Cardiac anomalies-short stature-joint hypermobility-facial dysmorphism syndrome (ORPHA:228410)
A rare multiple congenital anomalies syndrome characterized by the combination of cardiac anomalies (most commonly mitral valve defects and cardiomyopathy), short stature, facial dysmorphism and sometimes mild developmental delay.
Epidemiology
70 individuals have been described in literature: 34 individuals with TAB2 variants, 36 individuals with TAB2 deletions.
Clinical description
Almost all individuals present with a specific facial appearance including: broad forehead, hypertelorism, up/downslanting palpebral fissures, ptosis, low set ears, broad/short neck, and half of the individuals have a face suggestive for Noonan syndrome. Cardiac disease is seen in most individuals and includes mainly mitral valve defects, sometimes in combination with another valve defect, and (dilated) cardiomyopathy. Cardiomyopathy can be present from birth or develop between infancy and adulthood. Other cardiovascular defects are variably reported, including dysplasia of the tricuspid, aortic and pulmonary valves, atrial and/or ventricular septal defects, coarctation of the aorta and thoracic aneurysms. Short stature is often disproportionate (short limbs). Connective tissue abnormalities can include joint hypermobility, umbilical and inguinal hernias, pes planus, pectus excavatum and other skeletal and/or skin abnormalities. Some individuals have mild developmental delay. More severe developmental delay can be seen in larger deletions (>6.47 Mb) containing TAB2, but was never reported in individuals with TAB2 variants. Hearing loss and vision problems are also reported. Hypotonia is reported in individuals with TAB2 deletions, but rarely in TAB2 variants.
Etiology
This syndrome is caused by heterozygous pathogenic variants in the TAB2 gene, or by chromosome 6 deletions including TAB2 (6q25.1). Both TAB2 variants and deletions including TAB2 lead to a highly comparable phenotype.
Diagnostic methods
Diagnosis is based on clinical examination, and cytogenetic and molecular studies.
Differential diagnosis
The differential diagnosis includes Noonan syndrome/RASopathies, cardiospondylocarpofacial syndrome (MAP3K7 gene), cardiac valvular dysplasia (FLNA gene), connective tissue disorders with cardiac valve involvement such as Loeys Dietz type 3 (SMAD3 gene) or 5 (TGFB3 gene).
Antenatal diagnosis
Detection of the TAB2 variant or deletion by chorion villus biopsy or amniocentesis should be discussed with adults carrying the deletion or variant.
Genetic counseling
Transmission is autosomal dominant. TAB2 deletions often arise de novo, but are also reported in families (largest known familial deletion: 8.67 Mb) and therefore should be excluded in parents before counselling a low recurrence risk. Genetic counselling should be offered to all individuals with a TAB2 variant or deletion. For patients with a heterozygous TAB2 variant or deletion, each pregnancy carries a 50% risk of transmission to offspring. Sibling recurrence in de novo mutations may occur due to mosaicism, but has not been reported.
Management and treatment
Regular cardiac evaluation and evaluation of overall development, hearing, vision and connective tissue abnormalities is recommended for all affected individuals. Cardiac follow-up is needed as valvular heart disease, thoracic aneurysm and cardiomyopathy may manifest later in life. Surgical intervention for cardiac anomalies may be required. The relevance of growth hormone therapy for short stature in this syndrome is not clear and should be studied further.
Prognosis
Life expectancy can be limited due to severe cardiac disease. Three children died due to dilated cardiomyopathy and four adults died between the age of 40-60 from the (late) effects of structural heart disease.

                            Last update: 
                            October 2021


                            - Expert reviewer(s): 
                             A. [Aafke] ENGWERDA | ITHACA* - Dr W.S. [Mieke] KERSTJENS-FREDERIKSE | ITHACA*


                                * European Reference Network