midface hypoplasia

GAPO Syndrome

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is considered part of this syndrome but it is not a consistent feature.  One patient with the suspected diagnosis had papilledema while other individuals may have congenital glaucoma, buphthalmos, band keratopathy, and keratoconus.  White eyelashes have been described.  Myelinated nerve retinal nerve fibers may be prominent.

Systemic Features: 

This is a rare congenital disorder with so far incomplete phenotypic delineation. The diagnosis can be made soon after birth from the general facial and body morphology.  The dysmorphism is secondary to marked bone growth retardation and metaphyseal dysplasia, resulting in a flat midface, frontal bossing, micrognathism, chest deformities, and vertebral anomalies. Psychomotor retardation is common but the extent of cognitive deficits is unknown.  The permanent teeth may begin to develop but fail to erupt (pseudoanodontia). Even primary dentition is often abnormal.  Alopecia is a feature although some individuals do have sparse body hair, at least for a period of time.  Anomalous blood vessels such as dilated scalp veins are sometimes evident.   Hypogonadism has been reported in both sexes.  Individuals are subject to recurrent ear and respiratory infections. 

Genetics

GAPO occurs in both sexes.  Homozygous mutations in the ANTXR1 gene (2p13.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at individual problems.  Prompt treatment of respiratory infections is important.

References
Article Title: 

Mutations in ANTXR1 cause GAPO syndrome

Stranecky V, Hoischen A, Hartmannova H, Zaki MS, Chaudhary A, Zudaire E, Noskova L, Baresova V, Pristoupilova A, Hodanova K, Sovova J, Hulkova H, Piherova L, Hehir-Kwa JY, de Silva D, Senanayake MP, Farrag S, Zeman J, Martasek P, Baxova A, Afifi HH, St Croix B, Brunner HG, Temtamy S, Kmoch S. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet. 2013 May 2;92(5):792-9.

PubMed ID: 
23602711

Ophthalmic findings in GAPO syndrome

Ilker SS, Ozturk F, Kurt E, Temel M, Gul D, Sayli BS. Ophthalmic findings in GAPO syndrome. Jpn J Ophthalmol. 1999 Jan-Feb;43(1):48-52.

PubMed ID: 
10197743

Gurrieri Syndrome

Clinical Characteristics
Ocular Features: 

Tapetoretinal degeneration has been described in several patients.  Some patients have keratoconus with lens and corneal opacities.  Visual acuities have not been reported.  The full ocular phenotype must be considered unknown since most patients have not had full ophthalmic evaluations.

Systemic Features: 

Features of an osteodysplasia are among the most striking in this syndrome.  Short stature, brachydactyly, delayed bone age, osteoporosis, and hypoplasia of the acetabulae and iliac alae are usually present.  Birth weight is often low.  Joints may be hyperflexible as part of the generalized hypotonia. The eyes are deep-set, the nasal bridge is prominent, the midface is flat, and the supraorbital ridges are prominent giving the face a rather coarse look.  Prognathism with a prominent lower lip and dental malocclusion reinforce this appearance.  Seizures beginning in early childhood may be difficult to control.  Most patients have severe psychomotor retardation and never acquire speech.

Genetics

The genetics of this familial disorder remain unknown.  No locus or mutation has been identified but one patient had an absent maternal allele of the proximal 15q region as found in Angelman syndrome.

Orofaciodigital syndrome IX (258865) is another autosomal recessive syndrome sometimes called Gurrieri syndrome.  In Gurrieri’s original description of two brothers, chorioretinal lacunae, similar to those seen in Aicardi syndrome (304050), were present.  The systemic features are dissimilar, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Treacher Collins-Franceschetti Syndrome

Clinical Characteristics
Ocular Features: 

Lid fissures often have an antimongoloid slant.  Many patients (69%) have a coloboma of the lower eyelid (in contradistinction to Goldenhar spectrum syndrome [164210] in which the lid colobomas involve the upper eyelid) with a paucity of lashes and meibomian glands medially.  Colobomas may also involve the iris, choroid and optic nerve.  Other ocular features include blepharoptosis, hypoplasia of the supraorbital ridges, absent lacrimal puncti, underdevelopment of the orbicularis oculi muscle, absence of the tarsal plate, and abnormalities of the lateral canthal tendons.  Strabismus and amblyopia have been reported in a significant number of individuals.

