What are the other Names for this Condition? (Also known as/Synonyms)

• Anophthalmia Waardenburg Syndrome
• Anophthalmos-Syndactyly
• Ophthalmoacromelic Syndrome

What is Anophthalmos with Limb Anomalies? (Definition/Background Information)

• Anophthalmos with Limb Anomalies, also known as Microphthalmia with limb anomalies, is a rare developmental disorder characterized by bilateral microphthalmia or anophthalmia, synostosis, syndactyly, oligodactyly and/or polydactyly
• The majority of cases are caused by mutations in the SPARC-related modular calcium binding protein 1 SMOC1 gene (14q24.1), which may be involved in the regulation of bone morphogenetic proteins
• The existence of other causative genes is possible but they have not yet been discovered
• The FNBP4 gene (11q12.1) was identified in a case with a phenotype similar to OAS but further studies are necessary to conclude if it is indeed causative of OAS
• The prevalence of Anophthalmos with Limb Anomalies is unknown, but more than 35 cases have been reported to date, mainly from consanguineous parents.

(Source: Microphthalmia with limb anomalies; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Anophthalmos with Limb Anomalies? (Age and Sex Distribution)

• Anophthalmos with Limb Anomalies is a rare congenital disorder. The incidence of the condition is unknown, although over 35 cases have been described in the medical literature
• The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Anophthalmos with Limb Anomalies? (Predisposing Factors)

• A positive family history can be an important risk factor, since Anophthalmos with Limb Anomalies may be inherited
• Offspring of parents, who are closely related to each other, carry a higher risk for the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Anophthalmos with Limb Anomalies? (Etiology)

• The majority of Anophthalmos with Limb Anomalies cases (or Ophthalmo-Acromelic Syndrome) are caused by mutations in the SPARC-related modular calcium binding protein 1 SMOC1 gene (14q24.1), which may be involved in the regulation of bone morphogenetic proteins
• The existence of other causative genes is possible but they have not yet been discovered
• The FNBP4 gene (11q12.1) was identified in a case with a phenotype similar to OAS, but further studies are necessary to conclude if it is indeed causative of OAS
• The disorder is inherited autosomal recessively so genetic counseling is possible in affected families and can help in informing parents of the recurrence risk of OAS in subsequent pregnancies

(Source: Microphthalmia with limb anomalies; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Anophthalmos with Limb Anomalies?

The signs and symptoms of Anophthalmos with Limb Anomalies may include:

• Abnormality of the cardiovascular system
• Abnormality of the hair
• Anophthalmia
• Deep philtrum
• Downslanted palpebral fissures
• Flared nostrils
• Fused fourth and fifth metacarpals
• Intellectual disability
• Low-set ears
• Posteriorly rotated ears
• Postnatal growth retardation
• Retrognathia
• Short nose
• Short palpebral fissure
• Single transverse palmar crease

Based on the frequency of symptoms observed, the following information may be noted:

Very frequently present symptoms in 80-99% of the cases:

• Abnormality of the eyebrow
• Abnormality of the metacarpal bones
• Blepharophimosis
• Finger syndactyly
• Frontal bossing
• Hypoplasia of the maxilla
• Microphthalmia
• Prominent forehead
• Sandal gap
• Synostosis of carpal bones
• Toe syndactyly
• True anophthalmia

Frequently present symptoms in 30-79% of the cases:

• Abnormal form of the vertebral bodies
• Bilateral single transverse palmar creases 
• Camptodactyly of 2nd-5th fingers
• Cleft upper lip
• Clinodactyly of the 5th finger       
• Fibular hypoplasia 
• Foot oligodactyly 
• Hand oligodactyly
• Intellectual disability, moderate
• Intellectual disability, severe
• Large earlobe
• Low-set, posteriorly rotated ears 
• Optic atrophy 
• Postaxial hand polydactyly
• Short tibia 
• Tarsal synostosis
• Tibial bowing

Occasionally present symptoms in 5-29% of the cases:

• Arrhinencephaly
• Broad thumb
• Cryptorchidism 
• Elbow dislocation
• High palate 
• Hip dislocation 
• Horseshoe kidney
• Hydrocephalus 
• Joint hyperflexibility
• Long philtrum    
• Macrodontia 
• Micrognathia
• Postaxial foot polydactyly
• Talipes equinovarus
• Thin vermilion border     
• Venous insufficiency

(Source: Anophthalmos with limb anomalies; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Anophthalmos with Limb Anomalies Diagnosed?

• Diagnosis of Anophthalmos with Limb Anomalies is based on the presence of characteristic clinical findings
• Computed tomography (CT) scans and magnetic resonance imaging (MRI) can also be helpful in identifying the presence or absence of the globe, optic nerve and extra ocular muscles
• Identifying a mutation in the SMOC1 gene confirms diagnosis
• Differential diagnoses include isolated cryptophthalmia and other forms of syndromic microphthalmia such as microphthalmia, Lenz type, oculofaciocardiodental syndrome and anophthalmia/microphthalmia-esophageal atresia (see these terms)
• Prenatal testing via CVS or amniocentesis is possible if the causative mutation in a family has been identified
• Ultrasound can also be utilized to identify the limb anomalies associated with OAS

(Source: Microphthalmia with limb anomalies; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Anophthalmos with Limb Anomalies?

The complications of Anophthalmos with Limb Anomalies may include:

• Failure to thrive 
• Limb deformities
• Intellectual disability
• Death in infancy 

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Anophthalmos with Limb Anomalies Treated?

There is no cure for Anophthalmos with Limb Anomalies (or Ophthalmo-Acromelic Syndrome).

• Treatment for anophthalmia/microphthalmia may be discussed with an oculoplastic surgeon and ocularist
  • For anophthalmia, expansion of the eyelids, socket and orbital bones is recommended as soon as possible after birth and is done via conformer therapy by an ocularist or by oculoplastic surgery using hydrogel socket expanders followed by orbital implants or dermis-fat grafts
  • This can help patients with achieving a more typical appearance by preventing facial deformity
  • Those with some vision (if the microphthalmia is not severe) may benefit from visual aids
• Some limb abnormalities may also be surgically corrected to help the patient gain mobility or function, therefore orthopedic evaluation is necessary
• All individuals with OAS should receive evaluation by a vision teacher and special education may be necessary

(Source: Anophthalmos with limb anomalies; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Anophthalmos with Limb Anomalies be Prevented?

Currently, Anophthalmos with Limb Anomalies may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Anophthalmos with Limb Anomalies? (Outcomes/Resolutions)

• Little is known about the prognosis of Anophthalmos with Limb Anomalies given the rarity, but quality of life is usually affected due to intellectual disability, visual impairment and limb anomalies.

(Source: Anophthalmos with Limb Anomalies; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Anophthalmos with Limb Anomalies:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/