Graziella Pinto

Mutations in the iodotyrosine deiodinase gene and hypothyroidism.

DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of iodotyrosine deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in iodotyrosine deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.

Long-Term Outcome of Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Aims: Conflicting results exist regarding bone mineral density (BMD), metabolism and reproductive function of adult patients with congenital adrenal hyperplasia (CAH). We evaluated the long-term outcome and the impact of chronic glucocorticoid replacement in these patients. Methods: Physical characteristics, serum hormone concentrations, BMD and metabolism were studied in 45 consecutive CAH adult patients. Results: Among the 36 women, only 14 (39%) had regular menses. Among the 27 women with classical CAH, the mean number of surgical reconstructions of virilized genitalia was 2.1 ± 0.2. Twenty of them (74%) were sexually active. Three men presented with testicular adrenal rest tumors. Twenty-five patients (55%) had decreased BMD at the femoral neck and/or at the lumbar spine. BMI was correlated with the BMD T-score at the femoral neck (p < 0.001) and at the lumbar spine (p < 0.01). Hydrocortisone dose was negatively correlated with the BMD T-score at the femoral neck (p = 0.04). Subjects with osteopenia had a significantly lower BMI and received higher hydrocortisone dose than those with normal BMD. Overweight was found in 21 patients (47%). There was a significantly positive correlation between HOMA and BMI (p < 0.001), and between HOMA and 17-OHP levels (p = 0.016). Conclusions: Adult patients with CAH treated with long-term glucocorticoids are at risk for decreased BMD, increased BMI, and disturbed reproductive function.

Childhood Craniopharyngioma: Hypothalamus-Sparing Surgery Decreases the Risk of Obesity

CONTEXT Craniopharyngioma is a brain tumor whose high local recurrence rate has for a long time led to a preference for extensive surgery. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment. OBJECTIVE We compared weight gain and local recurrence rates after extensive resection surgery (ERS) and hypothalamus-sparing surgery (HSS). DESIGN Our observational study compared a historical cohort managed with ERS between 1985 and 2002 to a prospective cohort managed with HSS between 2002 and 2010. SETTING The patients were treated in a pediatric teaching hospital in Paris, France. PATIENTS Thirty-seven boys and 23 girls were managed with ERS (median age, 8 years); 38 boys and 27 girls were managed with HSS (median age, 9.3 years). MAIN OUTCOME MEASURES Data were collected before and 6 months to 7 years after surgery. Body mass index (BMI) Z-score was used to assess obesity and the number of surgical procedures to assess local recurrence rate. RESULTS Mean BMI Z-score before surgery was comparable in the 2 cohorts (0.756 after ERS vs 0.747 after HSS; P = .528). At any time after surgery, mean BMI Z-score was significantly lower after HSS (eg, 1.889 SD vs 2.915 SD, P = .004 at 1 year). At last follow-up, the HSS cohort had a significantly lower prevalence of severe obesity (28% vs 54%, P < .05) and higher prevalence of normal BMI (38% vs 17%, P < .01). Mean number of surgical procedures was not significantly different in the 2 cohorts. CONCLUSIONS Hypothalamus-sparing surgery decreases the occurrence of severe obesity without increasing the local recurrence rate.

Social and psycho-intellectual outcome following radical removal of craniopharyngiomas in childhood. A prospective series.

BackgroundA prospective study on childhood craniopharyngiomas (CPs) was conducted from 1994 to 1998 to appreciate the pre- and postoperative clinical, endocrine, mental, and intellectual status of the patients and to determine the incidence and severity of the postoperative hypothalamic syndrome.MethodsThe series included 14 consecutive CPs. Twelve were retrochiasmatic and intraventricular, and two were partly prechiasmatic and extraventricular. All were treated with the aim of “total” removal. The removal was “total” in nine cases but incomplete in the other five. Immediate postoperative follow-up was uncomplicated in all cases.ConclusionAt 2-year follow-up, the two children with an extraventricular CP and a “total” tumor removal were intellectually normal, had no hypothalamic syndrome, and attended normal school with good results. The 12 others, although still intellectually normal, were more or less severely affected by a hypothalamic syndrome which altered their social insertion and caused academic failure. The authors conclude from this study that radical surgery should be reserved to extraventricular CPs only.

Paternal deletion of the GNAS imprinted locus (including Gnasxl ) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties

Deletions of the long arm of chromosome 20 are rare. Here, we report on two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and post-natal growth retardation, intractable feeding difficulties, abnormal subcutaneous adipose tissue, similar facial dysmorphism, psychomotor retardation and hypotonia. Standard cytogenetic studies were normal, but high-resolution chromosomes analysis showed the presence of a chromosome (20)(q13.2–q13.3) interstitial deletion. Karyotypes of both parents were normal. Molecular studies using FISH and microsatellite polymorphic markers showed that the deletion was of paternal origin and was approximatively 4.5 Mb in size. A review of other reported patients with similar deletions of the long arm of chromosome 20 shows that the observed phenotype might be explained in the light of the GNAS imprinted locus in particular by the absence of the Gnasxl paternally imprinted gene and the TFA2PC gene in the deleted genetic interval.

Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome.

