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Ichthyosis prematurity syndrome: A well-defined congenital ichthyosis subtype
Ichthyosis prematurity syndrome: A well-defined congenital ichthyosis subtype Anette Bygum, MD,a Per Westermark, MD,b and Flemming Brandrup, MDa Odense, Denmark, and Uppsala, Sweden Ichthyosis prematurity syndrome is a rare syndrome characterized by the clinical triad of premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. We describe two siblings with ichthyosis prematurity syndrome. The index patient was born at gestational week 34. Immediately after birth he developed respiratory distress and needed intubation. Remarkable skin changes were noticed with universal red, edematous and desquamating, spongy skin giving an impression of excessive vernix caseosa. Marked regression of the edema and ichthyotic scaling was observed within a few weeks. The parents recalled that his elder sister had similar but milder skin changes and respiratory distress syndrome at birth. Ichthyosis prematurity syndrome was suggested and the diagnosis supported by electron microscopy of a skin biopsy specimen showing pathognomonic trilamellar membrane aggregations in the stratum corneum and stratum granulosum. Diagnosing this syndrome is important to reassure parents, obstetricians, and pediatricians about its benign course after complications in the perinatal period. ( J Am Acad Dermatol 2008;59:S71-4.)
I
chthyosis prematurity syndrome (IPS) is a rarely recognized syndrome belonging to the heterogeneous group of recessive inherited disorders of cornification. We describe the clinical characteristics of two Danish siblings with IPS where the diagnosis was confirmed ultrastructurally by electron microscopy of a skin biopsy specimen. To our knowledge, these are the first two patients given the diagnosis of IPS in Denmark.
CASE REPORTS Case 1 The proband was a boy born at gestational week 34 with a birth weight of 2970 g, after an uneventful pregnancy and delivery. The parents were unrelated. Immediately after birth he developed respiratory distress and was intubated for a short time and later treated by continuous positive airway pressure in a neonatal care department for 1 week. Radiography showed bilateral pulmonary infiltrations, possibly a sign of aspiration pneumonia. He had a normal cord blood IgE less than 0.1 kU/L (\0.3) but a peripheral blood smear with eosinophilia of 9% (\5%) in his newborn period. From the Department of Dermatology, Odense University Hospital,a and Department of Genetics and Pathology, Uppsala University.b Funding sources: None. Conflicts of interest: None declared. Reprint requests: Anette Bygum, MD, Department of Dermatology, Odense University Hospital, 5000 Odense C, Denmark. E-mail: [email protected]. 0190-9622/$34.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.06.014
Remarkable skin changes were noticed at birth in the form of an almost universal red, edematous and desquamating, spongy skin. The hyperkeratosis covering the scalp, face, and upper extremities gave an impression of excessive vernix caseosa (Fig 1). The edema resolved gradually in 1 to 2 weeks but a widespread ichthyotic scaling persisted. The redness faded within the next months but the skin stayed dry with minimal superficial scaling. From the age of 6 months he developed asthma and signs of atopic dermatitis with fine follicular keratoses on his trunk and proximal upper extremities. Normal developmental milestones were recorded and the boy was otherwise healthy. A skin biopsy specimen at the age of 2 months examined by electron microscopy showed trilamellar lamellae in swollen corneocytes in stratum corneum and stratum granulosum characteristic of ichthyosis congenita type IV (Fig 2). Case 2 The parents could tell that his 4-year-old sister presented strange reptilelike skin changes at birth, especially at the distal extremities (Fig 3, A) and transient respiratory distress syndrome treated in a pediatric care department, which was elucidated retrospectively through a survey of the case notes. She was a twin born at gestational week 33 with a birth weight of 1587 g (the dizygotic twin had a birth weight of 2199 g). At birth her skin was described as dry and ichthyotic. It was noticed that the amniotic fluid was greenish discolored in an unusual way. Because of respiratory insufficiency she was intubated and treated on a respirator for 2 days and after S71
S72 Bygum, Westermark, and Brandrup
J AM ACAD DERMATOL NOVEMBER 2008
Fig 2. Electron microscopy: note curved multilamellar membranous structure in corneocyte.
