malar hypoplasia

Meester-Loeys Syndrome

Clinical Characteristics
Ocular Features: 

A variety of nondiagnostic facial features are present at birth including hypertelorism, downward slanting lid fissures, proptosis, frontal bossing, and midface hypoplasia.

Systemic Features: 

Aortic aneurysms with or without dissection have been diagnosed as early as 1 year of age but may not be apparent until teenage years.  Pectus deformities, joint hypermobility, and skin striae may be seen. Hypertrichosis, evidence of skeletal dysplasia such as hip dislocation, platyspondyly, phalangeal dysplasia, joint hypermobility, relative macrocephaly, dysplastic epiphyses of the long bones, and cervical spine instability are often present.

Genetics

This X-linked disorder is caused by a mutation in the BGN gene (Xp28).  No male-to-male transmission has been reported although both sexes are affected.

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

Individual deformities might be surgically repaired.

References
Article Title: 

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections

Meester JA, Vandeweyer G, Pintelon I, Lammens M, Van Hoorick L, De Belder S, Waitzman K, Young L, Markham LW, Vogt J, Richer J, Beauchesne LM, Unger S, Superti-Furga A, Prsa M, Dhillon R, Reyniers E, Dietz HC, Wuyts W, Mortier G, Verstraeten A, Van Laer L, Loeys BL. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections. Genet Med. 2016 Sep 15. doi: 10.1038/gim.2016.126. [Epub ahead of print].

PubMed ID: 
27632686

Retinal Dystrophy, Cataracts, and Short Stature

Clinical Characteristics
Ocular Features: 

Patients develop progressive night vision problems in the first decade of life.  However, central acuity remains in the 20/20 to 20/30 range at least through the second decade.  Cataracts are noted during this time period as well.  Visual field constriction is present.

Pigmentary retinopathy is present, especially in the posterior poles.  Macular mottling is evident at an early age with attenuation and narrowing of the retinal arterioles.  The pigmentary changes are salt-and-pepper in appearance but there are also areas of RPE atrophy with relative sparing of the fovea.  Pigment clumping in the shape of bone spicules has been observed in the periphery.  Full field ERGs show generalized rod-cone dysfunction with scotopic function more affected.  OCT examination reveals a disruption of the outer retinal layers from the parafoveal region into the periphery.

Systemic Features: 

Early childhood psychomotor delays are evident in early childhood by the lack of fine motor and coordination skills along with learning difficulties.  Patients have facial dysmorphism with hypoplasia of the ala nasae, upslanting palpebral fissures, and malar hypoplasia.  The teeth are widely spaced and there is malocclusion.  Short stature is characteristic (fifth percentile).

Genetics

This disorder results from homozygosity of mutations in the RDH11 gene (14q24) encoding retinol dehydrogenase 11.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this condition but patients may benefit from correction of the malocclusion, special education classes, cataract removal, and low vision aids.  Physical therapy may also be helpful.

References
Article Title: 

Roberts Syndrome

Clinical Characteristics
Ocular Features: 

The eyes often appear prominent as the result of shallow orbits.  Hypertelorism and microphthalmia can be present.  The sclerae can have a bluish hue.   Cataracts and central corneal clouding plus scleralization and vascularization of the peripheral corneas are sometimes seen.  Lid colobomas and down-slanting palpebral fissures may be present.

Systemic Features: 

Failure of both membranous and long bones to grow properly lead to a variety of abnormalities such as craniosynostosis, hypomelia, syndactyly, oligodactyly, malar hypoplasia, short neck, micrognathia, and cleft lip and palate.  The long bones of the limbs may be underdeveloped or even absent.  Contractures of elbow, knee, and ankle joints are common as are digital anomalies.  Low birth weight and slow postnatal growth rates are usually result in short stature.  The hair is often sparse and light-colored. 

Mental development is impaired and some children are diagnosed to have mental retardation.  Cardiac defects are common.  Facial hemangiomas are often present as are septal defects and sometimes a patent ductus arteriosus.  External genitalia in both sexes appear enlarged.  The kidneys may be polycystic or horseshoe-shaped.

