Diverse deletions in the growth hormone receptor gene cause growth hormone insensitivity syndrome.

Growth hormone insensitivity syndrome (GHIS; also known as Laron syndrome), is characterized by severe postnatal growth failure and normal growth hormone. The syndrome is frequently caused by point mutations in the growth hormone receptor gene (GHR). Here we report five families with GHIS and partial deletions of the GHR gene. The deletion breakpoints were sequenced and PCR-based diagnostic tests were developed. In a Cambodian family, a novel deletion removed part of exon 5 and 1.2 kb of the preceding intron. The deletion occurred by recombination within four identical nucleotides. In the mutant transcript, skipping of the truncated exon 5 leads to a frameshift and premature termination codon (PTC). A previously reported discontinuous deletion of GHR exons 3, 5, and 6 was identified in three Oriental Jewish families. An unaffected individual was heterozygous for the exon 5 and 6 deletion, but homozygously deleted for exon 3 suggesting that the exon 3 deletion is a polymorphism. The pathogenic deletion of exons 5 and 6 spans about 7.5 kb. Sequence analysis of the breakpoints revealed an imperfect junction between introns 4 and 6, with a four basepair insertion. A novel deletion of 13 nucleotides within exon 9 was identified in a Caucasian girl with GHIS who carries the I153T missense mutation on her other allele. The exon 9 deletion leads to a frameshift and PTC. The predicted protein retains the transmembrane domain and a short cytoplasmic tail. Four family members in three generations were carriers of this deletion, but only two of them were below normal for height, suggesting that this mutation by itself does not act as a dominant negative, as was reported for two other GHR mutations which lead to truncation of the intracellular domain.

Familial disseminated infection due to atypical mycobacteria with childhood onset.

We describe two brothers of consanguineous Pakistani parents who lived in Norway and had disseminated infections due to nontuberculous mycobacteria. The first boy developed clinical signs of disseminated BCG infection after vaccination. He was successfully treated with antimycobacterial agents. Two and one-half years later, he developed disseminated Mycobacterium avium complex infection and died at 6 years of age. The second boy, born 5 years after the death of his brother, did not receive BCG vaccine. At 2 years of age, he developed disseminated M. avium complex infection. Because he responded only partly to specific chemotherapy, empirical interferon gamma treatment was added to the antimycobacterial regimen. After 2 years of combined therapy, his condition is stable. Studies of peripheral blood mononuclear cells from the second boy demonstrated reduced surface expression of the ligand binding chain of interferon gamma receptor 1. This defect explains the increased susceptibility to mycobacterial disease in the two brothers.

Abnormal regulation of interferon-gamma, interleukin-12, and tumor necrosis factor-alpha in human interferon-gamma receptor 1 deficiency.

Mycobacterial infections are critically controlled by interferon-gamma (IFN-gamma) and the cellular responses it elaborates, as shown by patients with mutations in the IFN-gamma receptor ligand-binding chain (IFN-gamma R1) who have disseminated nontuberculous mycobacterial infections. The immunologic sequelae of IFN-gamma R1 deficiency were characterized in 2 unrelated patients from the Indian subcontinent with novel homozygous recessive IFN-gamma R1 mutations. In vitro, these patients' peripheral blood mononuclear cells produced 10% of normal IFN-gamma and interleukin-12 (IL-12) in response to phytohemagglutinin (PHA) but normal amounts of IFN-gamma in response to PHA plus IL-12. Tumor necrosis factor-alpha (TNF-alpha) production was normal in response to endotoxin and to PHA but was not augmented by the addition of IFN-gamma. An abnormal phenotype was not found in heterozygous patient relatives. These patients demonstrate the critical role that the IFN-gamma receptor plays in the regulation of IFN-gamma, IL-12, and TNF-alpha.

[47,XYY syndrome. Is diagnosis of significance?]. / Syndromet 47,XYY. Har diagnosen betydning?

Over a 10-year period, from 1984-1995, in the Norwegian county of Vest-Agder, five patients in a paediatric clinic were diagnosed as having chromosome constitution 47,XYY. There are 1,250 males born a year in Vest-Agder. The patients were identified with bias, and not in a routine or prospective screening programme. All patients except one, a child who was diagnosed by chance at the age of one week; were admitted because of moderate conduct disorders or problems at school and striking tallness of stature. The half-brother of one of the 47,XYY boys had Klinefelter's syndrome 47,XYY. We conclude that identification of 47,XYY syndrome and information about it were of significance and help in counselling the patients and their families.

[Growth hormone resistance. Genetic defects and therapy in Laron syndrome and similar conditions]. / Veksthormoninsensitivitet. Genetiske defekter og terapi ved Larons syndrom og liknende tilstander.

Two siblings with Laron syndrome from Cambodia, Asia, are described. They fulfilled the strict diagnostic criteria for the syndrome, including an IGF-1 generation test with growth hormone. The growth hormone binding protein levels where lower than 2%. Genetic investigation revealed an unique structural abnormality of the extracellular domain that included deletion of exon 5 (Mary An Berg and Uta Francke, Beckman Center, Stanford University, California, USA. Personal communication, 1995). In May 1994 the height of the boy (eight years old) was 87.6 cm and the girl (six years old) was 78.6 cm. Treatment was started with IGF-I (Pharmacia AB, Sweden) 40 micrograms/kg b.i.d. subcutaneously and was progressively increased to 120 micrograms/kg. The pre-treatment growth velocities were 2.7 cm/year (boy) and 2.4 cm/year (girl). The mean growth velocities after 30 months of therapy were 5.7 cm/year (boy) and 6.3 cm/year (girl). There were no adverse events during IFG-I treatment. The genetics, heterogeneity and therapy of growth hormone insensitivity are discussed.

