hypertelorism

Noonan Syndrome

Clinical Characteristics
Ocular Features: 

Noonan syndrome has prominent anomalies of the periocular structures including downward-slanting lid fissures, hypertelorism, epicanthal folds, high upper eyelid crease, and some limitation of ocular mobility most commonly of the levator.  Ptosis and strabismus are present in nearly half of patients. Amblyopia has been found in one-third of patients and almost 10% have nystagmus.  Corneal nerves are prominent and a substantial number of individuals have optic nerve abnormalities including drusen, hypoplasia, colobomas and myelinated nerves.  Evidence of an anterior stromal dystrophy, cataracts, or panuveitis is seen in a minority of patients.  About 95% of patients have some ocular abnormalities.

Systemic Features: 

Patients are short in stature.  Birth weight and length may be normal but lymphedema is often present in newborns.  The neck is usually webbed (pterygium colli) and the ears low-set.  The sternum may be deformed.  Cardiac anomalies such as coarctation of the aorta, pulmonary valve stenosis, hypertrophic cardiomyopathy, and septal defects are present in more than half of patients.  Dysplasia of the pulmonic valve has been reported as well.  Thrombocytopenia and abnormal platelet function with abnormalities of coagulation factors are found in about 50% of cases resulting in easy bruising and prolonged bleeding.  Cryptorchidism is common in males.  Some patients have intellectual disabilities with speech and language problems.  Most have normal intelligence.   

Parents of affected children often have subtle signs of Noonan Syndrome.

Genetics

This is an autosomal dominant disorder that can result from mutations in at least 8 genes.  Nearly half are caused by mutations in the PTPN11 gene (12q24.1) (163950).  Mutations in the SOS1 gene (2p22-p21) cause NS4 (610733) and account for 10-20% of cases, those in the RAF1 gene (3p25) causing NS5 (611553) for about the same proportion, and mutations in the KRAS gene (12p12.1) (NS3; 609942) cause about 1%.  Mutations in BRAF (7q34) causing NS7 (613706), NRAS (1p13.2) responsible for NS6 (613224), and MEK1 genes have also been implicated and it is likely that more mutations will be found.  The phenotype is similar in all individuals but with some variation in the frequency and severity of specific features.  New mutations are common. 

Several families with autosomal recessive inheritance (NS2) (605275) patterns have been reported with biallelic mutations in LZTR1.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for most of the developmental problems but some patients benefit from special education. Cardiac surgery may be required in some cases to correct the developmental defects.  Bleeding problems can be treated with supplementation of the defective coagulation factor.  Growth hormone therapy can increase the growth velocity.

References
Article Title: 

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants

Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schaffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C; Members of the Undiagnosed Diseases Network, Zenker M, Lee B, Biesecker LG. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. 2018 Oct;20(10):1175-1185.

PubMed ID: 
29469822

Update on turner and noonan syndromes

Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on turner and noonan syndromes. Endocrinol Metab Clin North Am. 2012 Dec;41(4):713-34. Epub 2012 Sep 28.

PubMed ID: 
23099266

Potter Disease, Type I

Clinical Characteristics
Ocular Features: 

As part of the facial morphology said to be characteristic of Potter disease, there is usually hypertelorism, telecanthus and epicanthal folds.  Cataracts and angiomas of the optic disc area have also been described.

Systemic Features: 

Polycystic kidney disease and hepatic system anomalies are major features of Potter disease.   Pulmonary hypoplasia with neonatal respiratory distress, however, is often the most immediate cause of death in most infants.  Antenatal oligohydramnios and low birth weight are commonly present.  As many as 33% of fetuses die in utero, often the result of bilateral renal agenesis.  Infants that survive can have chronic lung disease and renal dysfunction.  Congenital heart malformations are common, including septal defects, tetralogy of Fallot and patent ductus arteriosis.  Vertebrae may have a ‘butterfly’ shape but other skeletal findings include hemivertebrae and sacral agenesis.  The neck has been described as short and the skull is brachycephalic.

