ABSTRACT
Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.
Subject(s)
Bone and Bones/metabolism , Coat Protein Complex I/genetics , Coatomer Protein/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Osteoporosis/genetics , Animals , Ascorbic Acid/pharmacology , Bone and Bones/drug effects , Bone and Bones/pathology , Brain/diagnostic imaging , Brain/drug effects , Brain/metabolism , Brain/pathology , Child , Child, Preschool , Coat Protein Complex I/deficiency , Coatomer Protein/chemistry , Coatomer Protein/deficiency , Collagen Type I/genetics , Collagen Type I/metabolism , Developmental Disabilities/diagnostic imaging , Developmental Disabilities/metabolism , Developmental Disabilities/pathology , Embryo, Nonmammalian , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/pathology , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Expression Regulation, Developmental , Golgi Apparatus , Haploinsufficiency , Humans , Intellectual Disability/diagnostic imaging , Intellectual Disability/metabolism , Intellectual Disability/pathology , Male , Mice , Osteoporosis/drug therapy , Osteoporosis/metabolism , Osteoporosis/pathology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Severity of Illness Index , ZebrafishABSTRACT
Achaete-Scute Family basic-helix-loop-helix (bHLH) Transcription Factor 1 (ASCL1) is a proneural transcription factor involved in neuron development in the central and peripheral nervous system. While initially suspected to contribute to congenital central hypoventilation syndrome-1 (CCHS) with or without Hirschsprung disease (HSCR) in three individuals, its implication was ruled out by the presence, in one of the individuals, of a Paired-like homeobox 2B (PHOX2B) heterozygous polyalanine expansion variant, known to cause CCHS. We report two additional unrelated individuals sharing the same sporadic ASCL1 p.(Glu127Lys) missense variant in the bHLH domain and a common phenotype with short-segment HSCR, signs of dysautonomia, and developmental delay. One has also mild CCHS without polyalanine expansion in PHOX2B, compatible with the diagnosis of Haddad syndrome. Furthermore, missense variants with homologous position in the same bHLH domain in other genes are known to cause human diseases. The description of additional individuals carrying the same variant and similar phenotype, as well as targeted functional studies, would be interesting to further evaluate the role of ASCL1 in neurocristopathies.
Subject(s)
Homeodomain Proteins , Transcription Factors , Humans , Basic Helix-Loop-Helix Transcription Factors/genetics , Homeodomain Proteins/genetics , Mutation , Mutation, Missense/genetics , Phenotype , Transcription Factors/geneticsABSTRACT
BACKGROUND: Growth is one of the fundamental processes of adolescent development. Careful history and examination, and relevant tar-geted investigations, can streamline the referral process, highlighting the important role of primary healthcare clinicians. OBJECTIVE: This article will provide a guide for clinicians to categorise growth patterns in adolescents, and recognise patients who may have a growth disorder. It will assist clinicians in considering appropriate investigations, and provide guidance for when to refer the adolescent to appropriate paediatric specialists. DISCUSSION: Causes of tall and short stature can often be distinguished on history, physical examination, and accurate pubertal staging. The height of the adolescent should always be considered in the context of their genetic potential. Physiological variants re-main the most common reason for short stature, but awareness of the features of pathological causes is critical. One of the most common presentations is maturational delay in males, and an approach to this issue is discussed.
Subject(s)
Disease Management , General Practice/methods , Growth Disorders , Physical Examination/methods , Referral and Consultation , Adolescent , Global Health , Growth Disorders/diagnosis , Growth Disorders/epidemiology , Growth Disorders/therapy , Humans , IncidenceABSTRACT
INTRODUCTION: Achondroplasia is a heritable disorder of the skeleton that affects approximately 300,000 individuals worldwide. Until recently, treatment for this condition has been purely symptomatic. Efficacious treatment options for children are now approved or are in clinical trials. AREAS COVERED: This review discusses key advances in the therapeutic management of children with achondroplasia, including vosoritide, the first approved drug, and other emerging precision therapies. These include navepegritide, a long-acting form of C-type natriuretic peptide, and infigratinib, a tyrosine kinase receptor inhibitor, summarizing trial outcomes to date. EXPERT OPINION: The advent of the first approved precision therapy for achondroplasia in vosoritide has been a paradigm shifting advance for children affected by this condition. In addition to changing their natural growth history, it is hoped that it will decrease their medical complications and enhance functionality. These new treatment options highlight the importance of prompt prenatal identification and subsequent testing of a suspected fetus with achondroplasia and counseling of families. It is hoped that, in the near future, families will have the option to consider a range of effective targeted therapies that best suit their child with achondroplasia, starting from birth should they choose.
