ichthyosis

HELIX Syndrome

Clinical Characteristics
Ocular Features: 

Alacrimia has been confirmed with Schirmer test strips but the ocular examination has been described as otherwise normal.

Systemic Features: 

All patients have anhidrosis resulting in alacrima and xerostomia with heat intolerance.  Nails and hair are normal.  Muscle weakness, heart palpitations, and post-exertional cramping may be experienced with mild exercise beginning in the first decade.  Polydipsia and polydipsia may be additional complaints.  Severe dental enamel wear is often evident.  The skin has a fine, white scaliness.  Adolescent-onset nephrocalcinosis has been reported in some patients.

The majority of patients have elevated serum Mg++ levels.  Mild renal failure occurs with loss of NaCl and secondary hyperaldosteronism and hypokalemia.

Genetics

Homozygous mutations in the CLDN10 gene (13q32.1) are responsible for this disorder.  Consanguinity is present in some families.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Dental resins has been reported to be beneficial as a protective coating of the teeth.  Ocular evaluations for corneal damage from alacrima have not been reported but moisturizing preparations should be used as indicated. 

References
Article Title: 

Multiplex epithelium dysfunction due to CLDN10 mutation: the HELIX syndrome

Hadj-Rabia S, Brideau G, Al-Sarraj Y, Maroun RC, Figueres ML, Leclerc-Mercier S, Olinger E, Baron S, Chaussain C, Nochy D, Taha RZ, Knebelmann B, Joshi V, Curmi PA, Kambouris M, Vargas-Poussou R, Bodemer C, Devuyst O, Houillier P, El-Shanti H. Multiplex epithelium dysfunction due to CLDN10 mutation: the HELIX syndrome. Genet Med. 2017 Aug 3. doi: 10.1038/gim.2017.71. [Epub ahead of print].

PubMed ID: 
28771254

Cataracts and Ichthyosis

Clinical Characteristics
Ocular Features: 

Cortical cataracts have been reported.

Systemic Features: 

Icthyosis is associated with cataracts in some family members.

Genetics

Three families have been reported in which cataracts and ichthyosis were associated.  Two male offspring of normal Japanese parents had cortical cataracts and ichthyosis.  In another family of unknown ethnicity, three sisters had cataracts but only two had ichthyosis.  In a third in which the mother had cataracts and ichthyosis, two of her female children had cataracts.

Treatment
Treatment Options: 

Treatment is unknown.

References
Article Title: 

Neu-Laxova Syndrome 2

Clinical Characteristics
Ocular Features: 

The eyes appear prominent, an effect that is sometimes exaggerated by absent or malformed eyelids.

Systemic Features: 

Intrauterine growth retardation is common and infants are born with significant deformities including microcephaly, limb malformations, flexion deformities, ichthyosis, and edema of the hands and feet.   Brain malformations may be present as well.

Genetics

This disorder has a transmission pattern consistent with autosomal recessive inheritance.  Homozygous or compound heterozygous mutations in the PSAT1 gene (9q21.2) are responsible. 

This condition has similar features to Neu-Laxova syndrome 1 (256520) but is less severe and results from a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjold M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M. Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet. 2014 Sep 4;95(3):285-93.

PubMed ID: 
25152457

Neu-Laxova Syndrome 1

Clinical Characteristics
Ocular Features: 

The globes are prominent, an appearance that is exaggerated sometimes by absence of the eyelids or ectropion.  The lashes may be absent in other patients.  Cloudy corneas and cataracts have been described.

Systemic Features: 

This is a lethal dysplasia-malformation syndrome in which some infants are stillborn while others do not live beyond a few days.  The placenta is often small and the umbilical cord is short.  Decreased fetal movements and polyhydramnios are often noted.  Microcephaly can be striking at birth but there is overall intrauterine growth retardation.  The skin is ichthyotic and dysplastic containing excess fatty tissue beneath the epidermis.  Digits are often small and may be fused (syndactyly).  There is generalized edema with ‘puffiness’ of the hands and feet.  The lungs are frequently underdeveloped and cardiac defects such as septal openings, patent ductus arteriosus and transposition of great vessels are common.  Males often have cryptorchidism while females have a bifid uterus and renal dysgenesis has been reported.

The face is dysmorphic with prominent globes (in spite of microphthalmia), the ears are large and malformed, the forehead is sloping, the nose is flattened and the jaw is small.  Some infants have a cleft lip and palate while the mouth is round and gaping.  The neck is usually short.

Severe brain malformations such as lissencephaly, cerebellar hypoplasia, and dysgenesis/agenesis of the corpus callosum are frequently present.

Genetics

This is an autosomal recessive disorder secondary to mutations in the PHGDH gene (1p12).

This condition has some clinical overlap with Neu-Laxova syndrome 2 (616038) but the latter is less severe and is caused by a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjold M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M. Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet. 2014 Sep 4;95(3):285-93.

