REVSTO-250; No of Pages 3
Received: 28 August 2015 Accepted: 25 November 2015
Available online at
ScienceDirect www.sciencedirect.com
Case report
Facial features in Harlequin ichthyosis: Clinical findings about 4 cases Les caracte´ristiques faciales dans l’ichtyose d’Harlequin : description clinique a` propos de 4 cas J.-D. Ku ¨n-Darboisa,*, A. Molinb, C. Jeanne-Pasquierb, A. Pare´a, H. Be´nateaua, A. Veyssie`rea a
Service de chirurgie maxillo-faciale, hoˆpital Coˆte de Nacre, CHU de Caen, 14033 Caen cedex, France b Service d’anatomopathologie, hoˆpital Coˆte de Nacre, CHU de Caen, 14033 Caen cedex, France
Summary
Re´sume´
We report 4 cases of Harlequin ichthyosis, which is a rare and severe congenital ichthyosis involving the face. Facial appearance consists in severe ectropion, conjonctival edema, eclabium, flattened ears, broadened nose and large, thick, plate-like skin scales. Recent advances in neonatal care have been made, such as retinoid therapy, and have led to an increased survival rate. Early surgical correction of ectropion may be required because of ocular complications. ß 2015 Elsevier Masson SAS. All rights reserved.
Les auteurs rapportent 4 cas d’ichtyose d’Harlequin, une forme rare et se´ve`re d’ichtyose conge´nitale. Les caracte´ristiques faciales consistent en un ectropion se´ve`re, un œde`me conjonctival, un eclabium, des oreilles mal ourle´es, un nez aplati, des squames cutane´es e´paisses se´pare´es de crevasses. Des progre`s re´cents en soins ne´onataux, telle l’utilisation de re´tinoı¨des, ont permis une ame´lioration du taux de survie. La correction chirurgicale de l’ectropion peut eˆtre indique´e pre´cocement de manie`re a` pre´venir les complications oculaires. ß 2015 Elsevier Masson SAS. Tous droits re´serve´s.
Keywords: Harlequin fetus, Congenital ichthyosis, Facial abnormalities Mots cle´s : Fœtus Harlequin, Ichtyose conge´nitale, Anomalies faciales
Introduction Harlequin ichthyosis (HI) is a severe autosomal recessive congenital ichthyosis (OMIM 242500). It is due to recessive mutations in the ABCA12 gene. Its prevalence is less than 1/1,000,000. Its mortality rate is 44% [1]. It is characterized in neonate by the presence of large, thick, plate-like scales covering the whole body associated with severe ectropion, eclabium, and flattened ears, that later develops into a severe
* Corresponding author. e-mail: [email protected] (J.-D. Ku ¨n-Darbois).
scaling erythroderma. We report 4 cases of HI in 2 different families and describe facial features of HI.
Case reports A 24-year-old pregnant woman was admitted to the Caen university hospital for her third pregnancy. Gestational age was approximately 37 weeks. No remarkable complication was noted in the last ultrasound examinations before birth. A female baby was born via normal spontaneous delivery. The baby presented with a typical harlequin appearance consisting in hyperkeratinization of the skin, deep truncal fissures and
http://dx.doi.org/10.1016/j.revsto.2015.11.007 Rev Stomatol Chir Maxillofac Chir Orale 2015;xxx:1-3 2213-6533/ß 2015 Elsevier Masson SAS. All rights reserved.
1
REVSTO-250; No of Pages 3 J.-D. [(Figure_1)TD$IG] Ku¨n-Darbois et al.
Rev Stomatol Chir Maxillofac Chir Orale 2015;xxx:1-3
Figure 1. Neonate (aged 3 days) showing typical harlequin ichthyosis: skin fissures, bilateral ectropion, eclabium and flattened nose and ears.
