Belma Haliloglu

An atypical case of familial glucocorticoid deficiency without pigmentation caused by coexistent homozygous mutations in MC2R (T152K) and MC1R (R160W).

Context: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency. Mutations in the gene encoding the ACTH receptor (MC2R) account for 25% of cases. One significant feature is generalized skin hyperpigmentation, which is thought to be due to elevated ACTH acting on the melanocortin 1 receptor (MC1R). Objective: The aim of the study was to determine the cause of a nonhyperpigmented case of FGD. Patients: The patient presented at 4 yr of age with hypoglycemia after prolonged fasting during a respiratory tract infection. She had further hypoglycemic attacks and was diagnosed with isolated glucocorticoid deficiency at 6 yr of age. Her parents were consanguineous, and she had two unaffected sisters. Her physical examination was normal, except that her height and weight were greater than the 97th centile for a sex- and age-matched reference population. Interestingly, she had no hyperpigmentation despite very high ACTH levels. Results: Nucleotide sequence analysis revealed homozygous mutations c.478C>T in MC1R and c.455C>A in MC2R leading to R160W and T152K changes in the amino acid sequences, respectively. The R160W MC1R change has previously been implicated in a red hair/pale skin phenotype, and MC2R -T152K is trafficking defective. Both parents and two unaffected sisters were heterozygous for the MC1R mutation; additionally, one unaffected sister was heterozygous for the MC2R mutation, and the other was wild-type. Conclusion: We report an unusual case of FGD without hyperpigmentation due to coexistent MC1R/MC2R mutations. This case is important because it demonstrates for the first time that the assumption that the action of ACTH on MC1R causes skin hyperpigmentation is correct.

Hypothalamic obesity in children: pathophysiology to clinical management

Abstract Hypothalamic obesity (HyOb) is a complex neuroendocrine disorder caused by damage to the hypothalamus, which results in disruption of energy regulation. The key hypothalamic areas of energy regulation are the ARC (arcuate nucleus), the VMH (ventromedial hypothalamus), the PVN (paraventriculer nuclei) and the LHA (lateral hypothalamic area). These pathways can be disrupted mechanically by hypothalamic tumors, neurosurgery, inflammatory disorders, radiotherapy and trauma or functionally as such seen in genetic diseases. Rapid weight gain and severe obesity are the most striking features of HyOb and caused by hyperphagia, reduced basal metabolic rate (BMR) and decreased physical activity. HyOb is usually unresponsive to diet and exercise. Although, GLP-1 and its anologs seem to be a new agent, there is still no curative treatment. Thus, prevention is of prime importance and the clinicians should be alert and vigilant in patients at risk for development of HyOb.

Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS

CONTEXT Loss-of-function GNAS mutations lead to hormone resistance and Albrights hereditary osteodystrophy (AHO) when maternally inherited, i.e. pseudohypoparathyroidism-Ia (PHPIa), but cause AHO alone when located on the paternal allele, i.e. pseudoPHP (PPHP). OBJECTIVE We aimed to establish the molecular diagnosis in a patient with AHO and evidence of hormone resistance. CASE The patient is a female who presented at the age of 13.5years with short stature and multiple AHO features. No evidence for TSH or gonadotropin-resistance was present. Serum calcium and vitamin D levels were normal. However, serum PTH was elevated on multiple occasions (64-178pg/mL, normal: 9-52) and growth hormone response to clonidine or L-DOPA was blunted, suggesting hormone resistance and PHP-Ia. The patient had diminished erythrocyte Gsα activity and a novel heterozygous GNAS mutation (c.328 G>C; p.A109P). The mother lacked the mutation, and the fathers DNA was not available. Hence, a diagnosis of PPHP also appeared possible, supported by low birth weight and a lack of AHO features associated predominantly with PHP-Ia, i.e. obesity and cognitive impairment. To determine the parental origin of the mutation, we amplified the paternally expressed A/B and biallelically expressed Gsα transcripts from the patients peripheral blood RNA. While both wild-type and mutant nucleotides were detected in the Gsα amplicon, only the mutant nucleotide was present in the A/B amplicon, indicating that the mutation was paternal. CONCLUSION These findings suggest that PTH and other hormone resistance may not be an exclusive feature of PHP-Ia and could also be observed in patients with PPHP.

Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet.

BACKGROUND NSHPT is a life-threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice. OBJECTIVE To describe a case of NSHPT unresponsive to cinacalcet. PATIENT AND RESULTS A 23-day-old girl was admitted with hypercalcemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10-2.62), P: 0.83 mmol/l (1.55-2.64), PTH: 1096 pg/ml (9-52) and urinary Ca/Cr ratio: 0.5mg/mg. First, calcitonin was given (10 IU/kg × 4/day), and then 2 days later, pamidronate (0.5mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l but, thereafter, rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation. CONCLUSION The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.

