Immunodeficiency 35

A number sign (#) is used with this entry because of evidence that immunodeficiency-35 (IMD35) is caused by homozygous mutation in the TYK2 gene (176941) on chromosome 19p13.

Description

Immunodeficiency-35 is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to localized or disseminated mycobacterial infection after BCG vaccination. Some patients may have increased susceptibility to infection with other intracellular organisms and/or viral infections. Fungal infections are not observed. Laboratory studies show normal levels of immune cells but defective signaling in specific immunologic pathways (summary by Kreins et al., 2015).

Clinical Features

Minegishi et al. (2006) described a 22-year-old Japanese male clinically diagnosed with autosomal recessive hyper-IgE syndrome (HIES) (see 243700), a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE. The patient had a history of susceptibility to various microorganisms, including virus, fungi, and mycobacteria. He had an episode of Bacille Calmette-Guerin (BCG) infection at age 22 months and non-typhi salmonella gastroenteritis at age 15 years. The patient had normal numbers of natural killer, B, and T cells, but the patient's cells showed defects in multiple cytokine signaling pathways. The patient's parents were consanguineous, suggesting a recessive hereditary disorder.

Woellner et al. (2007) noted that the patient with TYK2 deficiency reported by Minegishi et al. (2006) had clinical features atypical for autosomal recessive HIES, including BCG lymphadenitis and non-typhi salmonella infection. They suggested that TYK2 deficiency is clinically distinct from autosomal recessive HIES. In a response, Minegishi et al. (2007) proposed that TYK2 deficiency be categorized as a disease entity with characteristic features of both autosomal recessive HIES and susceptibility to mycobacterial disease (see 209950).

Kilic et al. (2012) reported a Turkish boy, born of consanguineous parents, who presented in infancy with disseminated BCG infection. Laboratory studies showed mildly increased serum IgE. He developed neurobrucellosis causing permanent neurologic sequelae at age 8 years, followed by herpes zoster at age 11 years. He did not have atopy, asthma, or fungal skin infections. Kilic et al. (2012) noted that the phenotype in this patient overlapped with but was slightly different from that in the patient reported by Minegishi et al. (2006).

Kreins et al. (2015) reported 6 patients from 4 unrelated families with IMD35. The patients were of various origins, including Morocco, Iran, and Argentina. All received BCG vaccination, and all but one had variable systemic responses to vaccination. One patient presented with disseminated extrapulmonary tuberculosis at age 13 years after being vaccinated at birth, whereas others showed localized BCG lymphadenopathy soon after vaccination in infancy. One patient never showed adverse response to BCG vaccination, but had disseminated cutaneous herpetic lesions associated with aseptic herpes meningitis. Another patient had recurrent otitis and urinary tract infections, as well as asthma and eczema, but was alive at age 15 years. None of the patients had documented pyogenic infections, including staphylococcal infections, or fungal infections, including mucocutaneous candidiasis. Laboratory studies showed normal levels of T lymphocytes, but detailed immunologic workup showed impaired, but not abolished, responses to IL12 (see 161560) and alpha/beta-interferon (IFNA1, 147660 and IFNB1, 147640), accounting for mycobacterial and viral infections, respectively, as well as impaired gamma-interferon (IFNG; 147570) response to IL12 stimulation, which also may have accounted for susceptibility to intracellular bacteria. There was also impaired response to IL23 (see 605580) with normal levels of circulating IL17+ T cells, which may have accounted for the lack of mucocutaneous candidiasis, and impaired response to IL10 (124092), with no apparent clinical consequences. Serum IgE levels were determined on multiple occasions, but were never elevated in these 6 patients and in the patient reported by Kilic et al. (2012). These 7 patients all had normal responses to IL6 (147620); only the patient with HIES reported by Minegishi et al. (2006) had impaired IL6 response, which was independent of TYK2, suggesting that the patient may have had a different molecular defect responsible for the HIES. Kreins et al. (2015) concluded that impaired IL6 responses and HIES are not intrinsic features of TYK2 deficiency.

Inheritance

The transmission pattern of IMD35 in the families reported by Minegishi et al. (2006) and Kilic et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In their patient with autosomal recessive hyper-IgE syndrome and atypical mycobacteriosis, Minegishi et al. (2006) identified a homozygous deletion of GCTT at nucleotide 550 in the TYK2 gene (176941.0001), resulting in a frameshift and premature termination of the protein at amino acid 90. Immunoblot analysis detected no TYK2 protein in the patient's T cells. Both of the patient's parents, who were healthy, were heterozygous for the TYK2 mutation. Introduction of wildtype TYK2 into the patient's T cells rescued the cytokine signaling defects.

Because the patient reported by Minegishi et al. (2006) had some features of autosomal recessive HIES, Woellner et al. (2007) analyzed the TYK2 gene in 15 families with autosomal recessive HIES. Affected individuals in 5 families were homozygous for a marker within 1 Mb of the TYK2 gene. Four of these 5 families had at least 1 unaffected child, and in 3 of these 4 the genotype data were consistent with linkage to TYK2. However, Woellner et al. (2007) failed to identify mutations in the coding regions of exons and the adjacent intronic sequences of TYK2 in patients from these 5 families. They concluded that TYK2 deficiency is genetically distinct from autosomal recessive HIES. In a response, Minegishi et al. (2007) noted that analysis of coding regions of exons and the adjacent intronic sequences is not sufficient to identify all genetic alterations. They suggested that further analysis is needed to exclude TYK2 deficiency as the cause of autosomal recessive HIES in these patients.

In a Turkish male, born of consanguineous parents, with IMD35, Kilic et al. (2012) identified a homozygous truncating mutation in the TYK2 gene (176941.0002), resulting in complete loss of function. Kilic et al. (2012) suggested that lack of TYK2 resulted in defective IL12 (see 161560) signaling and impaired production of gamma-interferon (IFNG; 147570).

In 6 patients from 4 unrelated families with IMD35, Kreins et al. (2015) identified 4 different homozygous truncating mutations in the TYK2 gene (176941.0003-176941.0006). The mutations, which were found by whole-exome sequencing or targeted next-generation sequencing, segregated with the disorder in the families. Western blot analysis of patient cells showed no detectable TYK2 protein, consistent with a complete loss of function. Detailed studies of patient cells showed impairment of several TYK2-related immunologic signaling pathways.