Lamb-Shaffer syndrome

Lamb-Shaffer syndrome
Autosomal dominant pattern is the inheritance manner of this condition
Specialty	Medical genetics

Lamb-Shaffer syndrome is a rare autosomal dominant condition.^[1] Less than 40 cases have been reported by 2018.

Signs and symptoms

Clinical features include^[2]

• Global developmental delay
• Significant speech delay
• Hypotonia
• Micrognathia
• Scoliosis
• Defects in motor function both fine and gross
• Optic atrophy
• Ocular motor apraxia
• Strabismus
• Frontal bossing
• Ear abnormalities
• Low nasal bridge
• Epicanthal folds
• Midline tongue groove

Genetics

This condition is caused by mutations in the SRY-related HMG-box (SOX5) gene.^[3] This gene encodes a protein in the family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate.

The gene is located on the short arm of chromosome 12 (12p12).

A study published in 2019 examining 34 families shows that 74% (25/34 families) of the condition are likely to be of de novo occurrence, as the variants could not be detected in parental blood samples. In 15% (5/34 families) of the patients the condition was likely inherited from a mosaic parent. In 3% (1/34), the condition was inherited from an affected parent.^[4] This means that the majority of the patients have parents who are unaffected whereas inheritance is also possible.

Pathogenesis

How this mutation causes the clinical picture is not currently clear.^{[citation needed]}

Diagnosis

The diagnosis may be suspected on the basis of the constellation of clinical features but may only be determined by a genetic test. The full exome sequencing test is used to determine the partial deletion, deletion,or mutation to the SOX5 gene. It is made by sequencing the SOX5 gene responsible for the cells that facilitate information transferring in the brain. Symptoms of Lamb-Shaffer syndrome include fine and gross motor delays, speech delay, global developmental delay,hypotonia and issues with vision, commonly misdiagnosed for autism.

Treatment

There is currently no curative treatment for this condition. Supportive management is all that is currently available.

Epidemiology

This is a rare condition with a prevalence of < 1/10⁶. The total number of cases reported to date is <550. ^[5]

History

This condition was first described by Lamb et al in 2012^[6]

References

1. Lamb AN, Rosenfeld JA, Neill NJ, Talkowski ME, Blumenthal I, Girirajan S., Keelean-Fuller D, Fan Z, Pouncey J, Stevens, C., Mackay-Loder L, Terespolsky D, and 31 others. Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. Hum Mutat 33: 728-740
2. Nesbitt A, Bhoj EJ, McDonald Gibson K, Yu Z, Denenberg E, Sarmady M, Tischler T, Cao K, Dubbs H, Zackai EH, Santani A (2015) Exome sequencing expands the mechanism of SOX5-associated intellectual disability: a case presentation with review of SOX-related disorders. Am J Med Genet 167A: 2548-2554
3. Lee RWY, Bodurtha J, Cohen J, Fatemi A, Batista D (2013) Deletion 12p12 involving SOX5 in two children with developmental delay and dysmorphic features. Pediat Neurol 48: 317-320
4. Ash, Zawerton (3 October 2019). "Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency". Genetics in Medicine: 3 – via Researchgate.net.
5. http://www.lambshaffer.org/
6. Lamb AN, Rosenfeld JA, Neill NJ, Talkowski ME, Blumenthal I, Girirajan S., Keelean-Fuller D, Fan Z, Pouncey J, Stevens, C., Mackay-Loder L, Terespolsky D, and 31 others. Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. Hum Mutat 33: 728-740