Risk of thyroid neoplasms in patients with 22q11.2 deletion and DiGeorge-like syndromes: an insight for follow-up.

Introduction: The chromosome 22q11.2 deletion syndrome comprises phenotypically similar diseases characterized by abnormal development of the third and fourth branchial arches, resulting in variable combinations of congenital heart defects, dysmorphisms, hypocalcemia, palatal dysfunction, developmental or neuropsychiatric disorders, and impairment of the immune system due to thymic dysfunction. Other genetic syndromes, often called DiGeorge-like, share clinical and immunological features with 22q11.2 deletion syndrome. This syndrome has been rarely associated with malignancies, mainly hematological but also hepatic, renal, and cerebral. Rarely, malignancies in the head and neck region have been described, although no aggregate of data on the development of thyroid neoplasms in patients with this clinical phenotype has been conducted so far. Materials and methods: To characterize this possible association, a multicenter survey was made. Thus, we present a case series of five pediatric patients with 22q11.2 deletion syndrome or DiGeorge-like syndrome who were occasionally found with confirmed or highly suspected neoplasms of the thyroid gland during their follow-up. In three cases, malignancies were histologically confirmed, but their outcome was good due to an early recognition of suspicious nodules and precocious surgery. Conclusions: This study underlines for clinicians the higher risk of neoplasms in the head and neck district for patients affected by these syndromes. It also emphasizes the importance of a prolonged clinical and ultrasound follow-up for patients with this clinical and immunological phenotype.

Towards an individualized management of pubertal induction in girls with hypogonadism: insight into the best replacement outcomes from a large multicentre registry.

OBJECTIVE: An evidence-based pubertal induction scheme in hypogonadal girls is still to be established. Interestingly, literature data report a suboptimal uterine longitudinal diameter (ULD) in >50% of treated hypogonadal women, negatively influencing their pregnancy outcomes. This study aims to investigate auxological and uterine outcomes of pubertal induction in girls in the light of underlying diagnosis and therapeutic schemes used. DESIGN: Retrospective analysis of longitudinal data from a multicentric registry. METHODS: Auxological, biochemical, and radiological data were collected at baseline and during follow-up in 95 hypogonadal girls (chronological age > 10.9 years, Tanner stage ≤ 2) treated with transdermal 17ß-oestradiol patches for at least 1 year. Induction was started at a median dose of 0.14 mcg/kg/day with a 6-monthly increase and was considered completed for 49/95 patients who started progesterone with a concomitant oestrogen adult dose. RESULTS: At the end of induction, the achievement of the complete breast maturation was associated with a 17ß-oestradiol dose at progesterone introduction. ULD showed a significant correlation with a 17ß-oestradiol dosage. Final ULD was >65 mm in only 17/45 girls. At multiple regression analysis, pelvic irradiation represented the major determinant of reduced final ULD. After correction for uterine irradiation, ULD was associated with the 17ß-oestradiol dose at progesterone introduction. Final ULD was not significantly different from the one assessed after progesterone introduction. CONCLUSIONS: Our results provide evidence that progestins, hampering further changes in uterine volume and breast development, should be introduced only in the presence of a concomitant adequate 17ß-oestradiol dose and an appropriate clinical response.

Endocrine Disorders in Children with Brain Tumors: At Diagnosis, after Surgery, Radiotherapy and Chemotherapy.

INTRODUCTION: Brain tumors are the second most frequent type of all pediatric malignancies. Depending on their localization, patients with brain tumors may present neurological or ophthalmological symptoms, but also weight anomalies and endocrine disorders ranging from growth hormone deficiency, anomalies of puberty, diabetes insipidus to panhypopituitarism. Immediately at diagnosis, all patients with brain tumors require a complete assessment of the hypothalamic-pituitary function in order to address eventual endocrine disorders. Moreover, children and adolescents undergoing brain surgery must receive peri- and postoperative hydrocortisone stress therapy. Post-operative disorders of water homeostasis are frequent, ranging from transient diabetes insipidus, as well as syndrome of inappropriate antidiuretic hormone secretion to persistent diabetes insipidus. Late endocrine disorders may result from surgery near or within the hypothalamic-pituitary region. Pituitary deficits are frequent after radiotherapy, especially growth hormone deficiency. Thyroid nodules or secondary thyroid cancers may arise years after radiotherapy. Gonadal dysfunction is frequent after chemotherapy especially with alkylating agents. CONCLUSION: Early detection and treatment of specific endocrine disorders at diagnosis, perioperatively, and during long-term follow-up result in improved general and metabolic health and quality of life.