A novel homozygous TMEM70 mutation results in congenital cataract and neonatal mitochondrial encephalo-cardiomyopathy.

Mutations in the TMEM70 gene are the most common cause of nuclear encoded ATP synthase deficiency resulting in a syndrome characterized by neonatal lactic acidosis, cardiomyopathy, and encephalomyopathy. Here we report on the first Turkish patient who presented after birth with lactic acidemia, severe hpotonia, hypertrophic cardiomyopathy and bilateral congenital cataract. TMEM70 genetic analysis revealed the causative homozygous c.535C>T novel mutation that result in substitution of a highly conserved tyrosine into histidine at position 179. In this report we focused on a detailed description of the clinical features of this syndrome with special emphasis on the typical facial dysmorphic features. Our report underscores TMEM70 deficiency as a pan-ethnic well defined phenotype. In cases with high suspicion sequencing of TMEM70 should be performed even before the traditional invasive muscle biopsy to confirm the diagnosis.

Higher insulin detemir doses are required for the similar glycemic control: comparison of insulin detemir and glargine in children with type 1 diabetes mellitus

We aimed to compare hemoglobin A1c (HbA1c), total and basal insulin doses, basal insulin injection frequencies, and body mass index (BMI) in children with type 1 diabetes mellitus (T1DM) who are receiving detemir and glargine as basal insulin in a basal‐bolus therapy.

Premature pubarche, hyperinsulinemia and hypothyroxinemia: Novel manifestations of congenital portosystemic shunts (Abernethy Malformation) in children

Congenital portosystemic shunt (CPSS) is persistence of an anomalous embryological connection of the portal vein with a large vein of the vena cava system. Clinical presentations include neonatal cholestasis, liver tumors, and encephalopathy, but can be variable in timing and symptomatology. We report 2 girls who presented 10 years apart with the same complaint of early pubarche at age 7 years, with inappropriately low DHEAS levels. In addition to hyperandrogenemia (elevated testosterone and androstenedione) and advanced bone age, both had hyperinsulinemia, and hypothyroxinemia. The 2nd case also had symptomatic hypoglycemia. Presentation of CPSS with this combination of findings in prepubertal children has not been reported previously. With further investigations, we proposed novel mechanisms explaining these manifestations. Hyperandrogenemia is caused by decreased hepatic sulfation of DHEA to less active DHEAS due to shunting of DHEA to systemic circulation. Elevated DHEA is then used for synthesis of more potent androgens. Shunting of postabsorbtive glucose from portal to systemic circulation causes early hyperglycemia leading to exaggerated insulin secretion. Insulin bypasses the hepatic metabolism directly entering into the systemic circulation, which results in hyperinsulinemia, then in turn causes late hypoglycemia. Finally, hypothyroxinemia was linked to thyroxin-binding globulin deficiency, which has not been reported in CPSS.

Complementary and Alternative Medicine in Children with Type 1 Diabetes Mellitus

Objective: Complementary and alternative medicine (CAM) is increasingly utilized in adults and children for treatment of various conditions. Studies on CAM in diabetes have mainly focused on the adult population and its application in children has not been well established. The aim of this study was to examine the prevalence and characteristics of CAM use in Turkish children with type 1 diabetes mellitus (T1DM). Methods: The information was acquired by a questionnaire completed by a face-to-face interview with the parents of children with T1DM. Results: A total of 195 subjects (mean age: 14.02±4.7 years; F/M: 103/92) were included in this survey. Use of CAM was reported in 85 subjects (43.6%). Herbal medicines were used in 64 subjects (75.3%). Sixty-nine subjects (81.2%) did not inform the diabetes specialist about CAM use. Thirty-eight subjects (44.7%) evaluated CAM as efficacious. Only 3 subjects (3.5%) interrupted the insulin injections to use CAM. No relationships were found between CAM use and parental education or insulin dose. There were significant correlations between CAM use and higher family income (p=0.027), urban residence (p=0.05), presence of complications (p=0.03), dissatisfaction with medical therapy (p=0.034) and prior CAM use among parents (p=0.001). Conclusion: CAM use is a frequent practice among diabetic children, which is usually not shared with their physicians and sometimes leads to cessation of medical treatment. Conflict of interest:None declared.

Hypoglycemia is common in children with cystic fibrosis and seen predominantly in females

To determine the prevalence of hypoglycemia in children and adolescents with cystic fibrosis (CF) in 2‐hour oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) under free‐living conditions.

Risk factors for mortality caused by hypothalamic obesity in children with hypothalamic tumours

Hypothalamic obesity (HyOb) is a common complication of childhood hypothalamic tumours. Patients with HyOb probably have a higher mortality rate than those with other types of obesity due in many cases to obstructive sleep apnoea/hypoventilation.