Late Onset Central Hypoventilation Syndrome associated with Hypothalamic Dysfunction (LO-CHS/HD) is a distinct entity among the clinical and genetic heterogeneous group of patients with late onset central hypoventilation. Here we report a series of 13 patients with LO-CHS/HD. Rapid onset obesity is the first symptom of HD followed by hypoventilation with a mean delay of 18 mos. The outcome remains poor for this group of patients and would benefit from early diagnosis to anticipate ventilation and possible metabolic disorders. Tumor predisposition is more frequent than initially suspected and as high as 40% in this series. These tumors of the sympathetic nervous system (TSNS) are usually differentiated and do not significantly worsen the prognosis. We report a familial case with recurrence in siblings. The cause underlying LO-CHS/HD remains poorly understood although recurrence in siblings argues for a monogenic disorder. We ruled out PHOX2B, ASCL1, and NECDIN as disease-causing genes by direct sequencing in our series of patients and discuss possible disease-causing mechanisms.

Hormonal Factors Influencing Weight and Growth Pattern in Craniopharyngioma

Patients operated on for craniopharyngioma frequently suffer from hyperphagia and are obese, but their statural growth is normal despite growth hormone (GH) deficiency. We have evaluated the hormonal factors influencing changes in weight and growth in 17 children before and 1, 3–6, 12, and/or 24 months after surgical resection of a craniopharyngioma performed at 7.7 ± (SE) 1 years of age. Of these, 15 patients had a GH deficiency before surgery, and all had complete pituitary deficiency after it. The plasma fasting insulin concentrations before surgery were positively correlated with body mass index (BMI, kg/m2; p < 0.05), plasma insulin-like growth factors (IGFI, p = 0.03, and IGFII, p = 0.04), and leptin (p = 0.03). They increased significantly 1 month after surgery and continued to increase thereafter, whereas leptin increased significantly only 3–6 months after surgery, paralleling changes in BMI. The plasma fasting insulin concentrations before surgery were also positively correlated with the weight changes (12.3 ± 2.3 kg, p < 0.01) during the 12 months after surgery, but not with changes in BMI SDS (3.1 ± 0.5, p = 0.07). Both expressions of weight change were correlated with the concomitant growth rates (4.8 ± 0.7 cm, p < 0.01). IGFI was above the 10th percentile for children with idiopathic short stature in 10 of 15 patients with craniopharyngioma-induced GH deficiency and IGF-binding protein 3 in 14 of 15 patients. Craniopharyngioma itself modified the control of insulin secretion, and surgery increased the insulin secretion which continued in the same way in a given patient after surgery. The increased insulin secretion in turn increases weight and keeps IGFI nearly normal. This may explain the normal growth rate despite the complete lack of GH.

Mastoiditis, meningitis and venous sinus thrombosis caused byFusobacterium necrophorum

The authors report a case of septic venous sinus thrombosis (VST) and meningitis occurring as an early complication of mastoiditis caused byFusobacterium necrophorum. CT scan was normal, and cerebral angiography was required to diagnose the VST. The evolution was favourable with appropriate antimicrobial therapy and steroids.

Growth Hormone Therapy for Children and Adolescents with Prader-Willi Syndrome Is Associated with Improved Body Composition and Metabolic Status in Adulthood

CONTEXT Children with Prader-Willi syndrome (PWS) who receive GH treatment have improved growth and body composition; however, data are lacking for adults when treatment is discontinued after completion of growth. OBJECTIVES Our aim was to compare body composition and metabolic status in adults with PWS according to GH treatment in childhood and adolescence. DESIGN 64 adults (mean age: 25.4 years) with a genetic diagnosis of PWS were evaluated: 20 received GH in childhood (T), which had been discontinued at the time of this study, and 44 did not receive GH (C). Mean duration of treatment in the T group was 4.4 ± 2.7 years, age at baseline was 11.8 ± 2.7 years, mean time between the end of treatment and the current evaluation was 7.0 ± 4.4 years. MAIN OUTCOMES MEASURES Dual-energy X-ray absorptiometry was used to assess body composition and fasting biological analyses evaluated metabolic status. RESULTS (MEAN ± SD): Body mass index and percentage of fat mass were significantly lower in the T group (32.4 ± 10.3 vs 41.2 ± 11.1 kg/m(2), P = 0.05 and 44.0 ± 9.6 vs 50.1 ± 7.2%, P = 0.02, respectively). Insulinemia and HOMA-IR in non-diabetic subjects were significantly lower in the T group (5.8 ± 5.9 vs 13.9 ± 11.6 μUI/ml, P = 0.03, and 1.6 ± 1.3 vs 2.7 ± 2.1, P = 0.04, respectively). Non-diabetic and diabetic subjects from the T group had a significantly lower HbA1c. Lipid profiles were similar between groups. CONCLUSIONS GH treatment in childhood and adolescence is associated with significantly decreased body mass index and improved body composition and metabolic status in adults with PWS at several years after discontinuing treatment.

A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone

CONTEXT RTHα is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TRα1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T4/free T3 (FT4/FT3) ratio. OBJECTIVE A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated. DESIGN Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives. RESULTS The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T3. rT3, SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c.1075A>T), which affected both the TRα1 and the non-receptor isoform TRα2. The mutant TRα1 had a decrease in transcriptional activity related to decreased T3 binding and a dominant-negative effect on the wild-type receptor. CONCLUSIONS This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TRα1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTHα.