Dagfinn Aarskog

Mutations in the Insulin Gene Can Cause MODY and Autoantibody-Negative Type 1 Diabetes

OBJECTIVE—Mutations in the insulin (INS) gene can cause neonatal diabetes. We hypothesized that mutations in INS could also cause maturity-onset diabetes of the young (MODY) and autoantibody-negative type 1 diabetes. RESEARCH DESIGN AND METHODS—We screened INS in 62 probands with MODY, 30 probands with suspected MODY, and 223 subjects from the Norwegian Childhood Diabetes Registry selected on the basis of autoantibody negativity or family history of diabetes. RESULTS—Among the MODY patients, we identified the INS mutation c.137G>A (R46Q) in a proband, his diabetic father, and a paternal aunt. They were diagnosed with diabetes at 20, 18, and 17 years of age, respectively, and are treated with small doses of insulin or diet only. In type 1 diabetic patients, we found the INS mutation c.163C>T (R55C) in a girl who at 10 years of age presented with ketoacidosis and insulin-dependent, GAD, and insulinoma-associated antigen-2 (IA-2) antibody-negative diabetes. Her mother had a de novo R55C mutation and was diagnosed with ketoacidosis and insulin-dependent diabetes at 13 years of age. Both had residual β-cell function. The R46Q substitution changes an invariant arginine residue in position B22, which forms a hydrogen bond with the glutamate at A17, stabilizing the insulin molecule. The R55C substitution involves the first of the two arginine residues localized at the site of proteolytic processing between the B-chain and the C-peptide. CONCLUSIONS—Our findings extend the phenotype of INS mutation carriers and suggest that INS screening is warranted not only in neonatal diabetes, but also in MODY and in selected cases of type 1 diabetes.

A familial syndrome of short stature associated with facial dysplasia and genital anomalies

The natural history and clinical findings of a probably X-linked recessive growth disorder, found in 7 affected males from 2 generations of the same family, have been described. Growth was normal for the first 2 to 4 years of age but then fell below normal curves. Bone age was retarded, corresponding to height age. Spontaneous puberty occurred at the expected age and was accompanied by a growth spurt. All patients had a similar pattern of anomalies consisting of a round facies, slight antimongoloid palpebral slant, hypertelorism, short stubby nose with anteverted nostrils, broad upper lip with marked philthrum, inguinal hernia, undescended testes, and a bifid scrotum with a scrotal skin fold extending ventrally around the base of the penis. The natural history demonstrated a favorable prognosis for ultimate height, sexual and mental development, and fertility.

Final height after long-term growth hormone treatment in Turner syndrome

OBJECTIVES To study final height after long-term growth hormone (GH) treatment in girls with Turner syndrome (TS). PATIENTS One hundred fifty three patients with TS, participating in five European trials, were included. They started GH treatment in 1987-1989 at an age of 10 years or older. Mean age at start of treatment ranged between 11.7 and 14.6 years among countries and mean bone age between 9.4 and 11.8 years. Fourteen girls were lost to follow-up, leaving 139 for analysis. Most girls have now attained final height (FH), defined as a linear growth velocity (GV) of 4 mm/yr or less, measured over at least 6 months (group 1, n = 56), or near-FH, defined as a GV of 5 to 9 mm/yr (group 2, n = 22). Sixty-one girls were still growing 10 mm/yr or more. METHODS AND MAIN RESULTS At the last measurement, mean (SD) height was 150.7 (4.9) cm in group 1 and 148.5 (5.1) cm in group 2. The differences between FH and projected final height based on extrapolation of the initial height-standard deviation score on Turner syndrome reference values, were 2.9 (3.8) and 3.0 (3.3) cm, respectively. The mean gain over the Bayley-Pinneau prediction of FH was 3.3 (3.9) cm in both groups. No significant differences between countries were found. The range of gains over projected height (-4.7 to 12.1 cm) was large, and 25% of gains were 5 cm or more. Gain over initial projection was strongly related to initial growth delay and to growth response during the first 2 years of treatment. A logistic regression model is presented that predicts gain of more than 5 cm with a positive predictive value of 62% and a negative predictive value of 84%. CONCLUSIONS Long-term GH treatment in girls with TS, starting treatment at a relatively advanced age ( > 10 years) resulted in a modest mean gain in FH of 3 cm, with wide interindividual variation.

Expression of leukocyte differentiation antigens during the differentiation of HL-60 cells induced by 1,25-dihydroxyvitamin D3: comparison with the maturation of normal monocytic and granulocytic bone marrow cells.

1,25‐Dihydroxyvitamin D3 [1,25‐(OH)2D3] induces monocytic differentiation of the HL‐60 leukemic cell line. The present study investigated whether and to what extent this differentiation resembles the normal maturation of monocytic cells in the bone marrow. Multidimensional flow cytometry was used to identify changes in antigen expression that occur in normal bone marrow cells at distinct stages of monocytic and granulocytic maturation. HL‐60 cells were analyzed in the same manner after exposure to 1,25‐(OH)2D3 to determine whether the hormone induces a similar sequence of phenotypic changes. In the leukemic cells, monocytic features were sequentially induced and several maturational steps could be resolved. CD14, CD32, CD53, CD15, CDw65, CD29, CD16, and CD66b were modulated in 1,25‐(OH)2D3‐induced HL‐60 cells as in the normal monocytic maturational pathway. Differences were observed for CD15s and CDw17. The expression pattern of CD44 during differentiation of HL‐60 cells resembled that in granulocytic cells. The results therefore suggest that 1,25‐(OH)2D3 induces a differentiation program in HL‐60 cells that in many ways resembles that of normal monocytic cells in the bone marrow but also carries elements of the granulocytic pathway.

