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 3 is a 9-year-old female, born to third degree consanguineous parents at term by cesarean section for breech presentation. Birth weight was 3.25 kg (normal). She cried immediately after birth. She was referred for evaluation in view of bilateral dislocation of hip and knee joints and bilateral clubfeet. She has undergone multiple corrective orthopedic surgeries for club feet and hip dislocation. She started walking at 1 year and spoke simple sentences at 2 years.\nAt 2 years and 2 months, her height was 90 cm, OFC 48.5 cm and weight 11 kg (all are normal for age). She had prominent forehead, depressed nasal bridge, and telecanthus (Fig. ). She had spatulate thumbs, broad fingertips (Fig. ), and joint laxity. Joint laxity was noted in both knee joints (Fig. ), bilateral club feet and broad great toes were also noted (Fig. ). Bilateral elbow and wrist joints were normal. Skin, hair, and nails were normal. At 9 years of age, there was no evidence of hearing defect or compressive myelopathy. She is presently in 3rd grade and is good at studies.\nRadiographs revealed cervical kyphosis, subluxation at C3-C4 (Fig. ), and failure of fusion of posterior elements of cervical spine with mild scoliosis (Fig. ). Accessory calcaneal ossification (Fig. ) and clubfeet with metatarsus adductus (Fig. ) were also noted. Advanced carpal ossification was seen in radiographs at 22 months (Fig. ) of age though carpal ossification was age appropriate at 4 years and 7 months (Fig. ). She had normal right hip joint but increased medial joint space on left hip joint (Fig. ). Echocardiography was normal. Her complete blood counts, serum calcium, serum phosphorous, alkaline phosphatase, thyroid profile, and complete urine analysis were unremarkable.