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Autosomal recessive congenital ichthyosis 4B(ARCI4B)

MedGen UID:
Concept ID:
Disease or Syndrome
Synonyms: ARCI4B; Harlequin Fetus; Harlequin ichthyosis; Ichthyosis congenita, Harlequin fetus type; Ichthyosis, congenital, autosomal recessive 4B (harlequin)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
Concept ID:
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Gene (location): ABCA12 (2q35)
Monarch Initiative: MONDO:0009443
OMIM®: 242500
Orphanet: ORPHA457

Gabriele Richard   view full author information

Additional descriptions

From GeneReviews Overview
Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management. Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection. Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma. Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.
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).  http://www.omim.org/entry/242500
From MedlinePlus Genetics
Harlequin ichthyosis is a severe genetic disorder that affects the skin. Infants with this condition are born prematurely with very hard, thick skin covering most of their bodies. The skin forms large, diamond-shaped plates that are separated by deep cracks (fissures). These skin abnormalities affect the shape of the eyelids, nose, mouth, and ears, and limit movement of the arms and legs. Restricted movement of the chest can lead to breathing difficulties and respiratory failure in babies with harlequin ichthyosis. Affected infants also have feeding problems.

The skin normally forms a protective barrier between the body and its surrounding environment. The skin abnormalities associated with harlequin ichthyosis disrupt this barrier, making it difficult for affected infants to control water loss, regulate their body temperature, and fight infections. Infants with harlequin ichthyosis often experience an excessive loss of fluids (dehydration) and develop life-threatening infections in the first few weeks of life. 

Following the newborn period, the hard, skin plates are shed and the skin develops widespread scales and redness.

It used to be very rare for affected infants to survive the newborn period. However, with intensive medical support and improved treatment, babies with this disorder now have a better chance of living into childhood and early adulthood.  https://medlineplus.gov/genetics/condition/harlequin-ichthyosis

Clinical features

From HPO
Short finger
MedGen UID:
Concept ID:
Anatomical Abnormality
Abnormally short finger associated with developmental hypoplasia.
Failure to thrive
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Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Motor delay
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Concept ID:
A type of Developmental delay characterized by a delay in acquiring motor skills.
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Concept ID:
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
MedGen UID:
Concept ID:
Disease or Syndrome
An outward turning (eversion) or rotation of the eyelid margin.
Everted lower lip vermilion
MedGen UID:
Concept ID:
An abnormal configuration of the lower lip such that it is turned outward i.e., everted, with the Inner aspect of the lower lip vermilion (normally opposing the teeth) being visible in a frontal view.
Congenital ichthyosiform erythroderma
MedGen UID:
Concept ID:
Disease or Syndrome
An ichthyosiform abnormality of the skin with congenital onset.
Premature birth
MedGen UID:
Concept ID:
Pathologic Function
The birth of a baby of less than 37 weeks of gestational age.
MedGen UID:
Concept ID:
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.

Recent clinical studies


Khalili A, Schear M, Greaves G, Schwartzstein HR, Kodsi S, Gorski M
J AAPOS 2019 Dec;23(6):352-354. Epub 2019 Oct 3 doi: 10.1016/j.jaapos.2019.08.274. PMID: 31586585

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