An Infant and Mother With Hypertelorism

A 9-month-old boy presented to our Medical Genetics clinic for concern for dysmorphic features, including concern for bilateral ptosis and abnormal ear placement. He was the product of a healthy, uneventful gravida 4, para 1 pregnancy to nonconsanguineous parents. His mother recently immigrated to the United States from Guatemala. He was born at 37 weeks and 4 days’ gestation and was discharged at 2 days of life without complications. He had difficulty with eye opening for the first 2 weeks of life, which resolved without intervention. At 2 months of life, he had bilateral conjunctivitis, which was treated successfully with erythromycin. At 7 months of age, there was concern for bilateral ptosis and abnormal ear placement, for which he was referred to our Medical Genetics clinic.In our clinic, at 9 months of age, his mother reported that he was meeting his developmental milestones appropriately. On physical examination, he was noted to have hypertelorism with elongated palpebral fissures (Figure 1). His inner canthal distance was 3.5 cm (>99th percentile; reference range, 2.3 +/− 0.4 cm), and his outer canthal distance was 8.6 cm (>99th percentile; reference range, 7.1 +/− 0.4 cm). There was no eversion of the lateral lower eyelids. He was accompanied to the visit by his 32-year-old mother, who was noted to have even more significant hypertelorism, a vertical median nasal groove, and longitudinal splits in her fingernails. She reports that the fingernail changes have been present throughout her life. The child’s fingernails were normal. The mother reports a normal developmental history for herself. The family history was notable for 1 maternal half-brother, now 11 years of age, with normal development and normal eye spacing. The mother reports neither her parents nor her siblings have widely spaced eyes.Exome sequencing identified an EFNB1 deletion in the son, consistent with a diagnosis of EFNB1-related craniofrontonasal dysplasia. The initial report called this change de novo, meaning that it was new in the child and not inherited from the mother. We requested a rereview of the results, which identified mosaicism for the EFNB1 deletion in the mother that was below the reporting threshold for the laboratory results, consistent with a diagnosis of mosaic craniofrontonasal dysplasia (CFND) in the mother.CFND is a rare X-linked disorder with recognizable dysmorphic feature.1–13 Despite being an X-linked disorder, CFND severity follows an unusual pattern, with female individuals being more severely affected than male individuals. CFND is characterized by craniofacial abnormalities, including facial asymmetry and hypertelorism noted in our patient and his mother. Other key clinical features often seen in CFND include short stature in male individuals, brachycephaly, and frontal bossing.10 Ocular findings may include strabismus, nystagmus, and downslanting palpebral fissures. Nasal anomalies such as a broad root and bifid or hypoplastic tip are common, along with orofacial clefts and dental irregularities. Skeletal manifestations may include a Sprengel deformity, pectus excavatum, clavicle pseudarthrosis, asymmetrical limb shortening, syndactyly, brachydactyly, joint laxity, and/or broad halluces. Craniosynostosis is common and often requires surgical correction.8 Dermatological signs such as axillary pterygia; brittle or grooved nails; and thick, wiry hair are also frequently observed. Development is typically normal, although variable cognitive delay and brain malformations have been noted in a subset of patients.11CFND is caused by hemizygous or heterozygous loss-of-function variants in the EFNB1 gene.3,4EFNB1 encodes ephrin B1, a protein that contributes to defining the midline during embryonic development.3,4,14,15 Loss of ephrin B1 leads to midline abnormalities in fusion, leading to characteristic features, including the hypertelorism seen in our patient and his mother. Other uncommon and CFND-specific features that clued us in the diagnosis in this case were the median nasal groove and longitudinal splits in the fingernails of the mother.Only 2 X-linked disorders, to our knowledge, follow this unusual pattern of being more severe in female individuals than in male individuals. These disorders include (1) EFNB1-related CFND and (2) PCDH19-related epilepsy. Both EFNB1 and PCDH19 are transmembrane proteins involved in cell-cell adhesion.14–16 Because male individuals have only 1 X chromosome, they have only 1 copy of the EFNB1 gene. Female individuals have 2 copies of the EFNB1 gene, but, owing to X-chromosome inactivation, only 1 copy of EFNB1 is active in a given cell. This leads to functional mosaicism for cells with normal and abnormal EFNB1 function. Because X-chromosome inactivation is a random process that occurs in each individual cell, skewing of X-chromosome inactivation can also influence the severity of disease.Work in induced pluripotent stem cells derived from patients with CFND shows that mosaic EFNB1 cells form distinct populations.15 That is, cells with ephrin-B1 (EFNB1) expression prefer to cluster near other cells with EFNB1 expression, and cells without EFNB1 expression prefer to be near other cells without EFNB1. Presumably, this preference for cells to segregate based on EFNB1 expression underlies the midline fusion abnormalities leading to hypertelorism, widening of the midline of the nose leading to a median nasal groove, and longitudinal splits in the fingernails.The mother is mosaic for the EFNB1 deletion, meaning that the deletion arose new in the mother during embryonic development. The mother has 1 population of cells with 2 normal copies of EFNB1 and another population with 1 deletion and 1 normal copy. The mother’s risk of having another affected child is as high as 50% in each pregnancy.5The son has a risk of passing on CFND to his daughters, but not his sons. Any sons he may have will inherit his Y chromosome and therefore will not inherit his deletion located on the X chromosome. His daughters will all inherit his X chromosome with the EFNB1 deletion and would be expected to be affected with CFND.Dysmorphic features are an important clue to the etiology of inherited disease.17 In this case, the diagnosis could be made from the clinic with a physical examination and pedigree alone. Molecular confirmation in the son was straightforward and fit with our clinical suspicion. Molecular confirmation in the mother was challenging. The mother’s EFNB1 deletion was mosaic and below the commercial laboratory’s reporting limit. We were able to arrive at the correct diagnosis for the mother and son by the strength of the physical examination findings in mother and son.This case highlights how the clinical evaluation can guide reevaluation of molecular testing. In an era of ever more detailed molecular testing, it is important to continue to value some of our most-valuable and least-technological tools, ie, a detailed physical examination and family history.At 14 months of age, the patient continues to have normal developmental progress. Follow-up with ophthalmology is scheduled to evaluate for vision concerns because strabismus is common in the presence of CFND.18 Counseling was provided to his mother regarding reproductive risk for the mother and for the son.SummaryThe physical examination and family history remain central to rare disease diagnosis. Here, the hypertelorism in the son was best understood in the context of more-severe hypertelorism in the mother. Additional features in the mother, including a median nasal groove and longitudinal splits in the fingernails, established the clinical diagnosis. Molecular testing confirmed the diagnosis of EFNB1-related CFND.Very few X-linked disorders are more severe in female individuals than in male individuals. This pattern of inheritance was an important clue that led to our diagnosis of EFNB1-related CFND. EFNB1-related CFND and PCDH19-related epilepsy follow this pattern owing to X-chromosome inactivation driving mosaicism of cell-cell adhesion proteins.15,16