Effective Long-term Pediatric Pegvisomant Monotherapy to Final Height in X-linked Acrogigantism.

X-linked acrogigantism (X-LAG) is characterized by extreme tall stature from early childhood resulting from duplication of the gene, in turn resulting in GH excess. Most cases present with pituitary tumors secreting GH and prolactin. Diffuse pituitary hyperplasia is uncommon and normal prolactin is rare.

Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome - neuro-endocrine tumours (ROHHAD-NET): case series and learning points.

Objectives: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity and mortality. Diagnosis is often challenging. We describe three cases of ROHHAD with heterogeneous presentations but some consistent clinical features, including hyperprolactinaemia at diagnosis.

Patient-reported experience of clinical care of osteogenesis imperfecta (OI) during the COVID-19 pandemic.

Background: Research on the effects of the COVID-19 pandemic on people with rare diseases is limited. Few studies compare healthcare throughout the progression of the ongoing pandemic.

Aims: To assess the impact of the pandemic on individuals with osteogenesis imperfecta across two consecutive years, understand what challenges were encountered, and analyse the experience of remote consultation.

A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project.

Background: Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data.

Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies.

Background: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 () gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1-3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia.

Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant.

Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the gene. One mutation results in an in frame stop codon (Rstop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (GR) that, surprisingly, does not affect the Ca permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 GR and Rstop mutants and combinations with wild type TRPV6.

Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study.

Background/objectives: In England, children (0-18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a 'Highly Specialised Service' (HSS OI); affected children with a genetic origin for their disease that is not in or form the majority of the 'atypical' group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country.

Methods: Children with atypical OI were identified through the HSS OI service database.

Monitoring Skull Base Abnormalities in Children with Osteogenesis Imperfecta - Review of Current Practice and a Suggested Clinical Pathway.

Objectives: In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI.

Methods: A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor's technique) and basilar invagination (McRae's technique)), and clinical features at the time of imaging.

AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination.

Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy. Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination. Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1.

Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for osteoclast-poor autosomal recessive osteopetrosis.

Unlabelled: Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.

Case: This child with compound heterozygous novel loss-of-function pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.

The third case of TNFRSF11A-associated dysosteosclerosis with a mutation producing elongating proteins.

Dysosteosclerosis (DOS) is a distinct form of sclerosing bone disease characterized by platyspondyly and progressive osteosclerosis. DOS is genetically heterogeneous. Three causal genes, SLC29A3, CSF1R, and TNFRSF11A are reported.

Expanding the phenotypic spectrum of IFT81: Associated ciliopathy syndrome.

Short-rib polydactyly syndromes are a heterogeneous group of disorders characterized by narrow thorax with short ribs, polydactyly and often other visceral and skeletal malformations. To date there have only been six reported patients with homozygous and compound heterozygous variants in IFT81, causing a short-rib thoracic dysplasia, with, or without, polydactyly (SRTD19: OMIM 617895). IFT81 is a protein integral to the core of the intraflagellar transport complex B (IFT-B), which is involved in anterograde transport in the cilium.

Improvement in glycaemic parameters using SGLT-2 inhibitor and GLP-1 agonist in combination in an adolescent with diabetes mellitus and Prader-Willi syndrome: a case report.

Objectives Prader-Willi Syndrome (PWS) is characterised by hyperphagia often leading to obesity; a known risk factor for insulin resistance and type 2 (T2) diabetes. We present a prepubertal girl with PWS who developed diabetes. Case presentation Our case was diagnosed with PWS in infancy following investigation for profound central hypotonia and feeding difficulties.

PAPSS2-related brachyolmia: Clinical and radiological phenotype in 18 new cases.

Brachyolmia is a skeletal dysplasia characterized by short spine-short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity.

Challenges of delivery of dental care and dental pathologies in children and young people with osteogenesis imperfecta.

Background: Osteogenesis imperfecta (OI) is the most common inherited disorder of bone fragility in children, increasing fracture risk 100-fold and can feature dental and facial bone involvement causing additional morbidities.

Aim: To assess the utilisation of tertiary dental services by children and young people with OI attending a supra-regional multi-disciplinary OI service and review of the pathology identified and interventions undertaken.

Design: Case notes review of the current caseload of children and young people (0-18 years) with OI at a large regional OI specialist centre (n = 92).

TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton.

Transient receptor potential vanilloid 6 (TRPV6) functions in tetramer form for calcium transport. Until now, TRPV6 has not been linked with skeletal development disorders. An infant with antenatal onset thoracic insufficiency required significant ventilatory support.

Pamidronate "zebra lines": A treatment timeline.

Osteogenesis imperfecta is a hereditary bone dysplasia characterized by bone fragility, deformity, and short stature. Treatment focuses on preventing bone fractures and symptom relief. Pamidronate, a second-generation bisphosphonate drug that minimizes bone loss, is the chosen treatment in osteogenesis imperfecta.

Gonadotrophin abnormalities in an infant with Lowe syndrome.

Summary: This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic-pituitary-gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis.

Improving patient outcomes in fibrous dysplasia/McCune-Albright syndrome: an international multidisciplinary workshop to inform an international partnership.

Unlabelled: To develop consensus on improving the management of patients, we convened an international workshop involving patients, clinicians, and researchers. Key findings included the diagnostic delay and variability in subsequent management with agreement to develop an international natural history study. We now invite other stakeholders to join the partnership.