Table 2.

Immunological abnormalities in ribosomopathy syndromes.

Syndrome	Ribosomal gene and chromosomal location (% patients with mutation)	Clinical and laboratory features	Immunological abnormalities
Diamond–Blackfan anaemia (DBA) OMIM: #105650	RPS 19 19q13·2 (25%) [10]RPS 24 10q22-q23 (2%) [11]RPS 17 15q[12]RPL35A 3q29-qter [22] (3%) RPL 5 and 11 (11%) [23]RPS10 and 26[24]	Pallor, growth retardation, congenital anomalies of the head, neck, upper limbs and urogenital system (40%), macrocytic anaemia, raised HbF, EPO and eADA levels, leukaemia [25]RPL5 and RPL11 associated with craniofacial (cleft palate) and abnormal thumbs, respectively [23]Parvovirus B19 seropositivity reaches 50% by age 15 years [26]	Transient low T cells (in three patients), reduced T cell responses to hrIL-2; low B cell number with normal sIg+, absent ConA-induced CD8+ T cell production [7], CVID with reduced T cell mitogen responses (index case)
Shwachman–Diamond syndrome (SDS) OMIM: #260400	SBDS 7q11·21 (90%) ?EFL1[8,27,28]SBDS mutations affect development of 60S subunit	Recurrent infections (85%), pancreatic exocrine insufficiency, metaphyseal chondrodysplasia, short stature, malabsorption, increased risk of malignancy (AML, MDS), neutropenia (95%), thrombocytopenia, aplastic anaemia	Neutrophil chemotaxis defect, defect in B and T cell function and survival, low immunoglobulins, low B cells [10,21], low specific antibodies [10,21], increased apoptosis of CD34+ marrow cells [29–31]; CVID [10]
Dyskeratosis congenita •X-linked (OMIM: #305000)•Autosomal dominant •Autosomal recessive	DKC1 at Chr. Xq28 encodes dyskerin TERC (Chr. 3q26); TERT (5p15·53); TINF2 (14q12) NOP10 (NOLA3) Chr. 15q14–15 60% lack an identifiable mutation [32–35]Mutations affect rRNA pseudo-uridylation	Reticulated skin pigmentation, nail dystrophy, mucosal leukoplakia, cerebellar hypoplasia (Hoyeraal–Hreidarsson syndrome), serious infections, osteoporosis, liver and lung fibrosis, aplastic anaemia, early ageing due to reduced telomere length, tumour susceptibility [25]	Low IgM, severe B lymphopenia (X-linked DC); T + B − NK − SCID with DKC1 mutation reported in Hoyeraal–Hreidarsson syndrome [36]
Cartilage hair hypoplasia (CHH) OMIM: #250250	RNase mitochondrial RNA processing (RMRP) RNA gene Chr. 9p21–p12 70A > G (founder mutation, 92% Finnish and 48% non-Finnish) [37]Certain mutations correlate with severe immunogical and haematological abnormalities [38]RMRP mutations affect pre5·8S (part of 60S subunit)	Short stature, hypoplastic hair, metaphyseal chondrodysplasia (±cone-shaped epiphysis), some excess risk of malignancy (lymphoma, liver, duodenal, skin), anaemia (6% dependent on blood transfusions), neutropenia, lymphopenia, infections 56% (Pneumocystis, CMV) [39–41]	Hypogammaglobulinaemia, low IgA and IgG subclass [39], decreased T cell count and proliferation (low CD4+ with increased apoptosis) and CD8 lymphopenia [40,42–44], low B cells [44], defective B cell and fibroblast proliferation [44], severe combined immunodeficiency (Omenn syndrome) [43,45]
Treacher–Collins syndrome OMIM: #154500	Treacle gene TCOF1 5q32–q33·1 (93%) TCOF1 mutations cause 18S rRNA methylation defect that leads to insufficient nucleolar phosphoprotein treacle, and defects in craniofacial development [46]18S is part of 40S ribosomal subunit	Anti-mongoloid slant of eyes, cataracts, coloboma of lid/uveal tract, micrognathia, ear deformities, hypoplastic zygomatic arches, macrostomia, conductive hearing loss, cleft palate, craniosynostosis, anaemia [47]	T cell abnormalities, impaired mitogen responses, decreased B cells with low immunoglobulins (in some craniofacial syndromes) [6]
Turner's syndrome	Human sex-linked genes RPS4X and RPS4Y encode 2 isoforms of ribosomal protein S4; RPS4 is a component of 40S subunit; haploinsufficiency of RPS4X hypothesized to lead to Turner's syndrome [48,49]	Girls with 45 XO karyotype, ring X chromosome with mental retardation and kyphoscoliosis, short stature, webbed neck, gonadal failure, cardiovascular and renal malformations, hearing loss, diabetes	CVID [50,51], hypogammaglobulinaemia, T cell immunodeficiency, selective IgA deficiency, coeliac disease [50–56]

AML: acute myeloid leukaemia; CMV: cytomegalovirus; ConA: concanavalin A; CVID: common variable immunodeficiency disorder; eADA: erythrocyte adenosine deaminase; EPO: erythropoietin; HbF: fetal haemoglobin; hrIL: human recombinant interleukin; Ig: immunoglobulin; MDS: myelodysplastic syndrome; NK: natural killer; rIL: recombinant interleukin; SCID: severe combined immunodeficiency.