Increased neutrophil insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced functional capacity in patients with untreated Laron syndrome.

Insulin-like growth factor-I (IGF-I) is a growth hormone-dependent peptide with growth and immunoregulatory properties, and in Laron syndrome growth hormone insensitivity induces impaired production of IGF-I. In the present study we have determined the neutrophil expression of IGF-I receptors (IGF-I-Rs), as well as the IGF-I-induced priming of neutrophil functional capacity, in two children with Laron syndrome treated with recombinant human IGF-I, and in age-matched controls. Before treatment, the patient neutrophil expression of IGF-I-Rs was significantly increased. However, with replacement therapy the neutrophil IGF-I-R expression was downregulated to levels similar to those of the controls within one month. In the patients, the phagocytic capacity and oxidative burst of unprimed neutrophils were normal and similar to controls before the start of treatment. Moreover, IGF-I efficiently primed both patient and control neutrophils to increase their phagocytic capacity and oxidative burst in vitro. However, before therapy, the priming response to IGF-I was significantly stronger in the neutrophils in the patients than in the controls. The present data support earlier studies by us and others demonstrating that IGF-I is a potent regulator of mature neutrophil function, but also suggest that these leukocytes may function normally in the presence of very low levels of IGF-I in vivo.

[Infant mortality in Kristiansand. The 150-year anniversary of doctor Lochmann and comparison with current statistics]. / Barnedødelighet i Kristiansand. Et 150-årsminne om doktor Lochmann og en sammenlikning med vår egen tid.

Professor Ernst Ferdinand Lochmann (1820-91) was born in Kristiansand, Norway. His ideas on infectious diseases, e.g. tuberculosis, were far ahead of his time. He worked for better prophylactic treatment in communicable diseases and was concerned about the high death rates in children in his home town. In Kristiansand, during the 25 years from 1850 to 1874, there were 128 deaths among children under one year of age per 1,000 births. In the same period nearly one-third of the children died before the age of 14 years (8,426 births, 2,592 deaths). In 1995 the death rate for children under one year was four per 1,000 in Kristiansand (Vest-Agder county), and the perinatal mortality (stillbirths and deaths among children under one week) was three per 1,000 births. Priorities in health care are often debated in Norway. The death rate among children is extremely low, and politicians focus on geriatrics and psychiatry. However, even in the last decade (1985-94) significant changes in perinatal mortality and cot deaths (sudden infant death syndrome) are recorded.

[Diagnosis and treatment of familial hypercholesterolemia in children and adolescents]. / Diagnose og behandling av familiaer hyperkolesterolemi hos barn og ungdom.

The identification and management of hyperlipidemias in children are currently limited to persons regarded as being at very high risk, such as those with familial hypercholesterolemia. Universal screening of children is not recommended, but it is important to screen the subset of children and adolescents at highest risk, i.e. those with a family history of premature cardiovascular disease or familial hypercholesterolemia. Treatment of children and adolescents with hypercholesterolemia requires a multidisciplinary approach. Cholesterol-lowering medication may be required in addition to dietary therapy in children with a history of premature coronary heart disease among close relatives.

[Familial hypercholesterolemia in children. A management program. Procedures for diagnosis and treatment in our pediatric departments]. / Familiaer hyperkolesterolemi hos barn. Handlingsprogram prosedyrer til diagnostisering og behandling ved våre barneavdelinger. Gruppen som har utarbeidet handlingsprogrammet er nedsatt av Norsk barnelegeforening, 1995.

A Norwegian programme for treatment and selective screening of familial hypercholesterolaemia has been developed which takes into account family history and levels of hypercholesterolaemia. The programme includes recommendations on when and whom to screen for familial hypercholesterolaemia. With regard to treatment, special emphasis is placed on diet. The working group suggests that small lipid clinics with a dietitian should be established in some paediatric departments.

Aplasia cutis congenita associated with limb, eye, and brain anomalies in sibs: a variant of the Adams-Oliver syndrome?

Aplasia cutis congenita (ACC) may occur in isolation or with other congenital malformations. Peripheral limb anomalies and ACC are major elements of the Adams-Oliver syndrome, which is usually inherited as an autosomal dominant disorder. We report on a sister and brother with ACC and brain, eyes, and transverse limb anomalies. The phalanges of the hands and feet were either short or absent. The girl also had absence of right patella, was severely mentally retarded and blind with retinal nonattachment. The boy had a falciform fold in the left eye. He died at age one week and autopsy showed partial agenesis of corpus callosum. The findings in the sibs may represent a severe variant of the Adams-Oliver syndrome, or a previously unrecognized syndrome involving vascular disruption.

Ehlers-Danlos syndrome and diverticula of the bladder.

Cases of two boys, 6 and 4 years old respectively, with Ehlers-Danlos syndrome (EDS) and large bladder diverticula, are reported. Diverticulectomies were performed, but large diverticula reappeared in both patients. A connection between the increased extensibility of the connective tissue in EDS and the development of bladder diverticula is suggested.

Case report: maldescent of the thymus in a hypoparathyroid infant with Pharyngeal Pouch Syndrome.

The clinical and pathological findings in a 6-month-old boy with III-IV pharyngeal puoch syndrome are reported. The infant had multiple congenital anomalies including absence of the parathyroid glands, maldescent of the thymus, aberrant right subclavian artery and dysfunction of the glossopharyngeal nerve. Because of persistence of the thymus in the cervical area, a thymic shadow was not found on roentgenographic examination of the anterior mediastinum. The weight and histology of the thymus were normal, as were studies of humoral and cellular immunity.