Systemic Features: 

A variety of defects in facial development have been reported, most involving the ears, eyelids, lower jaw, and zygomatic arch.  The characteristic facial phenotype is usually evident at birth.  One-third of patients have a cleft palate.  Microtia or even anotia may be present and a conductive hearing loss can result, especially when the ossicles are malformed or absent.  The pinnae are often malformed, appearing 'crumpled', low-set, and rotated posteriorly.  There may be ear tags and blind fistulas anywhere between the tragus and angle of the mouth.  The mandible and its rami may be hypoplastic causing severe micrognathia that can result in feeding and speaking difficulties, especially when pharyngeal hypoplasia is also present.  The zygomatic arches are often underdeveloped (or even absent) and the midface is flattened.  Arhinia and cleft palate are sometimes seen.  A low hairline may be present.  Intelligence is usually normal.

Genetics

This is an autosomal dominant syndrome secondary to mutations in the TCOF1 gene located at 5q32-q33.1.  A parental gender influence is suggested by at least one study which found an increase in the number of affected offspring from affected mothers compared with those from affected fathers.  Many cases (60%) result from new mutations but a paternal age effect has not been established.  Inter- and intrafamilial clinical variation is wide.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Auditory testing should be done early since corrective action is important in the prevention of developmental delays.  Reconstructive facial surgery can be of great benefit to both cosmesis and function.  Lid reconstruction may be required for corneal protection.

References
Article Title: 

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

Teber OA, Gillessen-Kaesbach G, Fischer S, Bohringer S, Albrecht B, Albert A, Arslan-Kirchner M, Haan E, Hagedorn-Greiwe M, Hammans C, Henn W, Hinkel GK, Konig R, Kunstmann E, Kunze J, Neumann LM, Prott EC, Rauch A, Rott HD, Seidel H, Spranger S, Sprengel M, Zoll B, Lohmann DR, Wieczorek D. Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. Eur J Hum Genet. 2004 Nov;12(11):879-90.

PubMed ID: 
15340364

Smith-Magenis Syndrome

Clinical Characteristics
Ocular Features: 

Ocular abnormalities have been found in the majority of patients.  Microcornea, myopia, strabismus and iris dysplasia are the most common.  Rare patients have iris colobomas or correctopia.  The eyes appear deep-set and lid fissures are upward slanting.

Systemic Features: 

The facial features are considered to be distinctive, characterized by a broad, square face, prominent forehead, broad nasal bridge, and midface hypoplasia.  These and other features appear more pronounced with age as in the size of the jaw which is underdeveloped in infancy and eventually becomes prognathic.  Most patients have developmental delays, speech and motor deficits, cognitive impairments and behavioral abnormalities.  Hypotonia, hyporeflexia, failure to thrive, lethargy, and feeding difficulties are common in infants.  Older individuals have REM sleep disturbances with self-destructive behaviors, aggression, inattention, hyperactivity, and impulsivity.  Short stature, hypodontia, brachydactyly, hearing loss, laryngeal anomalies, and peripheral neuropathy are common. Seizures are uncommon.

The behavioral profile of this syndrome can resemble that of autism spectrum disorders although symptoms of compulsivity are more mild.

A related developmental disorder known as Potacki-Lupski syndrome (610883) involving the same locus on chromosome 17 has a similar behavioral profile.  Ocular and systemic malformations may be less severe though.

Genetics

Most patients (90%) with the Smith-Magenis syndrome have interstitial deletions in the short arm of chromosome 17 (17p11.2).  However, it is included here since a few have heterozygous molecular mutations in the RAI1 gene which is located in this region.  While there is considerable phenotypic overlap, individuals with chromosomal deletions have the more severe phenotype as might be expected.  For example, those with RAI1 mutations tend to be obese and are less likely to exhibit short stature, cardiac anomalies, hypotonia, hearing loss and motor delays than seen in patients with a deletion in chromosome 17.  However, the phenotype is highly variable among patients with deletions depending upon the nature and size of the deletion.

The retinoic acid induced 1 gene (RAI1) codes for a transcription factor whose activity is reduced by mutations within it.

Familial cases are rare and reproductive fitness is virtually zero.  If parental chromosomes are normal, the risk for recurrence in sibs is less than 1%.  Males and females are equally affected.

In Potocki-Lupski syndrome (610883) there is duplication of the 17p11.2 microdeletion as the reciprocal recombination product of the SMS deletion.   

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Medical monitoring, psychotropic medications and behavioral therapies are all useful.  Special education and vocational training may be helpful for those less severely affected.

References
Article Title: 

Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and

Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM,
Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C,
Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski
JR. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and
delineation of a dosage-sensitive critical interval that can convey an autism
phenotype. Am J Hum Genet. 2007 Apr;80(4):633-49.

