Eur J Pediatr DOI 10.1007/s00431-015-2560-2 SHORT COMMUNICATION Three cases with L1 syndrome and two novel mutations in the L1CAM gene Rosario Marín1 & Miriam Ley-Martos3 & Gema Gutiérrez4 & Felicidad Rodríguez-Sánchez5 & Diego Arroyo6 & Francisco Mora-López2 Received: 28 October 2014 /Revised: 24 April 2015 /Accepted: 27 April 2015 # Springer-Verlag Berlin Heidelberg 2015 Abstract Mutations in the L1CAM gene have been identified are currently considered different phenotypes of a single entity in the following various X-linked neurological disorders: con- known as L1 syndrome. We present three families with L1 genital hydrocephalus; mental retardation, aphasia, shuffling syndrome. Sequencing of the L1CAM gene allowed the iden- gait, and adducted thumbs (MASA) syndrome; spastic para- tification of the following mutations involved: a known splic- plegia; and agenesis of the corpus callosum. These conditions ing mutation (c.3531-12G>A) and two novel ones: a missense mutation (c.1754A>C; p.Asp585Ala) and a nonsense muta- tion (c.3478C>T; p.Gln1160Stop). The number of affected Communicated by Beat Steinmann males and carrier females identified in a relatively small pop- Revisions received: 14 March 2015/23 March 2015/21 April 2015/24 ulation suggests that L1 syndrome may be under-diagnosed. April 2015 Conclusion: L1 syndrome should be considered in the dif- ferential diagnosis of intellectual disability or mental retarda- * Francisco Mora-López tion in children, especially when other signs such as hydro- [email protected] cephalus or adducted thumbs are present. Rosario Marín [email protected] What is Known: Miriam Ley-Martos • Mutations in L1CAM have been identified in various X-linked recessive [email protected] neurological disorders. Gema Gutiérrez • L1CAM mutations are a cause of intellectual disability in children. [email protected] What is New: • Felicidad Rodríguez-Sánchez L1 syndrome should be considered in the differential diagnosis of [email protected] intellectual disability in children. • We describe three families with L1 syndrome, and we report two Diego Arroyo previously undescribed L1CAM mutations. [email protected] 1 Clinical Genetics Unit, Hospital Universitario Puerta del Mar, Keywords L1 syndrome . L1CAM . X-linked mental Cádiz, Spain retardation . Adducted thumbs . X-linked hydrocephalus 2 Molecular Diagnosis Laboratory, Immunology Department, Hospital Universitario Puerta del Mar, Cádiz, Spain 3 Department of Paediatrics, Hospital Universitario Puerta del Mar, Cádiz, Spain Abbreviations 4 Department of Paediatrics, Hospital Universitario de Jerez, L1CAM L1 cell adhesion molecule Jerez, Spain MRI Magnetic resonance imaging 5 Division of Genetics, Human Anatomy Department, Universidad de MASA syndrome Mental retardation, aphasia, Cádiz, Cádiz, Spain shuffling gait, and adducted 6 Progenie molecular S. L. Laboratory, Valencia, Spain thumbs syndrome Eur J Pediatr Introduction The sequence of L1CAM gene showed an A>C substitution at the nucleotide 1754 (c.1754 A>C) involving the replace- Mutations in the gene encoding the L1 cell adhesion molecule ment of an aspartic acid in position 585 by an alanine in the (L1CAM) cause a wide phenotypic spectrum syndrome asso- extracellular domain of the protein (p.Asp585Ala). The muta- ciated with hydrocephalus, developmental delay, and brain tion was inherited from the mother. This missense variant has malformation [7]. The syndrome is a manifestation of an X- not been previously reported. linked recessive disorder. The term L1 syndrome includes hydrocephalus due to congenital stenosis of the aqueduct of Case 3 Sylvius (OMIM #307000), mental retardation, aphasia, shuf- fling gait, and adducted thumbs (MASA) syndrome (OMIM A 2-year-old boy with psychomotor developmental delay was #303350), X-linked complicated hereditary spastic paraplegia referred to our department. He was the only child of healthy, type 1 (OMIM #303350), and X-linked agenesis of the corpus non-consanguineous parents. He had no relatives with a he- callosum (OMIM #304100). L1CAM plays an important role reditary disease or mental retardation. He showed bilateral in the development of the central nervous system where it is adducted thumbs. Brain MRI revealed corpus callosum agen- involved in neuronal migration and differentiation as well as esis. At 4 years of age, he presented spastic paraplegia. in complex cognitive and memory processes. LICAM gene sequence analysis detected a C>T base substitu- tion (c.3478 C>T). This change produces the replacement of glutamine at codon 1160 with a stop signal (p.Gln1160Stop) Case reports yielding a truncated protein, which loses the 97 carboxyl- terminal amino acids. To our knowledge, this variant has not Case 1 been previously