DISCUSSION
Fig 1. Case 1. A, Red, edematous, and caseous skin on the face at birth. B, Edematous, desquamating, spongy skin on the scalp and upper arm at birth.
that treated with continuous positive airway pressure for a further 10 days. Aspiration pneumonia was suggested because of a radiograph showing severe bilateral pulmonary infiltrates (Fig 4). As a newborn she had blood eosinophilia of 13% in differential count (\5%). This value has not been checked since and we have no information about IgE. Her skin has been persistently dry with a tendency to prurigo and periodic flexural dermatitis that suggests atopic dermatitis. When evaluated at the age of 4 years, dry skin with a texture like sandpaper caused by follicular keratoses was found on her trunk and proximal extremities. The skin on her hands was dry and lichenified (Fig 3, B). She has had lifelong eye problems with slight photophobia, epiphora, and frequent purulent conjunctivitis. Both children have fair skin and light hair with fine white scaling on the scalp. Light and polarization microscopy results of hair shafts have been normal in both children. They both have a tendency for accumulation of cerumen and detritus in the external auditory canals requiring frequent visits to an otologist. In addition to the proband and his sister there are several family members with atopy and dry skin. Both parents have dry skin and the father had asthma in childhood. The other dizygotic twin is completely healthy.
IPS was suspected in the boy because of the clinical triad: premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. The diagnosis was confirmed by ultrastructural analysis of a skin biopsy specimen. Furthermore, linkage to a locus on chromosome 9q34 was established in the affected children in a study of Scandinavian cases of IPS with identical linkage.1 Haplotype analysis confirmed a strong founder effect for the disorder.1 However, it has not been possible to trace the ancestry of this family back to the other Scandinavian kindred although we have information on the family 6 generations back. IPS belongs to the heterogeneous group of autosomal recessive congenital ichthyoses. However, the literature with regard to the clinical findings in IPS is very sparse. The first descriptions were published as ichthyosis congenita type IV identifying IPS as a separate entity by its characteristic ultrastructural features.2,3 In fact, the ultrastructural findings seem to be pathognomonic with conspicuous membrane inclusions in the stratum corneum, although the subcellular origin for these membrane structures has not been determined. In 1993, Niemi et al4 published the clinical features in two Finnish children with recessive ichthyosis congenita type IV, one of these died at age 2 days old in respiratory distress. The descriptive name of the syndrome was given by Gedde-Dahl5 in 1996 according to Klar et al.6 The frequency of IPS is probably underestimated because of insufficient knowledge of this specific disease. In a recent French article, the condition was descriptively reported as ‘‘self-healing congenital verruciform hyperkeratosis’’ and published as a new phenotype.7 The initial finding of a thick caseous desquamating epidermis in IPS seem to be rather specific in the
J AM ACAD DERMATOL
Bygum, Westermark, and Brandrup S73
VOLUME 59, NUMBER 5
Fig 4. Bilateral pulmonary infiltrates on radiograph in patient 2 at birth. Fig 3. Neonatal cobblestone ichthyosis (A) and current skin status (B) of patient 2.
spectrum of autosomal recessive congenital ichthyoses. However, vernix caseosa-like covering has been found occasionally in KID syndrome. The finding is distinct from the collodion membrane in, for instance, lamellar ichthyosis and the massive constrictive scales in harlequin ichthyosis. The specificity of the IPS phenotype is supported by linkage analysis in cases with identical phenotype.1 In IPS, the pregnancy is complicated by polyhydramnion and an opaque amnion fluid because of the shedding of large amounts of epidermal cells (described as starry-sky appearance by ultrasound7). Ultrasound descriptions from the pregnancies were not available in our cases. The birth is always premature and delivery typically takes place at gestational weeks 30 to 34. Asphyxia is characteristically found after delivery probably because of aspiration of amniotic debris. The skin is covered by a thick, caseous, desquamating epidermis at birth. Soon after the critical neonatal period the child’s health improves rapidly, changing to dryness of the skin, follicular hyperkeratosis, and fine white scaling at the scalp that persists into adulthood. The clinical features were described by Brusasco et al,8 who noted hypereosinophilia and a strongly positive Darier sign as well. In fact, both our children showed positive urticarial dermographism and slight blood eosinophilia in a single blood test. Flexural dermatitis and an association with atopic dermatitis has been found. In the articles by Niemi et al4 and Brusasco et al,8 the very characteristic persistent follicular goose-skin-like
accentuation of the follicles is illustrated. These follicular hyperkeratoses seem to be more widespread and monomorphous than ordinary keratosis pilaris. IPS is very rare, except in a region of Norway and Sweden with an estimated heterozygote carrier frequency of 1 in 50.6 In 2004, a Scandinavian group performed a genomewide linkage analysis in 16 families with IPS from Norway and Sweden. The IPS locus was mapped to chromosome 9q34.6 A refined mapping of this region was published in 2006. Linkage was confirmed to chromosome 9q and the IPS haplotype refined to a 76-kilobase core region (9q33.334.13).1 The gene and gene-product is unknown, but may be related to a disturbed lipid metabolism in the skin. It is tempting to speculate that the atopic manifestations develop secondary to an impaired skin barrier similar to the association between atopic dermatitis and ichthyosis vulgaris based on filaggrin mutations. However, this cannot be the entire story, as in some of the severe variants such as lamellar ichthyosis, atopy is not an associated feature. The background of preterm birth is still an enigma. IPS has obstetric, pediatric, and dermatologic implications. The syndrome is potentially fatal, as unrecognized cases might have a high risk of death from asphyxia. Diagnosing this syndrome is also important to reassure parents and pediatricians about the benign course of the disease after complications in the perinatal period and to offer genetic counseling. We thank radiologist Bo Elle for his description and radiographic image of aspiration pneumonia.
