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Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies(THC11)

MedGen UID:
1846947
Concept ID:
C5882734
Disease or Syndrome
Synonym: THC11
 
Gene (location): RAP1B (12q15)
 
Monarch Initiative: MONDO:0958000
OMIM®: 620654

Definition

Thrombocytopenia-11 with multiple congenital anomalies and dysmorphic facies (THC11) is a syndromic disorder characterized by dysmorphic facial features, multiple congenital anomalies that may involve the heart, brain, genitourinary, endocrine, and/or skeletal systems, chronic and persistent thrombocytopenia, sometimes with leukopenia or anemia, poor growth with microcephaly, hypotonia, and mildly impaired intellectual development or learning disabilities. The disorder results from constitutive activation of the RAS signaling pathway and can be considered a RASopathy (Niemann et al., 2020; Miller et al., 2022). For a discussion of genetic heterogeneity of thrombocytopenia, see 313900. [from OMIM]

Clinical features

From HPO
Vesicoureteral reflux
MedGen UID:
21852
Concept ID:
C0042580
Disease or Syndrome
Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).
Unilateral renal agenesis
MedGen UID:
75607
Concept ID:
C0266294
Congenital Abnormality
A unilateral form of agenesis of the kidney.
Renal hypoplasia
MedGen UID:
120571
Concept ID:
C0266295
Congenital Abnormality
Hypoplasia of the kidney.
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Bicuspid aortic valve
MedGen UID:
57436
Concept ID:
C0149630
Congenital Abnormality
Aortic valve disease-2 (AOVD2) is characterized by bicuspid aortic valve (BAV) and dilation of the ascending aorta. Calcification of the valve and the aorta has been observed, and some patients exhibit coarctation of the aorta (Tan et al., 2012; Luyckx et al., 2019; Park et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of aortic valve disease, see AOVD1 (109730).
Ventricular hypertrophy
MedGen UID:
87400
Concept ID:
C0340279
Disease or Syndrome
Enlargement of the cardiac ventricular muscle tissue with increase in the width of the wall of the ventricle and loss of elasticity. Ventricular hypertrophy is clinically differentiated into left and right ventricular hypertrophy.
Aortic root aneurysm
MedGen UID:
720712
Concept ID:
C1298820
Anatomical Abnormality
An abnormal localized widening (dilatation) of the aortic root.
Pulmonic stenosis
MedGen UID:
408291
Concept ID:
C1956257
Disease or Syndrome
A narrowing of the right ventricular outflow tract that can occur at the pulmonary valve (valvular stenosis), below the pulmonary valve (infundibular stenosis), or above the pulmonary valve (supravalvar stenosis).
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Anteverted ears
MedGen UID:
384047
Concept ID:
C1857055
Finding
Underdeveloped tragus
MedGen UID:
861866
Concept ID:
C4013429
Anatomical Abnormality
Decreased posterolateral protrusion of the tragus.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Gray matter heterotopia
MedGen UID:
452349
Concept ID:
C0266491
Finding
Heterotopia or neuronal heterotopia are macroscopic clusters of misplaced neurons (gray matter), most often situated along the ventricular walls or within the subcortical white matter.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar vermis hypoplasia
MedGen UID:
333548
Concept ID:
C1840379
Finding
Underdevelopment of the vermis of cerebellum.
Cavum septum pellucidum
MedGen UID:
327087
Concept ID:
C1840380
Finding
If the two laminae of the septum pellucidum are not fused then a fluid-filled space or cavum is present. The cavum septum pellucidum is present at birth but usually obliterates by the age of 3 to 6 months. It is up to 1cm in width and the walls are parallel. It is an enclosed space and is not part of the ventricular system or connected with the subarachnoid space.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Hippocampal malrotation
MedGen UID:
1611479
Concept ID:
C4539733
Congenital Abnormality
Hippocampal malrotation, also termed incomplete inversion of the hippocampus or hippocampal malformation, is an increasingly recognized neuroimaging finding of undetermined clinical significance. It is characterized by features including (i) Round or pyramidal shape instead of ovoid shape; (ii) Medial position of the hippocampus on the hippocampal sulcus; (iii) The collateral sulcus is excessively deep or verticalized; (iv) Fimbria located medial to the hippocampus; (v) Small or displaced fornix; (vi) Enlarged temporal horn and empty choroid fissure; (vii) Thickened subiculum; (viii) Reduced upper horizontal portion of the parahippocampal gyrus.
Thin corpus callosum
MedGen UID:
1785336
Concept ID:
C5441562
Anatomical Abnormality
An abnormally thin corpus callous, due to atrophy, hypoplasia or agenesis. This term is intended to be used in situations where it is not known if thinning of the corpus callosum (for instance, as visualized by magnetic resonance tomography) is due to abnormal development (e.g. a leukodystrophy) or atrophy following normal development (e.g. neurodegeneration).
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
Protrusion of the contents of the abdominal cavity through the inguinal canal.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Retrognathia
MedGen UID:
19766
Concept ID:
C0035353
Congenital Abnormality
An abnormality in which the mandible is mislocalised posteriorly.
