Loss of the Y chromosome PAR2 region and additional rearrangements in two familial cases of satellited Y chromosomes: cytogenetic and molecular analysis.

Two cases of rare structural aberrations of the Y chromosome were detected: a del(Y) (q12) chromosome in a child with mild dysmorphic features, obesity and psychomotor delay, and two identical satellited Y chromosomes (Yqs) in a normal twin, which were originally observed during routine prenatal diagnosis. In both cases a Yqs chromosome was detected in the father which had arisen from a reciprocal translocation involving the short arm of chromosome 15 and the heterochromatin of the long arm of the Y chromosome (Yqh). Cytogenetic and molecular studies demonstrated that in the reciprocal product of chromosomes 15 and Y PAR2 could not be detected, showing that PAR2 had been deleted. It is discussed whether the translocation of the short arm of an acrocentric chromosome to the heterochromatin of the long arm of the Y chromosome causes instability of this region which results either in loss of genetic material or interference with the normal mechanism of disjunction.

The implications of S-phase exchanges for the mechanisms of radiosensitivity in trisomy 21.

Human lymphocytes obtained from four patients with Down syndrome and from two normal individuals were irradiated with X-rays during their S phase and examined for chromatid type aberrations. It is suggested that the significantly increased frequency of asymmetrical chromatid interchanges found in trisomic cells is related to an altered DNA repair system. This altered repair system is probably responsible for the increased frequency of chromosome aberrations that can be induced in these cells by x-rays and the increased tendency for leukemia observed in Down syndrome as well.

Severe proteus syndrome in an 18-month-old boy.

We describe an 18-month-old Greek boy with macrocephaly, partial gigantism of hands and feet, hemihypertrophy, pigmented nevi, and other anomalies compatible with the Proteus syndrome. Cerebral involvement in a most severe form and at an early age concurs with the suggestion that encephalocraniocutaneous lipomatosis may represent a more circumscriptive manifestation of Proteus syndrome. Localized triggering of several growth factors is a challenging pathogenetic consideration of the syndrome.

Growth and growth hormone therapy in children with achondroplasia: a two-year experience.

The efficacy and safety of recombinant human growth hormone (hGH) administration was studied in children with achondroplasia. Fifteen children with achondroplasia, seven boys (4.8-12.2 years of age) and 12 girls (5.7-2.2 years of age), were treated daily with hGH at a dosage of 1 IU/kg/week. Auxological assessments were performed 6 months before, at initiation of, and at 6, 12, and 24 months following initiation of growth hormone (GH) therapy. Before initiating GH therapy, hypothalamic-pituitary and thyroid functions were evaluated. Levels of serum insulin-like growth factor (IGF)-I and IGF binding protein (BP)-3 (IGFBP-3) were assessed, as was GH response to provocative stimuli. GH responses in two stimulation tests were normal for all but three children. During the first semester of GH treatment, a significant increase in height velocity (HV), from 3.2 to 8.3 cm/year, was observed in all children. However, during the second semester, a relative decrease in growth rate was observed. By the end of the first year, HV had increased from 3.2 to 6.9 cm/year (mean, 3.7 cm/year; range, 1.1-8 cm/year) in 13 children and remained unchanged in two children. HV declined progressively during the next 12 months and, by the end of the second year of treatment, had increased in seven of the nine children who had completed 2 years of therapy (mean increase, 3.1 cm/year); two children did not respond to GH therapy, as shown by the lack of increase in HV. Sitting-height (SH) to standing-height ratio % (SH%) remained unchanged throughout GH therapy, and no significant change in skeletal maturation was observed. In conclusion, hGH treatment resulted in an increased growth rate in some children with achondroplasia; however, this increase waned during the second year of treatment. Children with the lowest pretreatment HVs seemed to benefit most from GH therapy. Nonetheless, the usefulness of GH treatment in achondroplasia will be known only when a study of final height is completed.

Myocardial trophic effects of blood pressure in children with insulin-dependent diabetes mellitus.

To evaluate the effect of blood pressure (BP) on the left ventricular mass index (LVMI), 66 children with IDDM 13 +/- 3 years of age were studied and compared with 58 healthy age-matched siblings. The 24 h BP recordings disclosed that children with diabetes had higher DBP (68 vs. 65 mm Hg, P = 0.002), especially at night (60 vs. 55 mm Hg, P = 0.00007), with a minimisation of the normal nocturnal hypotension (-9.9 vs. -12.4 mm Hg, P = 0.04). Their LVMI was higher (79 vs. 71 g/m2, P = 0.02); it was independent of BP values and variability (P = NS), but it was positively correlated with heart rate (r = -0.46, P = 0.0005). In the control group, LVMI was significantly correlated with the mean SBP (r = 0.46, P = 0.0005); with its variability (r = 0.32, P = 0.02) and, to a lower extent, with heart rate (r = -0.29, P = 0.03). It is concluded that in children with diabetes mellitus the participation of BP in myocardial hypertrophy is not so obvious, although the BP load is increased. The increase of the LVMI occurs early in life and before the onset of hypertension.

Serum levels of IGFBP-3: usefulness in diagnosis of GH deficiency and relationship to measurements of GH secretion in children.

Aims of the study were to assess the relationship between serum levels of IGFBP-3 with IGF-I serum levels, peak GH levels in response to two stimulation tests (PKGH) and GH urinary excretion in children, and to examine the usefulness of IGFBP-3 for diagnosis of GH deficiency. Our study group consisted of 86 children with normal stature, 12 children with normal short stature and 12 children with GHD. In all children, serum levels of IGF-I and IGFBP-3 were measured and GH urinary excretion was assessed in overnight urine collections. Children with short stature had two stimulation tests and the peak GH level was used in the analysis. IGFBP-3 SDS was strongly correlated with IGF-I SDS (r = 0.63, p < 0.001), significantly correlated with peak GH (r = 0.42, p < 0.05) and weakly, but not significantly, correlated with urinary GH excretion. Among the 12 children with GHD, only two had normal IGFBP-3 values (sensitivity 83%). In contrast, all normal short children except one had IGFBP-3 levels within the normal range, defined by the 5th and 95th percentile (specificity 92%). Sensitivity and specificity of IGF-I were respectively 67% and 50%. In conclusion, IGFBP-3 levels are strongly correlated with IGF-I levels, weakly correlated with peak GH response to provocative tests and may serve as a valuable parameter, in combination with others, in the evaluation of the GH-IGF axis.

Endothelin 1-21 plasma concentrations in children and adolescents with insulin-dependent diabetes mellitus.

This study is based on the hypothesis that endothelins (ETs), which are 21-amino acid peptides with vasoactive and proliferative properties, could be implicated in the development of complications of insulin dependent diabetes mellitus (IDDM) in children and adolescents. We determined plasma ET 1-21 concentrations by radioimmunoassay in 59 patients with IDDM (32 male, 27 female) and in 41 healthy siblings (20 male, 21 female) and investigated the association of ET 1-21 concentrations with age, sex, control of diabetes (expressed as % of glycosylated hemoglobin), duration of disease and presence of complications. Plasma ET 1-21 concentrations (mean +/- SEM) were 14.12 +/- 0.30 pg/ml in IDDM and 15.34 +/- 0.47 pg/ml in healthy siblings. The difference was statistically significant (p = 0.01) after controlling for age and sex by multiple logistic regression. In the group with IDDM, analysis of covariance showed duration of disease to be the only variable associated with ET 1-21 values (b = 0.2179 pg/ml/yr, p = 0.04). It is concluded that in youngsters with IDDM ET plasma concentrations are lower than in healthy controls, negatively associated with duration of the disease and not directly implicated in diabetic angiopathy.

Long bone fracture healing: IGF-I concentrations and specific binding to erythrocytes.

Animal experiments suggested a possible interaction between GH or GH-dependent growth factors and bone healing. The aim of this study was to determine whether there were any significant changes in serum levels of IGF-I and/ or the activity of its receptors while a fractured bone was healing. Serum concentrations of IGF-I and its specific binding to erythrocyte receptors (IGF-I SB) were determined in a group of 12 prepubertal children treated for long bone fractures. Results were compared to those obtained from a group of age- and sex-matched controls. Blood samples were taken from all patients two weeks following the fractures, when bone formation rate should have been maximal. We found no difference in IGF-I SB between the two groups. However, serum IGF-I levels were increased in the group of children with fractures compared to controls. Results are suggestive of a possible interaction between IGF-I and bone repair processes as other investigators have suggested on the basis of animal experiments.

