Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients’ lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.

Twenty-five medical centers and the Prader-Willi Syndrome (PWS) Association collaborated on a study which attempted to identify all people with genetically confirmed diagnosis of PWS living in Italy. Investigators of the participating centers contacted PWS subjects and/or their family, filled in a specially developed form with the required data and forwarded this information by email. The study identified 425 subjects (209 males and 216 females, between the ages of 0.4-46.7). Two hundred thirty-eight patients had del15, 104 had UPD15, 4 demonstrated a translocation affecting chromosome 15 and 79 showed a positive methylation test. There were fewer subjects found over the age of 35, probably due to the low rate of identification of older PWS patients as well as the high mortality rate. There were a greater number of male children and adolescents with PWS whilst, amongst adults, there were more females. As expected, the majority of subjects with PWS were obese, especially in adult life. Nevertheless, it is noteworthy that 26% of patients aged between 6 and 17 were normal weight. A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity-related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case. Overall, there was no increase in number of deaths during GH treatment, suggesting that GH administration in patients with PWS, as a group, does not increase the risk of death. ß

It is well known that fat children tend to be taller than their peers and to present a slight acceleration of skeletal and pubertal maturation. To verify this tendency and to examine some of the points that are still controversial, auxological data were studied concerning 303 subjects (141 males and 162 females, aged 6-16 years) affected by simple obesity. Subjects were seen to be taller than average by about 1 SD from 6 to 9 years of age, becoming close to or shorter than average at later ages. Height below the 10th percentile was common in 17% of males and 8% of females, due to hereditary shortness, growth delay or late puberty. Girls had early puberty and menarche; the rate of sexual maturation was variable in boys.

With the aim of determining fetal growth kinetics, prenatal data were analysed which had been longitudinally collected in the framework ofa perinatal growth survey. The sample comprised 238 singleton normal pregnancies, selected in Genoa and Turin (between 1987 and1990), and repeatedly assessed by ultrasound scans (five to nine per pregnancy). Five morphometric traits were considered: BPD (biparietal diameter), OFD (occipitofrontal diameter), HC (head circumference), FDL (femur diaphysis length) and AC (abdomen circumference).Growth rate seemed to increase in the early part of the second trimester, and decrease subsequently: velocity peaks were steeper and earlier for head diameters and circumference (about 18 weeks) than for femur length (20 weeks) and abdomen circumference (22 weeks). Velocity standards were traced using a longitudinal two-stage linear model: this ensures unbiased description of the shape of the growth curve, even when growth kinetics are asynchronous, and efficient estimation of the outer centiles -the most useful for diagnostic purposes. Before the development of ultrasonography, there was no harmless and reliable technique available for providing information on physiological fetal growth kinetics, and the so-called intrauterine growth standards were therefore based on anthropometric measures ofneonates with different gestational ages. As the assumption that prenatal growth in full term and preterm babies follows the same pattern is hardly tenable,' these norms are intrinsically a tool for evaluating body size and proportion of neonates, and not true growth standards for monitoring fetal development.2

We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced maximal transactivation, although its binding characteristics and ED(50) of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease.

Activating mutations of the Gsalpha gene are detected in different endocrine tumors, such as GH-secreting adenomas and toxic thyroid adenomas, and in hyperfunctioning glands from patients with McCune-Albright syndrome (MAS). There is increasing evidence that the Gsalpha gene is subjected to imprinting control and that Gsalpha imprinting plays a key role in the pathogenesis of different human diseases. The aim of this study was to investigate the presence of a parent specificity of Gsalpha mutations in 10 patients affected with MAS and 12 isolated tumors (10 GH-secreting adenomas, one toxic thyroid adenoma, and one hyperfunctioning adrenal adenoma). The parental origin of Gsalpha mutations was assessed by evaluating NESP55 and exon 1A transcripts, which are monoallelically expressed from the maternal and paternal alleles, respectively. By this approach, we demonstrated that in isolated GH-secreting adenomas, as well as in MAS patients with acromegaly, Gsalpha mutations were on the maternal allele. By contrast, the involvement of other endocrine organs in MAS patients was not associated with a particular parent specificity, as precocious puberty and hyperthyroidism were present in patients with mutations on either the maternal or the paternal allele. Moreover, isolated hyperfunctioning thyroid and adrenal adenomas displayed the mutation on the maternal and paternal alleles, respectively. These data confirm the importance of Gsalpha imprinting in the pituitary gland and point out the high degree of tissue specificity of this phenomenon.

