Paternal uniparental disomy of chromosome 14

Case presentation

A large-for-gestation-age, 2555-g infant girl was born at 33 weeks gestation to a 23-year-old Gravida 2, para 1 mother by cesarean section because of fetal anomalies including omphalocele. The mother had presented initially at 24 weeks gestation in labor without prior prenatal ultrasound imaging. A fetal sonographic examination at that time had demonstrated an omphalocele, containing liver, arthrogryposis and polyhydramnios. After delivery, the baby was noted to have a large omphalocele, small chest, short palpebral fissures, posteriorly rotated auricles, short limbs, bowing of the lower extremities and multiple joint contractures. Although the baby cried spontaneously after birth, she later required continuous positive airway pressure ventilation to maintain oxygen saturation above 90%. A skeletal survey was ordered (Figure 1).

Figure 1

Anteroposterior radiograph of the chest reveals a small thorax, coat hanger deformity of the ribs and slightly small scapulae with hypoplastic glenoids (S). Coat hanger deformity of the ribs with an upward slanting of the posterior part of the ribs (arrows) and downward slanting of the anterior part of the ribs (arrowheads).

Discussion

The skeletal survey demonstrated a bell-shaped thorax with coat hanger deformity of the ribs, omphalocele, multiple wormian bones, short bilateral upper extremities and small scapulae (Figures 2, 3, 4). The ‘coat hanger’ rib appearance and omphalocele combination has been found to be a useful marker of the rare condition, paternal uniparental disomy (UPD) of chromosome 14,¹ which was confirmed by subsequent DNA analysis.

Figure 2

Lateral radiograph of the abdomen shows a large omphalocele containing bowel loops (arrows) and liver.

Figure 3

Anteroposterior radiograph of the right upper extremity shows a relatively short humerus.

Figure 4

Anteroposterior radiograph of the left upper extremity shows a relatively short humerus, as well as an anterior radial head dislocation (curved arrowhead).

The infant was very difficult to ventilate because of the small thorax, making repair of the omphalocele essentially impossible. Therefore, she was given comfort care, listed as not requiring resuscitation, and died at 4 months of age because of worsening hypoxia and apnea.

UPD of chromosome 14 is a rare genetic entity with distinct radiologic and clinical manifestations. UPD occurs when both chromosomes of a pair are inherited from a single parent. UPD can be maternal or paternal.^{2, 3} Paternal UPD of chromosome 14 is characterized by omphalocele, short-bell-shaped thorax with coat hanger rib deformity, small posteriorly rotated auricles, bowed tibiae, short upper limbs, arthrogryposis, developmental delay and mental retardation.^{4, 5, 6} Maternal UPD of chromosome 14 is relatively more common and has less specific manifestations, including growth retardation, hypotonia, motor delay, precocious puberty and relatively normal cognitive development.⁷

Other conditions associated with UPD include Prader–Willi syndrome (maternal UPD of chromosome 15), Angelman syndrome (paternal UPD of chromosome 15), Russell Silver syndrome (maternal UPD of chromosome 7) and Beckwith–Wiedemann syndrome (paternal UPD of chromosome 11).^{2, 4} Confirmatory diagnosis of paternal UPD requires DNA polymorphism studies.⁶

Various mechanisms may be responsible for UPD of a chromosome. One such mechanism is initial trisomy in a fetus for a particular chromosome, with subsequent loss of one of the three chromosomes, resulting in a normal, diploid chromosome complement. UPD occurs if both retained chromosomes came from the same parent. Errors in either meisosis I or II can result, respectively, in heterodisomic UPD (two different homologous chromosomes from one parent, but from both grandparents) or isodisomic UPD (identical homologous chromosomes from single parent). Heterodisomic UPD is a benign condition, whereas isodisomic UPD is associated with other malformations.

Bell-shaped thorax and coat hanger rib configuration are highly suggestive of paternal UPD of chromosome 14.¹ Coat hanger configuration refers to an upward slanting of the posterior ends of ribs and downward slanting of the anterior ends of ribs.^{4, 5} Other radiographic manifestations of the paternal UPD of chromosome 14 include omphalocele, disproportionate shortened upper extremities, shortened iliac wings with flaring, thin and elongated clavicles, hypoplastic scapular neck with hypoplastic glenoid fossae, kyphoscoliosis, wide sutures and multiple wormian skull bones, and contractures of the wrists with ulnar deviation.^{4, 5}

Differential diagnoses for a neonate with small thorax on chest radiograph include various lethal skeletal dysplasias, including asphyxiating thoracic dystrophy, short-rib polydactyly syndrome, and thanatophoric dysplasia. Paternal UPD can be differentiated from these conditions by the characteristic coat hanger deformity of the ribs and presence of omphalocele. Asphyxiating thoracic dystrophy is characterized by short horizontal ribs with bulbous anterior ends, trident acetabula, mesomelic shortening of extremities and hypoplastic phalanges. Patients with short-rib polydactyly syndrome have a small thorax with small hypoplastic ribs that are horizontally oriented. Thanatophoric dysplasia is associated with ‘telephone receiver’-shaped femors (type I), clover-leaf skull (type II), platyspondyly and rhizomelic shortening of extremities in addition to a small thorax.

Paternal UPD can be suggested on prenatal ultrasonography. Facial abnormality, small bell-shaped thorax with coat hanger rib deformity, abdominal wall defects and placentomegaly, and polyhydramnios can be detected on prenatal three-dimensional fetal sonograms.^{7, 8, 9}

Prognosis of patients with paternal UPD is poor due to respiratory insufficiency and neurodevelopmental retardation.⁷ Hepatoblastoma also has been reported in a patient with paternal UPD of chromosome 14.¹⁰