ABSTRACT
Early onset medullary thyroid carcinoma, later pheochromocytomas, and nonspecific extra-endocrine features (hypermobility and persistent constipation) are part of the clinical phenotype of Multiple Endocrine Neoplasia type 2B (MEN2B). A de novo pathogenic M918T variant in the rearranged during transfection proto-oncogene is usually identified. Affected children are often seen by multiple clinicians over a long period before consideration of a diagnosis of MEN2B, with metastatic medullary thyroid carcinoma often the precipitator. We describe the clinical presentation and course of 5 children ultimately diagnosed with MEN2B in New South Wales and the Australian Capital Territory, Australia between 1989 and 2021. All cases had intestinal ganglioneuromatosis that could have prompted an earlier diagnosis. Population wide newborn genomic screening for rare diseases is on the horizon. We propose that MEN2B genomic screening should be included in newborn screening programs and that careful exclusion of intestinal ganglioneuromatosis would allow earlier identification leading to improved clinical outcomes.
ABSTRACT
INTRODUCTION: Craniopharyngiomas are rare brain tumours (incidence 1.1-1.7 cases/million/year). Although non-malignant, craniopharyngioma causes major endocrine and visual morbidities including hypothalamic obesity, yet mechanisms leading to obesity are poorly understood. This study investigated the feasibility and acceptability of eating behaviour measures in patients with craniopharyngioma to inform the design of future trials. METHODS: Patients with childhood-onset craniopharyngioma and controls matched for sex, pubertal stage, and age were recruited. After an overnight fast, participants received the following measures: body composition, resting metabolic rate, oral glucose tolerance test including magnetic resonance imaging (patients only), appetite ratings, eating behaviour, and quality of life questionnaires, ad libitum lunch, and an acceptability questionnaire. Data are reported as median ± IQR, with effect size measure (Cliff's delta) and Kendall's tau for correlations, due to the small sample size. RESULTS: Eleven patients (median age = 14 years; 5 F/6 M) and matched controls (median age = 12 years; 5 F/6 M) were recruited. All patients had received surgery, and 9/11 also received radiotherapy. Hypothalamic damage post-surgery was graded (Paris grading): grade 2 n = 6; grade 1 n = 1; grade 0 n = 2. The included measures were deemed highly tolerable by participants and their parent/carers. Preliminary data suggest a difference in hyperphagia between patients and controls (d = 0.5), and a relationship between hyperphagia with body mass index standard deviation score (BMISDS) in patients (τ = 0.46). DISCUSSION: These findings demonstrate that eating behaviour research is feasible and acceptable to craniopharyngioma patients and there is an association between BMISDS and hyperphagia in patients. Thus, food approach and avoidance behaviours may be useful targets for interventions to manage obesity in this patient group.
Subject(s)
Craniopharyngioma , Pediatric Obesity , Pituitary Neoplasms , Humans , Adolescent , Child , Craniopharyngioma/complications , Feasibility Studies , Pediatric Obesity/epidemiology , Pediatric Obesity/complications , Quality of Life , Pituitary Neoplasms/epidemiology , Pituitary Neoplasms/complications , Hyperphagia/complications , Feeding Behavior , HomeostasisABSTRACT
The physiology and regulation of bone minerals in the fetus and the newborn is significantly different from children and adults. The bone minerals calcium, phosphate and magnesium are all maintained at higher concentrations in utero to achieve adequate bone accretion. This is an integral component of normal fetal development which facilitates safe neonatal transition to post-natal life. When deciphering the cause of bone mineral disorders in newborns, the potential differential diagnosis list is broad and complex, including several extremely rare conditions. Also, significant discoveries including new embryological molecular genetic transcription factors, the role of active placental mineral transport, and hormone regulation factors have changed the understanding of calcium and phosphate homeostasis in the fetus and the newborn. This article will guide clinicians through an updated review of calcium and phosphate physiology, then review specific conditions pertinent to successful neonatal care. Furthermore, with the advancement of increasingly rapid molecular genetic testing, genomics will continue to play a greater role in this area of fetal diagnostics and prognostication.
ABSTRACT
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 TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation. MANAGEMENT: She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures. CONCLUSION: This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
ABSTRACT
Background Congenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic ß cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI. Case presentation A term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide. Conclusions Biallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.