A number sign (#) is used with this entry because of evidence that thrombocytopenia-8 with dysmorphic features and developmental delay (THC8) is caused by heterozygous mutation in the ACTB gene (102630) on chromosome 7p22.

Thrombocytopenia-8 with dysmorphic features and developmental delay (THC8) is an autosomal dominant syndromic disorder characterized by early-childhood onset of chronic thrombocytopenia with anisotropy and immature enlarged platelets, usually without spontaneous bleeding episodes. Affected individuals have dysmorphic facial features and variable developmental delay with speech delay and mildly impaired intellectual development (Latham et al., 2018).

For a discussion of genetic heterogeneity of thrombocytopenia, see 313900.

Nunoi et al. (1999) reported a 15-year-old Japanese girl with recurrent infections since early childhood, thrombocytopenia since age 8 years, developmental delay with impaired intellectual development (IQ of 54), short stature, polyarthralgia with positive rheumatoid factor, and skin photosensitivity. Laboratory studies showed leukopenia, hyper-IgE, and increased C-reactive protein (CRP; 123260). Bone marrow studies showed increased numbers of megakaryocytes. The patient developed cardiomegaly, hepatosplenomegaly, and hypothyroidism; she died of sepsis at age 15. Patient neutrophils demonstrated decreased chemotactic responses and impaired superoxide generation. There was no mention of dysmorphic features in the report.

Latham et al. (2018) reported 6 patients from 4 unrelated families with a syndromic form of thrombocytopenia. The 4 probands were children, ranging from 4 to 5.5 years of age, who presented in early childhood with thrombocytopenia without episodes of spontaneous bleeding. Two of the probands had mildly affected parents. There was platelet anisotropy with enlarged immature platelets in the peripheral blood. Bone marrow examination (P5) showed increased megakaryocytes. Two patients (P1 and P5) had leukocytosis with increased eosinophil count. Of note, thrombocytopenia resolved spontaneously in P6, who was 5 years old. All affected individuals (except for the father in family A, P2), had mild developmental delay with speech delay and impaired intellectual development. Common dysmorphic facial features included microcephaly, flared and straight eyebrows, synophrys, telecanthus, epicanthal folds, deep-set eyes, upslanting palpebral fissures, broad nasal bridge and tip, high palate, and thin upper vermilion border. Brain imaging in 1 patient (P6) showed 2 periventricular nodular heterotopias. The father and son in family A had mild congenital heart defects.

Sandestig et al. (2018) reported a 4-year-old Swedish girl with thrombocytopenia from birth, ventricular arrhythmia, cleft palate, and developmental delay. Brain imaging showed mild gray matter heterotopia and periventricular leukodystrophy. Dysmorphic features included metopic ridge, deep-set eyes, telecanthus, midface hypoplasia, broad nose, small jaw, and posteriorly rotated dysplastic ears. She also had astigmatism and hyperopia, but no coloboma.

Fouassier et al. (2023) reported a 13-year-old girl with a history of intrauterine growth retardation and failure to thrive who showed microcephaly (-3 SD), mild developmental delay, and thrombocytopenia. Although she had frequent ecchymoses, she had several minor surgeries without hemorrhagic complications. Platelets were enlarged, immature, and contained abnormal granules, suggesting disorganization of cytoskeleton fibers. Genetic analysis identified a heterozygous mutation in exon 5 of the ACTB gene.

The transmission pattern of THC8 in 2 families reported by Latham et al. (2018) was consistent with autosomal dominant inheritance. Two patients with THC8 carried heterozygous de novo mutations in the ACTB gene.

In 6 patients from 4 unrelated families with THC8, Latham et al. (2018) identified heterozygous mutations affecting exons 5 and 6 of the ACTB gene (see, e.g,. 102630.0018-102630.0020). The mutations were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Two mutations were inherited from mildly affected parents and 2 occurred de novo. There was 1 missense variant in exon 5 (M313R), 1 in-frame deletion in exon 6, 1 frameshift in exon 6, and 1 frameshift with protein extension in exon 6. The mutations in exon 6 affected the conserved SD1 domain, which is important for interactions with actin-binding proteins (ABPs). Studies of fibroblasts and platelets derived from affected members of 2 families showed decreased ACTB levels compared to controls. Patient-derived fibroblasts were small and demonstrated impaired migration speed, trajectories, and displacement area compared to controls. There was compensatory upregulation of ACTG1 (102560) and ACTA2 (102620) expression, and ACTB filaments bundled into abnormally thick fibers that incorporated ACTA2. Patient fibroblasts also showed increased recruitment of ABPs associated with macrothrombocytopenia phenotypes (see, e.g. ACTN1, 102575). Patient-derived platelets, which were frequently enlarged, showed abnormal microtubule organization patterns at the platelet cortex. Abnormal microtubule organization patterns were also observed in patient megakaryocytes. The findings suggested that the ACTB mutations inhibit the final stages of platelet maturation by perturbing membrane-associated cytoskeletal filaments.

Latham et al. (2018) referred to the report of Nunoi et al. (1999), who described a 15-year-old Japanese girl with THC8 associated with a heterozygous missense mutation in exon 6 of the ACTB gene (E364K; 102630.0017). Studies of patient B cells showed that although the mutant actin was able to polymerize and depolymerize normally, it had decreased binding efficiency to profilin (see PFN1, 176610). The authors postulated a dominant-negative effect. Although dysmorphic features were not noted in the original report of this child, Latham et al. (2018) stated that the phenotype in this patient was consistent with the disorder described by them.

In a 4-year-old Swedish girl with THC8, Sandestig et al. (2018) identified a de novo heterozygous missense mutation in the ACTB gene (L171F; 102630.0021). The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that the mutation affects a domain involved in interactions with actin-binding proteins.