SHORT Syndrome with Partial Lipodystrophy Due to Impaired Phosphatidylinositol 3 Kinase Signaling

The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85α regulatory subunit, encoded by PIK3R1. Using whole-exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85α and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling.

Expression of cell surface antigens during the differentiation of HL-60 cells induced by 1,25-ihydroxyvitamin D3, retinoic acid and DMSO

HL-60 cells were induced to differentiate by 1,25-dihydroxyvitamin D3, retinoic acid or DMSO. In order to investigate to which extent this maturation mimics the in vivo monocytic or myeloid differentiation, we compared induced HL-60 cells with peripheral blood monocytes and granulocytes by using a panel of mAbs directed against myeloid cell surface antigens. Upon exposure to 1,25-(OH)2D3, HL-60 cells acquired a differentiation phenotype close to that of mature monocytes. The changes in myeloid cell surface antigens induced by retinoic acid or DMSO paralleled the expression pattern of these molecules in normal granulopoiesis, although maturation was not achieved and partially defective.

McCune-Albright's syndrome following adrenalectomy for Cushing's syndrome in infancy

This report adds a new example to the curious association of polyostotic fibrous dysplasia with various endocrine disorders. A girl developed symptoms of Cushings syndrome at the age of 1 month. Total bilateral adrenalectomy was carried out when the infant was 4 months of age. Both glands showed nodular adrenal cortical hyperplasia. Within a period of 8 to 44 months following surgery, the clinical picture of McCune-Albrights syndrome became apparent, including skin pigmentation, polyostotic fibrous dysplasia, and sexual precocity.

Treatment of Cushing's disease in childhood and adolescence by stereotactic pituitary irradiation.

ABSTRACT. Eight children with Cushings disease aged 6‐18 years were treated with external radiation to the pituitary gland using 60Co gamma radiation given with stereotactic technique. The dose given varied between 50 and 70 Gy. The observation time was 2.6 to 6.75 years. Seven children had a clinical remission with normal urinary Cortisol excretion. One child had insufficent effect of two irradiations and underwent bilateral adrenalectomy. In the patients in remission the growth velocity increased during the first year after treatment but growth retardation occurred again during the second year. Insufficient growth hormone secretion was demonstrated in all subjects. Two patients were given thyroxine substitution and three showed evidence for secondary hypogonadism. In conclusion, stereotactic pituitary irradiation was effective in normalizing the excessive glucocorticoid production in children with Cushings disease. However, with the doses used, it was not possible to maintain a normal anterior pituitary function.

Pituitary dwarfism in the R271W Pit-1 gene mutation

AbstractThe Pit-1 gene encodes the POU-domain transcription factor Pit-1 which is important for the differentiation of the anterior pituitary and regulation of the PRL, GH and TSH genes. As a member of the POU domain transcription factors, Pit-1 contains a DNA-binding region, consisting of a POU-specific domain and a POU homeodomain. Mutation of the Pit-1 gene causes hypoplasia of the pituitary gland and deficiencies of GH, PRL and TSH. In a DNA sample from a 3-month-old girl with severe growth deficiency from birth, single stranded conformational polymorphism analysis of the Pit-1 gene identified a gel shift in exon 6. DNA-sequencing disclosed a single base mutation in codon 271 (CGG to TGG) that changes arginine to tryptophan (R271W) in the POU homeodomain. The patient presented distinct facial features with prominent forehead, marked mid-facial hypoplasia with depressed nasal bridge, deep-set eyes and a short nose with anteverted nostrils. MRI examination showed a hypoplastic pituitary gland. Low serum GH did not respond to insulin-arginine provocation or GHRH tests. PRL levels below the detection limit did not increase in response to a TRH test. T4 and free T4 was below detection limit (<20 nmol/l and <4 pmol/l). TSH was 2.0 mU/l and showed a blunt response to 6.0 mU/l following TRH test. TBG was normal. In spite of inappropriately low TSH and very low T4, T3 was in the low normal range (1.4–1.6 nmol/l) and she was clinically euthyroid. The thyroid function tests are consistent with increased monodeiodination activity and increased conversion of T4 to T3, possibly related to the Pit-1 gene mutation. GH and T4 treatment resulted in catch-up growth continued during 5 years of therapy. Conclusion Reports of nine other cases of R271W mutations of different populations as well as the present Norwegian patient suggest codon 271 of exon 6 to be a “hot spot” for Pit-1 mutations. To enable rapid and simple detection of this type of de novo mutation we have designed a specific amplification-created-restriction-site assay to check for the R271W mutation in patients suspected to have this rare form of genetic defect in growth hormone production.

Plasma concentrations of vitamin D metabolites during puberty of diabetic children

SummaryPlasma concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D and vitamin D binding protein were determined in 87 serum samples from 46 Type 1 (insulin-dependent) diabetic children and adolescents at the various stages of puberty. The results were compared with data similarly obtained from healthy pubertal children. The diabetic patients had lower mean 1,25-dihydroxyvitamin D concentrations (p<0.05) and higher molar ratios of 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D (p<0.05) than their healthy counter parts. In contrast to the reference group, the diabetic patients failed to attain the increase in 1,25-dihydroxyvitamin D normally seen during the pubertal stages of maximal growth velocity. The mean plasma levels of vitamin-D binding protein did not differ between the two groups, and a calculated ‘free’ 1,25-dihydroxyvitamin D value followed a pattern similar to that of total 1,25-dihydroxyvitamin D throughout puberty for both groups. The results suggest that the regulatory mechanisms of the vitamin D endocrine system are altered in diabetic children at puberty, resulting in a relative decrease in 1,25-dihydroxyvitamin D plasma concentration and increased 24,25-dihydroxyvitamin D levels.