Band 29, Heft 5

In the past 3 years, 15 patients with resistance to thyroid hormone α (RTHα), nine THRA gene mutations have been reported, reforming classification of RTH. RTHα exhibits distinguished clinical manifestations from RTHβ, including growth retardation, skeletal dysplasia, impaired neurodevelopment, cardiovascular dysfunction, constipation and specific thyroid axis type. This review focuses on possible pathogenesis by revelatory basic science of RTHα animal models in vivo, and patients’ mutant thyroid hormone receptor α (TRα) in vitro. Clinical manifestations and L-T4 effects are summarized, showing strong correlation to the severity of mutation mostly within the domain which dominated TR interaction with T3 and its corepressors/coactivators. In particular, we propose the diagnosis clues and promising treatment for clinicians.

Background : We evaluated a methylation-specific multiplex-ligation-dependent probe amplification (MS-MLPA) assay for the molecular diagnosis of transient neonatal diabetes mellitus (TNDM) caused by 6q24 abnormalities and assessed the clinical utility of using this assay in combination with next generation sequencing (NGS) analysis for diagnosing patients with neonatal diabetes (NDM). Methods : We performed MS-MLPA in 18 control samples and 42 retrospective NDM cases with normal bi-parental inheritance of chromosome 6. Next, we evaluated 22 prospective patients by combining NGS analysis of 11 NDM genes and the MS-MLPA assay. Results : 6q24 aberrations were identified in all controls and in 19% of patients with normal bi-parental inheritance of chromosome 6. The MS-MLPA/NGS combined approach identified a genetic cause in ~64% of patients with NDM of unknown etiology. Conclusions: MS-MLPA is a reliable method to identify all known 6q24 abnormalities and comprehensive testing of all causes reveals a causal mutation in ~64% of patients.

Background: Annually, many children and adolescents with type 1 diabetes mellitus (T1DM) insist on fasting for Ramadan despite being exempted and despite knowing all the risks. We aimed to assess the safety and metabolic impact of Ramadan fasting in children with T1DM using different insulin regimens. Methods: Children with T1DM who choose to fast during Ramadan 1434/2013 (29 days) were recruited 3 months before Ramadan. They received pre-Ramadan intensive education. Three insulin regimens were included; Regimen-I (regular insulin/NPH); Regimen-II (regular insulin/insulin glargine) and Regimen-III (premixed insulin). Changes in weight, insulin dose, HbA 1c , fructosamine and lipid profile were evaluated. Results: Out of total 53 patients (24 male), 28 patients (52.8%) completed Ramadan fasting (fasting group). The remaining 25 patients were included in (broke-fasting group). Positive correlation between fructosamine changes and number of days fasted during Ramadan. Significant decrease in post-Ramadan fructosamine (<0.001) and increase in post-Ramadan total cholesterol and low density lipoprotein (LDL) levels were detected within fasting, broke-fasting and insulin regimen groups. Significant higher blood glucose at three time points, pre-Iftar, pre-Sohur and midday in Regimen-I compared to Regimen-II and Regimen-III (p=0.004). Conclusions : Fasting during Ramadan is feasible and is associated with significant improvement in fructosamine level in children with T1DM using different insulin regimens. Mandatory consideration to the quality and quantity of food offered to patients with T1DM during Ramadan to guard against adverse changes in lipid profile.

