Alternative titles; symbols
SNOMEDCT: 205548006, 268245001; ICD10CM: Q80.4; ORPHA: 457; DO: 0060713;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q35 | Ichthyosis, congenital, autosomal recessive 4B (harlequin) | 242500 | Autosomal recessive | 3 | ABCA12 | 607800 |
A number sign (#) is used with this entry because of evidence that the harlequin fetus type of congenital ichthyosis, here symbolized ARCI4B, is caused by homozygous or compound heterozygous mutation in the ABCA12 gene (607800) on chromosome 2q35.
Mutation in the ABCA12 gene can cause another form of ichthyosis, ARCI4A (601277).
Harlequin ichthyosis is a rare severe form of congenital ichthyosis, which may be fatal. The neonate is encased in an 'armor' of thick scale plates separated by deep fissures. There is bilateral ectropion and eclabium, and the nose and ears are flattened and appear rudimentary. Constricting bands around the extremities can restrict movement and cause digital necrosis. As the skin barrier is severely compromised, neonates are more prone to sepsis, dehydration, and impaired thermoregulation. Treatment with oral retinoids encourages shedding of the grossly thickened skin. Babies who survive into infancy and beyond develop skin changes resembling severe nonbullous congenital ichthyosiform erythroderma (see 242300) (summary by Rajpopat et al., 2011).
Tonofibrils are fibrillar structural proteins in keratinocytes which, although already present in dividing basal cells, are formed in increasing amounts by the differentiating cells. They are the morphologic equivalent of the biochemically well-characterized prekeratin and precursors of the alpha-keratin of horn cells. Four genetic disorders of keratinization are known to have a structural defect of tonofibrils (Anton-Lamprecht, 1978): (1) In the harlequin fetus, an abnormal x-ray diffraction pattern of the horn material points to a cross-beta-protein structure instead of the normal alpha-protein structure of keratin. (2) Bullous ichthyosiform erythroderma (113800) is characterized by an early formation of clumps and perinuclear shells due to an abnormal arrangement of tonofibrils. (3) In the Curth-Macklin form of ichthyosis hystrix (146590), concentric unbroken shells of abnormal tonofilaments form around the nucleus. (4) In ichthyosis hystrix gravior (146600) only rudimentary tonofilaments are found with compensatory production of mucous granules.
At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass lamellar ichthyosis (LI), nonbullous congenital ichthyosis erythroderma (NCIE), and harlequin ichthyosis (Oji et al., 2010).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).
Nix et al. (1963) claimed that this recessive form of ichthyosis is distinct from the lamellar exfoliative type of congenital ichthyosis (see 242300). Goldsmith (1976) agreed with the distinctness of this entity from lamellar ichthyosis. It carries a more grave prognosis (Shelmire, 1955). The baby is usually of low birth weight for dates and, as a rule, dies under 1 week of age. Plaques, measuring up to 4 or 5 cm on a side, have a diamond-like configuration resembling the suit of a harlequin clown.
Unamuno et al. (1987) described 3 affected males and 1 affected female from a consanguineous mating. The infants were covered with an enormous horny shell, similar to armor, with deep creases which fragmented the hard surface into large polygonal plates. The limbs remained in rigid semiflexion. The nose and external ear were hidden in the keratotic layer. Severe ectropion and eclabion were present. All 4 sibs were born prematurely. Two were alive at birth but 1 died soon after delivery and the other 4 days after delivery.
Lawlor (1988) presented an experience suggesting that harlequin fetus may be a severe form of nonbullous ichthyosiform erythroderma. All except 1 previously reported harlequin fetus died during the first few weeks of life. Lawlor (1988) described an infant who survived to 2 and a half years, progressing to the picture of nonbullous ichthyosiform erythroderma.
Temtamy (1989) described a family with 3 affected sibs and first-cousin parents; the eyes were bulging in the infants and a typically characteristic feature was markedly hypoplastic fingers. It appeared that the tight skin did not permit growth of the fingers.
Prenatal Diagnosis
Blanchet-Bardon et al. (1983) achieved prenatal diagnosis of harlequin fetus by skin biopsies done by fetoscopy at 22 weeks' gestation. The parents were second cousins; of 4 previously born children, 2 had the harlequin syndrome and died at birth. Arnold and Anton-Lamprecht (1985) concluded that prenatal diagnosis of the ichthyosis congenita group cannot be based on disturbance of keratinization because of the late onset of normal keratinization.
