These 62 patients with the Kabuki make-up syndrome (KMS) were collected in a collaborative study among 33 institutions and analyzed clinically, cytogenetically, and epidemiologically to delineate the phenotypic spectrum of KMS and to learn about its cause. Among various manifestations observed, most patients had the following five cardinal manifestations: 1) a peculiar face (100%) characterized by eversion of the lower lateral eyelid; arched eyebrows, with sparse or dispersed lateral one-third; a depressed nasal tip; and prominent ears; 2) skeletal anomalies (92%), including brachydactyly V and a deformed spinal column, with or without sagittal cleft vertebrae; 3) dermatoglyphic abnormalities (93%), including increased digital ulnar loop and hypothenar loop patterns, absence of the digital triradius c and/or d, and presence of fingertip pads; 4) mild to moderate mental retardation (92%); and 5) postnatal growth deficiency (83%). Thus the core of the phenotypic spectrum of KMS is rather narrow and clearly defined. Many other inconsistent anomalies were observed. Important among them were early breast development in infant girls (23%), and congenital heart defects (31%), such as a single ventricle with a common atrium, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of aorta, patent ductus arteriosus, aneurysm of aorta, transposition of great vessels, and right bundle branch block. Of the 62 KMS patients, 58 were Japanese, an indication that the syndrome is fairly common in Japan. It was estimated that its prevalence in Japanese newborn infants is 1/32,000. All the KMS cases in this study were sporadic, the sex ratio was even, there was no correlation with birth order, the consanguinity rate among the parents was not high, and no incriminated agent was found that was taken by the mothers during early pregnancy. Three of the 62 patients had a Y chromosome abnormality involving a possible common breakpoint (Yp11.2). This could indicate another possibility, i.e., that the KMS gene is on Yp11.2 and that the disease is pseudoautosomal dominant. These findings are compatible with an autosomal dominant disorder in which every patient represents a fresh mutation. The mutation rate was calculated at 15.6 X 10(6).

We isolated NSD1 from the 5q35 breakpoint in an individual with Sotos syndrome harboring a chromosomal translocation. We identified 1 nonsense, 3 frameshift and 20 submicroscopic deletion mutations of NSD1 among 42 individuals with sporadic cases of Sotos syndrome. The results indicate that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploinsufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45%) and 16 point mutations (14%) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non-Japanese patients was noted: 49 (52%) of the 95 Japanese patients and only one (6%) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal breakpoints of the common deletion, This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non-Japanese cases in our study may have been caused by patient-selection bias.

We constructed the standard growth (length/height and weight) curves for Japa-nese individuals with Prader-Willi syndrome (PWS). Crude height and weight data were collected from 153 males and 99 females with the syndrome, and the collected data were arranged by a mathematical method to construct the curves. Height growth patterns were quite different between PWS and normal children. Mean height of individuals with the syndrome by puberty is −2 SD for normal children, and it drops off far below −2 SD value after puberty. Final mean height is 141.2 ± 4.8 cm for females (n = 13) and 147.7 ± 7.7 cm for males (n = 17), showing 15.8 and 21.9 cm below the average height for normal Japanese girls and boys, respectively. Thus, the degree of shortness is more pronounced in male than in female patients. There was no difference in height between those with chromosome 15q deletion and those without. Mean weight at birth of girls (n = 88) and boys (n = 131) were 2.70 ± 0.45 Kg and 2.62 ± 0.47 Kg, respectively. These values were smaller than those for normal neonates (P < 0.05, t-test). The weight of PWS children was under the mean value for normal infants by age 2 years, but gradually increase above the mean values for normal children around ages 2-4 years. Overweight in both males and females becomes obvious during prepu-berty. Growth patterns are not different between Japanese and Caucasian children with the syndrome. Short stature is more prominent in boys of both ethnic groups, whereas the degree of overweight appears much more severe in Caucasians. Am. J. Med. Genet. 95:130-134, 2000.

Many of these Japanese nurses did not perform at satisfactory levels of diagnostic competency with these two written case studies. Factors that influenced diagnostic competency were length of clinical experience, decision-making responsibility, and frequency of studying nursing diagnosis.