The facial appearance, known as Potter facies, is said to be characteristic and may be helpful in distinguishing this type of polycystic kidney disease.  In addition to the ocular findings, the nares are often anteverted, and the external ears are large and often posteriorly rotated.

Genetics

The uniqueness of this syndrome remains to be established.  There are several polycystic kidney disorders which have a monogenic basis. These often have overlapping renal features with the condition described here but lack the facial features said to be characteristic of Potter type I disease.  Autosomal recessive inheritance has been suggested on the basis of several reported families with affected sibs from consanguineous parents but so far no gene locus or mutation has been identified.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the condition but symptoms of respiratory distress and renal failure may need to be addressed acutely.  Long-term therapy for pulmonary disease and renal dysfunction can be considered for older individuals.  Many infants die in the neonatal period.

References
Article Title: 

Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p

Hallermann C, M?ocher G, Kohlschmidt N, Wellek B, Schumacher R, Bahlmann F, Shahidi-Asl P, Theile U, Rudnik-Schoneborn S, M?ontefering H, Zerres K. Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p. Am J Med Genet. 2000 Jan 17;90(2):115-9. Review.

PubMed ID: 
10607948

Manitoba Oculotrichoanal Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been completely defined because of the limited number of families reported.    Colobomas, unilateral and bilateral, of the upper eyelids seems to be the most consistent finding. Clinical hypertelorism is also a common finding. Nasolacrimal duct obstruction, unilateral clinical anophthalmia, cryptophthalmos, and a cloudy cornea have also been reported.

Systemic Features: 

The anterior scalp hairline is abnormally low, sometimes extending to the eyebrows.  The anus is anomalous and may be stenotic in some cases.  The nasal tip is often broad and has a notch.  Several patients had omphaloceles.

Genetics

Autosomal recessive inheritance has been assumed as no direct transmission from parent to child has been reported, and most affected individuals (including sibs) have been found in an isolated population of Manitoba Indians with a high rate of consanguinity.  Homozygous deletions of exons 8-23 in FREM1 as well as simple 4bp deletions (9p22.3) have been found in several families confirming the presumed autosomal recessive mode of inheritance.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Lid colobomas and anal stenosis should be repaired.

References
Article Title: 

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1

Slavotinek AM, Baranzini SE, Schanze D, Labelle-Dumais C, Short KM, Chao R, Yahyavi M, Bijlsma EK, Chu C, Musone S, Wheatley A, Kwok PY, Marles S, Fryns JP, Maga AM, Hassan MG, Gould DB, Madireddy L, Li C, Cox TC, Smyth I, Chudley AE, Zenker M. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. J Med Genet. 2011 Jun;48(6):375-82.

PubMed ID: 
21507892

Keratoconus Posticus Circumscriptus

Clinical Characteristics
Ocular Features: 

The posterior corneal surface has area(s) of excavation (indentation) associated with overlying opacification.  The lens-corneal separation is reduced and iridocorneal adhesions are often present.  The clinical picture has been described as ‘posterior conical cornea’ or posterior keratoconus.

Systemic Features: 

The neck is short and has webbing.  The facies appear ‘coarse’, the posterior hairline is low, the nose is prominent, digits are short, and the vertebral anomalies may lead to scoliosis.  Individuals are short of stature and brachydactyly is often present.  Developmental delays and mental retardation are usually features.  Other variable anomalies have been reported.

Genetics

Autosomal recessive inheritance seems most likely in view of the family patterns.  Based on the few families reported, it is uncertain if this is a single entity with variable expression or a combination of disorders.  No gene or locus has been associated with this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond surgical repair of the cleft lip and palate or scoliosis is available.  Peripheral iridotomies have been done in the presence of shallow anterior chambers.

References
Article Title: 

Cornelia de Lange Syndrome

Clinical Characteristics
Ocular Features: 

Many patients have few ocular findings beyond the usual synophyrs, a highly arched brow with hypertrichosis, and long eyelashes.  Synophrys is often prominent.  However, some also have significant ptosis, nystagmus, and high refractive errors.  Optic pallor and a poor macular reflex have also been reported.