M-mode echocardiographic evaluation of systolic function, LV volume and mass in children on growth hormone therapy.

Since abnormal endogenous growth hormone (GH) secretion in adults is associated with cardiac dysfunction, it is important to ensure that GH therapy in children and adolescents does not cause similar effects. Forty-two growth hormone-deficient children (Group 1) (19 girls, 23 boys) were evaluated. Six girls and seven boys were prepubertal with a mean age of 6.65 yr (range 4.37-9.73 yr). Twenty-nine were pubertal (13 girls, 16 boys), mean age 13.57 yr (range 10.08-16.76 yr). The patients had been on long-term GH therapy for 34.97 +/- 18.78 months with an average weekly dose of 17.61 IU/m2/wk. The mean height SDS was -2.85 +/- 1.22 for boys and -2.5 +/- 0.64 for girls at the onset of therapy, and at the time of examination -1.8 +/- 1.32 for the boys and 1.87 +/- 0.94 for the girls. Thirty-four normal control subjects (Group 2) matched for age, sex and body size were also studied. Left ventricular volume (LV), mass and systolic function [shortening fraction (FS)] were evaluated by two-dimensional guided M-mode echocardiography. Blood pressure was also measured. No differences in blood pressure were observed between patients and controls. There was no correlation of GH dose and duration of therapy with LV measurements. No significant differences were found between Group 1 and Group 2. These observations suggest that long term administration of GH does not produce adverse cardiac effects in GH deficient children. Nevertheless, longer follow-up studies are still needed to confirm the safety of long-term rhGH treatment.

Ultrasonography of the pancreas, as a function index, in children with beta-thalassemia.

Increased echogenicity of the pancreas, due to hemosiderosis, is a frequent laboratory finding in children and adolescents with beta-thalassemia. The aim of this study was to investigate whether increased echogenicity of the pancreas is associated with dysfunction. The ultrasonic image of the pancreas was examined in 34 children aged 12+/-3.8 years old and was compared to the endocrine and exocrine functioning of the gland. Oral glucose tolerance test (OGTT) was performed with simultaneous measurement of insulin and serum trypsin. Twenty-six of the 34 patients (76.5%) presented increased echogenicity, while 8 (23.5%) had a normal ultrasonic pancreatic image. 77% of the patients with increased echogenicity had abnormal OGTT, 46%, with subnormal or increased insulin values, and 32.5% manifested low levels of trypsin. Among the patients with normal ultrasound, 25% had abnormal OGTT and 37.5% abnormal insulin values. Statistical analysis with Student's t-test revealed that patients with increased echogenicity had significantly higher glucose values on OGTT at 60: 7.6 +/- 1.8 mmol/l (137.3 +/- 33.7 mg/dl) as compared to the patients with normal ultrasound: 6.1 +/- 1.2 mmol/l (110.75 +/- 21.72 mg/dl) (p<0.05). Insulin values were significantly affected at 30, 60, and 90 min: 570+/-301, 332+/-156, 294+/-158 pmol/l (79.54 +/- 42, 46.4 +/- 21.8, 41.04 +/- 22 mU/l) respectively in patients with increased echogenicity in comparison to those with normal ultrasonographic image of the gland: 301 +/- 170, 192 +/- 52, 135 +/- 63 pmol/l (42 +/- 23.7, 26.85 +/- 7.36, 18.9 +/- 8.8 mU/l) (p<0.05). No statistical significance was observed between the two groups regarding trypsin levels, even though abnormal values were observed in more children with increased echogenicity than in patients with a normal ultrasound. The above findings confirm that increased echogenicity of the pancreas is associated with disturbance of its function. This simple imaging method could be used as a rough early index of detection of an increased risk for developing diabetes mellitus in patients with beta-thalassemia.

Education and certification of genetic counselors.