A pair of monozygotic twin girls with trichorhinophalangeal syndrome type I (TRPS I), followed from 8.3 to 16.1 years of age, is described. Both showed typical dysmorphic features and severe short stature, but only one had Perthes-like changes in the right capital femoral epiphysis. The radiographic findings and evolutionary changes of phalangeal cone-shaped epiphyses (PCSE) of the hands are illustrated in this report. The unusual bone maturation and growth of the twins are also described. Both presented poor growth and delayed bone age until about 13 years, followed by marked acceleration of bone age and stunted pubertal height spurt.

Physiologic interindividual differences in neonatal size are traditionally thought of as determined by differences in fetal growth occurring only in the second half of pregnancy. Whether possible differences in early intrauterine growth velocity are the effect of random growth fluctuations or may affect size at birth is still debated. This article aims at evaluating to what extent differences in neonatal size are accounted for by differences in fetal growth velocity. We analyzed the fetal growth of 130 healthy singletons for whom head (HC) and abdomen (AC) circumferences and femur diaphysis length (FDL) longitudinal profiles were available, together with the measures of weight (BW), length (BL), and head circumference (BHC) at birth. Individual profiles were fitted with ad-hoc models. Neonatal traits were transformed into standard deviation scores (SDS). Neonates in the upper third of BW-SDS distribution (3618 Ϯ 43 g, mean Ϯ SEM) had, at 22 wk of gestational age, AC growth velocity higher by 0.55 Ϯ 0.10 mm/wk than those in the lower third (2902 Ϯ 36 g). Neonates in the upper third of BL-SDS distribution (51.7 Ϯ 0.21 cm) had, at 20 wk, FDL growth velocity higher by 0.11 Ϯ 0.05 mm/wk than those in the lower third (48.2 Ϯ 0.18 cm). Neonates in the upper third of BHC-SDS distribution (35.7 Ϯ 0.13 cm) had, at 18 wk, HC growth velocity higher by 0.57 Ϯ 0.20 mm/wk than those in the lower third (33.3 Ϯ 0.11 cm). The differences in growth velocity remain constant throughout the second and third trimester for AC, and tend to vanish in the third trimester for HC and FDL. The differences in fetal growth velocity, which in our study were observed as early as mo 4, suggest that the genetic component plays an important role in fetal growth and is precociously expressed. Abbreviations AC, abdomen circumference BHC, head circumference at birth BL, birth length BPD, biparietal diameter BW, birth weight CRL, crown-rump length FDL, femur diaphysis length GA, gestational age HC, head circumference SDS, standard deviation score Physiologic interindividual differences in neonatal size are traditionally thought of as determined by differences in fetal growth occurring only in the second half of pregnancy (1,2). Actually, the assessment of GA derived from the measurement of CRL during the late first trimester (3), as well as of BPD, HC, and FDL during the second trimester (4), rests on the assumption that in this period fetuses of the same size have nearly the same GA. Empirical evidence against the above assumption is unlikely to be provided, inasmuch as differences in size in the first half of pregnancy are expected to be small, growth being a cumulative process, and measurement error being relatively large with respect to size. On the other hand, negligible interindividual differences in size at a given gestational age do not necessarily imply negligible differences in growth velocity, which may be estimated only by means of longitudinal studies.Longitudinal studies presently available, although based on few subjects and limited to t...