Biochemical and ultrastructural abnormalities have suggested genetic heterogeneity and division into 3 subtypes of harlequin ichthyosis (Dale et al., 1990; Akiyama et al., 1998). In types 1 and 2 profilaggrin is expressed but not processed to filaggrin, whereas type 3 lacks profilaggrin; types 2 and 3 both have keratins 6 (see 148041) and 16 (148067) in addition to normal keratins 5/14 (148040, 148066) and 1/10 (139350, 148080) seen in all 3 subtypes.
Saunders et al. (1992) reported 2 patients with harlequin ichthyosis. From the photographs taken in the neonatal period, they looked very similar; however, whereas one died in the first day or so of life, the second required assisted ventilation for 5 days but survived thereafter and was alive at the age of almost 6 years at the time of report. Investigation at 15 months for failure to thrive indicated protein malnutrition as a consequence of enormous losses of protein in desquamated skin. Institution of a very high intake of protein led to satisfactory growth and development.
Prasad et al. (1994) reported the follow-up and management of 2 affected male Saudi sibs. The first sib was cared for with the frequent application of paraffin ointment to the whole body and oral etretinate. The skin gradually softened. Improvement in the skin around the mouth allowed the infant to suck from a bottle by day 4 and to breastfeed by the age of 1 week. The range of movement in all the limbs improved and the fingers and toes assumed a more normal shape. The baby was discharged home at the age of 51 days. Although his weight gain was poor, with weight remaining below the third percentile, at the age of 18 months he was alert, able to make cooing and babbling sounds, and had normal hearing and vision. He had good neck control, but could not crawl or sit up unaided. At the age of 22 months, he was admitted to hospital where he was found to have blood cultures positive for Staphylococcus aureus and died 24 hours after admission. The second sib succumbed to infection complicated by disseminated intravascular coagulation at the age of 44 days. The second sib had developed areas of ischemia and gangrene on bony prominences and the tips of the fingers and toes.
Culican and Custer (2002) reported the successful use of an Apligraf human skin equivalent for repair of bilateral cicatricial ectropion in a patient with harlequin ichthyosis.
Evidence for recessive inheritance of this disorder was provided by several reports (Bustamente and Tejeda, 1950; Kingery, 1926; Lattuada and Parker, 1951; Smith, 1880; Thomson and Wakeley, 1921), and by parental consanguinity (Edmonds and Dolan, 1951).
Castiglia et al. (2009) reported a female newborn with harlequin ichthyosis due to complete paternal isodisomy as shown by parental segregation studies and microsatellite analysis. Chorionic villus karyotyping of the fetus had revealed a nonmosaic chromosome 2 trisomy, whereas postnatal peripheral blood karyotype was normal, indicating trisomic rescue.
Stewart et al. (2001) reported a male with harlequin ichthyosis with a de novo deletion of the long arm of chromosome 18; the karyotype was 46,XY,del(18)(q21.3). The authors proposed that a gene for this condition may lie within the deleted region.
Using SNP chip technology and homozygosity mapping, Kelsell et al. (2005) identified a common region of homozygosity in the chromosomal region 2q35 in 5 patients with harlequin ichthyosis.
By sequencing of the ABCA12 gene, which maps within the critical region of chromosome 2q35 for harlequin ichthyosis, Kelsell et al. (2005) identified disease-associated mutations, including large intragenic deletions and frameshift deletions (see, e.g., 607800.0006-607800.0009) in 11 of the 12 screened individuals with harlequin ichthyosis. Since the epidermis in harlequin ichthyosis displays abnormal lamellar granule formation, Kelsell et al. (2005) suggested that ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder.
In 5 patients with harlequin ichthyosis from 4 unrelated families, Akiyama et al. (2005) identified either compound heterozygosity or homozygosity for 5 mutations in the ABCA12 gene.
