2023.01.17 | Questions 21-22
A newborn with a missing thumb
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Questions
Question 21
A newborn is found to have a congenital defect of her upper limb. Her left hand is smaller than her right hand and she is missing her left thumb. Initial O2 saturation is 88%, and a follow-up echocardiogram shows a ventricular septal defect. Genetic sequencing reveals a pathogenic variant in TBX5. What is the most likely diagnosis?
Question 22
The patient’s upper limb anomaly in Question 21 is an example of which of the following types of congenital anomalies?
Explanations
The patient in Question 21 has Holt-Oram syndrome (HOS), a disorder that affects the bones in the upper limb and the heart. HOS is caused by mutations in the gene TBX5, which encodes a transcription factor that regulates the development of the upper limb bones and the heart during embryonic development. Upper extremity anomalies include absent or triphalangeal thumb, phocomelia, and hypoplasia of the radius, and may be unilateral or bilateral. ~75% of patients with HOS also have a cardiac anomaly, the most common of which are ventricular septal defects (VSD) and atrial septal defects.
Distinguishing between the different types of congenital anomalies is high-yield for board exams (Question 22). The patient's upper limb anomaly is an example of a malformation. A malformation is a congenital anomaly that is due to an underlying issue in the developmental program (e.g. a pathogenic variant in a transcription factor active during development). In Holt-Oram syndrome, the upper limb malformation is caused by a mutation in the TBX5 gene, which encodes a transcription factor that is required for proper formation of the limbs and heart.
In contrast, deformations occur when a normally formed structure or organ is bent or distorted, usually due to an external force, rather than due to an underlying gene mutation. An example of a deformation would be arthrogryposis in triplets due to intrauterine crowding. Deformations may be reversible in certain cases (e.g. with serial casting). Disruptions occur when a normal developmental process is interrupted, resulting in the absence or incomplete formation of a structure or organ. In contrast to deformations, disruptions are generally irreversible. An example of a disruption is amniotic bands that can result in constriction or amputation of digits. A sequence occurs when one or more secondary anomalies cascade from a single primary anomaly. One example is the Pierre-Robin sequence, in which a small jaw (the primary anomaly) displaces the tongue posteriorly (causing upper airway obstruction). The posteriorly displaced tongue, in turn, prevents closure of the palatal shelf (causing a cleft palate).
Incorrect answers
Duane-radial ray syndrome (DRRS) is caused by mutations in the gene SALL4 and is characterized by underdevelopment of the bones in the arm and hand, specifically the radius and the thumb. However, it is not common to have associated cardiac defects.
Poland anomaly is characterized by an underdeveloped pectoral (chest) muscle and sometimes a webbed or missing finger and/or a small or missing thumb. However, patients typically do not have concomitant cardiac defects. The genetic basis of Poland anomaly has not been elucidated. To remember the Poland anomaly, think “Polhand” for Pectoralis and hand anomalies.
Proximal symphalangism, type 1A is characterized by absence or fusion of the bones in the fingers and toes, specifically the proximal interphalangeal joint, with a normal thumb and radius. Patients also do not have congenital heart defects.
Learning objective
Holt-Oram syndrome (aka “Heart and Hand syndrome”) is characterized by cardiac defects and abnormalities in the development of the upper limbs. Holt-Oram can be distinguished from other disorders that affect development of the upper extremity by the presence of concurrent cardiac defects. A pathogenic variant in TBX5 on molecular testing confirms the diagnosis.
2023 ABMGG General Exam Blueprint | V. Single Gene Inheritance → d. Single Gene Disorders (page 3)
References
Elements of Morphology: General Terms for Congenital Anomalies (2013)