Coincidental Central Precocious Puberty and Wilms Tumor in a 5-Year-Old Girl.

Wilms tumor is the most frequent pediatric renal malignancy, and its usual presentation is an abdominal mass or hematuria. Unusual presentations have also been reported, such as paraneoplastic syndromes (acquired von Willebrand disease, sudden death due to pulmonary embolism, and Cushing syndrome). These conditions can precede, occur concomitantly, or present in a later phase of tumor development. Precocious puberty, as paraneoplastic endocrine syndrome, has already been described in children with malignant tumors (brain, gonadal, adrenal tumors, and hepatoblastoma). However, little is known about central precocious puberty, as paraneoplastic manifestation of nephroblastoma or secondary to its specific chemotherapy. Here, we report a case of Wilms tumor and simultaneous precocious puberty in a 5-year-old girl. The initial diagnosis was premature telarche, but the clinical and biological pubertal progression changed our diagnosis to idiopathic central precocious puberty. Chemotherapy and nephrectomy were well tolerated, and we began treatment with a gonadotropin-releasing hormone agonist which showed favorable outcomes over the short term. We highlight the need for early diagnosis and work-up in all patients of precocious puberty, in order to institute timely management.

Vitamin D-Resistant Rickets and Cinacalcet-One More Favorable Experience.

Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder characterized by early onset of severe rickets, with a complete triad of clinical, biochemical and skeletal abnormalities. Homozygous or heterozygous mutations in the vitamin D receptor (VDR) gene leading to complete or partial target organ resistance to the action of 1α, 25-dihydroxyvitamin D3 (the active form of vitamin D) are responsible for HVDRR. Theoretically the therapeutic goal is to overcome this tissue resistance, and to normalize calcium and phosphate homeostasis. Practically, the treatment could be oriented to correct the secondary hyperparathyroidism to avoid long-term negative impact on bone health. The conventional therapeutic strategy (high-dose calcium plus active vitamin D metabolites) gives variable responses in magnitude and duration. We report a case of HVDRR with heterozygous mutation in the VDR gene, neonatal alopecia, and a severe clinical phenotype diagnosed at the age of 30 months who showed unsatisfactory response to traditional therapy. The short-term responsiveness to cinacalcet was encouraging, with adequate correction of phosphate-calcium homeostasis and significant improvement of clinical and radiological status at 6 months of treatment.

CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability.

OBJECTIVE: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step. METHODS: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (ntotal = 145). RESULTS: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations. CONCLUSIONS: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.

Diabetes Mellitus in a Patient With Lafora Disease: Possible Links With Pancreatic ß-Cell Dysfunction and Insulin Resistance.

Lafora disease (LD) is a rare autosomal recessive disorder characterized by progressive myoclonic epilepsy followed by continuous neurological decline, culminating in death within 10 years. LD leads to accumulation of insoluble, abnormal, glycogen-like structures called Lafora bodies (LBs). It is caused by mutations in the gene encoding glycogen phosphatase (EPM2A) or the E3 ubiquitin ligase malin (EPM2B/NHLRC1). These two proteins are involved in an intricate, however, incompletely elucidated pathway governing glycogen metabolism. The formation of EPM2A and malin signaling complex promotes the ubiquitination of proteins participating in glycogen metabolism, where dysfunctional mutations lead to the formation of LBs. Herein, we describe a 13-years-old child with LD due to a NHLRC1 (c.386C > A, p.Pro129His) mutation, who has developed diabetes mellitus and was treated with metformin. We discuss how basic mechanisms of LD could be linked to ß-cell dysfunction and insulin resistance.

Neonatal pulmonary hemosiderosis.

Idiopathic pulmonary hemosiderosis (IPH) is a rare complex entity characterized clinically by acute or recurrent episodes of hemoptysis secondary to diffuse alveolar hemorrhage. The radiographic features are variable, including diffuse alveolar-type infiltrates, and interstitial reticular and micronodular patterns. We describe a 3-week-old infant presenting with hemoptysis and moderate respiratory distress. Idiopathic pulmonary hemosiderosis was the first working diagnosis at the Emergency Department and was confirmed, 2 weeks later, by histological studies (bronchoalveolar lavage). The immunosuppressive therapy by 1 mg/kg/d prednisone was immediately started, the baby returned home on steroid therapy at a dose of 0,5 mg/kg/d. The diagnosis of idiopathic pulmonary hemosiderosis should be evocated at any age, even in the neonate, when the clinical presentation (hemoptysis and abnormal radiological chest images) is strongly suggestive.

