Expanding the spectrum of skeletal dysplasia with immunodeficiency: a commentary on identification of biallelic EXTL3 mutations in a novel type of spondylo-epi-metaphyseal dysplasia

The association of skeletal dysplasia with immunodeficiency has been recognized as a distinctive feature of Schimke immune-osseous dysplasia (MIM: 242900), cartilage hair hypoplasia (MIM: 250250) and phosphoglucomutase 3 deficiency (MIM: 172100).¹ In this issue, Guo et al.² report on a novel form of autosomal recessive skeletal dysplasia with immunodeficiency, due to mutations of the exosostin-like 3 (EXTL3) gene (MIM: 605744). This report follows shortly similar publications by two other groups.^{3, 4} Altogether, these studies unequivocally identify EXTL3 deficiency as a novel form of epispondylometaphyseal dysplasia with immunodeficiency and severe neuromotor development delay.

Description of the clinical, imaging and laboratory data among the 14 patients reported in these studies (Table 1) permits to define the phenotypic spectrum of the disease. Severe platyspondyly, brachydactyly and kyphoscoliosis were cardinal features.^{2, 3, 4} Narrowing of the craniocervical canal resulting in spinal cord compression and requiring neurosurgery early in life was observed in several infants. The vast majority of the patients presented facial dysmorphisms, with coarse features, upslanting palpebral fissures, frontal bossing, prominent nose and broad nasal tip.^{2, 3, 4} Truncal hypotonia and severe motor development delay were common, and several patients had a history of seizures. Liver and kidney cysts have been also frequently reported.^{2, 3, 4} The immunodeficiency of the syndrome is largely restricted to T-cell lymphopenia. Two of the patients had undetectable or very low levels of T-cell receptor excision circles at birth,⁴ indicative of severe combined immune deficiency. Some patients manifested Omenn syndrome (with oligoclonal T cells, erythroderma, eosinophilia and elevated serum IgE);^{3, 4} and eosinophilia and hyper-IgE were observed also in other patients without features of Omenn syndrome,^{3, 4} suggesting that immune dysregulation may be part of the disease phenotype.

Table 1 Clinical and laboratory features of 14 patients with EXTL3 deficiency^{2, 3, 4}

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