Billuart-type X-linked Intellectual Developmental Disorder; MRX60; MRXSBL; Oligophrenin-1 Syndrome; Oligophrenin-1 Syndrome / OPHN1 Deficiency; Oligophrenin-1; OPHN1 Deficiency; OPHN1 Neurodevelopmental Disorder; OPHN1 Related XLID; OPHN1-related Syndrome; X-linked Intellectual Disability 60; X-Linked Intellectual Disability-Cerebellar Hypoplasia Syndrome

OPHN1 syndrome is a rare disorder characterized by intellectual disability and changes in the part of the brain (cerebellum) which controls movement, balance, and motor skills. Affected individuals may have moderate to severe intellectual disability, low muscle tone (hypotonia), developmental and cognitive delay, early-onset seizures, abnormal behavior, small or underdeveloped genitals, characteristic facial features (long face, bulging forehead, under eye creases, deep-set eyes, and large ears), crossed eyes (strabismus), and inability to coordinate movements. OPHN1 syndrome mainly affects males who usually show the full, often severe range of symptoms due to having only one X chromosome. Females are generally carriers of the genes that cause OPHN1 syndrome and tend to show milder features of the syndrome, such as mild learning difficulties or slight facial differences. OPHN1 syndrome is caused by mutations in the OPHN1 gene.

Diagnostic testing: The diagnosis of OPHN1 syndrome is based on:

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  Clinical evaluation;

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  Clinical phenotype (observable, measurable, and physical features) in males;

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  Carrier detection in females;

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  Molecular genetic testing for mutations in the OPHN1 gene;

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  Magnetic resonance imaging (MRI) imaging of the brain;

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  Next generation sequencing panels for intellectual disability; and

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  Chromosomal microarray.

Physical findings: Signs and symptoms of OPHN1 syndrome may include:

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  Early-onset epilepsy;

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  Hypotonia (low muscle tone);

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  Cerebellar hypoplasia;

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  Characteristic facial features (i.e., long face, bulging deep-set eyes, prominent forehead);

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  Infraorbital (the region below the eye socket) creases;

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  Large ears;

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  Long tubular nose;

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  Strabismus (crossed eyes);

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  Nystagmus (involuntary rapid and repetitive eye movements); and

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  Genital hyperplasia in males.

ICD-9: 319; 759.89

ICD-10: Q04.3

The symptoms of OPHN1 syndrome may start to appear in neonatal/infants and early childhood with symptoms of severe neonatal hypotonia (low muscle tone), motor delays, and treatment resistant seizures. Some males may exhibit moderate to severe neurological degeneration, with some, but not all, having autism spectrum disorder. The severity of intellectual disability and behavioral issues varies.

Currently, there is no cure for OPHN1 syndrome. Treatment focuses on supportive care to improve quality of life, maximize function, and reduce complications. Treatment is symptom specific and involves the management of intellectual disability and cerebellar hypoplasia. Occupational therapy, physical therapy, and speech therapy are recommended to address developmental delays.

Suggested MER for Evaluation:

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  Clinical history and physical examination that describes the diagnostic features of the impairment;

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  Genetic sequencing tests confirming mutation of the OPHN1 gene; and

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  MRI imaging of the brain.

Suggested Listings for Evaluation:

12.02

12.05

12.10

12.11

110.08

111.02

112.02

112.05

112.10

112.11

112.14