Niels Thomas Hertel

Expanding the Spectrum of Mutations in GH1 and GHRHR: Genetic Screening in a Large Cohort of Patients with Congenital Isolated Growth Hormone Deficiency

CONTEXT It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Response to growth hormone treatment and final height in Noonan syndrome in a large cohort of patients in the KIGS database.

BACKGROUND Noonan syndrome (NS) is an autosomal dominant inherited disease, characterized by a distinctive facial appearance, congenital heart defects, and short stature. Treatment with growth hormone (GH) is an option to enhance height, but long-term effects are still unclear. PATIENTS AND METHODS A cohort of 402 patients (269 males, 133 females), mean age 9.7 years at start with GH, was studied within the KIGS International growth database with respect to long-term response to GH therapy and final height after GH therapy. RESULTS At the start of GH therapy median height was -2.61 SDS (Tanner 1966 standards). Seventy-three patients who were followed longitudinally for 3 years had an increment in height SDS (Ht SDS) over the first 3 successive years of 0.54, 0.13 and 0.13, respectively. Twenty-four patients had reached their final height after 4-12 years of GH treatment. Their Ht SDS increased from a median of -3.28 to a median of -2.41 at final height. CONCLUSION This group of patients with NS showed an early response to GH treatment, with an attenuation of this effect thereafter. At final height the median increment of final height was 0.61 SDS according to Tanner standards and 0.97 SDS according to Noonan standards. No serious side effects were reported.

A Study of the Clinical and Radiological Features in a Cohort of 93 Patients with a COL2A1 Mutation Causing Spondyloepiphyseal Dysplasia Congenita or a Related Phenotype

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance‐like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler‐like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38–74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto‐axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10–54) in whom flexion‐extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35–56), and retinal detachment had occurred in 12% (95% CI 6–21; median age 14 years; youngest age 3.5 years). Thirty‐two patients complained of hearing loss (37%, 95% CI 27–48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype–phenotype correlations in this cohort, we propose guidelines for the management and follow‐up in this group of disorders.

Late relapse of adrenocortical carcinoma in Beckwith-Wiedemann syndrome. Clinical, endocrinological and genetic aspects

We report on a girl with an unusual Beckwith‐Wiedemann syndrome (BWS) and hemihypertrophy, who developed an adrenocortical carcinoma with atypical clinical behaviour. At 4 y of age the girls was admitted to hospital with cushingoid features, virilization, increased excretion of steroids and low serum ACTH. A right‐sided adrenocortical carcinoma was removed. At age 12.5 y the cushingoid features reappeared together with a tumour in the left thigh. A CT scan of the thorax and abdomen revealed pulmonary metastasis only. Corticosteroid excretion was increased and serum ACTH level suppressed. The femoral and the pulmonary metastases were removed and histology showed adrenocortical carcinoma. Excretion of corticosteroids subsequently normalized. Meningeal and pulmonary metastases with similar histologies appeared one year later with normal hormone values. Twenty‐two months after the recurrence the girl died of an intracranial metastasis. Southern blot analysis of the LIT1 transcript in the KvLQT1 gene in the BWS region on chromosome 11p15 revealed hypomethylation of the maternal allele.

Asn540Lys mutation in fibroblast growth factor receptor 3 and phenotype in hypochondroplasia

Hypochondroplasia is characterized by a disproportionate short stature with rhizomelic shortening of the limbs. Amino acid substitutions Asn540Lys, Asn540Thr and Ile538Val in the fibroblast growth factor receptor 3 (FGFR3) are considered to cause hypochondroplasia. In this study we examined the FGFR3 gene for the previously described hypochondroplasia mutations and the phenotype of 23 probands with clinically and radiologically diagnosed hypochondroplasia. For the phenotype comparison, the patients were divided into two groups: Group 1: hypochondroplasia with Asn540Lys substitution; Group 2: hypochondroplasia with no mutations identified so far. A three‐generation family negative for the known hypochondroplasia mutations was examined with polymorphic markers flanking the FGFRI, FGFR2 and FGFR3 genes. Nine (39%) of 23 probands were found to be heterozygous for the Asn540Lys substitution. The individuals positive for the Asn540Lys substitution were significantly more disproportionate than the individuals without this mutation. In this respect, a genotype–phenotype correlation was found in our patients. However, some individuals belonging to the group without mutations identified so far showed similarly abnormal proportions. Genotyping/haplotyping in the three‐generation family with hypochondroplasia showed that FGFR1, FGFR2 and FGFR3 genes were not linked to the hypochondroplasia phenotype in this family, thus further confirming the genetic heterogeneity of hypochondroplasia.