abnormalities were noticed. Histological examination revealed normal dermis and hypodermis but epidermal abnormalities (massive hyperkeratosis). The same woman was pregnant for the sixth time at the age of 35. Prenatal diagnosis of HI was established since mutations in the ABCA12 gene were found in fetal tissues after trophoblast biopsy. Medical termination by curettage was performed at 14 weeks of gestational age. Macroscopic examination was not contributive. Histological examination of the skin revealed no abnormality. Another pregnant woman, aged 38, was admitted at hospital for her third pregnancy. Gestational age was approximately 34 weeks. It was a twin pregnancy. No remarkable complication was noticed in the last ultrasound examinations before birth. Premature male babies were born. One baby presented with a typical harlequin syndrome. He was hospitalized and received proper treatment (in facial area: vaseline applications, ophtalmic ointment with vitamin A, eye and nose washes) and multidisciplinary monitoring. Improvement of the skin condition (less hyperkeratinization and fissures) and disappearance of ectropions and eclabium were noticed. There was no keratitis. He died at week 7 from respiratory failure due to regurgitation and inhalation. Macroscopic examination revealed massive hyperkeratinization, large and flat nasal bridge, flat philtrum, thin lips and flattened ears (fig. 3). A few fingers and toes presented syndactylies and camptodactylies. Autopsy revealed bilateral pneumonitis. Histological examination revealed normal dermis and hypodermis but
scales, bilateral ectropion, eclabium (fish mouth appearance due to a turning outwards of the lips) and flattened ears (fig. 1). The newborn baby died at day 3 from respiratory failure. Genetic analysis revealed mutations of the ABCA12 gene in both parents: c.7444C>T (p.Arg2482X) in exon 51 and c.1210C>T (p.Arg404X) in exon 11. The same woman was pregnant for the fourth time at the age of 30. Prenatal 3D ultrasonography was performed at 22 weeks of gestational age. Features suggestive of HI were noticed: nasal hypoplasia, flattened rudimentary external ears, everted eyelids, diffuse scaling and eclabium with open mouth and protruding tongue. Medical termination was performed at 26 weeks of gestational age. The male fetus presented with a typical harlequin appearance with thick skin, truncal and facial fissures and scales, bilateral ectropion, conjunctival edema, eclabium, flattened nose and ears and flexion contractures at the knees (fig. 2). No other macroscopic
[(Figure_3)TD$IG]
[(Figure_2)TD$IG]
Figure 2. Fetus (26 weeks of gestational age) showing typical harlequin ichthyosis: facial fissures and plates, bilateral ectropion, conjonctival edema, eclabium, flattened nose and ears.
2
Figure 3. Newborn (aged 7 weeks) showing improvement of harlequin appearance: massive hyperkeratinization, large and flat nasal bridge, flat philtrum, thin lips and flattened ears but no ectropion, no conjonctival edema, no eclabium and no fissures.
REVSTO-250; No of Pages 3
Facial features in Harlequin ichthyosis: Clinical findings about 4 cases
massive epidermal hyperkeratosis. No other macroscopic or histological abnormalities were noticed. The other baby presented no sign of HI and is still alive and healthy. Parents were found consanguineous (first cousins). Genetic analysis revealed the same mutation of the ABCA12 gene in both parents: c.7351G>T (p.Glu2451*).
Discussion Typical facial Harlequin appearance consists in severe bilateral ectropion of the four eyelids, conjunctival edema, eclabium, flattened ears, lacking retro-aural folds, broadened nose with anteverted nostrils and large, thick, plate-like scales on the skin [1]. Despite this extremely distorted initial appearance, facial features progressively improve within a few months. Skin abnormalities (keratoderma, poor hair growth, skin infections) and extracutaneous manifestations remain throughout life [1]. In one reported case, prenatal diagnosis of HI was established since typical facial Harlequin appearance was found in prenatal 3D ultrasonography performed at 22 weeks of gestational age. This is possible only if the risk is already known. Prenatal diagnosis of HI is usually established since mutations in the ABCA12 gene are found in DNA analysis in fetal tissues after trophoblast biopsy. There is a 25% risk of disease for subsequent pregnancies since HI is transmitted as an autosomal recessive trait. Affected families should therefore receive genetic counseling. Recent evidence showed spontaneous improvement of HI phenotype and justify intensive neonatal care that can impact short- and long-term outcomes and increase survival rate [2– 4]. A multidisciplinary approach involving surgeons, ophthalmologists, dermatologists, pediatricians, dieticians and psychologists is necessary. It has been shown recently that early systemic retinoid therapy leads to an increased survival rate (83%) [1,2,5]. As in our second case report, respiratory problems are very common in the neonatal and early infancy periods and are a major cause of death in neonates. The other main cause of death in neonates is fulminant sepsis [1]. Early surgical correction of major ectropion may be required to reduce the risk of early complications which may lead to blindness and deprivation amblyopia (lagophtalmos, conjunctivitis, keratitis, exposure keratopathy) [6–8]. A standard procedure for ectropion release surgery with skin graft is performed and Frost sutures must be applied [7]. The main difficulty is the lack of intact donor sites for harvesting a graft. Surgical repairs with full-thickness postauricular, supraclavicular, inguinal or penile skin autografts have been described
with successful outcomes [7]. The use of an engineered bilayered human skin equivalent composed of cultured dermal and epidermal layers has been described in case of no available donor site [9]. A postoperative monitoring is mandatory because of possible skin graft contractures leading to recurrence [10]. Reoperations are sometimes necessary to repair residual eyelid retraction [10]. No other facial surgical management seems to be required in HI newborns.
