Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (Kagami-Ogata syndrome)

Abstract

Paternal uniparental disomy 14 (UPD(14)pat) and epimutations and microdeletions affecting the maternally derived 14q32.2 imprinted region lead to a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with a coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios. In this study, we performed comprehensive clinical studies in patients with UPD(14)pat (n=23), epimutations (n=5), and microdeletions (n=6), and revealed several notable findings. First, a unique facial appearance with full cheeks and a protruding philtrum and distinctive chest roentgenograms with increased coat-hanger angles to the ribs constituted the pathognomonic features from infancy through childhood. Second, birth size was well preserved, with a median birth length of ±0 SD (range, -1.7 to +3.0 SD) and a median birth weight of +2.3 SD (range, +0.1 to +8.8 SD). Third, developmental delay and/or intellectual disability was invariably present, with a median developmental/intellectual quotient of 55 (range, 29-70). Fourth, hepatoblastoma was identified in three infantile patients (8.8%), and histological examination in two patients showed a poorly differentiated embryonal hepatoblastoma with focal macrotrabecular lesions and well-differentiated hepatoblastoma, respectively. These findings suggest the necessity of an adequate support for developmental delay and periodical screening for hepatoblastoma in the affected patients, and some phenotypic overlap between UPD(14)pat and related conditions and Beckwith-Wiedemann syndrome. On the basis of our previous and present studies that have made a significant contribution to the clarification of underlying (epi)genetic factors and the definition of clinical findings, we propose the name 'Kagami-Ogata syndrome' for UPD(14)pat and related conditions.

Figure 1

Photographs of patient #23 with UPD(14)pat and patient #27 with epimutation.

Figure 2

Chest roentgenograms of patient #12 of UPD-group, patient #31 of Del-S1, and patient #34 of Del-S3. RTL1 expression level is predicted to be ~5 times higher in patients #12 and #31, and ~2.5 times higher in patient #34. The CHA to the ribs remains above the normal range throughout the study period, whereas the M/W ratio (the ratio of the mid to widest thorax diameter) normalizes with age.

Figure 3

Developmental status. The orange, green, yellow, and blue bars represent the period before head control, the period after head control and before sitting without support, the period after sitting without support and before walking without support, and the period after walking without support, respectively. The gray bars denote the period with no information. DQ, developmental quotient; IQ, intellectual quotient; N.E., not examined; Age, age at the last examination or at death; and GA, gestational age.

Figure 4

Hepatoblastoma in patient #8 of UPD-group. (a) Macroscopic appearance of the hepatoblastoma with a diameter of ~8 cm. (b) Microscopic appearance of the hepatoblastoma exhibiting a trabecular pattern. The hepatoblastoma cells are associated with eosinophilic cytoplasm and large nuclei, and resemble fetal hepatocytes.

Figure 5

Kaplan–Meier survival curves according to the (epi)genetic cause and the gestational age (week), and summary of the causes of death. GA, gestational age; URI, upper respiratory infection; and RS, respiratory syncytial. Patients #8, #17, and #18 had hepatoblastoma.