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 4 is a 6-year-old boy, born to non-consanguineous parents at term by vaginal delivery with birth weight of 2.2 kg (−2 to −3 SD). He cried immediately after birth. He had one healthy elder brother. He was referred for evaluation with bilateral clubfeet, bilateral elbow and knee dislocations noted at birth. He achieved head holding at 5 months, roll over at 8 months, sitting at 9 months, standing at 13 months, walking with support at 15 months, and walking without support at 2 years.\nAt 6 years, his height was 110 cm and weight 22 kg (both normal for age). He had prominent forehead, mid face hypoplasia, telecanthus, downslanting palpebral fissures, and long philtrum (Fig. ). He had long cylindrical fingers with broad fingertips (Fig. ), and mild joint laxity. He also had bilateral elbow and knee dislocation and clubfeet (Fig. ). He had flexion deformity at bilateral elbow with pterygium over cubital fossa (Fig. ). Bilateral hip and wrist joints were normal. Skin, hair, and nails were normal.\nHe had normal cervical spine (Fig. ). Bilateral double ossification of calcaneum (Fig. ), bilateral elbow (Fig. and ) and knee dislocations (Fig. ), and bilateral metatarsus adductus (Fig. ) were noted. Radiographs of hip and thoracolumbar spine were unremarkable (Fig. ). Radiographs at 4 years, 5 years and 6 years of age revealed delayed carpal ossification (Fig. ) and showed abnormal distal phalanx of thumbs and small distal phalanges (Fig. ). Echocardiography was normal. His complete blood count, serum calcium, serum phosphorous, alkaline phosphatase, thyroid profile, and complete urine analysis were unremarkable.