Conclusion HI used to be considered as a fatal condition. Recent advances in neonatal cares have been made, such as retinoid therapy, and lead to an increased survival rate. Facial Harlequin appearance is stereotyped. Facial surgical procedures are sometimes indicated.
Disclosure of interest The authors declare that they have no competing interest.
References [1]
[2]
[3] [4]
[5] [6]
[7] [8] [9]
[10]
Rajpopat S, Moss C, Mellerio J, Vahlquist A, Ganemo A, Hellstrom-Pigg M, et al. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol 2011;147:681–6. Shibata A, Ogawa Y, Sugiura K, Muro Y, Abe R, Suzuki T, et al. High survival rate of harlequin ichthyosis in Japan. J Am Acad Dermatol 2014;70:387–8. Milstone LM, Choate KA. Improving outcomes for harlequin ichthyosis. J Am Acad Dermatol 2013;69:808–9. Koochek A, Choate KA, Milstone LM. Harlequin ichthyosis: neonatal management and identification of a new ABCA12 mutation. Pediatr Dermatol 2014;31:e63–4. Chang LM, Reyes M. A case of harlequin ichthyosis treated with isotretinoin. Dermatol Online J 2014;20. Ahmed H, O’Toole EA. Recent advances in the genetics and management of harlequin ichthyosis. Pediatr Dermatol 2014;31:539–46. Khan R, Arora S, El-Hindy N, Chang BY. Repair of cicatricial ectropion in a harlequin baby. J AAPOS 2009;13:415–6. Chua CN, Ainsworth J. Ocular management of harlequin syndrome. Arch Ophthalmol 2001;119:454–5. Culican SM, Custer PL. Repair of cicatricial ectropion in an infant with harlequin ichthyosis using engineered human skin. Am J Ophtalmol 2002;134:442–3. Zachara MG, Drozdowski PH, Latkowski IT. Surgical management of ichtyosis-related ectropion. Description of four cases and a literature review. J Plast Surg Hand Surg 2014;48:179–82.
3
Received: 28 August 2015 Accepted: 25 November 2015
Available online at
ScienceDirect www.sciencedirect.com
Case report
Facial features in Harlequin ichthyosis: Clinical findings about 4 cases Les caracte´ristiques faciales dans l’ichtyose d’Harlequin : description clinique a` propos de 4 cas J.-D. Ku ¨n-Darboisa,*, A. Molinb, C. Jeanne-Pasquierb, A. Pare´a, H. Be´nateaua, A. Veyssie`rea a
Service de chirurgie maxillo-faciale, hoˆpital Coˆte de Nacre, CHU de Caen, 14033 Caen cedex, France b Service d’anatomopathologie, hoˆpital Coˆte de Nacre, CHU de Caen, 14033 Caen cedex, France
Summary
Re´sume´
We report 4 cases of Harlequin ichthyosis, which is a rare and severe congenital ichthyosis involving the face. Facial appearance consists in severe ectropion, conjonctival edema, eclabium, flattened ears, broadened nose and large, thick, plate-like skin scales. Recent advances in neonatal care have been made, such as retinoid therapy, and have led to an increased survival rate. Early surgical correction of ectropion may be required because of ocular complications. ß 2015 Elsevier Masson SAS. All rights reserved.
Les auteurs rapportent 4 cas d’ichtyose d’Harlequin, une forme rare et se´ve`re d’ichtyose conge´nitale. Les caracte´ristiques faciales consistent en un ectropion se´ve`re, un œde`me conjonctival, un eclabium, des oreilles mal ourle´es, un nez aplati, des squames cutane´es e´paisses se´pare´es de crevasses. Des progre`s re´cents en soins ne´onataux, telle l’utilisation de re´tinoı¨des, ont permis une ame´lioration du taux de survie. La correction chirurgicale de l’ectropion peut eˆtre indique´e pre´cocement de manie`re a` pre´venir les complications oculaires. ß 2015 Elsevier Masson SAS. Tous droits re´serve´s.