Management of Childhood-onset Craniopharyngioma in Italy: A Multicenter, 7-Year Follow-up Study of 145 Patients.

CONTEXT: Nationwide data on children diagnosed with craniopharyngioma (CP) are not available in Italy. OBJECTIVE: This work aimed to identify patients' characteristics, type of surgical approach, complications and recurrences, number of pituitary deficits, and number of patients starting growth hormone (GH) treatment. METHODS: A retrospective multicenter collection took place of 145 patients aged 0 to 18 years who underwent surgery for CP between 2000 and 2018, and followed up in 17 Italian centers of pediatric endocrinology. RESULTS: Age at diagnosis was 8.4 ± 4.1 years. Duration of symptoms was 10.8 ± 12.5 months and headache was most frequent (54%), followed by impaired growth (48%) and visual disturbances (44%). Most lesions were suprasellar (85%), and histology was adamantinomatous in all cases but two. Surgical approach was transcranial (TC) in 67.5% of cases and transsphenoidal (TS) in 31.%. The TC approach was prevalent in all age groups. Postsurgery complications occurred in 53% of cases, with water-electrolyte disturbances most frequent. Radiotherapy was used in 39% of cases. All patients but one presented with at least one hormone pituitary deficiency, with thyrotropin deficiency most frequent (98.3%), followed by adrenocorticotropin (96.8%), arginine vasopressin (91.1%), and GH (77.4%). Body mass index (BMI) significantly increased over time. A hypothalamic disturbance was present in 55% of cases. GH therapy was started during follow-up in 112 patients at a mean age of 10.6 years, and 54 developed a recurrence or regrowth of the residual lesion. CONCLUSION: CP is often diagnosed late in Italy, with TC more frequent than the TS surgical approach. Postsurgery complications were not rare, and hypopituitarism developed almost in all cases. BMI shows a tendency to increase overtime.

Polycystic ovary syndrome in pediatric obesity and diabetes.

Polycystic ovary syndrome is characterized by anovulation (amenorrhea, oligomenorrhea, irregular menstrual cycles) combined with symptoms of androgen excess (hirsutism, acne, alopecia). The clear definition and diagnosis in adolescents could be challenging considering that most of symptoms occur as part of the expected physiological hormonal imbalance of puberty. Therefore, different diagnostic criteria have been elaborated. Polycystic ovary syndrome could be associated to obesity, diabetes mellitus, and metabolic syndrome. In adolescents with polycystic ovary syndrome, adiposity is associated with higher androgen concentrations and greater menstrual irregularity. Polycystic ovary syndrome in youth is considered a risk factor for type 2 diabetes mellitus in adulthood. On the other hand, increased prevalence of polycystic ovary syndrome has been shown in type 1 diabetes mellitus. The treatment of polycystic ovary syndrome in adolescents is controversial considering that adequate trials are lacking. First-line treatment comprises lifestyle modification (preferably multicomponent including diet, exercise and behavioral strategies) that should be recommended overall in the patients with polycystic ovary syndrome and overweight, central obesity and insulin resistance. Beyond non-pharmacological therapy, pharmacological agents include combined hormonal contraceptives, metformin and anti-androgens, used separately or in combination. The aim of therapy is to bring back ovulation, to normalize menses, to reduce hirsutism and acne, to reduce weight. Other important goal is the treatment of hyperlipidemia and of hyperglycemia. This narrative review aimed to review the most pertinent literature about polycystic ovary syndrome in adolescents with obesity or diabetes. We overviewed the diagnostic criteria, the pathophysiology and the possible treatment approaches.