Pectus carinatum
MedGen UID:
57643
Concept ID:
C0158731
Finding
A deformity of the chest caused by overgrowth of the ribs and characterized by protrusion of the sternum.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Developmental dysplasia of the hip
MedGen UID:
1640560
Concept ID:
C4551649
Congenital Abnormality
Congenital dysplasia of the hip (CDH) is an abnormality of the seating of the femoral head in the acetabulum. Its severity ranges from mild instability of the femoral head with slight capsular laxity, through moderate lateral displacement of the femoral head, without loss of contact of the head with the acetabulum, up to complete dislocation of the femoral head from the acetabulum. It is one of the most common skeletal congenital anomalies (summary by Sollazzo et al., 2000). Acetabular dysplasia is an idiopathic, localized developmental dysplasia of the hip that is characterized by a shallow hip socket and decreased coverage of the femoral head. Its radiologic criteria include the center-edge angle of Wiberg, the Sharp angle, and the acetabular roof obliquity. Most patients with acetabular dysplasia develop osteoarthritis (165720) after midlife, and even mild acetabular dysplasia can cause hip osteoarthritis (summary by Mabuchi et al., 2006). CDH occurs as an isolated anomaly or with more general disorders represented by several syndromes and with chromosomal abnormalities such as trisomy 18 (Wynne-Davies, 1970). Genetic Heterogeneity of Developmental Dysplasia of the Hip Developmental dysplasia of the hip-1 (DDH1) maps to chromosome 13q22; DDH2 (615612) maps to chromosome 3p21. DDH3 (620690) is caused by mutation in the LRP1 gene (107770) on chromosome 12q13.
Tracheomalacia
MedGen UID:
215296
Concept ID:
C0948187
Disease or Syndrome
Congenital tracheomalacia is a rare condition where the trachea is soft and flexible causing the tracheal wall to collapse when exhaling, coughing or crying, that usually presents in infancy, and that is characterized by stridor and noisy breathing or upper respiratory infections. Tracheomalacia improves by the age of 18-24 months.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
An abnormal decreased number of leukocytes in the blood.
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
Hypoplasia of teeth
MedGen UID:
852449
Concept ID:
C0235357
Congenital Abnormality
Developmental hypoplasia of teeth.
Open mouth
MedGen UID:
116104
Concept ID:
C0240379
Finding
A facial appearance characterized by a permanently or nearly permanently opened mouth.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Short palpebral fissure
MedGen UID:
98067
Concept ID:
C0423112
Finding
Distance between the medial and lateral canthi is more than 2 SD below the mean for age (objective); or, apparently reduced length of the palpebral fissures.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Sparse eyebrow
MedGen UID:
371332
Concept ID:
C1832446
Finding
Decreased density/number of eyebrow hairs.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Preauricular skin tag
MedGen UID:
395989
Concept ID:
C1860816
Finding
A rudimentary tag of skin often containing ear tissue including a core of cartilage and located just anterior to the auricle (outer part of the ear).
Increased nuchal translucency
MedGen UID:
869253
Concept ID:
C4023676
Finding
Nuchal translucency is the sonographic appearance of subcutaneous accumulation of liquid in the back of the fetal neck in the first trimester of pregnancy (11-14 gestational weeks of pregnancy).
Reduced circulating growth hormone concentration
MedGen UID:
82880
Concept ID:
C0271561
Disease or Syndrome
Concentration of growth hormone in the blood circulation below normal limits.
Astigmatism
MedGen UID:
2473
Concept ID:
C0004106
Disease or Syndrome
Astigmatism (from the Greek 'a' meaning absence and 'stigma' meaning point) is a condition in which the parallel rays of light entering the eye through the refractive media are not focused on a single point. Both corneal and noncorneal factors contribute to refractive astigmatism. Corneal astigmatism is mainly the result of an aspheric anterior surface of the cornea, which can be measured readily by means of a keratometer; in a small fraction of cases (approximately 1 in 10) the effect is neutralized by the back surface. The curvature of the back surface of the cornea is not considered in most studies, because it is more difficult to measure; moreover, in the case of severe corneal astigmatism, there is evidence that both surfaces have the same configuration. Noncorneal factors are errors in the curvature of the 2 surfaces of the crystalline lens, irregularity in the refractive index of the lens, and an eccentric lens position. Since the cornea is the dominant component of the eye's refracting system, a highly astigmatic cornea is likely to result in a similarly astigmatic ocular refraction (summary by Clementi et al., 1998).
Hypermetropia
MedGen UID:
43780
Concept ID:
C0020490
Disease or Syndrome
An abnormality of refraction characterized by the ability to see objects in the distance clearly, while objects nearby appear blurry.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Iris coloboma
MedGen UID:
116097
Concept ID:
C0240063
Anatomical Abnormality
A coloboma of the iris.
Retinal coloboma
MedGen UID:
761889
Concept ID:
C3540764
Disease or Syndrome
A notch or cleft of the retina.

