Lamb-Shaffer Syndrome

A number sign (#) is used with this entry because of evidence that Lamb-Shaffer syndrome (LAMSHF) is caused by heterozygous mutation in the SOX5 gene (604975) on chromosome 12p12. Some patients with a similar phenotype may have deletions of chromosome 12p12 including several genes in addition to SOX5.

Description

Lamb-Shaffer syndrome is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, and mild dysmorphic facial features. Additional variable skeletal abnormalities may also be present (summary by Nesbitt et al., 2015).

Clinical Features

Lamb et al. (2012) reported 9 unrelated patients with developmental delay and intellectual disability associated with haploinsufficiency of the SOX5 gene. Other common features included speech delay and dysmorphisms such as strabismus, frontal bossing, ear abnormalities, and low nasal bridge. Several patients had behavioral problems, including stereotypic behavior or pervasive developmental delay. Only 2 had seizures. More variable features included hypotonia, clumsiness, poor balance, articulation difficulties, and scoliosis.

Schanze et al. (2013) reported a 9-year-old boy (patient 2) with global developmental delay, poor early speech development, and dysmorphic features, including high forehead, downslanting palpebral fissures, thin upper lip, open mouth, and pointed chin. He had some ritualistic behavior and constipation.

Lee et al. (2013) reported a 32-month-old boy with global developmental delay and severe expressive language delay. Dysmorphic features included frontal bossing, depressed nasal bridge with bulbous nasal tip, epicanthal folds, strabismus, prominent philtral ridges, underdeveloped helices, and mild facial hypoplasia. Additional multisystem anomalies included right renal agenesis, ureteral stenosis, optic nerve hypoplasia, laryngotracheomalacia, and vertebral clefts. Lee et al. (2013) noted that the pregnancy was complicated by gestational diabetes that was controlled with glyburide; it was unknown whether this had a teratogenic effect.

Nesbitt et al. (2015) reported a 17-year-old girl with delayed psychomotor development, intellectual disability (IQ of 50), and mild dysmorphic features, including blepharoptosis, low-set and posteriorly rotated ears, retrognathia, prominent maxilla, midline tongue groove, and narrow palate with overcrowded teeth. She developed nonprogressive optic atrophy at age 10, and also had exotropia and mild myopia. Additional features included mild mitral regurgitation, thoracic kyphoscoliosis, lumbar lordosis, pectus carinatum, long fingers, and long halluces reminiscent of a marfanoid habitus. She also had anxiety.

Cytogenetics

By use of oligonucleotide-based array comparative genomic hybridization (array CGH) to test 24,081 probands referred for developmental delay or intellectual disability, Lamb et al. (2012) identified 10 patients with large deletions of chromosome 12p12 that involved all or part of the SOX5 gene and additional genes. Patients with larger deletions tended to have more dysmorphic features and more musculoskeletal anomalies compared to those with smaller deletions. Lamb et al. (2012) suggested that haploinsufficiency for the SOX5 may contribute to neurodevelopmental delay.

Schanze et al. (2013) reported 2 unrelated children (patients 1 and 3) with global developmental delay associated with heterozygous deletions of chromosome 12p21 including the SOX5 gene: the deletion in 1 patient encompassed 4 genes, whereas the deletion in the other patient encompassed 23 genes. The deletion was confirmed to be de novo in 1 of the patients. The patient with the shorter deletion had mild dysmorphic features, including downslanting palpebral fissures, epicanthal folds, strabismus, broad nasal bridge with upturned and bulbous tip, and open mouth.

Molecular Genetics

By use of oligonucleotide-based array comparative genomic hybridization (array CGH) to test 24,081 probands referred for developmental delay or intellectual disability, Lamb et al. (2012) identified 9 unrelated patients with variable deletions of chromosome 12p12 that involved only the SOX5 gene, including 1 patient with a translocation. The deletions ranged in size from 72 to 466 kb (see, e.g., 604975.0001 and 604975.0002). Depending on the size and location, the deletions were predicted to impact the different SOX5 protein isoforms to varying degrees. In 1 case, the deletion was inherited from an affected mother and was present in an affected sister. Two additional patients had deletions involving noncoding regions of the SOX5 gene; 1 of these patients had a milder phenotype and inherited the deletion from an unaffected father and paternal grandmother. In comparison, Lamb et al. (2012) identified 4 exonic deletions and 58 smaller intronic deletions in the SOX5 gene among the 8,329 controls in the dataset of Cooper et al. (2011). Lamb et al. (2012) suggested that haploinsufficiency for the SOX5 gene may contribute to neurodevelopmental delay.

In a boy with LAMSHF, Schanze et al. (2013) identified a de novo heterozygous intragenic deletion in the SOX5 gene (604975.0003). The deletion was found by array CGH. The results were confirmed by FISH. Functional studies and studies on patient cells were not performed.

In a boy with LAMSHF, Lee et al. (2013) identified a de novo heterozygous intragenic deletion in the SOX5 gene (604975.0004). The deletion was found by array CGH. The results were confirmed by FISH. Functional studies and studies on patient cells were not performed.

In a 17-year-old girl with LAMSHF, Nesbitt et al. (2015) identified a de novo heterozygous nonsense mutation in the SOX5 gene (G341X; 604975.0005). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies on patient cells were not performed, but the molecular findings were consistent with SOX5 haploinsufficiency.