Harlequin ichthyosis is a rare severe scaling disorder, which manifests in utero and is often fatal early in life.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal recessive 2. Pathogenesis
a. Lack of desquamation and massive accumulation of scale due to abnormal lamellar granules and absence of extracellular lamellar structures between the granular cells and the cornified cells
b. Defect in lipid synthesis or metabolism
c. A defect of conversion from profilaggrin to filaggrin i. Suggests possible defects of protein phosphatase
activity in the epidermis
ii. Leads to the clinical features of harlequin ichthyosis because protein phosphatase is thought to work both in the conversion from profilag- grin to filaggrin and in the synthesis of the lipid content of lamellar granules
3. Report of a male with harlequin ichthyosis with a de novo deletion of the long arm of chromosome 18 [46, XY, del(18)(q21.3)] suggesting the possible gene localization within the deleted region
CLINICAL FEATURES
1. Major clinical features
a. Large, thick and yellowish armor-like plaques (plate- like scales) with redish, moist, oozing fissures and cracks, covering the whole body
b. Severe ectropion (complete eversion of the nonkera- tinizing mucosa of the eyelids with occlusion of the eyes)
c. Eclabium (eversion of the nonkeratinizing mucosa of the lips)
d. “Frog-like” grostesque appearance of the face e. Crumpled and flattened ears
f. Flattened nasal tip with anteversion of the nares (nasal hypoplasia)
g. Permanently opened mouth unable to suck properly h. Swollen extremities secondary to tight sausage-like
encasement by the thickened stratum corneum i. Semiflexed rigid extremities (allowing little limb
movement) with hypoplastic fingers 2. Minor clinical features
a. Absent eyebrows and eyelashes b. Scalp hair may or may not be present 3. Associate anomalies
a. Renal tubular defects b. Altered thymic structures c. Pulmonary hypoplasia
4. Natural history
a. Restricted fetal movement caused by dense masses of hyperkeratotic scale
b. Prematurity in most cases
c. Perinatal death (usually in the first few weeks) secondary to:
i. Respiratory compromise due to mechanical lim- itation of ribcage excursion
ii. Sepsis iii. Hypothermia
iv. Dehydration v. Malnutrition vi. Severe anemia vii. Renal failure d. Rare survivals
i. Variable neurologic impairment ii. Short stature
iii. Failure to thrive
iv At risk for severe keratitis due to ectropion of all eyelids
DIAGNOSTIC INVESTIGATIONS
1. Light microscopy findings
a. Extraordinary compact orthohyperkeratosis (thick- ened orthokeratotic stratum corneum)
b. Keratin plugs in hair follicles and sweat ducts c. Absent lamellar bodies and abundant vesicles in both
the stratum granulosum and stratum corneum d. Abnormal lipid droplets and vacuoles in the cytoplasm
of keratinized cells in the thick stratum corneum 2. Ultrastructural findings
a. Abnormal lipid droplets and vacuoles in the cytoplasm of keratinized cells in the thick stratum corneum b. Absent normal lamellar granules in the cytoplasm of
granular layer keratinocytes
c. Lack of lamellar structure in the extracellular space between the first cornified cell and the granular cell 3. Biochemical analysis of skin samples: a defect of conver-
sion from profilaggrin to filaggrin
4. Family history for evidence of consanguinity
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib: 25%
b. Patient’s offspring: patient not surviving to reproductive age
2. Prenatal diagnosis possible in families at risk
a. Ultrasonography (2D and especially 3D) after 24 weeks i. Minimal fetal movement with stiff limbs in a
semiflexed position
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Harlequin Ichthyosis (Harlequin Fetus)
474 HARLEQUIN ICHTHYOSIS (HARLEQUIN FETUS)
ii. Swollen limbs with hypoplastic fingers and toes and short phalanges
iii. Shriveled hands that do not open iv. Abnormal facies
v. Absence of typical ear morphology vi. Large open mouth
vii. Absence of typical nasal morphology
viii. Partitioned cystic formations in front of the eyes ix. Thick skin
x. Hyperechogenic amniotic fluid
xi. Absence of associated visceral anomalies b. Amniocentesis: demonstration of clumping of ker-
atinocyte cells in the amniotic fluid containing lipid droplets and amorphous electron dense material c. Electron microscopy of the fetal skin biopsy speci-
men from fetoscopy at 20-22 weeks i. Abnormal vacuoles in keratinized cells ii. Abnormal lamellar granules in the hair canal 3. Management
a. Temperature control
b. Electrolyte and fluid balance c. Adequate caloric intake
d. Prevention of infection with antibiotics
e. Topical steroids to reduce secondary inflammation f. Tretinoin creams or ointments or oral retinoid treat-
ment to reduce the amount of scale
g. Pain management with anti-inflammatory drugs and morphine sulfate if necessary
h. Ocular management
i. Intensive topical eye ointment ii. Treat keratitis promptly
iii. Surgical management of the ectropion by skin- release surgery with autologous skin grafting in patients with severe exposure keratitis or cos- metically unacceptable ectropion
i. Careful handling to avoid hard friction and physical contract for prevention of blistering
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HARLEQUIN ICHTHYOSIS (HARLEQUIN FETUS) 475
Fig. 1. A newborn with harlequin ichthyosis, covered with yellowish plaques with moist fissures and cracks and grostesque appearance of face with ectropion, eclabium, a flat nose, crumpled/flat ears, and swollen/semiflexed rigid limbs.
