Table 2.

Differential Diagnosis of Autosomal Recessive Congenital Ichthyosis: Genetic Disorders with Ichthyosis Present at Birth

GeneDisorderMOISkin FindingsOther Findings / Comment
AARS1
ERCC2
ERCC3
GTF2E2
GTF2H5
MARS1
MPLKIP
RNF113A
TARS1 		Trichothiodystrophy w/ichthyosis (OMIM PS601675)AR
XL 1		Generalized CIE; less frequent collodion membrane at birth; later generalized ichthyosis w/variable size & color of scale; follicular hyperkeratosis reported
  • IUGR & prematurity
  • ≥1 of the following: brittle sulfur-deficient hair, nail dystrophy, photosensitivity (ERCC2, ERCC3, GTF2H5), infertility, DD, microcephaly, ataxia, abnormal brain MRI, short stature
ABHD5 Chanarin-Dorfman syndrome (neutral lipid storage disease) (OMIM 275630)ARMostly resembling CIE; very rarely ectropion, alopecia
  • Widespread lipid deposits result in hepatomegaly & fibrosis, cataracts, & sensorineural hearing loss.
  • DD is common.
  • Variable findings incl microcephaly, ataxia, short stature, splenomegaly, & renal insufficiency.
  • Lipid vacuoles in circulating granulocytes & monocytes on fresh peripheral blood smear
ALDH3A2 Sjögren-Larsson syndrome (OMIM 270200)ARGeneralized ichthyosis w/accentuated skin markings, PPK, mild/variable erythema, & pruritusPremature birth; spastic di- or tetraplegia; ID; white matter disease on MRI; juvenile macular dystrophy
EBP X-linked chondrodysplasia punctata 2 XLIn females, erythroderma & patchy, linear, or diffuse ichthyosis w/adherent scales that may resolve into atrophoderma, hyperpigmentation, & alopecia
  • In females, punctuate calcification in epiphyseal cartilage, asymmetric rhizomelic limb shortening, short stature, cataracts, & sensorineural hearing loss
  • Early gestational male lethality
EDA
EDAR
EDARADD
WNT10A 2		Hypohidrotic ectodermal dysplasia (HED)AD
AR
XL 3
  • Neonates may be diagnosed because of peeling skin (like that of "postmature" babies) & periorbital hyperpigmentation.
  • Later, persons develop dry skin & chronic eczema.
  • ↓ ability to sweat; sparse scalp & body hair, & congenital absence of teeth
  • Cardinal features of classic HED become obvious during childhood.
GBA1 (GBA)Gaucher disease (perinatal-lethal form)ARMay be assoc w/collodion membrane or generalized ichthyosis at birthNonimmune hydrops fetalis, akinesia & arthrogryposis, hepatosplenomegaly, pancytopenia, & facial dysmorphism (low-set & dysplastic ears, hypertelorism, & flat nasal bridge w/small, upturned nose)
GJB2 Keratitis-ichthyosis-deafness syndrome (OMIM 148210)ADMay present w/transient erythroderma at birth; symmetrical hyperkeratotic plaques & palmoplantar keratoderma develop later.Sensorineural hearing loss & progressive vascularizing keratitis; ↑ susceptibility to develop squamous cell carcinoma
KRT1
KRT10 		Epidermolytic ichthyosis (EI) (formerly epidermolytic hyperkeratosis) (OMIM 113800)AD
AR 4
  • Skin fragility, blistering, & erythema at birth & during infancy; transitions to pronounced ridged or cobblestone-like hyperkeratosis
  • Severe PPK is common in KRT1-related EI.
  • KRT2-related SEI is milder w/superficial "molting" of small areas of skin.
  • No collodion membrane at birth
  • Life-threatening complications in neonates are sepsis & fluid & electrolyte imbalances.
  • Later complications incl recurrent blistering & skin infections, heat intolerance, body odor, & gait abnormalities.
KRT2 Superficial epidermolytic ichthyosis (SEI) (formerly ichthyosis bullosa of Siemens) (OMIM 146800)AD
SPINK5 Netherton syndrome (OMIM 256500)AR
  • CIE often w/continuous skin peeling
  • Atopic manifestations
  • Hair shaft anomalies & poor weight gain
  • Life-threatening complications during infancy incl temperature & electrolyte imbalance, recurrent infections, & sepsis.
ST14 Autosomal recessive ichthyosis w/hypotrichosis (OMIM 602400)AR
  • Congenital ichthyosis w/white, fine scale & scalp involvement & possibly sparing of flexures
  • Follicular atrophoderma w/pitted ("orange peel") appearance of skin in face & dorsal hands
  • Generalized, diffuse, non-scarring hypotrichosis that improves w/age
  • Scalp hair is light colored, sparse, lusterless, & curly.
  • Hypohidrosis; eye involvement incl photophobia &/or inflammation of eyelids
ELOVL4 Ichthyosis, spastic quadriplegia, & impaired intellectual development (OMIM 614457)ARMay have collodion membrane at birth; generalized ichthyosis, variable erythema, & PPKProfound DD, poor weight gain, spastic quadriplegia, epilepsy, hypotonia, & severely delayed myelination on brain MRI

AD = autosomal dominant; AR = autosomal recessive; CIE = congenital ichthyosiform erythroderma; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; PPK = palmoplantar keratoderma; XL = X-linked

1.

Trichothiodystrophy is inherited in an autosomal recessive manner with the exception of RNF113A-related trichothiodystrophy, which is inherited in an X-linked manner.

2.

WNT10A pathogenic variants are also associated with odontoonychodermal dysplasia (OMIM 257980) and Schöpf-Schultz-Passarge syndrome (OMIM 257980), disorders in which hypohidrotic ectodermal dysplasia is a finding.

3.

EDA-related hypohidrotic ectodermal dysplasia (HED) is inherited in an X-linked manner. EDAR-, EDARADD-, and WNT10A-related HED are inherited in an autosomal recessive or an autosomal dominant manner.

4.

KRT1-related epidermolytic ichthyosis (EI) is inherited in an autosomal dominant manner; KRT10-related EI is inherited in autosomal dominant or rarely in an autosomal recessive manner.

From: Autosomal Recessive Congenital Ichthyosis

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