Lamb–Shaffer syndrome is a rare autosomal dominant genetic condition.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 Less than 40 cases have been reported by 2018.
Signs and symptoms
Clinical features includeNesbitt 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 Global developmental delay Significant speech delay Hypotonia Micrognathia Scoliosis Defects in motor function, both fine and gross Optic atrophy Oculomotor 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.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 This gene encodes a protein in the family of transcription factors involved in embryonic and cellular development.
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 cases 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. This means that the majority of the patients have parents who are unaffected whereas inheritance is also possible.
Pathogenesis
It is unclear how this mutation causes the clinical picture.
Diagnosis
The diagnosis may be suspected based on the constellation of clinical features, but may only be determined by a genetic test. The full exome sequencing test determines 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 transfer in the brain. Symptoms of Lamb-Shaffer syndrome include fine and gross motor delays, speech delay, global developmental delay, hypotonia, and vision issues, commonly misdiagnosed as an autism spectrum disorder.
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.
History
This condition was first described by Lamb et al in 2012.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
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