Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32-q27.2.

Partial duplications of the long arm of chromosome 3, dup(3q), are a rare but well-described condition, sharing features of Cornelia de Lange syndrome. Around two thirds of cases are derived from unbalanced translocations, whereas pure dup(3q) have rarely been reported. Here, we provide an extensive review of the literature on dup(3q). This search revealed several patients with caudal malformations and anomalies, suggesting that caudal malformations or anomalies represent an inherent phenotypic feature of dup(3q). In this context, we report a patient with a pure de novo duplication 3q26.32-q27.2. The patient had the clinical diagnosis of Currarino syndrome (CS) (characterized by the triad of sacral anomalies, anorectal malformations and a presacral mass) and additional features, frequently detected in patients with a dup(3q). Mutations within the MNX1 gene were found to be causative in CS but no MNX1 mutation could be detected in our patient. Our comprehensive search for candidate genes located in the critical region of the duplication 3q syndrome, 3q26.3-q27, revealed a so far neglected phenotypic overlap of dup(3q) and the Pierpont syndrome, associated with a mutation of the TBL1XR1 gene on 3q26.32.

Towards the perfect ARM center: the European Union's criteria for centers of expertise and their implementation in the member states. A report from the ARM-Net.

BACKGROUND: Pediatric surgeons and patient organisations agree that fewer centers for anorectal malformations with larger patient numbers are essential to reach better treatment. The European Union transacts a political process which aims to realize such centers of expertise for a multitude of rare diseases. All the centers on a specific rare disease should constitute an ERN on that disease. ARM-Net members in different countries report on first experiences with the implementation of national directives, identifying opportunities and risks of this process. METHODS: Relevant details from the official European legislation were analyzed. A survey among the pediatric surgeons of the multidisciplinary ARM-Net consortium about national implementation was conducted. RESULTS: European legislation calls for multidisciplinary centers treating children with rare diseases, and proposes a multitude of quality criteria. The member states are called to allocate sufficient funding and to execute robust governance and oversight, applying clear methods for evaluation. Participation of the patient organisations is mandatory. The national implementations all over Europe differ a lot in respect of extent and timeframe. CONCLUSIONS: Establishing Centers of Expertise and a ERN for anorectal malformations offers great opportunities for patient care and research. Pediatric surgeons should be actively engaged in this process.

European consensus meeting of ARM-Net members concerning diagnosis and early management of newborns with anorectal malformations.

The ARM-Net (anorectal malformation network) consortium held a consensus meeting in which the classification of ARM and preoperative workup were evaluated with the aim of improving monitoring of treatment and outcome. The Krickenbeck classification of ARM and preoperative workup suggested by Levitt and Peña, used as a template, were discussed, and a collaborative consensus was achieved. The Krickenbeck classification is appropriate in describing ARM for clinical use. The preoperative workup was slightly modified. In males with a visible fistula, no cross-table lateral X-ray is needed and an anoplasty or (mini-) posterior sagittal anorectoplasty can directly be performed. In females with a small vestibular fistula (Hegar size <5 mm), a primary repair or colostomy is recommended; the repair may be delayed if the fistula admits a Hegar size >5 mm, and in the meantime, gentle painless dilatations can be performed. In both male and female perineal fistula and either a low birth weight (<2,000 g) or severe associated congenital anomalies, prolonged preoperative painless dilatations might be indicated to decrease perioperative morbidity caused by general anesthesia. The Krickenbeck classification is appropriate in describing ARM for clinical use. Some minor modifications to the preoperative workup by Levitt and Peña have been introduced in order to refine terminology and establish a comprehensive preoperative workup.

Spectrum of HLXB9 gene mutations in Currarino syndrome and genotype-phenotype correlation.

Currarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle-shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development. Thus far, 43 different heterozygous mutations have been reported in patients fulfilling CS criteria. Mutation detection rate is about 50%, and reaches 90% in familial cases. Here, we report 23 novel mutations in 26 patients among a series of 50 index cases with CS, and review mutational reports published since the identification of the causative gene. Three cytogenetic anomalies encompassing the HLXB9 gene are described for the first time. Truncating mutations (frameshifts or nonsense mutations) represent 57% of those identified, suggesting that haploinsufficiency is the basis of CS. No obvious genotype-phenotype correlation can be drawn thus far. Genetic heterogeneity is suspected, since at least 19 of the 24 patients without HLXB9 gene mutation harbor subtle phenotypic variations.

[Congenital hyperinsulinism of infancy: surgical treatment in 60 cases of focal form]. / Hyperinsulinisme persistant du nouveau-né et du nourrisson: traitement chirurgical des lésions pancréatiques focales dans 60 cas.

Congenital hyperinsulinism of infancy is a severe disease that leads to important brain damage. Two different forms of the disease have been identified by pathologists: a diffuse and a focal form. A specific genetic anomaly identified in focal forms has never been described in diffuse ones. However, for most of authors, failure of medical treatment results in near-total pancreatectomy in all cases, which ends in diabetus. The aim of this retrospective study was to assess the results of elective partial pancreatectomy performed in 60 cases of focal form of hyperinsulinism over the last 18 years. Fifty-eight patients were cured with euglycemia at both fasting and hyperglycaemic tests without insulin-dependent diabetes mellitus. One patient is still in hypoglycaemia from unrecognized lesion; insulin-dependent diabetes mellitus occurred in one case nine years after surgery (a near-total pancreatectomy has been performed because of unknown focal form, in 1985).

Partial elective pancreatectomy is curative in focal form of permanent hyperinsulinemic hypoglycaemia in infancy: A report of 45 cases from 1983 to 2000.

BACKGROUND/PURPOSE: Permanent hyperinsulinemic hypoglycaemia in infancy (PHHI)I is a severe disease that leads to brain damage. Since 1989, pathologists have identified 2 different forms of the disease: a diffuse form (DiPHHI) and a focal form (FoPHHI). The purpose of this study was to adapt surgical techniques in case of FoPHHI to cure these infants without risk of diabetes. METHODS: All patients with PHHI underwent pancreatic venous sampling (PVS) and elective partial pancreatectomy (EPP). Molecular biology and immunohistochemistry were used to ascertain that FoPHHI was a different disease from DiPHHI. RESULTS: 45 EPPs were performed, guided by PVS and peroperative pathology. The lesions were 17 in the head, 4 in the isthmus, 6 in the body, 15 in the tail of the pancreas. Age at surgery ranged from 25 days to 4 years. Two patients already had been operated on elsewhere, and the focal lesion could be found at second operation. All 45 patients except one, were cured with euglycemia at both fasting and hyperglycaemic tests. Molecular biology has shown a specific anomaly in FoPHHI, which never has been encountered in DiPHHI. CONCLUSIONS: PHHI is not a homogeneous disease. In one third of cases, only a small amount of endocrine pancreas is abnormal, and conservative surgery is mandatory. The pre- and perioperative conditions to point out the focal pancreatic lesion are described.