The proband, patient 1, was a 3-day-old female of mixed (Caucasian, African American, and Hispanic) ancestry born via Cesarean section at 35 weeks 5 days gestational age (GA) to a 26-year-old gravida 4 para 2 mother. The pregnancy was complicated by polyhydramnios starting at 21 weeks GA and continuing throughout the pregnancy. At 22 weeks 3 days GA, an intracardiac echogenic focus and nuchal thickening were noted. A subsequent ultrasound at 23 weeks 1 days GA showed the intracardiac echogenic focus and nuchal thickening had resolved but noted a left clubfoot. Another follow-up ultrasound at 28 weeks 6 days was not consistent with left clubfoot.\nAt birth her APGAR scores were 8 and 8 at 1 and 5 min, respectively, but around 5 min, she developed respiratory distress requiring CPAP and admission to the NICU. She was found to have multiple anomalies and dysmorphic features, including cleft palate, flat midface, hypertelorism, creases under the eyes, a small nose with anteverted nares, arachnodactyly of fingers and toes, laterally deviated great toes, and mild pectus carinatum. She was in the 99th percentile for a length of 53.3 cm at birth. She failed her newborn hearing examination in both ears. She remained in the NICU for 6 weeks due to respiratory issues and slowing feeding.\nA karyotype sent at the birth hospital was normal (46, XX). During her NICU stay, a head ultrasound performed 2 days after birth showed mild prominence of the lateral ventricles and no evidence of hemorrhage. A brain MRI performed at 5 weeks of age was overall normal. At 9 weeks of age she was evaluated for bilateral wrist contractures.\nHer family history is significant for a brother and father with similar physical features. Her 17-month-old brother, patient 2, previously presented at 1 day of life with a long neck, excess nuchal skin, large hands and feet with long fingers and toes, and pectus excavatum. He also had a flat midface and a saddle nose. A postnatal chromosome microarray analysis was normal. At the time, the father (patient 3) was found to have similar features including long fingers and toes, pectus excavatum, and laterally deviated great toes (Figure a,b). He also had anteverted nares and mild hypertelorism (Figure c). The father had been in generally good health his entire life. An autosomal dominant disorder was suspected due to the phenotypic similarities between the siblings and their father (Figure ). Given the family history, we decided to offer further genetic testing to determine if there was an underlying hereditary syndrome responsible for their phenotypes.
Patient 5 is a 42-year-old man, the second son of unaffected and non-consanguineous parents. He was born, followed by unremarkable pregnancy, at 40 weeks of gestation with a birth weight of 3,580 g (+0.37 SD), length of 52 cm (+0.19 SD) and OFC of 37 cm (+1.92 SD). At birth, he presented with dislocation of knee joints, anterior dislocation of the tibia, bilateral pronounced club feet, and distinct dislocation of both hips. Facial dysmorphism with a flat face and nose, prominent forehead, telecanthus, and myopia was noted (Fig. ). He had broad distal phalanges of the hands (Fig. ), supernumerary carpal bones, and 13 pairs of ribs. During the neonatal period, knee dislocation was treated with manipulation and cast application. Later, club feet were treated with metatarsal osteotomy with posterior soft tissue release. The correction of feet was maintained with feet orthosis until 14 years of age. An arthrodesis of the right knee joint was performed for chronic pain. He later developed a cervical scoliosis with occipito-craniocervical instability. Cervical spine instability was treated with occipitocervical fusion and a return displacement of the soft palate was conducted. No abnormalities of the cardiovascular system were observed. At the age of 37 years, he developed chronic myeloid leukemia. The patient holds a degree in natural science. He is severely limited in his mobility due to the skeletal abnormalities.