PubMed ID: 
25152457

Congenital Disorder of Glycosylation, Type Iq

Clinical Characteristics
Ocular Features: 

Colobomas (iris, choroid, and sometimes optic nerve), optic nerve hypoplasia and nystagmus have been reported.  Visual acuity is variable depending upon the degree of nerve hypoplasia. The eyebrows may be highly arched, while downward slanting lid fissures, and hypertelorism may also be present.

Congenital cataracts, glaucoma and microphthalmia have been reported in several individuals.

Systemic Features: 

Onset of symptoms commonly begins in infancy with severe hypotonia while developmental delays soon become evident as most children do not achieve normal milestones.  The amount of cognitive impairment is variable.  Congenital cardiac defects, ichthyosis, and hypertrichosis may be present.  The skin over the dorsum of the hands and feet often appears dark.  Ataxia is sometimes present and MRIs may reveal vermal and cerebellar hypoplasia.

Facial dysmorphism is common.  Low-set malformed ears, low hairline, depressed nasal bridge, redundant facial skin, decreased subcutaneous tissue, large mouth, thin lips, and long face have been noted.

There is considerable variation in clinical manifestations and longevity varies from infancy to adulthood.

Genetics

This glycosylation disorder is one of a number of rare hepatic/intestinal disorders caused by a deficiency in N-oligosaccharide synthesis.  It is inherited in an autosomal recessive pattern as a result of mutations in SRD5A3 (4q12).  Both homozygous and compound heterozygous genotypes have been reported.  It is allelic to Kahrizi syndrome (612713) with a number of overlapping features including ocular colobomas and cognitive deficiencies.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The administration of caloric supplements through tube feeding may be required to maintain adequate nutrition.Orthopedic deformities can sometimes be corrected surgically.

References
Article Title: 

A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism

Morava E, Wevers RA, Cantagrel V, Hoefsloot LH, Al-Gazali L, Schoots J, van Rooij A, Huijben K, van Ravenswaaij-Arts CM, Jongmans MC, Sykut-Cegielska J, Hoffmann GF, Bluemel P, Adamowicz M, van Reeuwijk J, Ng BG, Bergman JE, van Bokhoven H, Korner C, Babovic-Vuksanovic D, Willemsen MA, Gleeson JG, Lehle L, de Brouwer AP, Lefeber DJ. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain. 2010 Nov;133(11):3210-20.

PubMed ID: 
20852264

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Bl?omel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010 Jul 23;142(2):203-17.

PubMed ID: 
20637498

KID Syndrome

Clinical Characteristics
Ocular Features: 

Superficial punctate keratopathy leads to recurrent corneal erosions and eventually scarring and neovascularization.  Progressive opacification requiring PK often occurs.  These individuals may also suffer loss of eyebrows and eyelashes with trichiasis and thickening of the lid margins.  Corneal erosions and keratoconjunctivitis sicca cause incapacitating symptoms.

Systemic Features: 

The skin may be diffusely erythematous and scaly.  This often becomes patchier with well-demarcated areas especially in skin folds of the neck, axillae, and groin.  Older patients with likely autosomal recessive disease have hepatomegaly and may suffer cirrhosis and liver failure.  Short stature and mental retardation have also been noted.  The hearing loss is neurosensory in type.  Epidermal glycogen deposition has been found in one patient with the presumed recessive disorder.

In the presumed autosomal dominant disease, growth failure, mental retardation and liver disease do not seem to be present.  However, oral and skin squamous cell carcinomas, as well as malignant pilar tumors of the scalp may lead to early death.

Genetics

It is uncertain if one or more entities are represented by the KID syndrome.  Many cases are sporadic but others seem to be transmitted in autosomal recessive or autosomal dominant patterns.  The locus of the mutation is unknown in the recessive form.  In the dominant form, a mutation has been found in the connexin-26 gene, GJB2, gene located at 13q12.11.

See Hereditary Mucoepithelial Dysplasia (158310) for a somewhat similar but unique genodermatosis.  Another is IFAP (308205) but cataracts and hearing loss are not features.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The use of ocular lubricating preparation may supply significant relief from symptoms but scarring may eventually necessitate penetrating keratoplasty.  The threat of skin cancers and fatal hepatic failure requires monitoring throughout life.

References
Article Title: 

Sjogren-Larsson Syndrome

Clinical Characteristics
Ocular Features: 

The retina often has glistening white intraretinal dots which may be concentrated in the macula.  They have been found in 1 to 2 year old infants.  The macula may have ‘punched out’ lesions.  A pigmentary retinopathy is present in about 50% of patients and fluorescein angiography reveals a mottled hyperfluorescence. The cornea often has grayish stromal opacities that become vascularized, most commonly in the lower half.  Most patients have punctate keratitis resulting in marked photophobia.  Visual acuities can range from about 20/40 to finger counting.  The retinal changes may be progressive but EOG and ERG studies do not reveal abnormalities of retinal function.  VEPs though are often abnormal.  Ichthyosis may involve the lids and periorbital areas.