Background: The epidemic of childhood obesity is associated with early atherosclerosis. Several reports have related this event to low-grade inflammation described in obesity. CRP and IL6 are markers that correlate with adiposity. The waist-to-height ratio (WtHR) is an anthropometric marker associated with insulin resistance and inflammation. The objective of this study was to assess the correlation between WtHR, metabolic complications and pro-inflammatory factors in obese children and adolescents. Methods: Weight, height, waist circumference, glycemia, insulin, CRP, TNF-α and IL-6 were measured in the baseline sample in 280 patients 6–19 years of age with overweight or obesity (OW/OB) and 112 normal-weight controls. Logistic regression was performed using WtHR as an independent variable. p>0.05 STATA11. Results: Mean WtHR was 0.6±0.06 in OW/OB and 0.43±0.02 in controls (p<0.01). WtHR was increased in 93% of the OW/OB vs. 2% of the controls. In the OW/OB inflammatory markers were significantly increased (p<0.01) compared to the controls (CRP 2.2 vs. 0.8; Il-6 2.9 vs. 2.1; and TNF-α 6.2 vs. 5.5). In the WtHR>0.5, insulin resistence and inflammatory markers were significantly increased (p<0.01) compared to the WtHR<0.5 (HOMA 3.4 vs. 1.4; CRP 2.3 vs. 0.6; Il-6 2.9 vs. 2.1; and TNF-α 6.4 vs. 5.55). In logistic regression, a significant independent association was found between WtHR with CRP (OR1.47), IL6 (OR1.60) and TNF-α (OR1.79). Conclusions: Obese children and adolescents have high inflammatory markers that may increase cardiovascular risk. WtHR is associated with low-grade inflammation and may be considered a relevant anthropometric marker in the clinical practice.

Background: Some obese children do not show cardiometabolic complications such as prediabetes, dyslipidemia or insulin resistance. The objective of the study was to classify obese children and adolescents as metabolically “healthy” obese (MHO) on the basis of three different definitions, and to compare cardiometabolic features with metabolically unhealthy obese (MUO) children and adolescents. Methods: The study included 156 obese children and adolescents aged between 10 and 18. Subjects were classified as MHO or MUO using three definitions based on the: (1) pediatric International Diabetes Federation (IDF) criteria; (2) homeostatic model assessment of insulin resistance (HOMA-IR); (3) combination of the previous two definitions. Cardiometabolic features were compared between MHO and MUO subjects. Results: Six to 19% obese children and adolescents were classified as MHO, and showed a better insulin sensitivity, lower prevalence of prediabetes, lower triglycerides and lower triglyceride-to-HDL-C ratio compared to MUO. Conclusions: Less than 20% obese children and adolescents are identified as MHO and show a healthier cardiometabolic profile as compared to MUO. Implementation of the proposed classifications in future clinical research could contribute towards the standardization of the MHO definition and offer new insights into the manifestation of the pediatric MHO phenotype.

Background: Phenylalanine hydroxylase deficiency causes various degrees of hyperphenylalaninemia (HPA). Tetrahydrobiopterin (BH4; sapropterin) reduces phenylalanine (Phe) levels in responders, enabling relaxation of dietary therapy. We aimed to assess long-term effects of BH4 treatment in HPA patients. Methods: Nine pre-pubertal BH4 responsive children were treated with BH4 for at least 2 years. The median dietary tolerance to Phe and levels of blood Phe, tyrosine (Tyr), zinc, selenium and vitamin B12 and anthropometric measurements, in the 2 years periods before and after the introduction of BH4 treatment were analyzed and compared. Adverse effects of BH4 were assessed. Results: The daily Phe tolerance had tripled, from pretreatment median value of 620 mg (IQR 400–700 mg) to 2000 (IQR 1000–2000 mg) after 2 years of follow up (p<0.001). The median blood Phe levels during the 2 years period before introducing BH4 did not change significantly during the 2 years on therapy (from 200 μmol/L; IQR 191–302 to 190 μmol/L; IQR 135–285 μmol/L), but the median blood Phe/Tyr ratio had lowered significantly from pre-treatment value 4.7 to 2.4 during the 2 years on therapy (p=0.01). Median zinc, selenium, vitamin B12 levels and anthropometric measurements did not change while on BH4 therapy (p=NS). No adverse effects were noticed. Conclusions: BH4 therapy enabled patients much higher dietary Phe intakes, with no noticeable adverse effects. Median blood Phe and Tyr levels, median zinc, selenium, vitamin B12 levels and anthropometric measurements did not change significantly on BH4 therapy, but median Phe/Tyr ratios had lowered.