Systemic Features: 

The facial features may be distinctive with low anterior hairline, anteverted nares, maxillary prognathism, long philtrum, crescent-shaped mouth and, of course, the bushy eyebrows and long lashes (in 98%).  Mental and growth retardation are common while many patients have features of the autism spectrum and tend to avoid social interactions.  The lips appear thin, the mouth is crescent-shaped, the head is often small, the teeth are widely spaced, and the ears are low-set.  The hands are often deformed with a proximally positioned thumb and metacarpophalangeal deformities.  It is stated that the middle phalanx of the index finger is always hypoplastic.  Other limb abnormalities of both upper (95%) and lower extremities are common.  Urinary tract abnormalities have been found in 41% of patients.  Middle ear effusions often lead to conductive hearing loss but 80% of patients have a sensorineural hearing deficit.

Genetics

This disorder is caused by mutations in genes encoding components of the cohesion complex.  Most cases occur sporadically but numerous familial cases suggest autosomal dominant inheritance. However, since at least three genes code for components of the cohesion complex including one located on the X-chromosome (610759), familial cases reported earlier without genotyping have created some confusion.  Hence, even autosomal recessive inheritance has been suggested in some families.  Genetic counseling should be family-specific based on the genotype and family pattern.

About 50% of cases result from mutations in the NIPBL gene (122470; 5p13.1) but less than 1% have an affected parent and the recurrence risk for sibs is similar.  The X-linked form of CDLS (300590; Xp11.22-p11.21) is caused by a mutation in the SMC1A gene, and a mild form (610759) results from mutations in the SMC3 gene (10q25).  Mutations in RAD21 (8q24) have been found in patients with milder disease and atypical presentations (614701).

A CDLS phenotype can also result from a specific duplication of a 3q 26-27 band.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No genetic treatment is available.

References
Article Title: 

Axenfeld-Rieger Anomaly, Plus

Clinical Characteristics
Ocular Features: 

This rare disorder has ocular features of Rieger anomaly with significant systemic features but different than those found in the Axenfeld-Rieger syndrome.  The iris is hypoplastic and the pupil may be distorted secondary to anterior synechiae.  Schwalbe line is prominent.  There are no reports of glaucoma but this may be biased by the small number of patients reported.  Hypertelorism, prominent eyes and strabismus have been described.  Several patients have had absence of the extraocular muscles.

Systemic Features: 

Hypotonia, lax joints, midface hypoplasia, prominent forehead, and short stature have been described.  Some, but not all patients have a degree of psychomotor retardation.  Mild hearing impairment has been reported.

Genetics

This is likely an autosomal dominant disorder in which mutations of the PITX2 and FOXC1 genes common in Axenfeld-Rieger syndrome have been ruled out.  No locus has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Baller-Gerold Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features are a rather minor part of this syndrome and are found in less than a third of patients.  These primarily involve lids and adnexae with telecanthus, downslanting lid fissures, and epicanthal folds.  Some individuals have nystagmus while strabismus, blue sclerae, and ectropion have also been reported.

Systemic Features: 

The cardinal features of this syndrome are craniosynostosis and radial defects.  However, a large number of variable defects such as imperforate or anteriorly placed anus, rectovaginal fistula, absent thumbs, polydactyly, and mental retardation may also be present.  The radius may be completely absent or abnormally formed and occasionally the ulnar bone is involved as well.  Some patients have a conductive hearing loss.

Genetics

This syndrome is caused by a mutation in the RECQL4 gene at 8q24.3 and seems to be an autosomal recessive disorder.  Its syndromal status as a unique syndrome is in some doubt because of considerable phenotypic overlap with other entities such as Roberts (268300) and Saethre-Chotzen (101400) syndromes.  The latter however is caused by a mutation in the TWIST1 gene and the former by mutations in the ESCO2 gene.

The same gene is mutated in Rothmund-Thomson syndrome (268400) suggesting allelism of the two disorders.  The phenotype is vastly different in the two disorders however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

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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