Electronic reporting of rare endocrine conditions within a clinical network: results from the EuRRECa project.

Objective: The European Registries for Rare Endocrine Conditions (EuRRECa, eurreb.eu) includes an e-reporting registry (e-REC) used to perform surveillance of conditions within the European Reference Network (ERN) for rare endocrine conditions (Endo-ERN). The aim of this study was to report the experience of e-REC over the 3.5 years since its launch in 2018. Methods: Electronic reporting capturing new encounters of Endo-ERN conditions was performed monthly through a bespoke platform by clinicians registered to participate in e-REC from July 2018 to December 2021. Results: The number of centres reporting on e-REC increased to a total of 61 centres from 22 countries. A median of 29 (range 11, 45) paediatric and 32 (14, 51) adult centres had reported cases monthly. A total of 9715 and 4243 new cases were reported in adults (age ≥18 years) and children, respectively. In children, sex development conditions comprised 40% of all reported conditions and transgender cases were most frequently reported, comprising 58% of sex development conditions. The median number of sex development cases reported per centre per month was 0.6 (0, 38). Amongst adults, pituitary conditions comprised 44% of reported conditions and pituitary adenomas (69% of cases) were most commonly reported. The median number of pituitary cases reported per centre per month was 4 (0.4, 33). Conclusions: e-REC has gained increasing acceptability over the last 3.5 years for capturing brief information on new encounters of rare conditions and shows wide variations in the rate of presentation of these conditions to centres within a reference network. Significance statement Endocrinology includes a very wide range of rare conditions and their occurrence is often difficult to measure. By using an electronic platform that allowed monthly reporting of new clinical encounters of several rare endocrine conditions within a defined network that consisted of several reference centres in Europe, the EuRRECa project shows that a programme of e-surveillance is feasible and acceptable. The data that have been collected by the e-reporting of rare endocrine conditions (e-REC) can allow the continuous monitoring of rare conditions and may be used for clinical benchmarking, designing new studies or recruiting to clinical trials.

The current landscape of European registries for rare endocrine conditions.

Objective To identify cross-border international registries for rare endocrine conditions that are led from Europe and to understand the extent of engagement with these registries within a network of reference centres (RCs) for rare endocrine conditions. Methods Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%. Results Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RCs were aware of 11 (41%). Of 21 registries identified by the RC, RD-Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RCs, the awareness and participation rate in an international registry was highest for rare diabetes at 75 and 56% respectively. Of the 37 sex development RCs, the corresponding rates were highest for disorders of sex development at 70 and 52%. Of the 33 adrenal RCs, the rates were highest for adrenocortical tumours at 68 and 43%. Of the 43 pituitary RCs, the rates were highest for pituitary adenomas at 43 and 29%. Of the 31 genetic tumour RCs, the rates were highest for MEN1 at 26 and 9%. For the remaining conditions, awareness and participation in registries was less than 25%. Conclusion Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries.

Beckwith-Wiedemann syndrome: growth pattern and tumor risk according to molecular mechanism, and guidelines for tumor surveillance.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with an increased risk of pediatric tumors. The underlying molecular abnormalities may be genetic (CDKN1C mutations or 11p15 paternal uniparental isodisomy, pUPD) or epigenetic (imprinting center region 1, ICR1, gain of methylation, ICR1 GOM, or ICR2 loss of methylation, ICR2 LOM). AIM: We aimed to describe a cohort of 407 BWS patients with molecular defects of the 11p15 domain followed prospectively after molecular diagnosis. RESULTS: Birth weight and length were significantly higher in patients with ICR1 GOM than in the other groups. ICR2 LOM and CDKN1C mutations were associated with a higher prevalence of exomphalos. Mean adult height (regardless of molecular subtype, n = 35) was 1.8 ± 1.2 SDS, with 18 patients having a final height above +2 SDS. The prevalence of tumors was 8.6% in the whole population; 28.6 and 17.3% of the patients with ICR1 GOM (all Wilms tumors) and 11p15 pUPD, respectively, developed a tumor during infancy. Conversely, the prevalence of tumors in patients with ICR2 LOM and CDKN1C mutations were 3.1 and 8.8%, respectively, with no Wilms tumors. CONCLUSION: Based on these results for a large cohort, we formulated guidelines for the follow-up of these patients according to the molecular subtype of BWS.

Ovarian-sparing surgery for ovarian teratoma in children.