S74 Bygum, Westermark, and Brandrup
J AM ACAD DERMATOL NOVEMBER 2008
REFERENCES 1. Melin M, Klar J, Gedde-Dahl T Jr, Fredriksson R, Hausser I, Brandrup F, et al. A founder mutation for ichthyosis prematurity syndrome restricted to 76 kb by haplotype association. J Hum Genet 2006;51:864-71. 2. Anton-Lamprecht I. Pra¨natale Diagnostik von Genodermatosen. Hautarzt 1988;39(Suppl):16-8. 3. Anton-Lamprecht I. The skin. In: Papadimitriou JM, Henderson DW, Spagnolo DV, editors. Diagnostic ultrastructure of nonneoplastic diseases. Edinburgh: Churchill and Livingstone; 1992. pp. 459-550. 4. Niemi KM, Kuokkanen K, Kanerva L, Ignatius J. Recessive ichthyosis congenita type IV. Am J Dermatopathol 1993;15: 224-8.
5. Gedde-Dahl T Jr. The ichthyosis-prematurity syndrome (IPS). Abstract presented at: Syndromdiagnostikk, Departments of Medical Genetics and Pediatrics, Ulleva˚l Hospital, Oslo, Norway; August 28, 1996. 6. Klar J, Gedde-Dahl T Jr, Larsson M, Pigg M, Carlsson B, Tentler D, et al. Assignment of the locus for ichthyosis prematurity syndrome to chromosome 9q33.3-34.13. J Med Genet 2004; 41:208-12. 7. Le´aute´-Labre`ze C, Boralevi F, Cony M, Maleville J, Lacombe D, Surle`ve-Bazeille JE, et al. Self-healing congenital verruciform hyperkeratosis. Am J Med Genet 2004;130A:303-6. 8. Brusasco A, Gelmetti C, Tadini G, Caputo R. Ichthyosis congenita type IV: a new case resembling diffuse cutaneous mastocytosis. Br J Dermatol 1997;136:377-9.
I
chthyosis prematurity syndrome (IPS) is a rarely recognized syndrome belonging to the heterogeneous group of recessive inherited disorders of cornification. We describe the clinical characteristics of two Danish siblings with IPS where the diagnosis was confirmed ultrastructurally by electron microscopy of a skin biopsy specimen. To our knowledge, these are the first two patients given the diagnosis of IPS in Denmark.
CASE REPORTS Case 1 The proband was a boy born at gestational week 34 with a birth weight of 2970 g, after an uneventful pregnancy and delivery. The parents were unrelated. Immediately after birth he developed respiratory distress and was intubated for a short time and later treated by continuous positive airway pressure in a neonatal care department for 1 week. Radiography showed bilateral pulmonary infiltrations, possibly a sign of aspiration pneumonia. He had a normal cord blood IgE less than 0.1 kU/L (\0.3) but a peripheral blood smear with eosinophilia of 9% (\5%) in his newborn period. From the Department of Dermatology, Odense University Hospital,a and Department of Genetics and Pathology, Uppsala University.b Funding sources: None. Conflicts of interest: None declared. Reprint requests: Anette Bygum, MD, Department of Dermatology, Odense University Hospital, 5000 Odense C, Denmark. E-mail: [email protected]. 0190-9622/$34.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.06.014
Remarkable skin changes were noticed at birth in the form of an almost universal red, edematous and desquamating, spongy skin. The hyperkeratosis covering the scalp, face, and upper extremities gave an impression of excessive vernix caseosa (Fig 1). The edema resolved gradually in 1 to 2 weeks but a widespread ichthyotic scaling persisted. The redness faded within the next months but the skin stayed dry with minimal superficial scaling. From the age of 6 months he developed asthma and signs of atopic dermatitis with fine follicular keratoses on his trunk and proximal upper extremities. Normal developmental milestones were recorded and the boy was otherwise healthy. A skin biopsy specimen at the age of 2 months examined by electron microscopy showed trilamellar lamellae in swollen corneocytes in stratum corneum and stratum granulosum characteristic of ichthyosis congenita type IV (Fig 2). Case 2 The parents could tell that his 4-year-old sister presented strange reptilelike skin changes at birth, especially at the distal extremities (Fig 3, A) and transient respiratory distress syndrome treated in a pediatric care department, which was elucidated retrospectively through a survey of the case notes. She was a twin born at gestational week 33 with a birth weight of 1587 g (the dizygotic twin had a birth weight of 2199 g). At birth her skin was described as dry and ichthyotic. It was noticed that the amniotic fluid was greenish discolored in an unusual way. Because of respiratory insufficiency she was intubated and treated on a respirator for 2 days and after S71
S72 Bygum, Westermark, and Brandrup
J AM ACAD DERMATOL NOVEMBER 2008
Fig 2. Electron microscopy: note curved multilamellar membranous structure in corneocyte.
