micrognathia

RAB18 Deficiency

Clinical Characteristics
Ocular Features: 

Microphthalmia with microcornea, lens opacities, small and unresponsive pupils, and optic atrophy are the outstanding ocular features of this syndrome.  The eyes appear deeply set.  Some but not all have ERG evidence of rod and cone dysfunction.  The VEP is usually abnormal.  Short palpebral fissures have been described. 

Systemic Features: 

Patients with the micro syndrome have many somatic and neurologic abnormalities.  Infants usually have feeding problems that is sometimes accompanied by gastroesophageal reflux.  Some degree of psychomotor retardation and developmental delays is common.  Both spasticity and hypotonia have been described.  Some patients have seizures.  Facial hypertrichosis, anteverted ears, and a broad nasal bridge are often noted.   There may be absence of the corpus callosum while diffuse cortical and subcortical atrophy, microgyria, and pachygyria may be evident on MRI imaging.  Hypogenitalism may be a feature in both sexes.  Males may also have cryptorchidism and a micropenis while females can have hypoplasia of the labia minora and clitoris and a small introitus.  Microcephaly is inconsistently present. 

Genetics

This is a clinically and genetically heterogeneous disorder caused by homozygous mutations in at least 4 genes: RAB3GAP1 (WARBM1), RAB3GAP2 (WARBM2), RAB18 (WARBM3), and TBC1D20 (WARBM4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.  Vision remains subnormal even after cataracts are removed.  Nutrition may be improved with placement of a gastrostomy tube.

References
Article Title: 

New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish

Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, M?oller L,Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010 Oct;18(10):1100-6.

PubMed ID: 
20512159

Rubinstein-Taybi Syndrome 1

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this disorder.  Few patients have all of the clinical features and there is much variation in the severity of these.  Almost all segments of the eye can be involved.  The lashes are often lush and the eyebrows may be highly arched and bushy.  Lid fissures are often downward slanting (88%).  Congenital glaucoma, nystagmus, cataracts, lacrimal duct obstruction (37%), ptosis (29%), colobomas and numerous corneal abnormalities including keratoglobus, sclerocornea, and megalocornea have been reported.  Abnormal VEP waveforms and cone and cone-rod dysfunction have been found in the majority (78%) of patients tested.  Retinal pigmentary changes have been seen in some patients.  Refractive errors (usually myopia) occur in 56% of patients.  Visual acuities vary widely but about 20% of patients are visually handicapped.

Fluorescein angiography in a single patient revealed generalized vascular attenuation and extensive peripheral avascularity.  The AV transit time was prolonged with delayed venous filling and late small vessel leakage. 

Systemic Features: 

The facial features are reported to be characteristic but there are few distinctive signs.  The face is often broad and round, the nose is beaked, the mouth is small, and the lower lip appears to pout and protrudes beyond a short upper lip.  Smiles have been described as 'grimacing'.  It is common for the columella to protrude beyond the alae nasi.  The palate is narrow and highly arched and the laryngeal walls collapse easily which may lead to feeding problems and respiratory difficulties.  The ears may be rotated posteriorly.  The anterior hairline can appear low.

Among the more distinctive signs are the broad thumbs and great toes which are often deviated medially.  However, the distal phalanges of all fingers may be broad as well.  Bone fractures are common and patellar dislocations can be present as seen in the first two decades of life.  Hypotonia is a feature.  Numerous dental anomalies have been reported including crowded teeth, enamel hypoplasia, crossbite, and abnormal numbers of teeth.

Developmental delays are common.  Infancy and childhood milestones are often delayed.  Many patients have cognitive delays and some are mildly retarded.  Postnatal growth is subnormal and obesity is common.  A third of patients have a cardiac abnormality including septal defects, valvular defects, coarctation of the aorta, pulmonic stenosis, and patent ductus arteriosus.  Renal abnormalities occur frequently and almost all males have undescended testes.  Patients are at increased risk of tumors, both malignant and benign, many of which occur in the central nervous system.  Other problems are constipation and hearing loss.

Genetics

Evidence points to an autosomal dominant mode of inheritance secondary to mutations in CREBBP (16p13.3) but there is some genetic heterogeneity as mutations in EP300 (22q13) have been associated with a similar disease (see Rubinstein-Taybi Syndrome 2; 613684).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific clinical features such as glaucoma and strabismus.  Special education and vocational training may be helpful.  Hearing loss may respond to standard treatment.  Fractures and dislocations should receive prompt attention.  Cardiac anomalies may require surgical correction.

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

Hallermann-Streiff Syndrome

Clinical Characteristics
Ocular Features: 

Nearly all patients (80+ %) have microphthalmia and bilateral congenital cataracts.  Microcornea is common.  The eyebrows may be hypoplastic and the eyelashes likewise are sparse.  The lid fissures often slant down and telecanthus has been noted.  The distance between the two eyes appears reduced.  Blue sclerae, nystagmus, strabismus, and glaucoma are present in 10 to 30% of patients.

Systemic Features: 

The facies are sometimes described as 'bird-like' with a beaked nose, brachycephaly, and micrognathia.  Microstomia with a shortened ramus and forward displacement of the termporomandibular joints is characteristic. Upper airway obstruction may occur with severe respiratory distress.  The forehead is relatively prominent, the palate is highly arched, and the teeth are often small and some may be missing with misalignment of others.  A few teeth may even be present at birth (natal teeth).  Children appear petite and are often short in stature.  Scalp hair is thin, especially in the frontal and occipital areas, and the skin is atrophic.  Developmental delays are common but most patients have normal or near-normal intelligence.

Genetics

Most cases are sporadic but some have mutations in the GJA1 gene (6q21-q23.2).  Both autosomal dominant and autosomal recessive inheritance have been postulated.  Reproductive fitness may be low but rare affected individuals have had affected offspring.  Males and females are equally affected.