Keywords: Harlequin fetus, Congenital ichthyosis, Facial abnormalities Mots cle´s : Fœtus Harlequin, Ichtyose conge´nitale, Anomalies faciales
Introduction Harlequin ichthyosis (HI) is a severe autosomal recessive congenital ichthyosis (OMIM 242500). It is due to recessive mutations in the ABCA12 gene. Its prevalence is less than 1/1,000,000. Its mortality rate is 44% [1]. It is characterized in neonate by the presence of large, thick, plate-like scales covering the whole body associated with severe ectropion, eclabium, and flattened ears, that later develops into a severe
* Corresponding author. e-mail: [email protected] (J.-D. Ku ¨n-Darbois).
scaling erythroderma. We report 4 cases of HI in 2 different families and describe facial features of HI.
Case reports A 24-year-old pregnant woman was admitted to the Caen university hospital for her third pregnancy. Gestational age was approximately 37 weeks. No remarkable complication was noted in the last ultrasound examinations before birth. A female baby was born via normal spontaneous delivery. The baby presented with a typical harlequin appearance consisting in hyperkeratinization of the skin, deep truncal fissures and
http://dx.doi.org/10.1016/j.revsto.2015.11.007 Rev Stomatol Chir Maxillofac Chir Orale 2015;xxx:1-3 2213-6533/ß 2015 Elsevier Masson SAS. All rights reserved.
1
REVSTO-250; No of Pages 3 J.-D. [(Figure_1)TD$IG] Ku¨n-Darbois et al.
Rev Stomatol Chir Maxillofac Chir Orale 2015;xxx:1-3
Figure 1. Neonate (aged 3 days) showing typical harlequin ichthyosis: skin fissures, bilateral ectropion, eclabium and flattened nose and ears.
abnormalities were noticed. Histological examination revealed normal dermis and hypodermis but epidermal abnormalities (massive hyperkeratosis). The same woman was pregnant for the sixth time at the age of 35. Prenatal diagnosis of HI was established since mutations in the ABCA12 gene were found in fetal tissues after trophoblast biopsy. Medical termination by curettage was performed at 14 weeks of gestational age. Macroscopic examination was not contributive. Histological examination of the skin revealed no abnormality. Another pregnant woman, aged 38, was admitted at hospital for her third pregnancy. Gestational age was approximately 34 weeks. It was a twin pregnancy. No remarkable complication was noticed in the last ultrasound examinations before birth. Premature male babies were born. One baby presented with a typical harlequin syndrome. He was hospitalized and received proper treatment (in facial area: vaseline applications, ophtalmic ointment with vitamin A, eye and nose washes) and multidisciplinary monitoring. Improvement of the skin condition (less hyperkeratinization and fissures) and disappearance of ectropions and eclabium were noticed. There was no keratitis. He died at week 7 from respiratory failure due to regurgitation and inhalation. Macroscopic examination revealed massive hyperkeratinization, large and flat nasal bridge, flat philtrum, thin lips and flattened ears (fig. 3). A few fingers and toes presented syndactylies and camptodactylies. Autopsy revealed bilateral pneumonitis. Histological examination revealed normal dermis and hypodermis but
scales, bilateral ectropion, eclabium (fish mouth appearance due to a turning outwards of the lips) and flattened ears (fig. 1). The newborn baby died at day 3 from respiratory failure. Genetic analysis revealed mutations of the ABCA12 gene in both parents: c.7444C>T (p.Arg2482X) in exon 51 and c.1210C>T (p.Arg404X) in exon 11. The same woman was pregnant for the fourth time at the age of 30. Prenatal 3D ultrasonography was performed at 22 weeks of gestational age. Features suggestive of HI were noticed: nasal hypoplasia, flattened rudimentary external ears, everted eyelids, diffuse scaling and eclabium with open mouth and protruding tongue. Medical termination was performed at 26 weeks of gestational age. The male fetus presented with a typical harlequin appearance with thick skin, truncal and facial fissures and scales, bilateral ectropion, conjunctival edema, eclabium, flattened nose and ears and flexion contractures at the knees (fig. 2). No other macroscopic
[(Figure_3)TD$IG]
[(Figure_2)TD$IG]
Figure 2. Fetus (26 weeks of gestational age) showing typical harlequin ichthyosis: facial fissures and plates, bilateral ectropion, conjonctival edema, eclabium, flattened nose and ears.
2
Figure 3. Newborn (aged 7 weeks) showing improvement of harlequin appearance: massive hyperkeratinization, large and flat nasal bridge, flat philtrum, thin lips and flattened ears but no ectropion, no conjonctival edema, no eclabium and no fissures.