Systemic Features: 

The skin changes are present at birth and consist of an ichthyosiform erythroderma.  Hyperkeratosis is also present at birth and full blown ichthyosis develops during infancy.  The skin changes are most marked about the neck, flexion creases, and lower abdomen.  Scales in these areas are often darker than the surrounding skin.  Mental retardation may be mild to severe and spastic diplegia or quadriplegia is common but there is little evidence of progression.  There does not seem to be any correlation of age with the severity of neurological disease.

Genetics

Mutations in the ALDH3A2 gene (17p11.2) are responsible for this autosomal recessive disorder resulting in a deficiency of fatty aldehyde dehydrogenase. This can lead to long-chain fatty alcohol accumulation as demonstrated in the brain with proton magnetic resonance spectroscopy.

A form of Sjogren-Larsson syndrome with more severe neurologic signs is caused by recessive mutations in ELOVL4 (6p14,1),  Mutations in the same gene have been identified in patients with autosomal dominant Stargardt disease 3 (600110).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder but moisturizing skin treatments can be beneficial.

References
Article Title: 

Refsum Disease, Adult

Clinical Characteristics
Ocular Features: 

A retinitis pigmentosa-like retinopathy is the major ocular manifestation of this disease.  There is typical night blindness and visual field constriction.   Rod ERG responses are usually subnormal.  However, central acuity is also reduced due to a degenerative maculopathy.   Cataracts and optic atrophy are common.  The macula may undergo progressive degeneration and optic atrophy is not uncommon.  Some patients have defective pupillary responses.

Systemic Features: 

Onset of symptoms is usually late in the first decade and sometimes into the third decade.  There is usually a polyneuropathy with impaired motor reflexes and paresis in the limbs.  A progressive sensorineural hearing loss occurs in many patients.  Sensory deficits also occur.  Some have ataxia and skin changes of ichthyosis.  Anosmia is a near universal feature.  Heart failure may occur and cardiac abnormalities such as conduction defects can occur.  A variety of skeletal abnormalities such as pes cavus, short fourth metatarsals, and evidence of epiphyseal dysplasia have been reported.  There is considerable clinical heterogeneity even within families.

Phytanic acid oxidase activity as measured in fibroblasts is often low while serum phytanic acid is increased.  The cerebrospinal fluid contains increased protein but no increase in cells.

Genetics

This disorder results from mutations in the PHYH (PAHX) gene (10pter-p11.2) encoding phytanoyl-CoA hydroxylase, or, more rarely in PEX7 (6q22-q24) encoding peroxin-7 resulting in an uncommon condition (10% of cases) sometimes called adult Refsum disease-2. 

Mutations in the latter gene also cause rhizomelic chondrodysplasia punctata type 1 (215100) which does not have all of the neurological features or the retinopathy.

There is also so-called infantile form of Refsum disease (266510).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A diet low in phytanic acid can lead to improvement in the neurologic symptoms such as the ataxia and polyneuropathy but must be instituted in early stages of the disease.  This approach may not be as beneficial for the visual or auditory symptoms.

References
Article Title: 

Rhizomelic Chondrodysplasia Punctata

Clinical Characteristics
Ocular Features: 

Congenital cataracts are the outstanding ocular feature of this syndrome and are present in over 70% of patients.  They are usually bilateral and symmetrical and may not be present for several months after birth.

Systemic Features: 

The name of this disorder comes from the punctate calcification seen in cartilage.   The vertebrae have coronal clefting.  The cartilage abnormalities result in defective bone growth with severe growth retardation, short stature, and joint contractures.  Many infants die during the neonatal period and few survive beyond the first decade of life. However, milder forms have been reported. The skin can be ichthyotic and severe mental retardation is often accompanied by seizures.  Red cells are deficient in plasmalogens while phytanic acid and very long chain fatty acids accumulate in the plasma, a biochemical profile characteristic of RCDP1.

Other types of chondrodysplasia punctata also exist (RCDP2 and RCDP3). The X-linked recessive (CDPX1; 302950), autosomal dominant tibia-metacarpal (118651), and humero-metacarpal types are not associated with cataracts.

A phenocopy sometimes results from maternal ingestion of dicoumarol in early pregnancy.

Genetics

This rare autosomal recessive condition results from mutations in the PEX7 gene (6q22-q24) causing a peroxisomal biogenesis disorder.  Some clinical features overlap with those of Zellweger syndrome (214100) and infantile Refsum disease (266510), also peroxisomal biogenesis disorders. 

Mutations in the same gene are responsible for adult Refsum disease-2 (266500).  The latter, however, has other neurological symptoms as well as clinical features of retinitis pigmentosa with night blindness and restricted visual fields.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available beyond supportive measures. Cataract removal may improve vision but the poor prognosis for longevity requires caution be used.

References
Article Title: 
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