Homozygous HESX1 and COL1A1 Gene Variants in a Boy with Growth Hormone Deficiency and Early Onset Osteoporosis.

We report on a patient born to consanguineous parents, presenting with Growth Hormone Deficiency (GHD) and osteoporosis. SNP-array analysis and exome sequencing disclosed long contiguous stretches of homozygosity and two distinct homozygous variants in HESX1 (Q6H) and COL1A1 (E1361K) genes. The HESX1 variant was described as causative in a few subjects with an incompletely penetrant dominant form of combined pituitary hormone deficiency (CPHD). The COL1A1 variant is rare, and so far it has never been found in a homozygous form. Segregation analysis showed that both variants were inherited from heterozygous unaffected parents. Present results further elucidate the inheritance pattern of HESX1 variants and recommend assessing the clinical impact of variants located in C-terminal propeptide of COL1A1 gene for their potential association with rare recessive and early onset forms of osteoporosis.

Usefulness of iodine-123 whole-body scan in planning iodine-131 treatment of the differentiated thyroid carcinoma in children and adolescence.

OBJECTIVE: Radioiodine treatment (RAI-T) of differentiated thyroid carcinoma (DTC) is important to avoid disease progression, in particular in pediatric patients. For these reasons, a diagnostic scan may be useful to assess therapeutic tailored activity. The purpose of our study was to evaluate the usefulness of diagnostic whole-body scan (WBS) with iodine-123 (I) in combination with recombinant human thyroid-stimulating hormone (rh-TSH; Thyrogen) (rh-TSH-Dx-WBS), in planning RAI-T or further surgery before RAI-T in pediatric DTC. PATIENTS AND METHODS: Among 101 rh-TSH-Dx-WBS of 55 patients (21 males, mean age: 15 years, range: 5-18 years) followed at the Bambino Gesù Pediatric Hospital for DTC from February 2004 to December 2016, 41 rh-TSH-Dx-WBS scans of 41 patients (20 male and 21 female, mean age: 14 years, range: 5-18 years) performed for staging before RAI-T were retrospectively evaluated. Thyroglobulin was determined at baseline and on day 5. RESULTS: Receiver operating characteristic curve analysis showed that thyroglobulin alone is not a good predictor for staging modification (area under the curve=0.6855). rh-TSH-Dx-WBS showed both remnant and lymph node in 11 (27%), lymph node localization alone in one (2.5%), lung alone in 1/41 (2.5%), both lymph node and lungs in 2/41 (5%), and thyroid remnant alone in 26/41 (63%) patients. rh-TSH-Dx-WBS modified staging in 12/41 (29%): in 3/12 (25%) for the presence of lung metastases and in 9/12 (75%) for lymph node involvement. In all these patients, administered activity for RAI-T was then modified or further surgery was planned. CONCLUSION: Although further studies are needed, our data showed that combined use of rh-TSH and I-Dx-WBS allows an accurate and complete staging of disease, to implement the best therapeutic plan.

[Smart-web support: a new tool to help information sharing in managing complex paediatric diseases. Study protocol.] / Smart-web support: un nuovo strumento per la condivisione delle cure in patologie pediatriche complesse. Protocollo di studio.

As devices for learning, smart-web support (SWS) multimedia hypertexts on the web now provide more versatile and interactive reading systems than those traditionally available in static printed texts. Designing similar tools for clinical practice would make complex scientific information easier to comprehend, and present the various therapeutic options to patients as minimally alarming graphical representations. In a pilot project we intend to produce a SWS tool for parents or tutors of children with primary differentiated thyroid cancer (DTC), a heretofore rare disease whose incidence has increased over recent years. The SWS hypertexts, "pre-digested" by the multidisciplinary team caring for these children, will be inserted in a single web page (canvas) including shared sheets explaining the best surgical options (decision aids). To make evidence-based information easier to understand and help information sharing, the decision aids will combine text and graphics. The canvas will store data for the multimedia files in a cloud storage system, opened via a link. To measure parents' and tutors' understanding and appreciation of the information provided on the web, the canvas will include questionnaires to investigate satisfaction, eventual barrier encountered, and type of surgical therapy chosen. The SWS tool should allow users to obtain all the information in a relatively short time and improve parents' and children's satisfaction with the surgical options proposed. The results obtained will be useful for developing similar SWS devices for other complex paediatric diseases.