Genetic counseling is defined by the American Society of Human Genetics as a communication process which deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family. The first graduate program (Master's degree) in genetic counseling started in 1969 at Sarah Lawrence College, NY, USA, while in 1979 the National Society of Genetic Counseling (NSGC) was established. Today, there are 29 programs in U.S.A. offering a Master's degree in Genetic Counseling, five programs in Canada, one in Mexico, one in England and one in S. Africa. Most of these graduate programs offer two year training, consisting of graduate courses, seminars, research and practical training. Emphasis is given in human physiology, biochemistry, clinical genetics, cytogenetics, molecular and biochemical genetics, population genetics and statistics, prenatal diagnosis, teratology and genetic counseling in relation to psychosocial and ethical issues. Certification for eligible candidates is available through the American Board of Medical Genetics (ABMG). Requirements for certification include a master's degree in human genetics, training at sites accredited by the ABMG, documentation of genetic counseling experience, evidence of continuing education and successful completion of a comprehensive ABMG certification examination. As professionals, genetic counselors should maintain expertise, should insure mechanisms for professional advancement and should always maintain the ability to approach their patients.

Melnick-Needles syndrome in a mother and her son.

The Melnick-Needles syndrome is a rare connective tissue disorder characterised by specific facial features (small facial bones, exophthalmos, hypertelorism, full checks and small mandible), skeletal defects and short stature. The syndrome is considered to be lethal in males. Nevertheless, five surviving males are considered to represent new mutations. We are presenting an affected surviving male with the Melnick-Needles syndrome born to an affected mother.

Phenotypic variability of mannosidosis type II: report of two Greek siblings.

Two patients, a 13-year-old boy and his 24-year-old sister, were diagnosed as mannosidosis type II cases, on the basis of both presenting extremely reduced plasma and white blood cell acid-alpha-mannosidase are reported. With the exception of mental retardation and neurosensory deafness the two siblings manifested a wide phenotypic variability. The boy had several facial features indicating a lysosomal storage disorder, as well as spondylolisthesis. His sister, apart from heavy eyebrows and lower jaw prognathism appeared normal.

Familial bilateral blepharoptosis and subvalvular aortic stenosis.

A boy and his mother with bilateral congenital blepharoptosis, downslanting palpebral fissures, hypertelorism, microcephaly, short nose with flattened nasal root, microstomia, prominent lateral palatine ridges, bifid (boy) hypoplastic (mother) uvula, generalized dental caries, short neck, peculiar voice and mild conductive deafness are reported. The boy had subvalvular aortic stenosis. The mother had pectus excavatum but not any signs or symptoms of cardiovascular defect.

Lysosomal storage diseases in Greece.

Over the last 13 years 2745 patients from all over Greece suspected to have a lysosomal storage disorder were referred to the Institute of Child Health. 1581 of those were suspected of having a mucopolysaccharidosis (MPS). 94 cases (3.42% of the total referrals) were positive: 36 patients with MPS, 6 with mucolipidosis (1 type I, 1 type II and 4 type III) and 3 with mannosidosis. Sanfilippo B was not only the most frequent type III MPS but also the most frequent MPS identified in our study. Sphingolipidoses and other lysosomal disorders were diagnosed in 47 cases and non-lysosomal disorders in 19 cases. In our experience Gaucher disease, Sanfilippo B and Hunter syndrome are the most frequent lysosomal disorders in Greece accounting for 23.4%, 17.0% and 7.6% respectively of all diagnosed cases. 13% of the patients originated from Thessaly including 5/16 Sanfilippo B, 2/3 Morquio B, 2/3 Maroteaux-Lamy, 2/6 Metachromatic leukodystrophy and 2/12 Gaucher type 1.

Genetic predisposition and IDDM in Greece.

Serological typing of HLA-DR antigens was performed on 116 patients with IDDM and 380 healthy controls. As expected a high incidence of HLA-DR3 and DR4 antigens was observed in patients with IDDM. However, the HLA-DR2 antigen, which rarely occurs in IDDM and is considered to confer protection against IDDM, was found in equal distribution (35%) in both patients and controls. HLA-DQ genotype analysis in 10 children with IDDM and 13 controls, all with the HLA-DR2 haplotype, showed that the great majority of affected children and normal controls carry the DR2 (16) or AZH-DQA1 *0102, DQB *0502 subtype. The high incidence of this subtype in normal individuals possibly explains why the DR2 antigen does not offer protection against IDDM in Greeks.