Prevalence of overweight and obesity in Danish preschool children over a 10-year period. A study of two birth cohorts in general practice

Aim:  To determine change in the prevalence of overweight and obesity in preschool children, over a 10‐year period and to identify possible predictors of overweight in 5‐year‐old children.

Complex multi-block analysis identifies new immunologic and genetic disease progression patterns associated with the residual β-cell function 1 year after diagnosis of type 1 diabetes

The purpose of the present study is to explore the progression of type 1 diabetes (T1D) in Danish children 12 months after diagnosis using Latent Factor Modelling. We include three data blocks of dynamic paraclinical biomarkers, baseline clinical characteristics and genetic profiles of diabetes related SNPs in the analyses. This method identified a model explaining 21.6% of the total variation in the data set. The model consists of two components: (1) A pattern of declining residual β-cell function positively associated with young age, presence of diabetic ketoacidosis and long duration of disease symptoms (P = 0.0004), and with risk alleles of WFS1, CDKN2A/2B and RNLS (P = 0.006). (2) A second pattern of high ZnT8 autoantibody levels and low postprandial glucagon levels associated with risk alleles of IFIH1, TCF2, TAF5L, IL2RA and PTPN2 and protective alleles of ERBB3 gene (P = 0.0005). These results demonstrate that Latent Factor Modelling can identify associating patterns in clinical prospective data – future functional studies will be needed to clarify the relevance of these patterns.

Danish Registry of Childhood and Adolescent Diabetes

Aim The aims of the Danish Registry of Childhood and Adolescent Diabetes (DanDiabKids) are to monitor and improve the quality of care for children and adolescents with diabetes in Denmark and to follow the incidence and prevalence of diabetes. Study population The study population consists of all children diagnosed with diabetes before the age of 15 years since 1996. Since 2015, every child followed up at a pediatric center (<18 years of age) will be included. Main variables The variables in the registry are the quality indicators, demographic variables, associated conditions, diabetes classification, family history of diabetes, growth parameters, self-care, and treatment variables. The quality indicators are selected based on international consensus of measures of good clinical practice. The indicators are metabolic control as assessed by HbA1c, blood pressure, albuminuria, retinopathy, neuropathy, number of severe hypoglycemic events, and hospitalization with ketoacidosis. Descriptive data The number of children diagnosed with diabetes is increasing with ∼3% per year mainly for type 1 diabetes (ie, 296 new patients <15 years of age were diagnosed in 2014). The disease management has changed dramatically with more children treated intensively with multiple daily injections, insulin pumps, and increased number of self-monitored blood glucose values per day. These initiatives have resulted in a significant improvement in HbA1c over the years and a decrease in the number of children experiencing severe hypoglycemia, diabetic nephropathy, and retinopathy. Conclusion The systematic collection of data in DanDiabKids documents improved quality of care over the last 12 years, despite a substantial increase in the number of patients cared for by pediatric departments in Denmark, fulfilling the purpose of the registry.

Recombinant human growth hormone treatment, using two dose regimens in children with chronic renal failure--a report on linear growth and adverse effects.

The aim of this study was to study the efficiency and the adverse effects of 2 or 4 IU/m2/day of growth hormone (GH) in the first year and 4 IU/m2/day in the second. Of 29 growth-retarded children with chronic renal failure (CRF) (aged 3.4-15.1 years), 23 completed the first year of therapy, and 16 completed the second year. Height velocity SDS (HVSDS) increased in the first year in the low-dose group with 3.0, and 3.8 in the high-dose group. In the second year, HVSDS increased by 1.3 in the low-dose group and by 2.1 in high-dose group (p < 0.05). The IGF-I/IGFBP-3 ratio rose identically during the first year (p < 0.01). The retarded bone age did not advance inappropriately. The integrated insulin levels (AUC) increased significantly after 1 year of therapy in both groups. HbA1c, levels did not change. The number of adverse events was highest in the low-dose group, in which one patient developed overt insulin dependent diabetes mellitus. In conclusion, glucose metabolism should be monitored in children with CRF during rhGH-treatment. GH therapy in our patients resulted in a significant increase in height velocity with no inappropriate bone age progression and few serious adverse effects, all without relation to the dose of rhGH. The low start dose (2 IU/m2/ day) was of no advantage compared to the high dose.

Treatment intensification without improved HbA1c levels in children and adolescents with Type 1 diabetes mellitus

To examine trends in diabetes treatment in Danish children and adolescents with Type 1 diabetes mellitus, comparing treatment intensity with metabolic outcomes in the population, and to describe the challenges of population‐based registries in a clinical setting with rapidly changing treatment methods.