼鳞病相关基因其实很多，其中4A型俗称丑胎，多与ABCA12基因相关。

司书斌 华大基因：

丑胎又称斑色鱼鳞病，是非常罕见的重型先天性鱼鳞病，发病率不详，有致死的可能。出生时即发病，特征是胎儿体表皮肤角质层异常增厚，新生儿被一层由深沟分裂开来的菱形裂纹角质层包裹，双侧眼睑及唇外翻，鼻子及耳朵扁平退化，四肢运动受角化的皮肤限制，并可能导致坏死。因为皮肤屏障被严重破坏，可能会引发新生儿败血症、脱水及温度调节障碍。口服类维生素A能够帮助增厚角质化的皮层脱落。

寻常型的鱼鳞病发病率约1/250，重症的发病率就比较低了。

基因不同遗传方式不同，常染色体隐性遗传、常染色体显性遗传、X连锁遗传的都有。

2014年华大基因还专门做了公益活动，其“晓明计划”启动将为100名鱼鳞病患者免费提供基因检测：http://szsb.sznews.com/html/2014-07/22/content_2947785.htm

陈敏玲 医师：

（她介绍了两例国外的鱼鳞病案例）

［案例一］

Nusrit "Nelly" Shaheen (born in 1984) is the oldest known survivor with the condition; she resides in Coventry, and was one of nine children in a Pakistani Muslim household. Four of her eight siblings also had the condition but died as young children.Shaheen lives an active lifestyle and in 2008 was studying sports coaching and leadership at Hereward College.

［案例二］

Title: A case of harlequin ichthyosis treated with isotretinoin

Journal Issue:Dermatology Online Journal, 20(2)

Author:Chang, Laura M, Kaiser Permanente Los Angeles Medical Center;Reyes, Melissa, Kaiser Permanente Los Angeles Medical Center

Publication Date:2014

Abstract

Harlequin ichthyosis is a rare congenital ichthyosis classified under the category of Autosomal Recessive Congenital Ichthyoses, which also include lamellar ichthyosis and congenital ichthyosiform erythroderma. It is caused by functional null mutations in the ABCA12gene, a keratinocyte lipid transporter associated with lamellar granule formation. Patients have a classic clinical presentation at delivery and need neonatal intensive care treatment to maximize their chances of survival. Early oral retinoid therapy has been shown to increase survival in patients with harlequin ichthyosis [1], and we present a case of a 9-month-old male with this condition who has been treated with isotretinoin since day 7 of life.

Introduction

Harlequin ichthyosis (HI) presents at birth with coarse, large plate-like scales with deep fissures, severe ectropion, eclabium, contractures of digits, and flattening of the ears and nose. Patients are usually born prematurely and do not have any brain or internal organ abnormalities. If patients survive the neonatal period, they continue with a persistent ichthyosiform erythroderma for life. We present a case of a 9-month-old male with HI who was started on treatment with isotretinoin on day 7 of life.

Case synopsis

At birth, a male infant presented with thick, hyperkeratotic plate-like scales covering his trunk, extremities, and head with deep fissures, prominent eclabium, and bilateral ectropion. In addition, he exhibited poorly formed and flattened ears and nose (Figure 1). In the NICU the patient was placed in a humidified incubator at 80% humidity, started on IV antibiotics, fluids and electrolytes, morphine as needed for pain, and a topical emollient ointment was applied to the entire cutaneous surface every 2 hours. Ophthalmology was consulted, and he received lubricant ointment to the eyes every 3 hours. He was initially placed on total parenteral nutrition and then subsequently switched to orogastric tube feedings with breast milk. After discussion with the parents, he was started on oral isotretinoin compounded in medium chain triglyceride (MCT) oil at 1mg/kg/day on day 7 of life (10mg isotretinoin capsule compounded in 5mL MCT oil for final concentration of 2mg/mL).