REVSTO-250; No of Pages 3
Facial features in Harlequin ichthyosis: Clinical findings about 4 cases
massive epidermal hyperkeratosis. No other macroscopic or histological abnormalities were noticed. The other baby presented no sign of HI and is still alive and healthy. Parents were found consanguineous (first cousins). Genetic analysis revealed the same mutation of the ABCA12 gene in both parents: c.7351G>T (p.Glu2451*).
Discussion Typical facial Harlequin appearance consists in severe bilateral ectropion of the four eyelids, conjunctival edema, eclabium, flattened ears, lacking retro-aural folds, broadened nose with anteverted nostrils and large, thick, plate-like scales on the skin [1]. Despite this extremely distorted initial appearance, facial features progressively improve within a few months. Skin abnormalities (keratoderma, poor hair growth, skin infections) and extracutaneous manifestations remain throughout life [1]. In one reported case, prenatal diagnosis of HI was established since typical facial Harlequin appearance was found in prenatal 3D ultrasonography performed at 22 weeks of gestational age. This is possible only if the risk is already known. Prenatal diagnosis of HI is usually established since mutations in the ABCA12 gene are found in DNA analysis in fetal tissues after trophoblast biopsy. There is a 25% risk of disease for subsequent pregnancies since HI is transmitted as an autosomal recessive trait. Affected families should therefore receive genetic counseling. Recent evidence showed spontaneous improvement of HI phenotype and justify intensive neonatal care that can impact short- and long-term outcomes and increase survival rate [2– 4]. A multidisciplinary approach involving surgeons, ophthalmologists, dermatologists, pediatricians, dieticians and psychologists is necessary. It has been shown recently that early systemic retinoid therapy leads to an increased survival rate (83%) [1,2,5]. As in our second case report, respiratory problems are very common in the neonatal and early infancy periods and are a major cause of death in neonates. The other main cause of death in neonates is fulminant sepsis [1]. Early surgical correction of major ectropion may be required to reduce the risk of early complications which may lead to blindness and deprivation amblyopia (lagophtalmos, conjunctivitis, keratitis, exposure keratopathy) [6–8]. A standard procedure for ectropion release surgery with skin graft is performed and Frost sutures must be applied [7]. The main difficulty is the lack of intact donor sites for harvesting a graft. Surgical repairs with full-thickness postauricular, supraclavicular, inguinal or penile skin autografts have been described
with successful outcomes [7]. The use of an engineered bilayered human skin equivalent composed of cultured dermal and epidermal layers has been described in case of no available donor site [9]. A postoperative monitoring is mandatory because of possible skin graft contractures leading to recurrence [10]. Reoperations are sometimes necessary to repair residual eyelid retraction [10]. No other facial surgical management seems to be required in HI newborns.
Conclusion HI used to be considered as a fatal condition. Recent advances in neonatal cares have been made, such as retinoid therapy, and lead to an increased survival rate. Facial Harlequin appearance is stereotyped. Facial surgical procedures are sometimes indicated.
Disclosure of interest The authors declare that they have no competing interest.
References [1]
[2]
[3] [4]
[5] [6]
[7] [8] [9]
[10]
Rajpopat S, Moss C, Mellerio J, Vahlquist A, Ganemo A, Hellstrom-Pigg M, et al. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol 2011;147:681–6. Shibata A, Ogawa Y, Sugiura K, Muro Y, Abe R, Suzuki T, et al. High survival rate of harlequin ichthyosis in Japan. J Am Acad Dermatol 2014;70:387–8. Milstone LM, Choate KA. Improving outcomes for harlequin ichthyosis. J Am Acad Dermatol 2013;69:808–9. Koochek A, Choate KA, Milstone LM. Harlequin ichthyosis: neonatal management and identification of a new ABCA12 mutation. Pediatr Dermatol 2014;31:e63–4. Chang LM, Reyes M. A case of harlequin ichthyosis treated with isotretinoin. Dermatol Online J 2014;20. Ahmed H, O’Toole EA. Recent advances in the genetics and management of harlequin ichthyosis. Pediatr Dermatol 2014;31:539–46. Khan R, Arora S, El-Hindy N, Chang BY. Repair of cicatricial ectropion in a harlequin baby. J AAPOS 2009;13:415–6. Chua CN, Ainsworth J. Ocular management of harlequin syndrome. Arch Ophthalmol 2001;119:454–5. Culican SM, Custer PL. Repair of cicatricial ectropion in an infant with harlequin ichthyosis using engineered human skin. Am J Ophtalmol 2002;134:442–3. Zachara MG, Drozdowski PH, Latkowski IT. Surgical management of ichtyosis-related ectropion. Description of four cases and a literature review. J Plast Surg Hand Surg 2014;48:179–82.
3