Epidemiology, presentation and long-term evolution of Graves' disease in children, adolescents and young adults with Turner syndrome.

BACKGROUND: Epidemiological studies on the association between Turner syndrome (TS) and Graves' disease (GD) are sparse and no studies are available on the clinical course of GD in TS. OBJECTIVES: To retrospectively investigate the GD prevalence in children and young adults with TS and to compare the GD course in patients with or without TS who were followed up for 4.1 ± 0.6 and 4.5 ± 3.7 years, respectively. DESIGN: The prevalence of GD in 408 TS patients was evaluated; presentation and evolution of GD under therapy were evaluated both in 7 patients with TS (group A) and in 89 patients without TS (group B). RESULTS: (a) The prevalence of GD in TS patients was 1.7%; (b) GD in TS was not associated with a specific karyotype; (c) with respect to group B patients, those of group A exhibited at presentation more advanced age, a lower fT4 level and more frequent association with other autoimmune diseases, and (d) the clinical course under methimazole therapy was not different in the two groups. CONCLUSIONS: The prevalence of GD in children and young adults with TS is 1.7% and in TS patients, GD presents later and its clinical course is not different than in those without TS.

Nocturnal hypoglycaemia in ACTH and GH deficient children: role of continuous glucose monitoring.

OBJECTIVES: To evaluate the usefulness of continuous glucose monitoring (CGM) to identify nocturnal hypoglycaemia in children affected by combined ACTH and GH deficiency and to optimize the hydrocortisone replacement therapy in these patients. STUDY DESIGN: Eleven patients with ACTH and GH deficiency (five boys and six girls, age 1·6-16·8 years) underwent CGM for 36 h, including two nights. At least two consecutive glucose levels <2·78 mm were considered hypoglycaemic episodes. The differences in age and doses of hydrocortisone and recombinant human growth hormone (rhGH) between children with and without hypoglycaemia were analysed. The percentage of the glucose values <3·33 mm and the mean glucose levels were also evaluated. RESULTS: Continuous glucose monitoring demonstrated nocturnal hypoglycaemia lasting from 30 to 155 min (1·5% of the total monitoring time) in three cases (27%). No statistically significant differences in age and rhGH dose were observed between children with or without hypoglycaemia. Conversely, the difference in the hydrocortisone doses between the patients with and without hypoglycaemia resulted statistically significant (5·9 vs 8·5 mg/m²/day; P = 0·04). Eight patients presented glucose values less than 3·33 mm during 5% of the total monitoring time. Hydrocortisone dose showed significant positive linear relation with mean glucose level (r = 0·79, P = 0·0035) and inverse relation with time lags of glucose levels under 3·33 mm (r = -0·65, P = 0·03). CONCLUSIONS: Our study shows that CGM may represent a valuable tool to detect nocturnal asymptomatic hypoglycaemic episodes and optimize the hydrocortisone therapeutic regimen in children with ACTH and GH deficiency.

Partially reversible hypopituitarism in an adolescent with a rathke cleft cyst.

Rathke cleft cysts are remnants of the Rathke pouch. Most of them are asymptomatic, but sometimes they can grow enough to cause compression of structures within and/or close to the sella, thus eliciting symptoms such as visual disturbance, pituitary defects, and headache. Asymptomatic cysts can safely be followed up with serial imaging, while the standard treatment for symptomatic lesions is surgical removal. We describe a 14-yr-old boy, admitted for anorexia, fatigue, weight loss, recurrent headache and vomiting. Magnetic resonance imaging showed an intra- and suprasellar cystic lesion, which was surgically removed. Histology was consistent with Rathke's cleft cyst. Diabetes insipidus and multiple anterior pituitary defects (GH, ACTH and TSH) were found preoperatively, and substitutive therapy was started. No additional hormonal defect appeared after surgery. After 4 yr of follow up, pituitary function was retested, and there were no confirmed GH or ACTH defects, allowing a partial withdrawal of replacement therapy. Our report confirms that pituitary defects, in patients with a Rathke cleft cyst, may recover even year after surgery. Thus, retesting of pituitary axes is indicated during long-term follow up.

Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche.

OBJECTIVE: Premature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP. PATIENTS AND METHODS: A total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects. RESULTS: Baseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values <2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was <18.2 µg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations. CONCLUSION: In children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.

Obese children with low birth weight demonstrate impaired beta-cell function during oral glucose tolerance test.

OBJECTIVE: Epidemiological studies have shown an association between birth weight and future risk of type 2 diabetes, with individuals born either small or large for gestational age at increased risk. We sought to investigate the influence of birth weight on the relation between insulin sensitivity and beta-cell function in obese children. SUBJECTS AND METHODS: A total of 257 obese/overweight children (mean body mass index-sd score, 2.2 +/- 0.3), aged 11.6 +/- 2.3 yr were divided into three groups according to birth weight percentile: 44 were small for gestational age (SGA), 161 were appropriate for gestational age (AGA), and 52 were large for gestational age (LGA). Participants underwent a 3-h oral glucose tolerance test with glucose, insulin, and C-peptide measurements. Homeostasis model of assessment for insulin resistance, insulinogenic index, and disposition index were calculated to evaluate insulin sensitivity and beta-cell function. Glucose and insulin area under the curve (AUC) were also considered. One-way ANOVA was used to compare the three groups. RESULTS: SGA and LGA subjects had higher homeostasis model of assessment for insulin resistance than AGA subjects, but they diverged when oral glucose tolerance test response was considered. Indeed, SGA subjects showed higher glucose AUC and lower insulinogenic and disposition indexes. Insulin AUC was not different between groups, but when singular time points were considered, SGA subjects had lower insulin levels at 30 min and higher insulin levels at 180 min. CONCLUSIONS: SGA obese children fail to adequately compensate for their reduced insulin sensitivity, manifesting deficit in early insulin response and reduced disposition index that results in higher glucose AUC. Thus, SGA obese children show adverse metabolic outcomes compared to AGAs and LGAs.

Bone and body composition analyzed by Dual-energy X-ray Absorptiometry (DXA) in clinical and nutritional evaluation of young patients with Cystic Fibrosis: a cross-sectional study.

BACKGROUND: the improved general therapy has led to reduced morbidity and mortality from Cystic Fibrosis (CF), and bone status may have a potentially greater clinical impact.We investigated the correlation between the severity of the clinical condition, bone status and body composition parameters, in a group of children and young adults with CF. METHODS: we measured lumbar spine bone density and total body composition by dual energy x-ray absorptiometry (DXA) in 82 consecutive CF patients (42 males; median age: 13 years - range: 5-30). Eighty-two healthy subjects, matched for age, gender, height and pubertal stage were recruited as a control group. RESULTS: 37 patients (45.1%) had a normal bone mineral density (BMD). A BMD reduction were observed in 45 (54.8%) patients. Lumbar spine Z score was positively related to Body Mass Index (BMI) and a higher Shwachman-Kulczycki score, and negatively related to Crispin-Norman score. A positive and significant correlation was also observed between lumbar spine Z score and total body composition. CONCLUSION: a significant BMD reduction can be present early in CF children and adolescents. A careful follow up of bone status is required starting in childhood.

Blood Pressure and Left Ventricular Characteristics in Young Patients with Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency.

High steroid doses are often necessary in congenital adrenal hyperplasia (CAH) to suppress androgens and may increase blood pressure (BP). We evaluated 24-hour BP profile (ambBP), BP during exercise (excBP), and echocardiography in 20 young CAH patients. Systolic and diastolic BP during ambBP and excBP was normal in all patients. None presented myocardial hypertrophy. Nocturnal diastolic BP was affected by testosterone (P: .016, 95% CI: 0.002 to 0.021, beta = 0.01). Left ventricular mass (LVM ) was affected by height SDS (P: .007, 95% CI: 2.67 to 14.17, beta = 8.42), age (P: < .0001, 95% CI: 2.12 to 5.82, beta = 3.97), and testosterone (P: .008, 95% CI: 0.01 to 0.09, beta = 0.053). Left ventricular mass index (LVMI) correlated with BMI SDS (P: .044, 95% CI: 0.09 to 6.17, beta = 3.13) and testosterone (P: .031, 95% CI: 0.002 to 0.035, beta = 0.018). Hydrocortisone dose did not influence ambBP, excBP, or myocardial hypertrophy.

