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

• Combination of Microcephaly, Exophthalmos, Hypoplastic Nose and Midface, Gum Hyperplasia, Cleft Palate, Apparently Low-Set Ears, and Osteosclerosis
• Lethal Osteosclerotic Bone Dysplasia
• RNS (Raine Syndrome)

What is Raine Syndrome? (Definition/Background Information)

• Raine Syndrome (RNS or Lethal Osteosclerotic Bone Dysplasia) is defined by generalized osteosclerosis with periosteal bone formation, characteristic facial dysmorphism, brain abnormalities including intracerebral calcifications, and neonatal lethal course
• The cranial features are a wide anterior fontanelle, expressed proptosis with everted lower eyelids, severely depressed nasal bridge, small nose, low-set ears, and severe midface hypoplasia leading to choanal atresia. The mouth is usually triangular, gum hypertrophy is expressed, and there may be natal teeth and cleft palate/uvula
• The radiological findings include generalized osteosclerosis of all bones and the base of the skull, with cortical hyperostosis and periosteal new bone formation. An obtuse mandibular angle is characteristic, as are irregularly formed ribs
• Radiologically, widespread bilateral calcification in the periventricular white matter, basal ganglia, and thalamus is found and in some cases calcifications are also seen in the corpus callosum, falx, tentorium, and meninges. Extra-skeletal features can be hydronephrosis and ureteral stenosis
• Diagnosis is based on clinical presentation and calcification demonstrable by ultrasound, plain X-rays and computing tomography (CT). Prenatal diagnosis by ultrasound or molecular testing is feasible
• The condition is transmitted in an autosomal recessive manner. Ten cases in eight families have been reported, the majority of a Middle East origin. Parental consanguinity was frequently present

(Source: Lethal osteosclerotic bone dysplasia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Raine Syndrome? (Age and Sex Distribution)

• Raine Syndrome is an extremely rare congenital disorder. 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. However, most of the cases have been reported in middle-eastern origin families

What are the Risk Factors for Raine Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Raine Syndrome can be inherited
• Offspring of parents who are close relatives (related to each other) may carry a higher risk for RNS

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 Raine Syndrome? (Etiology)

• Mutations in the FAM20C gene have a causative role in Lethal Osteosclerotic Bone Dysplasia (Raine Syndrome)
• The condition is transmitted in an autosomal recessive manner

(Source: Lethal osteosclerotic bone dysplasia; 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 Raine Syndrome?

The signs and symptoms of Raine Syndrome may include:

• Brachyturricephaly
• Cerebral calcification
• Choanal atresia
• Choanal stenosis
• Downslanted palpebral fissures
• Elevated alkaline phosphatase
• Gingival overgrowth
• High palate
• Hypertelorism
• Hypophosphatemia
• Increased bone mineral density
• Malar flattening
• Midface retrusion
• Narrow mouth
• Proptosis
• Protruding tongue
• Pulmonary hypoplasia
• Thoracic hypoplasia

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

• Anteverted nares
• Delayed cranial suture closure
• Depressed nasal ridge
• Large fontanelles
• Low-set ears
• Median cleft lip and palate
• Microcephaly
• Micrognathia
• Posteriorly rotated ears
• Retrognathia
• Short neck

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

• Gingival fibromatosis
• Intrauterine growth retardation
• Mandibular aplasia
• Proptosis
• Respiratory distress
• Respiratory failure
• Short nose

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

• Bowing of the long bones
• Brachydactyly
• Highly arched eyebrow
• Hydrocephalus
• Hydronephrosis
• Hypoplasia of dental enamel
• Long hallux
• Microdontia
• Micromelia
• Mixed hearing impairment
• Natal tooth
• Pectus excavatum
• Plagiocephaly
• Posteriorly rotated ears
• Protruding ear
• Wide mouth

(Source: Raine Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Raine Syndrome Diagnosed?

Diagnosis of Raine Syndrome is based on clinical presentation and calcification demonstrable by ultrasound, plain X-rays and computing tomography (CT).

• The radiological findings include generalized osteosclerosis of all bones and the base of the skull, with cortical hyperostosis and periosteal new bone formation. An obtuse mandibular angle is characteristic, as are irregularly formed ribs
• Radiologically, widespread bilateral calcification in the periventricular white matter, basal ganglia, and thalamus is found and in some cases calcifications are also seen in the corpus callosum, falx, tentorium, and meninges. Extra-skeletal features can be hydronephrosis and ureteral stenosis
• Prenatal diagnosis by ultrasound or molecular testing is feasible

(Source: Lethal osteosclerotic bone dysplasia; 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 Raine Syndrome?

The complications of Raine Syndrome may include:

• Physical abnormalities
• Neonatal death
• Dysfunction of vital organs

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

How is Raine Syndrome Treated?

There is no cure for Raine Syndrome, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complications that develops.

How can Raine Syndrome be Prevented?

Currently, Raine Syndrome 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 Raine Syndrome? (Outcomes/Resolutions)

• The prognosis of Raine Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Raine Syndrome:

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

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