Catch-up growth following fetal growth restriction promotes rapid restoration of fat mass but without metabolic consequences at one year of age.

BACKGROUND: Fetal growth restriction (FGR) followed by rapid weight gain during early life has been suggested to be the initial sequence promoting central adiposity and insulin resistance. However, the link between fetal and early postnatal growth and the associated anthropometric and metabolic changes have been poorly studied. METHODOLOGY/PRINCIPAL FINDINGS: Over the first year of post-natal life, changes in body mass index, skinfold thickness and hormonal concentrations were prospectively monitored in 94 infants in whom the fetal growth velocity had previously been measured using a repeated standardized procedure of ultrasound fetal measurements. 45 infants, thinner at birth, had experienced previous FGR (FGR+) regardless of birth weight. Growth pattern in the first four months of life was characterized by greater change in BMI z-score in FGR+ (+1.26+/-1.2 vs +0.58 +/-1.17 SD in FGR-) resulting in the restoration of BMI and of fat mass to values similar to FGR-, independently of caloric intakes. Growth velocity after 4 months was similar and BMI z-score and fat mass remained similar at 12 months of age. At both time-points, fetal growth velocity was an independent predictor of fat mass in FGR+. At one year, fasting insulin levels were not different but leptin was significantly higher in the FGR+ (4.43+/-1.41 vs 2.63+/-1 ng/ml in FGR-). CONCLUSION: Early catch-up growth is related to the fetal growth pattern itself, irrespective of birth weight, and is associated with higher insulin sensitivity and lower leptin levels after birth. Catch-up growth promotes the restoration of body size and fat stores without detrimental consequences at one year of age on body composition or metabolic profile. The higher leptin concentration at one year may reflect a positive energy balance in children who previously faced fetal growth restriction.

Adaptive changes in neonatal hormonal and metabolic profiles induced by fetal growth restriction.

CONTEXT: Birth weight (BW) is usually taken as a surrogate of fetal growth. However, BW per se is not relevant enough in assessing fetal growth restriction, which by itself may alter body composition, metabolic, and hormonal profiles at birth (irrespective of BW), reflecting the necessary adaptive changes in metabolism under poor fetal environment. OBJECTIVE: Our objective was to measure body composition, hormonal, and metabolic parameters at birth in relation to both BW and fetal growth velocity. METHODS: A total of 235 pregnancies at risk of low BW were included, and newborns were observed at birth. Fetal growth velocity was calculated as the change in customized percentiles of estimated fetal weight between 22 wk gestational age and birth. Newborns were ranked in descending order of fetal growth velocity and divided in three equal tertiles. RESULTS: The lower fetal growth velocity tertile showed a severe fetal growth restriction (-52% +/- 21%) and was significantly associated with reduced lean and fat mass (P < 0.001 and 0.02, respectively). Insulin concentration was significantly related to fetal growth velocity (P = 0.006) and fat mass (P = 004) but not to BW (grams), whereas fetal growth velocity (P = 0.002) and BW (P < 0.001) but not fat mass had a significant effect on IGF-I concentration at birth. CONCLUSION: Fetal growth restriction induces changes in body composition and metabolism suggestive of a higher insulin sensitivity independently from BW itself, reflecting adaptive changes to an adverse fetal nutritional environment.

Bone mineral content at birth is determined both by birth weight and fetal growth pattern.

Adult peak bone mass is related to birth weight, suggesting it could be affected by fetal growth pattern. Small-for-gestational-age (SGA) newborns have lower bone mineral content (BMC), but what about adapted-for-gestational-age (AGA) newborns with fetal growth restriction? The purpose of the study was to determine the respective role of birth weight and fetal growth pattern on BMC. Full-term newborns from SGA high-risk pregnancies were included (n = 185). Estimated fetal weight percentiles were measured monthly from mid-gestation to birth, and restricted fetal growth (FGR) was defined as a loss by more than 20 percentiles. BMC was measured at birth, using dual x-ray absorptiometry. Newborns were SGA (n = 56) or AGA (n = 129). Newborns with FGR (n = 111) were AGA (n = 71) or SGA (n = 41). BMC was significantly lower in SGA than AGA (1.48 +/- 0.02 vs. 1.87 +/- 0.04 g/cm) and lower when FGR irrespective of birth weight (1.66 g/cm +/- 0.03 vs. 1.89 g +/- 0.05). In multivariate analysis, FGR and SGA were significant and independent predictors of low BMC. In conclusion, fetal growth pattern affects BMC not only in SGA infants but also when birth weight is maintained in the normal range.