PubMed ID: 
17357070

Gorlin-Chaudhry-Moss Syndrome

Clinical Characteristics
Ocular Features: 

Orbital hypoplasia, short, abnormally slanted (up or down) lid fissures, and sometimes lid notching (colobomas?) are characteristic facial features as are bushy eyebrows and synophrys.  Lacrimal duct stenosis has been noted.  The eyes are described as 'small' but no ophthalmological examination has been performed to document microphthalmia or other ocular anomalies.  No mention is made of visual problems.

Systemic Features: 

Premature closure of the coronal suture and midface hypoplasia lead to striking brachycephaly.  The scalp hairline is low and scalp hair is abundant and coarse.  In fact, hypertrichosis is seen throughout the body.  Hypo- and microdontia with irregularly spaced teeth and a high arched palate are common features.  Clefts of the soft palate has been observed.  The ears can be small and rotated posteriorly.  The labia majora are hypoplastic as are the distal phalanges of the fingers and toes.  Mild syndactyly of the second and third fingers and toes have been described.  The nails may be abormally small.  Conductive hearing loss may be present.  Growth and psychomotor development seem to be normal although some patients have been described to have a 'stocky' build.  The facial features tend to coarsen over time.

Genetics

Autosomal recessive inheritance has been suggested but nothing is known about the gene locus.  All 5 reported patients have been female.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

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: 

Chondrodysplasia Punctata 2

Clinical Characteristics
Ocular Features: 

Early onset cataracts, often sectorial, are the major ocular feature of this syndrome.  Micropthalmia and microcornea have been observed.  There may be local vitreoretinal abnormalities leading to localized detachments and retinoschisis.

Systemic Features: 

The cartilage disease in this disorder leads to short stature that is often asymmetrical.  There is considerable variation in skeletal manifestations as the spine as well as the limbs can be involved.  The skin at birth may be scaly and erythrodermic.  Later the skin pigmentation may assume a whorled pattern and hyperkeratosis appears, often in a segmental pattern consistent with X-chromosomal mosaicism.  The skin may also be ichthyotic.  The nasal bridge is often flat with frontal bossing.  Flexion contractures are sometimes seen.  Cicatricial alopecia and coarse hair are often noted in adults.

Genetics

A number of skeletal disorders are classified as chondrodysplasia punctata, and there is considerable clinical and genetic heterogeneity (see also rhizomelic chondrodysplasia punctata [215100] in this database for an autosomal recessive form) which has yet to be worked out.  The disorder described here is an X-linked dominant disorder with lethality in males.  It results from a mutation in the EBP gene (Xp11.23-p11.22) causing difficulty in converting lanosterol to cholesterol.  The diagnosis can be confirmed by finding increased plasma accumulation of precursors of sterols 8(9)-cholestenol and 8-dehydrocholesterol. Rare severely affected males with hypotonia, seizures, cerebellar atrophy, agenesis of the corpus callosum, and developmental delays have been reported. 

The X-linked recessive (CDPX1;302950), autosomal dominant tibia-metacarpal (118651), and humero-metacarpal types are not associated with cataracts.

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

Cataract extraction may improve vision.  Sun protection is advised.

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

Marshall Syndrome

Clinical Characteristics
Ocular Features: 

Myopia is a common feature.  The globes appear prominent with evident hypertelorism, perhaps in part due to shallow orbits.  The vitreous is abnormally fluid.  The beaded vitreous pattern seen in Stickler syndrome type II (604841), with which Marshall syndrome is sometimes confused, is not seen in Marshall syndrome, nor is the same frequency of retinal detachments.  Congenital or juvenile cataracts were present in Marshall’s original family.

Systemic Features: 

The midface is flat with some features of the Pierre-Robin phenotype.  The nasal root is flat and the nares anteverted.  Patients tend to be short in stature and joints are often stiff.  Small iliac wings and a thickened calvarium can be seen radiologically together with other bone deformities.  Abnormal frontal sinuses and intracranial calcifications have also been reported.  Sensorineural hearing loss may be noted during the first year of life with age-related progression.  Osteoarthritis of the knees and lumbosacral spine begins in the 4th and 5th decades.  Features of anhidrotic ectodermal dysplasia such as hypohidrosis and hypotrichosis are present in some patients.  Individuals may have linear areas of hyperpigmentation on the trunk and limbs.

Genetics

The syndromal status of Marshall syndrome as a unique entity remains uncertain inasmuch as there are many overlapping clinical features with Stickler syndrome type II (604841) and both result from mutations in the COL11A1 gene (1p21).  Autosomal dominant inheritance is common to both although autosomal recessive inheritance has been proposed for a few families with presumed Marshall syndrome. Stickler syndrome type II (604841) and Marshall syndrome may be allelic or even the same disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder beyond cataract removal.  Patients need to be monitored for retinal breaks and detachments.

References
Article Title: 

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