Background: The objective of the study was to determine the genetic basis of goitrous congenital hypothyroidism (GCH) in Chinese siblings. Methods: The proband and her younger brother with GCH were enrolled for molecular analysis of the dual oxidase 2 ( DUOX2 ), dual oxidase maturation factor 2 ( DUOXA2 ), and thyroid peroxidase ( TPO ) genes. Mutation screening was performed by Sanger sequencing the fragments amplified from genomic DNA. The detected mutations were verified among the close relatives of the patients and 105 controls. All participants underwent clinical examination and laboratory tests. Results: Analysis of the TPO gene revealed two heterozygous mutations, the frameshift mutation c.2422delT in the exon14 of the TPO gene, that has been reported previously, and a novel missense mutation c.1682C>T (p.T561M) in the exon10 of the TPO gene. Nine family members of the patients were enrolled for mutation screening. The patients’ parents and grandfathers harbored a single heterozygous mutation. The germline mutations from this family were consistent with an autosomal recessive inheritance pattern. No mutations in the DUOXA2 and DUOX2 genes were observed. Conclusions: The inactivating mutations (c.2422delT and p.T561M) in the TPO gene were identified in the Chinese siblings with GCH. The compound heterozygous mutations can cause GCH.

Background: Growth hormone (GH) plays a role in the regulation of ovarian function but there are limited data in women with GH deficiency (GHD). Our aim was to evaluate the features of polycystic ovarian syndrome (PCOS) in women with previous GHD. Methods: Data of 22 adolescents previously GH-treated (group A) were compared with those of 22 women with classical PCOS (group B) and 20 controls (group C). Results : Group A showed higher testosterone (p=0.048) and prevalence of menstrual irregularities (p<0.001) than group C. Compared to the group B, group A showed lower diastolic blood pressure (p=0.004), degree of hirsutism (p=0.005), testosterone (p=0.003) and prevalence of polycsytic ovaries (POC) morphology (p=0.024), with higher HDL-cholesterol (p=0.035) and 17-β-estradiol (p=0.009). Conclusions : Adolescents with previous GHD show a higher prevalence of PCOS than controls, but with milder metabolic and hormonal features than adolescents with classical PCOS. A careful long-term follow-up is advisable in these patients.

Background: The present study evaluated the clinical value of dual-energy computed tomography (DECT) for detecting urate crystals in juveniles with symptomatic hyperuricemia. Methods: We recruited 24 juveniles (15 male and 9 female) who presented with symptomatic hyperuricemia. The mean body mass index (BMI) was 26.4 kg/m 2 (standard deviation, SD 11.3 kg/m 2 ). Fifteen juveniles (71.4%) were overweight. DECT scans of the feet were performed. For post-processing, a color-coding gout software protocol was used. Results: Urate crystals deposition was observed in 21/24 (87.5%) juveniles with symptomatic hyperuricemia. Urate crystals were detected in or around the anatomic site included the first metatarsophalangeal (MTP) joints (5/24, 20.8%); the calcaneus (5/24, 20.8%); any other toe joints (3/24, 12.5%); the astragalus (3/24, 12.5%); the ankle joints (3/24, 12.5%); the metatarsals (2/24, 8.3%); the cuboid (1/24, 4.2%); and other parts of the feet (2/24, 8.3%). Importantly, urate crystals deposition weas located in the soft tissue (tendon/tendon insertion sites/entheses) around the above-mentioned sites in a majority of these patients. Conclusions: Urate crystals deposition can be detected by dual-energy CT in the feet of symptomatic hyperuricemia juveniles. DECT can be a valuable diagnostic tool for helping diagnose in juvenile gout.