DISCUSSION
Fig 1. Case 1. A, Red, edematous, and caseous skin on the face at birth. B, Edematous, desquamating, spongy skin on the scalp and upper arm at birth.
that treated with continuous positive airway pressure for a further 10 days. Aspiration pneumonia was suggested because of a radiograph showing severe bilateral pulmonary infiltrates (Fig 4). As a newborn she had blood eosinophilia of 13% in differential count (\5%). This value has not been checked since and we have no information about IgE. Her skin has been persistently dry with a tendency to prurigo and periodic flexural dermatitis that suggests atopic dermatitis. When evaluated at the age of 4 years, dry skin with a texture like sandpaper caused by follicular keratoses was found on her trunk and proximal extremities. The skin on her hands was dry and lichenified (Fig 3, B). She has had lifelong eye problems with slight photophobia, epiphora, and frequent purulent conjunctivitis. Both children have fair skin and light hair with fine white scaling on the scalp. Light and polarization microscopy results of hair shafts have been normal in both children. They both have a tendency for accumulation of cerumen and detritus in the external auditory canals requiring frequent visits to an otologist. In addition to the proband and his sister there are several family members with atopy and dry skin. Both parents have dry skin and the father had asthma in childhood. The other dizygotic twin is completely healthy.
IPS was suspected in the boy because of the clinical triad: premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. The diagnosis was confirmed by ultrastructural analysis of a skin biopsy specimen. Furthermore, linkage to a locus on chromosome 9q34 was established in the affected children in a study of Scandinavian cases of IPS with identical linkage.1 Haplotype analysis confirmed a strong founder effect for the disorder.1 However, it has not been possible to trace the ancestry of this family back to the other Scandinavian kindred although we have information on the family 6 generations back. IPS belongs to the heterogeneous group of autosomal recessive congenital ichthyoses. However, the literature with regard to the clinical findings in IPS is very sparse. The first descriptions were published as ichthyosis congenita type IV identifying IPS as a separate entity by its characteristic ultrastructural features.2,3 In fact, the ultrastructural findings seem to be pathognomonic with conspicuous membrane inclusions in the stratum corneum, although the subcellular origin for these membrane structures has not been determined. In 1993, Niemi et al4 published the clinical features in two Finnish children with recessive ichthyosis congenita type IV, one of these died at age 2 days old in respiratory distress. The descriptive name of the syndrome was given by Gedde-Dahl5 in 1996 according to Klar et al.6 The frequency of IPS is probably underestimated because of insufficient knowledge of this specific disease. In a recent French article, the condition was descriptively reported as ‘‘self-healing congenital verruciform hyperkeratosis’’ and published as a new phenotype.7 The initial finding of a thick caseous desquamating epidermis in IPS seem to be rather specific in the
J AM ACAD DERMATOL
Bygum, Westermark, and Brandrup S73
VOLUME 59, NUMBER 5
Fig 4. Bilateral pulmonary infiltrates on radiograph in patient 2 at birth. Fig 3. Neonatal cobblestone ichthyosis (A) and current skin status (B) of patient 2.
