Jiaci

Practitioner's Corner

J Investig Allergol Clin Immunol 2019; Vol. 29(5): 378-398

derivative skin test was negative. There were no mutations

in the

MEFV, PSTPIP2

, or

IL1RN

genes. Autoantibody titers

(antinuclear antibody, antineutrophil cytoplasmic antibody,

rheumatoid factor) were negative. Echocardiography showed

minimal tricuspid valve regurgitation. Dermatitis herpetiformis

was ruled out by normal small bowel histopathology and

negative antigliadin and antiendomysial antibody titers. The

patient was treated with intravenous antibiotics and discharged

with trimethoprim/sulfamethoxazole prophylaxis.

IgA levels increased and IgG levels decreased over

time (IgG, 598 mg/dL) (Supplementary Material, Table 1).

Findings for lymphocyte proliferation were normal, as were

those for class-switched memory B cells. The patient’s coarse

facial appearance (large ears, broad flat nose, and prominent

forehead) and diffuse xerosis became increasingly evident

(Supplementary Material, Figure 1). At age 4 years, he began

to receive intravenous immunoglobulin therapy to control

recurrent skin and oral lesions following upper respiratory

tract infections. He benefited from regular intravenous

immunoglobulin, although he had severe episodes of oral

mucositis requiring hospitalization twice per year. He also had

peg teeth; his primary teeth had emerged quickly, with rapid

development of caries and short root anomaly (Supplementary

Material, Figure 1).

At age 6 years, a homozygous mutation in the

TTC37

gene (c.2210T>C,p.Val737Ala) was detected by TNGS

with a comprehensive Ion AmpliSeq PID Panel designed for

sequencing 264 PID genes (SupplementaryMaterial, Figure 2).

TTC37

mutations cause THES, which is characterized by

early-onset diarrhea. After the genetic diagnosis, the patient

was reevaluated for THES; liver values were normal, and

trichorrhexis nodosa was detected in the hair shafts (Figure).

He had mild intermittent diarrhea lasting 2-3 days following

infections. Colonoscopy findings were normal. The parents

were heterozygous for the same mutation.

THES is caused by loss-of-function mutations in the

tetratricopeptide repeat domain–containing protein 37 gene

(

TTC37

) and superkiller viralicidic activity 2 gene (

SKIV2L

)

[3,4]. The condition is characterized by intractable diarrhea,

facial dysmorphism, hair abnormality, intrauterine growth

retardation, immunodeficiency, skin abnormalities, liver

disease, and platelet abnormalities (Supplementary Material,

Table 2) [3-6].

The present case clearly shows that THES can cause

immunodeficiency and pyoderma gangrenosum–like skin

lesions without significant diarrhea. This patient had typical

facial features of THES, wooly and coarse hair, trichorrhexis

nodosa, and hypogammaglobulinemia. He did not have

chronic/intractable diarrhea or liver disease. His height

and weight percentiles were 50%, with normal intelligence

at 7 years of age (Supplementary Material, Figure 3). He also

had peg teeth and short root anomaly. Peg teeth were reported

in a patient with an

SKIV2L

mutation, although they had not

previously been reported in patients with a

TTC37

mutation [6].

Pyoderma gangrenosum is usually associated with systemic

diseases such as inflammatory bowel disease, rheumatologic

disorder, immunodeficiency, or autoinflammation [7,8]. The

presentation we report on here involved recurrent oral aphthous

lesions and pyoderma gangrenosum–like skin eruptions.

Deficiency of IL-1R-antagonist (DIRA) and IL-36R (DITRA)

and PAPA (pyogenic arthritis, pyoderma gangrenosum, acne)

are autoinflammatory disorders with cutaneous pustular

lesions [7,8]. No mutations were found in the

MEFV, PSTPIP2

IL1RN

genes. Half of all children with THES have cutaneous

abnormalities such as cafe-au-lait spots, xerosis, and rubbery

skin. To our knowledge, there are no previously described cases

of THES presenting with pyoderma gangrenosum.

Approximately90%ofTHEScases have immunodeficiency,

which takes the form of hypogammaglobulinemia, defective

specific antibody production, reduced memory B cell counts,

and abnormal T lymphocyte proliferation [6,9,10]. In the

present case, the patient had selective IgA deficiency at

admission, although he had decreasing IgG levels. IgA levels

returned to normal over time.

The spectrum of THES is widened by pyoderma-like

scarring skin lesions and dental abnormalities, in addition to

classic findings such as immunodeficiency and trichorrhexis

nodosa. To date, mutations have been described in more

than 300 different genes causing primary immunodeficiency

disorders. Diagnosis can be costly and time-consuming

because of the genetic and phenotypic heterogeneity of these

disorders. TNGS enables rapid genetic testing across a large

number of diseases in clinical practice and facilitates the

diagnosis of atypical PID presentations. The power of reverse

phenotyping needs to be emphasized in cases involving

uncertain features or when findings become obvious with age.

Funding

The authors declare that no funding was received for the

present study.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

1. Picard C, Bobby Gaspar H,Al-HerzW, Bousfiha A, Casanova JL,

Chatila T, et al. International Union of Immunological Societies:

Figure.

Pyoderma gangrenosum–like skin lesions.

397