Recent clinical studies

Diagnosis

Bianchi C, Margot H, Fernandes H, Pasquet M, Priqueler L, Roy-Peaud F, Bauduer F, Bayart S, Garnier N, Fain O, Van Gils J, Joly SB, Rialland F, Paillard C, Deparis M, Lambilliotte A, Leblanc T, Fahd M, Leverger G, Héritier S, Geneviève D, Rieux-Laucat F, Picard C, Neyraud C, Aladjidi N
Br J Haematol 2024 May;204(5):1899-1907. Epub 2024 Mar 3 doi: 10.1111/bjh.19387. PMID: 38432067
Takenouchi T, Miura K, Uehara T, Mizuno S, Kosaki K
Am J Med Genet A 2016 Oct;170(10):2587-90. Epub 2016 Jun 3 doi: 10.1002/ajmg.a.37761. PMID: 27256762
Liu AP, Chow PC, Lee PP, Mok GT, Tang WF, Lau ET, Lam ST, Chan KY, Kan AS, Chau AK, Cheung YF, Lau YL, Chung BH
Eur J Med Genet 2014 May-Jun;57(6):306-11. Epub 2014 Apr 8 doi: 10.1016/j.ejmg.2014.03.014. PMID: 24721633
Giordano P, Lassandro G, Sangerardi M, Faienza MF, Valente F, Martire B
Ital J Pediatr 2014 Jan 25;40:10. doi: 10.1186/1824-7288-40-10. PMID: 24460868Free PMC Article
Putoux A, Labalme A, André JM, Till M, Schluth-Bolard C, Berard J, Bertrand Y, Edery P, Putet G, Sanlaville D
Am J Med Genet A 2013 Feb;161A(2):331-7. Epub 2013 Jan 15 doi: 10.1002/ajmg.a.35708. PMID: 23322614

Therapy

Bianchi C, Margot H, Fernandes H, Pasquet M, Priqueler L, Roy-Peaud F, Bauduer F, Bayart S, Garnier N, Fain O, Van Gils J, Joly SB, Rialland F, Paillard C, Deparis M, Lambilliotte A, Leblanc T, Fahd M, Leverger G, Héritier S, Geneviève D, Rieux-Laucat F, Picard C, Neyraud C, Aladjidi N
Br J Haematol 2024 May;204(5):1899-1907. Epub 2024 Mar 3 doi: 10.1111/bjh.19387. PMID: 38432067
Giordano P, Lassandro G, Sangerardi M, Faienza MF, Valente F, Martire B
Ital J Pediatr 2014 Jan 25;40:10. doi: 10.1186/1824-7288-40-10. PMID: 24460868Free PMC Article

Clinical prediction guides

Takenouchi T, Miura K, Uehara T, Mizuno S, Kosaki K
Am J Med Genet A 2016 Oct;170(10):2587-90. Epub 2016 Jun 3 doi: 10.1002/ajmg.a.37761. PMID: 27256762

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