Review Question - QID 218077

The diagnosis is most likely Holt-Oram syndrome (HOS), which is an autosomal dominant (AD) condition characterized by congenital heart defect(s), radial longitudinal deficiency (RLD), and is associated with mutations in the gene coding for the transcription factor TBX5.

HOS is one of the more common syndromes seen in patients with RLD, and is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. The incidence of Holt-Oram Syndrome (HOS) is estimated to be about 0.7 in 100,000 live births. The cardiac and limb anomalies vary in presentation. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. While the thumb is most commonly affected, it is also associated with aplasia or hypoplasia of the radius as well as radioulnar synostosis. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. More than 70% of individuals with HOS have mutations in the gene for the transcription factor TBX5, located on the chromosome 12q24.1. Mutations in the gene, described as missense, deletion, or truncation, affect the protein’s ability to dimerize with other proteins that are necessary for cardiac and limb development.

Wall et al. investigated the distinguishing morphologic characteristics of children with RLD in HOS. 62 patients were retrospectively evaluated. They reported bilateral involvement in 84% of patients, and that a shortened distal radius was the most commonly identified forearm anomaly (40%). They noted that thumb aplasia (Blauth type V hypoplastic thumb) was the most common type of classifiable thumb abnormality and occurred in 35% of involved thumbs. They concluded that the upper extremity in Holt-Oram Syndrome differs from the typical presentation of radial longitudinal deficiency.

Bednar et al. provided a review on congenital radial and ulnar longitudinal deficiencies. They note that radial deficiency is 3 to 4 times more common than ulnar deficiency, and RLD is associated with a number of medical syndromes that require a comprehensive medical evaluation, while ulnar longitudinal deficiency (ULD) is associated with other musculoskeletal anomalies. Both conditions have a high incidence of ipsilateral thumb abnormalities.

Incorrect Answers:
Answer 1: TAR is characterized most specifically by bilateral absence of radii w/presence of both thumbs. Other manifestations that help differentiate TAR from HOS include thrombocytopenia (<50 platelets/nL), which is generally transient, as well frequent involvement of lower limbs.
Answer 2: Fanconi anemia is characterized by short stature, abnormal skin pigmentation, and malformations of the thumbs, forearms, eyes, ears, oral cavity, genitourinary system, heart, gastrointestinal system, and central nervous system. Patients often have progressive bone marrow failure w/ pancytopenia typically presenting in the 1st decade of life. They also have an increased risk for malignancy.
Answer 4: VACTERL (Vertebral anomalies, anal atresia, cardiac abnormalities, tracheoesophageal fistula, renal anomalies, and limb anomalies) is not likely given evidence of AD pathology, genetic mutation involving TBX5, and no other findings suggestive of this disorder.
Answer 5: Heart-hand syndrome II is an AD condition characterized by shortening of the distal phalanx of the thumb ± shortening of 4th & 5th metacarpals, as well as sloping shoulders, short upper limbs, bowing of distal radii, absence of the ulnar styloid process, mild dysmorphic facial features, and cardiac arrhythmias (e.g., supraventricular tachycardia) (as opposed to malformations). A genetic mechanism has not been identified.