Cardiovascular fitness, insulin resistance and metabolic syndrome in severely obese prepubertal Italian children.

AIM: To evaluate if insulin resistance (IR) and metabolic syndrome (MS) were associated with poor cardiovascular fitness in very obese prepubertal Italian subjects. METHODS: Children referred to the Endocrinology and Diabetes Unit of Bambino Gesù Children's Hospital underwent an OGTT with glucose and insulin assays. QUICKI, ISI and HOMA-IR were calculated. Total and HDL cholesterol, triglycerides and percentage of body fat (DEXA) were determined. Cardiovascular fitness (maximal treadmill time) was evaluated using a treadmill protocol. The MS was defined as having 3 or more of following risk factors: obesity, impaired glucose tolerance, high blood pressure, low HDL-cholesterol, high triglycerides. RESULTS: Fifty-five very obese prepubertal Italian children were enrolled in the study. Unadjusted correlation revealed maximal treadmill time negatively related to fasting insulin (r = -0.53, p < 0.0001) and HOMA-IR (r = -0.57, p < 0.0001) and positively to QUICKI (r = 0.51, p < 0.0001) and ISI (r = 0.46, p = 0.0035). These relationships remained significant when in multivariate analysis age, gender, BMI SD and body composition were accounted for (all p < 0.01). The presence of the MS was independently associated with maximal treadmill time. CONCLUSION: Poorcardiovascular fitness, IR and MS were independently related, suggesting that the relationship between fitness and insulin action develops early in life.

Non-conventional use of growth hormone therapy.

UNLABELLED: Human growth hormone therapy is allowed in certain clinical conditions according to national healthcare criteria. Growth hormone, however, produces a wide spectrum of effects. Linear growth is only one of the many expected results, and there are interesting possibilities to explore which could provide additional means of improving the quality of life for the ever-increasing numbers of chronic paediatric patients. CONCLUSION: In this review, we discuss the rationale for and possibility of using growth hormone therapy in some conditions not strictly related to growth hormone deficiency.

Autosomal-dominant isolated growth hormone deficiency (IGHD type II) with normal GH-1 gene.

BACKGROUND: Autosomal-dominant isolated GH deficiency (IGHD) is a rare disorder that is commonly believed to be due to heterozygous mutations in the GH-1 gene (GH-1). These mutations cause the production of a protein that affects the release of the product of the normal allele. Rarely, heterozygous mutations in the gene encoding for HESX-1 gene (HESX-1) may cause autosomal-dominant IGHD, with penetrance that has been shown to be variable in both humans and mice. SUBJECTS AND METHODS: We have sequenced the whole GH-1 in the index cases of 30 families with autosomal-dominant IGHD. In all the families other possible causes of GH deficiency and other pituitary hormones deficits were excluded. We here describe the clinical, biochemical and radiological picture of the families without GH-1 mutations. In these families, we also sequenced the HESX-1. RESULTS: The index cases of the five families with autosomal-dominant IGHD had normal GH-1, including the intronic sequences. They had no HESX-1 mutations. CONCLUSION: This study shows that GH-1 mutations are absent in 5/30 (16.6%) of the families with autosomal-dominant IGHD and raises the possibility that mutations in other gene(s) may be involved in IGHD with this mode of transmission.

Growth and pubertal growth spurt in dysmorphic syndromes.

We describe peculiar aspects of growth and the pubertal growth spurt in dysmorphic syndromes, focusing our attention on the accelerated pubertal growth pattern in some dysmorphic syndromes leading to short stature (DSS). A normal pubertal growth spurt was observed in other dysmorphic syndromes leading to overgrowth (ODS).