Genetics

This is an autosomal recessive condition caused by mutations in the ESCO2 gene (8p21.1).  Mutations in the same gene are also responsible for what some have called the SC phocomelia syndrome (269000) which has a similar but less severe phenotype.  Some consider the two disorders to be variants of the same condition and they are considered to be the same entity in this database.  The gene product is required for structural maintenance of centromeric cohesion during the cell cycle.  Microscopic anomalies of the centromeric region (puffing of the heterochromatic regions) are sometimes seen during cell division.

The Baller-Gerold syndrome (218600) has some phenotypic overlap with Roberts syndrome but is caused by mutations in a different gene (RECQL4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Severely affected infants may be stillborn or die in infancy.  Other individuals live to adulthood.  There is no treatment for this condition beyond specific correction of individual anomalies.

References
Article Title: 

Retinopathy with Neutropenia

Clinical Characteristics
Ocular Features: 

Pigmentary retinopathy was reported in a 25 year old female with moderately reduced visual acuity. Rare bone spicules pigment deposits were present in the periphery and macular edema was noted. Severely reduced scotopic and photopic responses were recorded.

Systemic Features: 

The single reported individual had congenital neutropenia and microcephaly. She had evident growth retardation and microcephaly at birth with subsequent recurrent upper respiratory infections and gingivitis. Speech and motor development were normal. Short stature was noted as well. The limbs were described as slender as in Cohen syndrome (216550) but no truncal obesity or joint hypermobility was present. The facial dysmorphism only vaguely resembled that found in Cohen syndrome (216550).

Genetics

This is a newly described condition whose unique identity remains to be established since only a single patient has been reported. This patient carried two heterozygous splicing mutations in the same VPS13B gene, the same gene in which more than 100 homozygous mutations have been found in individuals with Cohen syndrome (216550). Each parent carried a different splicing mutation in VPS13B.

Cohen syndrome (216550) however, has additional phenotypic features such as truncal obesity, intellectual disabilities, intermittent neutropenia, microcephaly, facial dysmorphism, myopia, and progressive chorioretinal dystrophy. Variable amounts of neutropenia were observed from age 5 years but the marrow was normocellular in appearance.

Isolated retinopathy with neutropenia may or may not be an autosomal recessive variant of Cohen syndrome (216550).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Stickler Syndrome, Type II

Clinical Characteristics
Ocular Features: 

Virtually all (85%) patients have a nonprogresssive axial myopia.  The vitreous degeneration has a beaded pattern without the veils of type I, claimed by some to be important in the distinction of the two types.  Paravascular lattice retinopathy is seen in 38% of patients and 64% have cataracts, sometimes with wedge opacities similar to those in type I Stickler syndrome.  Nearly half (42%) of patients are reported to have retinal detachments.

Systemic Features: 

Hearing loss occurs early and many individuals (80%) eventually require hearing aids.    Midline clefting is present frequently with bifid uvula, a highly arched palate, or an actual cleft palate.  Joint laxity is common.

Genetics

There are reasons to classify type II Stickler syndrome as a unique disorder apart from type I (108300).  In addition to phenotypic evidence (vitreoretinal disease, amount of hearing loss, and degree of epiphyseal disease), mutation in two different genes are involved.  Type II results from a mutation in the COL11A1 (1p21) and type I (108300) in COL2A1.  Both types are inherited in autosomal dominant patterns.

Type IV (614234) with vitreoretinal changes, myopia, and a high risk of retinal detachment is inherited in an autsomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Patients with type II Stickler disease need lifelong ophthalmologic monitoring because of the risk of retinal detachments and cataracts with treatment as indicated.
 

References
Article Title: 

Clinical features of type 2 Stickler syndrome

Poulson AV, Hooymans JM, Richards AJ, Bearcroft P, Murthy R, Baguley DM, Scott JD, Snead MP. Clinical features of type 2 Stickler syndrome. J Med Genet. 2004 Aug;41(8):e107.

PubMed ID: 
15286167
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