reported. Since the mother is not a carrier of this variant as judged by a DNA analysis of peripheral leuko- A 5-year-old boy was referred to the medical genetics depart- cytes, it is probably arisen de novo. ment. He was the first child of a healthy and non- consanguineous couple. He presented developmental delay, bilaterally flexed adducted thumbs, and bilateral clinodactyly Molecular analysis of the fifth finger (Fig. 1a). He did not present dysmorphic facial features. Prenatal ultrasound findings in the third trimes- Genomic DNA was extracted from peripheral leukocytes ac- ter had revealed congenital hydrocephalus. At birth, a cording to standard protocols from patients and their relatives. transfontanellar ultrasound examination had shown enlarged Analysis of the L1CAM gene was performed by Sanger se- lateral ventricles and corpus callosum agenesis. Nuclear mag- quencing of all coding exons. In order to exclude the possi- netic resonance on the sixth day of life confirmed these find- bility that the new variants detected were rare polymorphisms, ings (Fig. 1b). A family history suggested X-linked recessive we tested for their presence in 100 healthy subjects. mental retardation (Fig. 1c). One maternal granduncle had mental retardation and adducted thumbs without other signs of the disease. Another affected member of the family died Discussion without a clinical or genetic diagnosis. Nowadays, at 12 years old, our patient shows adducted thumbs, mild mental retarda- L1 syndrome shows an extremely variable presentation within tion, microcephaly, and behavioral alterations. Direct se- and between families. The most consistent clinical signs in L1 quencing of the L1CAM gene detected a single-base substitu- syndrome are variable degrees of mental retardation, hydro- tion located 12 base pairs upstream of the exon 27 (c.3531- cephalus with varying degrees of severity, spasticity of lower 12G>A). The mutation was also detected in the mother and in limbs, and flexion deformity of the thumbs. In the central the maternal granduncle. nervous system, the most frequent pathological findings are the complete or partial absence of the corpus callosum and the Case 2 bilateral absence of the pyramidal tracts. Hypoplasia of the corpus callosum may contribute to mental retardation, where- A healthy, non-consanguineous couple was referred for genet- as the absence of the pyramidal tracts explains the spasticity ic counseling because of a family history of mental retardation observed in the patients. We report three cases of the disease. (Fig. 1d). Although the male partner did not display any of the Sequencing of the L1CAM gene in the three index cases clinical findings associated with L1 syndrome, he has two allowed us to identify three mutations, two of which had never brothers with intellectual disability. He also has three healthy been reported before. sisters; all have male sons with clinical signs of L1 syndrome: Patient 1 carried a splicing mutation (c.3531-12G>A). This hydrocephalus, developmental delay, and adducted thumbs. mutation has been previously described and affects the Eur J Pediatr Fig. 1 a Case 1: hands showing adducted thumbs. b Case 1: brain MRI, coronal view showing the left (L) lateral ventricle larger than the right (R) lateral ventricle. c, d Pedigrees of cases 1 and 2, respectively. Persons molecularly examined are indicated by an asterisk cytoplasmic domain of the protein, a well-conserved region in frameshift mutations that produce a premature stop codon L1-like proteins. It contains an amino acid sequence with a leading to truncation in extracellular domains or abolishing high affinity for ankyrin, a molecule that acts as a linker be- expression of the protein produce the most severe form of tween L1-like proteins and the cellular cytoskeleton [5]. The the syndrome, usually with severe congenital hydrocephalus mutation would produce a truncated cytoplasmic domain and early mortality. Missense mutations affecting the extracel- lacking this ankyrin-binding motif. It has been previously de- lular domain and mutations affecting only the cytoplasmic scribed in a patient diagnosed with MASA syndrome [6]and domain tend to cause milder phenotypes, usually found in has also been found in another family with nine males show- patients described as having MASA syndrome. In this study, ing mental retardation and adducted thumbs [4]. Our patient two of the mutations detected truncate only the cytoplasmic showed similar clinical features and severity. domain of the protein and the third one was a missense muta- A first novel missense mutation (c.1754 A>C; tion located in the extracellular domain. In the three reported p.Asp585Ala) was identified in affected males and female cases, we observed