BACKGROUND: Ovarian teratoma (OT) is the most common ovarian neoplasm in children. Oophorectomy has been the standard treatment but may impair fertility. The aim of this study was to investigate the feasibility and outcome of ovarian-sparing surgery (OSS) for OT. PROCEDURE: We retrospectively studied all children treated for OT at a pediatric teaching hospital in Paris, France, between March 1992 and July 2006. OSS was performed when deemed technically feasible in patients who had no lymphadenopathy by preoperative imaging or surgical exploration, normal tumor marker levels, and calcifications on radiographs. RESULTS: We identified 30 patients, including 29 with unilateral OT and 1 with synchronous bilateral OT. Emergent surgery was performed in five patients, among whom four had ovarian torsion requiring oophorectomy and one underwent OSS. Of the 26 OTs in the 25 remaining patients, 10 were managed with OSS and 16 with oophorectomy. Subsequently, ultrasound monitoring detected OT development in the contralateral ovary in 4 (14%) patients, after a median of 3 years (range, 1-14 years); OSS was performed in all four cases. The patient with bilateral synchronous OT, managed by OSS initially, underwent unilateral oophorectomy 3 years later for a recurrence. Overall OSS was performed for 15 (42%) OTs. CONCLUSIONS: Our results suggest recommendations for preserving fertility whenever possible without compromising the oncological prognosis. In particular, OSS should be reserved for patients who meet all criteria for localized mature teratoma. Long-term follow-up is crucial.

Acute lymphocytic leukaemia in a child with Beckwith-Wiedemann syndrome harbouring a CDKN1C mutation.

Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth syndrome associated with an increased risk in childhood tumours. The phenotypic variability in BWS reflects its molecular heterogeneity. This syndrome is a multigenic disorder caused by dysregulation of imprinted growth regulatory genes in the 11p15.5 region. The most commonly reported tumours in this syndrome are tumours of embryologic origin such as Wilms tumours, hepatoblastomas, neuroblastomas, rhabdomyosarcomas and adrenocortical carcinomas. We report the case of a 10-year-old patient diagnosed with BWS, harbouring a CDKN1C (p57(KIP2)) mutation, who developed a T-type acute lymphoblastic leukaemia. To our knowledge it is the first report of an acute lymphoblastic leukaemia of T-type in a child with BWS. We discuss the possibility of a link between BWS and leukaemia via one of the few known negative regulator of hematopoiesis, the transforming growth factor beta pathway, depending upon the up-regulation of CDKN1C.

Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development.

The pathophysiology of combined pituitary hormone deficiency (CPHD) is just beginning to be elucidated, with mutations in genes encoding transcription factors expressed at different stages of pituitary development. Among them, the two closely related genes, LHX3 and LHX4, are believed to share redundant biological properties. The patients with a LHX3 mutation display a CPHD phenotype, associated with a rigid cervical spine. This latter feature, not reported in Lhx3-/- and Lhx4-/- mice nor in patients with a LHX4 defect, prompted us to study the molecular consequences of a previously identified LHX3 23-bp deletion and to determine the LHX3 and LHX4 expression patterns during early human development. This deletion, which results in the skipping of one coding exon, would lead to a protein with no transcriptional capability. Using in situ hybridization, we show that LHX3 and LHX4 are expressed in the developing human pituitary and along the rostro-caudal length of the spinal cord; here, both transcripts are detected in the ventral part giving rise to motorneurons and interneurons. However, whereas LHX3 is expressed at all stages studied, LHX4 expression is transient, and, at 6 weeks of development, is stronger at the caudal than at the cervical level.

Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.

Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development. We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.

Dysgenesis of the internal carotid artery associated with transsphenoidal encephalocele: a neural crest syndrome?

We describe two original cases of internal carotid artery dysgenesis associated with a malformative spectrum, which includes transsphenoidal encephalocele, optic nerve coloboma, hypopituitarism, and hypertelorism. Cephalic neural crest cells migrate to various regions in the head and neck where they contribute to the development of structures as diverse as the anterior skull base, the walls of the craniofacial arteries, the forebrain, and the face. Data suggest that the link between these rare malformations is abnormal neural crest development.

Extensive phenotypic analysis of a family with growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene.

GH secretion and release are complex phenomena depending on activation of several genes, including those encoding GH, GHRH, and its receptor (GHRH-R). The GH gene, which is the most extensively analyzed sequence in patients with familial GH deficiency (GHD), represents the main known target of mutations. To test the involvement of the GHRH-R gene in this disease phenotype, we investigated one candidate Tamoulean family originating from Sri Lanka. Two brothers, with extremely short stature (< -4 SD) and no dysmorphy, were diagnosed as having complete GHD, unresponsive to exogenous GHRH and associated with PRL levels within the lower normal range. Magnetic resonance imaging examination showed anterior pituitary hypoplasia with a normal pituitary stalk. Both patients increased their growth rate while under GH therapy. Molecular investigations revealed a homozygous GHRH-R gene mutation that introduces a stop codon at residue 72. This mutation, which predicts a severely truncated receptor lacking the seven membrane spanning domains, is identical to that recently reported in one Indian Moslem family, raising the possibility of a founder effect. There was no clear evidence for height reduction in the three heterozygous individuals studied. This observation, which underlines the phenotypic criteria associated with a loss of GHRH-R function, raises the question of the frequency of GHRH-R abnormalities among GHD patients.