Thomas et al. (2006) sequenced the ABCA12 gene in 14 patients with harlequin ichthyosis and identified mutations in all of them: 9 patients were homozygotes, 2 were compound heterozygotes, and in 3 patients, mutations were found on only 1 allele. The authors noted that the vast majority of ABCA12 mutations associated with harlequin ichthyosis are predicted to result in a truncated protein, although 1 patient was homozygous for a missense mutation (607800.0010). In a Caucasian British child born with severe ichthyosiform erythroderma, in whom Kelsell et al. (2005) did not identify any mutations by sequencing of the ABCA12 gene, Thomas et al. (2006) used a combination of oligonucleotide arrays, multiplex PCR analysis, and SNP genotyping to identify a heterozygous deletion (607800.0011). Thomas et al. (2006) concluded that ABCA12 is the major harlequin ichthyosis gene.
Exclusion Studies
Cystatin M/E (CST6; 601891) has a restricted expression pattern in humans which is largely limited to cutaneous epithelia. Zeeuwen et al. (2003) evaluated the involvement of the CST6 gene in harlequin ichthyosis by sequencing the entire coding region and intron-exon boundaries for mutations in 11 sporadic harlequin ichthyosis patients. No CST6 mutations were detected in this group, which comprised type 1 and type 2 harlequin ichthyosis patients. Disturbed transcription/translation due to mutations in regulatory and noncoding regions of cystatin M/E was unlikely because cystatin M/E protein expression was observed in all patients examined, as assessed by immunohistochemistry.
Akiyama (2010) reviewed mutations in the ABCA12 gene and stated that a total of 56 mutations had been reported in 66 ARCI families, including 48 with harlequin ichthyosis (HI), 10 with lamellar ichthyosis (LI), and 8 with ichthyosis of the congenital ichthyosiform erythroderma (CIE) type. Most of the mutations in HI patients were truncation mutations, and homozygosity or compound heterozygosity for truncating mutations in ABCA12 always resulted in the HI phenotype. In CIE families, at least 1 mutation on each allele was typically a missense mutation, and combinations of missense mutations in the first ATP-binding cassette of ABCA12 caused the LI phenotype.
The harlequin ichthyosis (ichq) mouse mutation arose spontaneously in 1989 in a colony of BALB/cJ mice at the Jackson Laboratory, Bar Harbor, Maine. Sundberg et al. (1997) described the phenotypic features and showed that the mutant gene locus maps to the proximal end of mouse chromosome 19. The disorder is inherited as a fully penetrant autosomal recessive and in general, its features are very similar to those of human harlequin ichthyosis.
Zeeuwen et al. (2002) reported the isolation and characterization of the mouse Cst6 ortholog and the assignment of the chromosomal localization to the proximal end of mouse chromosome 19. This region corresponds to the locus of the spontaneous harlequin ichthyosis (ichq) mouse mutation. Zeeuwen et al. (2002) found a frameshift deletion resulting in premature termination in the Cst6 gene of BALB/cJ-ichq/+ mice, which precluded the synthesis of functional protein. Immunohistochemistry confirmed the absence of cystatin M/E at the protein level in ichq/ichq mice. Mice that were homozygous for 2 null alleles displayed a hyperplastic, hyperkeratotic epidermis and abnormal hair follicles, and died between 5 and 12 days of age. In wildtype mice, cystatin M/E was found in the stratum granulosum and in the infundibulum of the hair follicle, indicating that the anatomic site in the skin where cystatin M/E is normally expressed correlates with the abnormalities at the tissue level in ichq/ichq mice. Zeeuwen et al. (2002) suggested that cystatin M/E is required for viability and for correct formation of cornified layers in the epidermis and hair follicles.
In the ichq (Cst6-null) mouse, Zeeuwen et al. (2004) reported unrestricted activity of the target protease legumain (602620) in hair follicles and epidermis. Analysis of stratum corneum proteins revealed a strong decrease of soluble loricrin (152445) monomers in skin extracts of ichq mice, although normal levels of loricrin were present in the stratum granulosum and stratum corneum. This suggested a premature or enhanced crosslinking of loricrin monomers in ichq mice by transglutaminase-3 (TGM3; 600238). Increased levels of TGM3 were processed into activated 30- and 47-kD subunits, compared to wildtype mice. The authors concluded that cystatin M/E and legumain form a functional dyad in epidermis in vivo. They further proposed that disturbance of this protease-antiprotease balance may cause increased enzyme activity of TGM3 that could explain the observed abnormal cornification.
Waring (1932) pointed to an early mention of a harlequin fetus in the diary of the Reverend O. Hart in 1750.
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