In This Issue


Schrier et al (p. 1865, DOI: 10.1002/ajmg.a.35415) propose an algorithm-based approach to diagnosis of Coffm-Siri syndrome (CSS) that they say will help increase certainty about this diagnosis. CSS is a rare, clinically heterogeneous disorder often considered in patients with cognitive/developmental delay and 5th finger/nail hypoplasia. Because facial and other features vary, CSS is often difficult to confirm clinically.

The researchers reviewed 80 previously reported cases to define features in patient that most closely correlated with a convincing diagnosis to develop the algorithm. The two most consistent features of the syndrome are 5th finger phalanx/nail hypo/aplasia and cognitive or developmental deficits, based on the current definitions of CSS. If either feature is absent, then a diagnosis of CSS can be functionally excluded, the authors write. Their findings suggest that many patients who are considered for the diagnosis of CSS should have additional diagnostic considerations, and that many of the published cases seem to fit into one of two subcategories. One includes patient with coarse features, specifically thick eyebrows and thick lip vermilion; the other includes less striking thin eyebrows and thin upper lip vermilion.

The authors applied their algorithm to 15 additional patients who had been previously characterized by chromosome microarray, including children who had both categories of CSS, and children who did not meet the criteria for CSS under the algorithm. The authors identified severa varied chromosomal aberrations in certain patients, suggesting a chromosomal basi for their features, rather than CSS.

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Figure 1. Illustrated is the hypoplastic 5th digit of the hands and feet.


All children with features of branchio-oculo-facial syndrome (BOFS) and hearing impairment should have sophisticated computed tomography of the temporal bone (TB-CT). It is useful for evaluating the bony structures of the middle and inner ear and for determining the etiology of hearing loss, write carter et al (p. 1977, DOI: 10.1002/ajmg.a.35436).

Hearing loss is common in BOFS, which is also characterized by particular branchial skin defects, ocular anomalies, and facial anomalies. The authors describe three new BOFS patients and delineate a variety of inner and middle ear abnormalities associated with BOFS.

Middle ear anomalies detected by TB-CT included deficient long process of the incus, misshapen malleus, and fusion of the incus and malleus. Detected inner ear abnormalities included bony atresia plate covering left oval window, small bone islands, enlarged vestibular aqueducts, cochlear dysplasia, small horizontally-oriented semicircular canals, and accessory right facial nerve canal with ectopic origin.

TB-CT aids proper determination of the etiology of hearing loss in these patients and guides management, the researchers note.

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Figure 2 A,B TB-CT findings in patient 2. Axial CT images demonstrate misshapen ossicles (arrows), while coronal views reveal a thin bony plate over the right oval window (arrow).


Parents of undiagnosed children may benefit from interventions that help them feel less uncertain by clarifying what is known about their child's condition and emphasizing those areas over which parents do have control, Madeo et al write (p. 1877, DOI: 10.1002/ajmg.a.35425).

Uncertainty has been suggested as both a barrier and a facilitator of adaptation to a health threat, but little research focuses on key constructs associated with perceptions of uncertainty, especially among parents of children facing health threats.

So, the researchers examined the factors that contribute to perceived uncertainty among 266 parents of children whose medical conditions had been undiagnosed for at least two years. The researchers administered an electronic mixed-methods survey assessing theoretical predictors of perceived uncertainty.

Parents who feel less control over children's health perceive greater uncertainty, particularly when parents are less optimistic and feel a child's disease is more severe. Identifying such parents may allow clinicians to focus interventions on those parents in the greatest need of support, the researchers found.

That support may include gathering information to enhance healthcare decisions, and guidance for parents on advocating for their child, ensuring the child's comfort, and caring for themselves.