spectrum of autosomal recessive congenital ichthyoses. However, vernix caseosa-like covering has been found occasionally in KID syndrome. The finding is distinct from the collodion membrane in, for instance, lamellar ichthyosis and the massive constrictive scales in harlequin ichthyosis. The specificity of the IPS phenotype is supported by linkage analysis in cases with identical phenotype.1 In IPS, the pregnancy is complicated by polyhydramnion and an opaque amnion fluid because of the shedding of large amounts of epidermal cells (described as starry-sky appearance by ultrasound7). Ultrasound descriptions from the pregnancies were not available in our cases. The birth is always premature and delivery typically takes place at gestational weeks 30 to 34. Asphyxia is characteristically found after delivery probably because of aspiration of amniotic debris. The skin is covered by a thick, caseous, desquamating epidermis at birth. Soon after the critical neonatal period the child’s health improves rapidly, changing to dryness of the skin, follicular hyperkeratosis, and fine white scaling at the scalp that persists into adulthood. The clinical features were described by Brusasco et al,8 who noted hypereosinophilia and a strongly positive Darier sign as well. In fact, both our children showed positive urticarial dermographism and slight blood eosinophilia in a single blood test. Flexural dermatitis and an association with atopic dermatitis has been found. In the articles by Niemi et al4 and Brusasco et al,8 the very characteristic persistent follicular goose-skin-like
accentuation of the follicles is illustrated. These follicular hyperkeratoses seem to be more widespread and monomorphous than ordinary keratosis pilaris. IPS is very rare, except in a region of Norway and Sweden with an estimated heterozygote carrier frequency of 1 in 50.6 In 2004, a Scandinavian group performed a genomewide linkage analysis in 16 families with IPS from Norway and Sweden. The IPS locus was mapped to chromosome 9q34.6 A refined mapping of this region was published in 2006. Linkage was confirmed to chromosome 9q and the IPS haplotype refined to a 76-kilobase core region (9q33.334.13).1 The gene and gene-product is unknown, but may be related to a disturbed lipid metabolism in the skin. It is tempting to speculate that the atopic manifestations develop secondary to an impaired skin barrier similar to the association between atopic dermatitis and ichthyosis vulgaris based on filaggrin mutations. However, this cannot be the entire story, as in some of the severe variants such as lamellar ichthyosis, atopy is not an associated feature. The background of preterm birth is still an enigma. IPS has obstetric, pediatric, and dermatologic implications. The syndrome is potentially fatal, as unrecognized cases might have a high risk of death from asphyxia. Diagnosing this syndrome is also important to reassure parents and pediatricians about the benign course of the disease after complications in the perinatal period and to offer genetic counseling. We thank radiologist Bo Elle for his description and radiographic image of aspiration pneumonia.
S74 Bygum, Westermark, and Brandrup
J AM ACAD DERMATOL NOVEMBER 2008
REFERENCES 1. Melin M, Klar J, Gedde-Dahl T Jr, Fredriksson R, Hausser I, Brandrup F, et al. A founder mutation for ichthyosis prematurity syndrome restricted to 76 kb by haplotype association. J Hum Genet 2006;51:864-71. 2. Anton-Lamprecht I. Pra¨natale Diagnostik von Genodermatosen. Hautarzt 1988;39(Suppl):16-8. 3. Anton-Lamprecht I. The skin. In: Papadimitriou JM, Henderson DW, Spagnolo DV, editors. Diagnostic ultrastructure of nonneoplastic diseases. Edinburgh: Churchill and Livingstone; 1992. pp. 459-550. 4. Niemi KM, Kuokkanen K, Kanerva L, Ignatius J. Recessive ichthyosis congenita type IV. Am J Dermatopathol 1993;15: 224-8.
5. Gedde-Dahl T Jr. The ichthyosis-prematurity syndrome (IPS). Abstract presented at: Syndromdiagnostikk, Departments of Medical Genetics and Pediatrics, Ulleva˚l Hospital, Oslo, Norway; August 28, 1996. 6. Klar J, Gedde-Dahl T Jr, Larsson M, Pigg M, Carlsson B, Tentler D, et al. Assignment of the locus for ichthyosis prematurity syndrome to chromosome 9q33.3-34.13. J Med Genet 2004; 41:208-12. 7. Le´aute´-Labre`ze C, Boralevi F, Cony M, Maleville J, Lacombe D, Surle`ve-Bazeille JE, et al. Self-healing congenital verruciform hyperkeratosis. Am J Med Genet 2004;130A:303-6. 8. Brusasco A, Gelmetti C, Tadini G, Caputo R. Ichthyosis congenita type IV: a new case resembling diffuse cutaneous mastocytosis. Br J Dermatol 1997;136:377-9.