This disorder is allelic to oculodentodigital dysplasia (257850, 164200).

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Airway obstruction may require intervention and its risks must be considered during administration of general anesthesia.  Lens opacification may be severe even early in life and requires prompt surgical intervention to prevent amblyopia.

References
Article Title: 

Smith-Lemli-Opitz Syndrome

Clinical Characteristics
Ocular Features: 

A large number of ocular anomalies have been found in SLO syndrome but the most common is blepharoptosis of some degree.  No consistent pattern of ocular abnormalities has been reported.  Atrophy and hypoplasia of the optic nerve, strabismus, nystagmus, and cataracts may be present.   Abnormally low concentrations of cholesterol and cholesterol precursors have been found in all ocular tissues studied.

Systemic Features: 

This is a syndrome of multiple congenital anomalies.  Among these are dwarfism, micrognathia, hard palate anomalies, hypotonia, anomalies of the external genitalia, polysyndactyly, microcephaly, and mental retardation.  It has been suggested that many individuals have a characteristic behavioral profile consisting of cognitive delays, hyperreactivity, irritability, language deficiency, and autism spectrum behaviors.  Some individuals exhibit aspects of self destructive behavior.  Tissue levels of cholesterol are low.

Genetics

SLO syndrome is an autosomal recessive disorder resulting from mutations in the sterol delta-7-reductase  (DHCR7) gene mapped to 11q12-q13. The result is a defect in cholesterol synthesis.

The clinical features significantly overlap those seen in Meckel (249000) and Joubert (213300) syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A high cholesterol diet has been reported to have a beneficial effect on behavior and general well-being.

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

Stickler Syndrome, Type I

Clinical Characteristics
Ocular Features: 

High myopia and vitreous degeneration dominate the ocular manifestations of Stickler syndrome, type I.  The vitreous often appears optically empty as it liquefies and the fibrils degenerate.  The vitreous is sometimes seen to form 'veils', especially in the retrolenticular region but they may also float throughout the posterior chamber.  They are often attached to areas of lattice degeneration in the retina as well as other areas.  Posterior vitreous detachments are common.  Vitreoretinal degeneration is progressive and by the second decade rhegmatogenous detachments occur in half of affected patients.  As many as three quarters of adult patients have retinal breaks.  The retina has pigmentary changes with deposition circumferentially near the equator and more peripherally.  Hypopigmentation is more common early creating a tessellated appearance.  Lenticular opacities occur also early with cortical flecks and wedge-shaped changes.

The ERG may be normal early but evidence of rod and cone dysfunction soon appears and is progressive.  Dark adaptation is defective later in the course of the disease.  The EOG is virtually always depressed.  The visual field is constricted and may show a ring scotoma coincident with the equatorial chorioretinal atrophy.

Glaucoma is not uncommon and may be infantile in onset and difficult to control.  

Phthisis is a significant risk especially for individuals who have multiple surgical procedures for retinal detachments. 

Systemic Features: 

It has been suggested that there is a nonsyndromic or ocular type of Stickler syndrome lacking many of the extraocular features characteristic of the complete syndrome.  However, the evidence for the ocular type described here as a distinct entity remains slim and the clinical picture may simply reflect variable expressivity of mutations in the same gene.  Type I Stickler syndrome has multiple systemic features such as cleft palate, hearing impairment, premature arthritis, micrognathia, kyphoscoliosis, and some signs such as arachnodactyly that are found in the Marfan syndrome.

Genetics

This is an autosomal dominant disease of collagen formation as a result of mutations in the COL2A1 gene (12q13.11-q13.2). The mutations causing both syndromal and the suggested nonsyndromal ocular type of Stickler disease are in the same gene.  Mutations in the same gene are known to cause autosomal dominant rhegmatogenous retinal detachments in patients who have none of the systemic clinical signs (609508).  These patients may lack the signs of vitreous degeneration seen in Kniest dysplasia (156550)  and in the disorder described here.

There is better evidence for a second type of Stickler syndrome, STL2 or type II (604841) based on phenotypic differences and the fact that a second locus (1p21) containing mutations in COL11A1 has been linked to it. 

Type III is caused by mutations in COL11A2 and has systemic features similar to types I and II but lacks the eye findings since this gene is not expressed in the eye.

Type IV also has important ocular features but is an autosomal recessive disorder caused by mutations in COL9A2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The combination of progressive vitreoretinal degeneration, frequency of posterior vitreous detachments, and axial myopia creates a lifelong threat of retinal tears and detachments.   Half to three quarters of all patients develop retinal tears and detachments.  Certainly all patients with Stickler syndrome deserve repeated and thorough retinal exams throughout their lives.  In addition to prompt treatment of tears and detachments, some have advocated prophylactic scleral banding to reduce vitreous traction, or applying 360 degree cryotherapy.

References
Article Title: 

Stickler syndrome in children: a radiological review

McArthur N, Rehm A, Shenker N, Richards AJ, McNinch AM, Poulson AV, Tanner J, Snead MP, Bearcroft PWP. Stickler syndrome in children: a radiological review. Clin Radiol. 2018 Apr 13. pii: S0009-9260(18)30118-1. doi: 10.1016/j.crad.2018.03.004. [Epub ahead of print].

PubMed ID: 
29661559

High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1

Richards AJ, Laidlaw M, Whittaker J, Treacy B, Rai H, Bearcroft P, Baguley DM, Poulson A, Ang A, Scott JD, Snead MP. High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. Hum Mutat. 2006 Jul;27(7):696-704. Erratum in: Hum Mutat. 2006 Nov;27(11):1156.

PubMed ID: 
16752401

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