proptosis

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

Pfeiffer Syndrome

Clinical Characteristics
Ocular Features: 

Patients may have extreme proptosis (95%) secondary to shallow orbits and exposure keratitis (41%) is a risk.  Hypertelorism, strabismus, and antimongoloid lid slants are common.  More rare signs include anterior chamber anomalies and optic nerve hypoplasia.

Systemic Features: 

Pfeiffer syndrome has been divided into 3 types, of which cases with types 2 and 3 often die young.  Type 1 has the more typical features with midface hypoplasia, broad thumbs and toes, craniosynostosis, and often some degree of syndactyly.  Adult patients with type 1 may be only mildly affected with some degree of midface hypoplasia and minor broadening of the first digits.  Hearing loss secondary to bony defects is relatively common.  Cleft palate is uncommon.  Airway malformations especially in the trachea can cause respiratory problems.

Genetics

This is a genetically heterogeneous disorder resulting from mutations in at least 2 genes, FGFR1 (8p11.2-p11.1) and FGFR2 (10q26).  The less common cases with the latter mutation are allelic to Apert (101200), Crouzon (123500), and Jackson-Weiss (123150) syndromes.  Inheritance is autosomal dominant but some cases are only mildly affected.  New mutations exhibit a paternal age effect.

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Beare-Stevenson Syndrome (123790), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Exposure keratitis requires the usual treatment.  Fronto-orbital advancement surgery for the midface underdevelopment is generally helpful for the complications of proptosis.  Airway obstruction may require tracheostomy or surgical correction of the air passages.

References
Article Title: 

FGFR2 mutations in Pfeiffer syndrome

Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D. FGFR2 mutations in Pfeiffer syndrome. Nat Genet. 1995 Feb;9(2):108.

PubMed ID: 
7719333

Crouzon Syndrome

Clinical Characteristics
Ocular Features: 

The primary ocular features result from pattern-specific, premature synostoses of cranial sutures.  The orbits are often shallow resulting in proptosis, sometimes to such an extent that exposure keratitis or even spontaneous subluxation of the globe results.  This is exacerbated by the midface hypoplasia that is often present.  As many as 22% of patients have optic atrophy, most likely secondary to chronic papilledema from elevated intracranial pressure.  Strabismus is common, often with a V-pattern exotropia.  Overaction of the inferior obliques and underaction of the superior obliques have been described.  One patient with narrow angle glaucoma has been reported.

Systemic Features: 

The coronal sutures are the most commonly affected by the premature synostosis and hence the skull is often brachycephalic and the forehead is prominent.  Increased intracranial pressure is a risk.  The nose is parrot-beaked and the upper lip is short.  Maxillary hypoplasia from the midface underdevelopment can cause crowding and displacement of the upper teeth.

Genetics

This type of craniosynostosis is caused by mutations in the fibroblast growth factor receptor-2 gene, FGFR2, located at 10q26.  It is generally considered an autosomal dominant disorder based on familial cases but most occur sporadically.  A paternal age effect on mutations has been found. 

The same gene is mutant in other craniosynostosis disorders sometimes clinically separated such as Pfeiffer Syndrome (101600), Jackson-Weiss syndrome (123150), Beare-Stevenson Syndrome (123790), Apert Syndrome (101200), and Saethre-Chotzen Syndrome (101400).  However, this entire group has many overlapping features making classification on clinical grounds alone difficult.  Only Apert syndrome (101200) is caused by a unique mutation whereas other syndromes seem to owe their existence to multiple mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Exposure keratitis must be treated.  Cranial surgery has been necessary for some patients to relieve the papilledema but the post operative outcome can be complicated by hydrocephalus.

References
Article Title: 

Glaucoma with Crouzon Syndrome

Alshamrani AA, Al-Shahwan S. Glaucoma with Crouzon Syndrome. J Glaucoma. 2018
Mar 19. doi: 10.1097/IJG.0000000000000946. [Epub ahead of print].

PubMed ID: 
29557836

Apert Syndrome

Clinical Characteristics
Ocular Features: 

In 10% of patients, keratitis and corneal scarring occur from the sometimes marked proptosis and corneal exposure.  Optic atrophy is present in over 20% of patients.  Strabismus, primarily exotropia, is found in more than 70% and various extraocular muscle anomalies may be detectable.  Usually the exotropia has a V-pattern with overaction of the inferior oblique muscles while the superior oblique is weak.  Amblyopia occurs in nearly 20%.  The lid fissures often slant downward and the eyebrows may be interrupted.

Systemic Features: 

This brachysphenocephalic type of acrocephaly is associated with syndactyly in the hands and feet.  Pre- and postaxial polydactyly may be present.  There is considerable variation in expression with some patients so mildly affected that they appear virtually normal, whereas others have extreme degrees of brachycephaly with high foreheads, midface hypoplasia, and proptosis secondary to shallow orbits.  Imaging often reveals one or more CNS anomalies such as defects of the corpus callosum, partial absence of the septum pellucidum, ventriculomegaly, and sometimes hydrocephalus.  A small but significant proportion of patients have some developmental delay and cognitive impairment.  Over 39% of patients have a normal IQ.

Genetics

This type of craniosynostosis is caused by mutations in the fibroblast growth factor receptor-2 gene, FGFR2, located at 10q26.13.  It is generally considered an autosomal dominant disorder based on familial cases but most occur sporadically.  A paternal age effect on mutations has been found.  The same gene is mutant in allelic disorders sometimes clinically separated and labeled Crouzon (123500) and Pfeiffer (some cases) (101600) syndromes.  Jackson-Weiss syndrome (123150) maps to the same locus.  However, this entire group has many overlapping features making classification on clinical grounds alone difficult.  Only Apert syndrome is caused by mutations in a single gene whereas other syndromes seem to result from mutations in multiple genes.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No specific treatment is available for this disorder but exposure keratitis may require surveillance and therapy.

References
Article Title: 

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