Immunoskeletal Dysplasia With Neurodevelopmental Abnormalities

A number sign (#) is used with this entry because of evidence that immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA) is caused by homozygous mutation in the EXTL3 gene (605744) on chromosome 8p21.

Clinical Features

Oud et al. (2017) reported 9 patients from 5 unrelated families who exhibited skeletal dysplasia and neurodevelopmental delay; in addition, patients from 3 of the families showed severe T-cell immunodeficiency. Seven patients from 4 families showed severe platyspondyly resulting in disproportionate short stature with progressive kyphosis. Other skeletal features included cervical malformations and hypoplastic odontoid peg with cervical instability, short stature due to limb shortening, and brachydactyly. Epiphyseal abnormalities of the long bones were observed in 3 families, and metaphyseal abnormalities were seen in 2 families. Intellectual disabilities ranged from mild learning difficulties to an inability to sit, crawl, walk, speak, or interact socially. Motor development also appeared to be seriously affected by the neuroskeletal features in most of the affected individuals. Severe combined immunodeficiency (SCID) with complete absence of T cells was observed in 5 patients from 3 of the families, and 1 patient from another family exhibited intermittent lymphopenia. Immunologic analysis confirmed the variable presence of a severe T-cell defect, and showed normal development of other hematopoietic cell lineages. Three patients died in the first year of life, including a Turkish girl (family A) at age 7 weeks and 2 Indian brothers (family E), at ages 6 months and 10 months; another patient (family D) died at age 30 years of unknown cause.

Volpi et al. (2017) studied a Tunisian brother and sister and an unrelated Hispanic girl who all presented at birth with short-limb skeletal dysplasia and severe T-cell immunodeficiency. Skeletal radiography in all 3 patients revealed similar abnormalities at birth, consisting of generalized platyspondyly with increased intervertebral spaces, narrowing of the greater sciatic notches with trident-shaped acetabula, and short and plump limb bones, metacarpals, and phalanges. Skull imaging showed premature craniosynostosis in the 2 sibs, with cloverleaf deformity in the sister. All 3 patients had narrowing of the cervical canal, and severe narrowing of the laryngotracheal tract was present in the sibs. Neurologic abnormalities included developmental delay in all 3 patients. The Tunisian brother also exhibited opisthotonus, hyperreflexia, and generalized seizures; his sister had clonic arm movements and nystagmus and the Hispanic girl had muscular hypotonia. Immunologic studies showed a T-, B+, NK+ SCID phenotype in both girls within the first month of life, whereas the presence of autologous, activated, and oligoclonal T cells, associated with generalized exfoliative dermatitis suggestive of Omenn syndrome (603554), was documented in the boy. All 3 patients showed eosinophilia and impaired proliferation to mitogens. The sibs had hypogammaglobulinemia with increased IgE serum levels. They died at age 11 months and 7 months, after recurrent infections. The Hispanic girl, who was alive at 2.5 years of age, showed partial recovery of T-cell count and function and had mounted antibody responses to killed and live vaccines.

Molecular Genetics

In 9 affected individuals from 5 families with immunoskeletal dysplasia and neurodevelopmental abnormalities, Oud et al. (2017) performed whole-exome sequencing and identified homozygosity for 4 different missense mutations in the EXTL3 gene, including a P461L substitution (605744.0001) in a Colombian girl (family C) and 3 affected Portuguese patients (family D), and an N657S substitution (605744.0002) in 2 brothers of Indian origin (family E). The mutations segregated fully with disease in each of the families, and were either not found in the ExAC database or were present in heterozygosity at low minor allele frequencies.

In 2 Tunisian sibs and a Hispanic girl with ISDNA, who were negative for mutation in the FGFR1 (136350), FGFR2 (176943), and FGFR3 (134934) genes, Volpi et al. (2017) performed exome sequencing and identified homozygosity for missense mutations in the EXTL3 gene in affected individuals from both families: the previously reported P461L substitution in the Hispanic girl, and an R339W substitution (605744.0003) in the Tunisian sibs. Functional analysis suggested that by altering heparan sulfate (HS) chain length and composition, EXTL3 mutations potentiate FGF2 (134920) signaling, thereby contributing to the pathophysiology of the skeletal dysplasia observed in the patients. In addition, defects in signaling responses to cytokines were observed in patient peripheral blood mononuclear cells.