Figure 1. At day one of life, the patient had thick, hyperkeratotic plate-like scales covering his trunk, extremities, and head with deep fissures, prominent eclabium, and bilateral ectropion. He exhibited poorly formed and flattened ears and nose.

He tolerated the medication well and the scales softened and began to desquamate. The ectropion and eclabium improved and the finger and toe contractures nearly resolved (Figure 2). The humidity in the incubator was decreased slowly to room air humidity, whereas oral isotretinoin and topical emollients were continued.

Figure 2. After two weeks of daily oral isotretinoin, the fissures in the skin had healed, the plate-like scales nearly resolved, and the eclabium and ectropion were much improved.

After discharge from the NICU, the patient required regular debridement of hyperkeratosis in the ear canals. An ophthalmologist regularly monitored him and had a few episodes of conjunctivitis treated with topical gentamicin. He was found to have a mild rise of his triglycerides to 157mg/dL (baseline 87mg/dL) as well as a decrease in his hemoglobin to 8.4gm/dL (baseline 12.6gm/dL) at 3.5 months. His isotretinoin dose was subsequently decreased to 0.3mg/kg/day and he was supplemented with iron. His lab abnormalities resolved and he has been continued on the lower dose of isotretinoin.

Figure 3A,B. At 9 months, the patient has a persistent ichthyosis with fine scale and erythroderma with resolution of the ectropion and eclabium.

（点击上图可放大查看）

At 9 months, he continues with scaly erythematous skin on his trunk, face and extremities (Figure 3A,B) as well as thick hyperkeratotic plaques on the frontal scalp which have almost resolved with daily topical application of tazarotene 0.1% cream [2]. He has been diagnosed with hyperopia and anisometropia and now wears glasses. He continues to require frequent debridement of his ears, and he has mild contractures of his bilateral thumbs for which he receives physical therapy.

Discussion

Harlequin ichthyosis presents at birth with coarse and large plate-like scales with deep fissures, severe ectropion, eclabium, contractures of the digits, and flattening of the ears and nose. Patients are usually born prematurely and do not have any brain or internal organ abnormalities. Pain from the fissures can discourage patients from taking deep breaths and lead to respiratory complications [2,3]. In fact, respiratory infections can be a major cause of death in the neonatal period [1]. Over time, the thick scale is shed leading to a persistent scaly erythroderma very similar to that in non-bullous congenital ichthyosiform erythroderma (CIE).

Harlequin ichthyosis is now classified under the category of Autosomal Recessive Congenital Ichthyoses, which also includes lamellar ichthyosis (LI) and CIE. HI was included in the classification with these disorders because functional null mutations in the ABCA12 gene leads to HI; missense mutations in this same gene can lead to collodion membrane formation and development of either LI or CIE [4]. Abnormalities in other genes and known to cause CIE and these include transglutaminase 1 (TGM1), 12Rlipoxygenase (ALOX12B), lipoxygenase-3 (ALOXE3), cytochrome P450 4F22 (CYP4F22), ichthyin (NIPAL4), and patatin-like phospholipase (PNPLA1). Individuals who have focal linear epidermolytic hyperkeratosis, which is indistinguishable clinically from epidermal nevi, may produce offspring with CIE.

Other disorders that can present with very tight skin include lethal restrictive dermopathy (OMIM #275210), Neu-Laxova syndrome (OMIM# 256520) [3], and LI and CIE, which present with collodion membrane at birth. Patients with Neu-Laxova syndrome present with ichthyosis at birth that can range in severity. In the most severe form, patients can have HI characteristics. Patients also may have severe intrauterine growth retardation, edema, microcephaly, and brain abnormalities [5].

Harlequin ichthyosis is caused by mutations in both ABCA12 alleles. ABCA12 is a keratinocyte lipid transporter associated with lamellar granule formation. Loss of normal ABCA12 function leads to defective lipid transport by lamellar granules in the upper epidermis and malformation of the stratum corneum lipid layers [6].

