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A rare genetic syndromic intellectual disability characterized by global developmental delay and speech delay, variable degrees of intellectual disability, and dysmorphic facial features (such as frontal bossing, epicanthal folds, strabismus, depressed nasal bridge, short philtrum, auricular abnormalities, micrognathia, or crowded teeth, among others). Additional reported manifestations are behavioral problems (stereotypies, aggression, anxiety, autism spectrum disorder), skeletal anomalies (scoliosis, pectus carinatum, clinodactyly of fingers and toes, among others), and seizures.
ORPHA:530983Classification level: Disorder
- SOX5 haploinsufficiency syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant
- Age of onset: Infancy
- ICD-10: Q87.8
- OMIM: -
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
Lamb-Shaffer syndrome (LAMSHF) is a rare disorder reported in less than 100 patients worldwide. The prevalence is not known.
In most cases, pregnancy and delivery are unremarkable and the neonatal period is uneventful. Developmental delay (delayed independent walking and speech) and truncal hypotonia during infancy are the usual first manifestations. In older children, mild-to-moderate intellectual disability is the main clinical feature, with some patients having either more severe or milder cognitive impairment. Behavioral disturbances are frequent, including autism spectrum disorder, stereotypies, isolation, tantrums and hyperactivity. Seizures may occur but epilepsy is relatively infrequent (<10%). Height, weight and occipitofrontal circumference are within normal ranges. Mild dysmorphological features are noted in most patients, including broad/full nasal tip, thin upper lip or full lips, small jaw or chin, strabismus, long face and/or epicanthus. Optic atrophy is a rare feature. Malformations of organs are infrequent, skeletal malformations mainly involve the spine (scoliosis, thoracic kyphosis, fused cervical vertebrae).
LAMSHF is an autosomal dominant disorder caused by haplo-insufficiency of the SOX5 gene (12p12.1) due to either a 12p12.1 microdeletion encompassing the gene or heterozygous point variants. Points variants are either truncating variants or missense variants affecting functional domains of the protein.
LAMSHF diagnosis may be suspected on clinical presentation and confirmed by micro-array analysis (SOX5 deletion) or sequencing of SOX5 (gene panel, exome sequencing, genome sequencing).
Many differential diagnoses may be considered, i.e. developmental disorders with mild-to-moderate intellectual disability and mild morphological features.
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
The disorder is autosomal dominant and whilst most cases arise sporadically, parental mosaicism is not exceptional. Genetic counseling should be offered to i) couples with an affected child informing them that there is a risk of having another affected child, ii) affected individuals informing them that there is a 50% risk of transmission.
Management and treatment
There is no specific treatment for LAMSHF. Management of patients requires medical and social care as for other patients with intellectual disability, including special schooling, speech therapy, etc.
Life expectancy of individuals with LAMSHF does not seem to be affected. The functional prognosis depends on the severity of intellectual disability.
A summary on this disease is available in Español (2021) Français (2021) Nederlands (2021)