Background: Alström syndrome (AS) is an extremely rare, autosomal recessive disorder characterised by multi-organ features that typically manifest within the first two decades of life. AS is caused by mutations in the Alström syndrome 1 ( ALMS1 ) gene located at 2p13.1. Methods: In the current study, two brothers from a first-cousin consanguineous family presented with a complex phenotype and were suspected of having AS. Results: Both brothers were found to be homozygous for a novel nonsense c.7310C>A (p.S2437X) mutation in exon-8 of ALMS1 gene. The consanguineous parents were sequenced and both were heterozygous for the same mutation. Conclusions: This particular mutation has never been reported before and confirmed the diagnosis of AS in the patients. Our work identifies a novel mutation in ALMS1 gene responsible for the complex phenotype of AS in these patients.

Background: X-linked recessive congenital nephrogenic diabetes insipidus (NDI) is caused by mutations of the arginine vasopressin type 2 receptor gene (AVPR2). More than 200 mutations of the AVPR2 gene with complete NDI have been reported although only 15 mutations with partial NDI has been reported to date. Methods: We herein report a Japanese kindred with partial NDI. The proband is an 8-year-old boy who was referred to our hospital for nocturnal enuresis. Water deprivation test and hypertonic saline test suggested partial renal antidiuretic hormone arginine vasopressin (AVP) resistance. Results: Analysis of genomic DNA revealed a novel missense mutation (p.L161P) in the patient. The patient’s mother was heterozygous for the mutation. Three-dimensional (3-D) modeling study showed that L161P possibly destabilizes the transmembrane domain of the V2 receptor, resulting in its misfolding or mislocalization. Conclusions: Distinguishing partial NDI from nocturnal enuresis is important. A clinical clue for diagnosis of partial NDI is an incompatibly high level of AVP despite normal serum osmolality.

Background: Pituitary gigantism (PG) is a rare pediatric disease with poorly defined long-term outcomes. Our aim is to describe the longitudinal clinical course in PG patients using a single-center, retrospective cohort study. Methods: Patients younger than 19 years diagnosed with PG were identified. Thirteen cases were confirmed based on histopathology of a GH secreting adenoma or hyperplasia and a height >2 SD for age and gender. Laboratory studies, initial pathology, and imaging were abstracted. Results: Average age at diagnosis was 13 years with an average initial tumor size of 7.4×3.8 mm. Initial transsphenoidal surgery was curative in 3/12 patients. Four of the nine patients who failed the initial surgery required a repeat procedure. Octreotide successfully normalized GH levels in 1/6 patients with disease refractory to surgery (1/6). Two out of five patients received pegvisomant after failing octreotide but only one patient responded to treatment. Five patients were ultimately treated with radiosurgery or radiation patients were followed for an average of 10 years. Conclusions: PG is difficult to treat. In most patients, the initial transsphenoidal surgery failed to normalize GH levels. If the initial surgery was unsuccessful, repeat surgery was unlikely to control GH secretion. Treatment with octreotide or pegvisomant was successful in less than half the patients failing surgery. Radiosurgery was curative, but is not an optimal treatment for pediatric patients. Despite the small sample, our study suggests that the treatment outcome of pediatric PG may be different than adults.

OTX2 mutations are reported in patients with eye maldevelopment and in some cases with brain or pituitary abnormalities. We describe a child carrying a novel OTX2 heterozygous mutation. She presented microphthalmia, absence of retinal vascularization, vitreal spots and optic nerve hypoplasia in the right eye and mild macular dystrophy in the left eye. Midline brain structures and cerebral parenchyma were normal, except for the ectopic posterior pituitary gland. OTX2 sequencing showed a heterozygous c.402del mutation. Most of OTX2 mutations are nonsense or frameshift introducing a premature termination codon and resulting in a truncated protein. More rarely missense mutations occur. Our novel OTX2 mutation (c.402del) is a frameshift mutation (p.S135Lfs*43), never reported before, causing a premature codon stop 43 amino-acids downstream, which is predicted to generate a premature truncation. The mutation was associated with microphthalmia and ectopic posterior pituitary.

Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder, which is mostly caused by mutations in the WFS1 gene. The WFS1 gene product, which is called wolframin, is thought to regulate the function of endoplasmic reticulum. The endoplasmic reticulum has a critical role in protein folding and material transportation within the cell or to the surface of the cell. Identification of new mutations in WFS1 gene will unravel the molecular pathology of WS. The aim of this case report study is to describe a novel mutation in exon 4 of the WFS1 gene (c.330C>A) in a 9-year-old boy with WS.

We report on a 33-year-old patient with mosaic interstitial duplication on chromosome 14q11.2–14q22.1~22.3 with severe physical and mental retardation and multiple dysmorphisms. This patient was admitted to our pediatric hospital due to severe dehydration and malnutrition as a result of food refusal. It is an actual phenomenon that patients with severe inborn clinical problems nowadays survive due to progress and care of modern medicine. Nevertheless, transition from pediatric care to adult medicine seems to remain a challenging problem. We demonstrate the clinical course as well as clinical and genetic findings of this adult patient. Comparisons are made to previously reported cases with mosaic trisomy 14 involving a proximal interstitial duplication on the long arm of chromosome 14.

Turner syndrome is a common genetic disorder with an incidence of 1 in 2500 live births. Spontaneous fertility is rare in such patients and is most likely in women with mosaicism or very distal Xp deletions. The authors report an unusual case of familial Turner syndrome in a woman with mosaicism 45,X/46,Xdel(Xp) karyotype with three documented spontaneous pregnancies, which resulted in two daughters with 46,Xdel(X)(p11.4)mat karyotype and a healthy son. The mother was first diagnosed by the age of 11 and did not receive contraceptive medication, due to information that she would be infertile. Both daughters were referred to an endocrinology unit and are now under growth hormone treatment, and have been growing in the 3rd percentile. This family illustrates the complexity and difficulties in counseling, follow-up and treatment in Turner syndrome, namely referring to a tertiary center, fertility and treatment such as growth hormone and hormonal replacement, due to the heterogeneity of the clinical spectrum.

A new missense mutation on the X chromosome ( PHEX ) at exon 4(c.442C>T) in a 4-generation Chinese Han pedigree is reported. The proband and four family members were clinically identified as the X-linked hypophosphatemic rickets (XLH) which is a dominant inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. The proband is identified as hemizygous with the four female family members to be heterozygous genotypes. The discovery was made through the complete sequencing of the exons and the intron-exon boundaries of the PHEX gene of this family. The mutation caused the S141 residue to change to Phe from Ser which is perfectly conserved among humans, mice, rats, cows and chickens. PolyPhen-2 software analysis of the mutation indicated it was probably damaging. The proband was also diagnosed with type 1 diabetes (T1D) and the relationship between XLH and diabetes phenotypes was discussed in the paper.

Background: Thyroid dyshormonogenesis continues to be a significant cause of congenital hypothyroidism. Over time, forms of thyroid dyshormonogenesis can result in goiter, which can lead to difficult management decisions as the pathologic changes can both mimic or lead to thyroid cancer. Methods: Herein we describe the cases of two brothers diagnosed with congenital hypothyroidism, with initial findings consistent with thyroid dyshormonogenesis. One brother eventually developed multinodular goiter with complex pathology on biopsy, resulting in thyroidectomy. Results: Whole exome sequencing revealed the brothers carry a novel frameshift mutation in thyroperoxidase; the mutation, while not previously described, was likely both deleterious and pathogenic. Conlcusions: These cases highlight the complex pathology that can occur within thyroid dyshormonogenesis, with similar appearance to possible thyroid cancer, leading to complex management decisions. They also highlight the role that a genetic diagnosis can play in interpreting the impact of dyshormonogenesis on nodular thyroid development, and the need for long-term follow-up in these patients.