Management of the neonate with HI includes the use of a humidified incubator, temperature regulation, nutrition replacement, pain control, and monitoring for infections [2]. Emollients should be applied liberally to the skin and bathing and soaking can reduce the risk of skin infection and promote shedding of the thickened skin. Eye care is critical and at least artificial tears should be initiated. If patients have contractures, surgical treatment may be necessary to prevent necrosis and gangrene formation of the distal fingers [2,3].

In a recent review of 45 patients with HI, early systemic retinoid therapy (the majority starting treatment within the first week of life) leads to an increased survival rate (83%) compared to the survival rate without retinoid use (24%). The majority received acitretin but some also received isotretinoin or etretinate. Mutation analysis found ABCA12 mutations in 38 of the 45 patients; they were classified as homozygous (both alleles with the same mutation) or compound heterozygous (each allele with a different mutation). All the patients that died in the cohort had homozygous mutations, whereas only 48% of the survivors had homozygous mutations [1].

Beyond the neonatal period, patients suffer from temperature dysregulation and may have heat and cold intolerance [1,4]. Patients can also have generalized poor hair growth, scarring alopecia, contractures of digits, arthralgias, failure to thrive, and short stature. Some patients may even develop a rheumatoid factor-positive polyarthritis [3,7]. Patients are prone to skin infections with Staphylococcus aureus, Streptococcus pyogenes, and Klebsiella [1]. Eye abnormalities such as persistent or recurrent ectropion, epiphora, recurrent conjunctivitis, keratitis, and nystagmus are also common [1]; thus patients need frequent evaluation by an ophthalmologist. Recurrent blockage of the ear canal may occur and frequent debridement is often needed. Patients are at risk of developmental delay, with one series reporting a 32% rate of developmental delay including not meeting developmental milestones and delay in motor skill development. Some patients, though, were able to attend higher education [1].

In conclusion, although HI was previously thought to be a fatal condition, more intensive care in the neonatal period and early use of retinoid therapy may increase survival of these patients. Unfortunately, the condition persists throughout life and can cause multiple medical complications after the neonatal period.

References

1. Rajpopat, A., Moss, C., Mellerio, J., et al. Harlequin Ichthyosis: A Review of Clinical and Molecular Findings in 45 Cases. Arch Dermatol. 2011 Jun;147(6):681-6. [PMID:15009320]

2. Harvey HB, Shaw MG, Morrell DS. Perinatal management of harlequin ichthyosis: a case report and literature review. J Perinatol. 2010 Jan;30(1):66-72. [PMID:20038941]

3. Dyer JA, Spraker M, Williams M. Care of the newborn with ichthyosis. 2013 Jan-Feb;26(1):1-15. [PMID: 23384016]

4. Oji V, Tadini G, Akiyama M, Blanchet Bardon C., et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010 Oct;63(4):607-41. [PMID:20643494]

5. Mancini, A, Paller, A. (2011) Hurwitz Clinical Pediatric Dermatology, 4th Edition. Philadelphia: Elsevier .

6. Akiyama M. Pathomechanisms of harlequin ichthyosis and ABCA transporters in human diseases. Arch Dermatol. 2006 Jul;142(7):914-8. [PMID: 16847209]

7. Chan YC, Tay YK, Tan LK, Happle R, Giam YC. Harlequin ichthyosis in association with hypothyroidism and juvenile rheumatoid arthritis. Pediatr Dermatol. 2003 Sep-Oct;20(5):421-6. [PMID: 14521561]

王若光，湖南省第二人民医院妇产科，医学博士，生物学博士后，教授，博士生导师。从事中西医结合妇产科学科研、教学、医疗工作30年，擅长妇科及生殖内分泌疾病中西医结合诊治。主要从事中西医结合妇科与生殖内分泌，不孕不育诊疗，出生缺陷产前诊断，中药药理学及新药研发，熟悉分子药理学、毒理学、药用植物与中药化学、药剂学、生物化学、分子生物学、生理学、分子病理生理学、妇产病理学、超声诊断学等。

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