Growth reference charts for children with hypochondroplasia.

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16 years. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials.

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 GPR101 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. We present a girl with tall stature from 3 years of age; her height was +4.25 SD score at 5 years, with no signs of syndromic disease. She had significant GH excess, serum IGF-1 4 times the upper limit of normal and normal circulating GHRH, with normal pituitary magnetic resonance imaging over 13 years. No abnormalities were found in either the AIP or MEN1 genes. Treatment with somatostatin analogues and dopamine agonists showed minimal therapeutic benefit, but significant side effects. She tested positive for duplication of GPR101 6 years after the initial diagnosis. She was then initiated on pegvisomant aged 12 years, achieving prompt IGF-1 normalization and growth cessation. Aged 16.5 years, she showed escape from IGF-1 control, and height velocity increased, but this responded well to a dose increase in pegvisomant, with reassuring long-term pediatric safety over 7 years. Her final height is +2.9 SD score. Currently, life-long pegvisomant treatment is planned with genetic counselling regarding future offspring.

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. We highlight when the diagnosis of ROHHAD should be considered at an early stage. CASE PRESENTATION: All three patients presented between 4 and 6 years old with rapid-onset obesity. They all have central hypoventilation requiring nocturnal BiPAP, varying degrees of hypothalamic dysfunction with hyperprolactinaemia being a consistent feature, and autonomic dysfunction. One patient has a neuro-endocrine tumour (NET) and two have glucose dysregulation. CONCLUSIONS: High prolactin was a consistent early feature. Central hypoventilation and NET may present later and therefore regular sleep studies and screening for NETs are required. A high suspicion of ROHHAD is warranted in patients with rapid, early-onset obesity and hyperprolactinaemia without structural pituitary abnormality.

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. METHODS: Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon-intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon-intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies. RESULTS: We show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed. CONCLUSIONS: Overall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases.

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 (FGFR3) 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. Objectives: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. Design: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6-24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. Methods and analysis: Children aged 3-11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. Ethics: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. Discussion: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. Registration: ClinicalTrials.gov: NCT04035811; NCT04265651.

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 COL1A1 or COL1A2 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. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children's Hospital Clinical Governance Department. RESULTS: One hundred of 337 children in the HSS met the 'atypical' criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6). CONCLUSION: Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.

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. Methods: An initial survey was distributed following the first lockdown in August 2020, and a second survey in April 2021. The surveys explored four themes- effects on therapy, alternatives to consultation, effect on mental health, and perceived risks of COVID-19. Results: In the 2020 survey, of the 110 respondents, 69 (63%) had at least one appointment delayed due to the lockdown, compared with 89 of the 124 respondents (72%) in 2021. Of the 110 respondents in 2020, 57 (52%) had a remote consultation, increasing to 92 of 124 (74%) in the follow-up survey. In the 2020 survey 63 of 91 respondents (69%) expressed anxiety due to lockdown, compared with 76 of 124 (61%) in 2021. The percentage of total respondents expressing a preference for remote consultation was 48% in 2020, increasing to 71% in 2021. Conclusions: The pandemic has had widespread effects on the mental and physical health of those with OI. These effects, alongside appointment delays, have increased as the pandemic progresses. Encouragingly, the increasing preference for remote consultation may indicate that this could be a viable long-lasting alternative to face-to-face appointments, especially for patients who previously traveled vast distances for specialist care.

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 TRPV6 gene. One mutation results in an in frame stop codon (R510stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G660R) that, surprisingly, does not affect the Ca2+ permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G660R and R510stop mutants and combinations with wild type TRPV6. We show that both the G660R and R510stop mutant subunits are expressed and result in decreased calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an increase in the expression of proteases.

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. We describe their clinical course and radiological and genetic findings, providing further insight into the natural history of this condition.

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. TNFRSF11A-associated DOS has been identified in two patients; however, TNFRSF11A is also a causal gene for osteopetrosis, autosomal recessive 7 (OP-AR7). Whole-exome sequencing in a patient with sclerosing bone disease identified novel compound heterozygous variants (c.414_427 + 7del, c.1664del) in TNFRSF11A. We examined the impact of the two variants on five splicing isoforms of TNFRSF11A by RT-PCR. We found that c.1664del resulted in elongated proteins (p.S555Cfs*121, etc.), while c.414_427 + 7del generated two aberrant splicing products (p.A139Wfs*19 and p.E132Dfs*19) that lead to nonsense mediated mRNA decay (NMD). In the previous two cases of TNFRSF11A-associated DOS, their mutations produced truncated TNFRSF11A protein isoforms. The mutations in all three cases thus contrast with TNFRSF11A mutations reported in OP-AR7, which does not generated truncated or elongated TNFRSF11A proteins. Thus, we identified the third case of TNFRSF11A-associated DOS and reinforced the genotype-phenotype correlation that aberrant protein-producing TNFRSF11A mutations cause DOS.

Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants.

ClC-7 is a chloride-proton antiporter of the CLC protein family. In complex with its accessory protein Ostm-1, ClC-7 localizes to lysosomes and to the osteoclasts' ruffled border, where it plays a critical role in acidifying the resorption lacuna during bone resorption. Gene inactivation in mice causes severe osteopetrosis, neurodegeneration, and lysosomal storage disease. Mutations in the human CLCN7 gene are associated with diverse forms of osteopetrosis. The functional evaluation of ClC-7 variants might be informative with respect to their pathogenicity, but the cellular localization of the protein hampers this analysis. Here we investigated the functional effects of 13 CLCN7 mutations identified in 13 new patients with severe or mild osteopetrosis and a known ADO2 mutation. We mapped the mutated amino acid residues in the homology model of ClC-7 protein, assessed the lysosomal colocalization of ClC-7 mutants and Ostm1 through confocal microscopy, and performed patch-clamp recordings on plasma-membrane-targeted mutant ClC-7. Finally, we analyzed these results together with the patients' clinical features and suggested a correlation between the lack of ClC-7/Ostm1 in lysosomes and severe neurodegeneration. © 2020 American Society for Bone and Mineral Research (ASBMR).

Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.

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.

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. We describe the case of a male infant with compound heterozygous variants in IFT81, who presented with short long bones, a narrow thorax, polydactyly, and multiple malformations. Three novel clinical features are reported including complete situs inversus, micropenis, and rectal atresia, which have not previously been associated with variants in IFT81. We reviewed the literature and identified the most consistent clinical features associated with this rare ciliopathy syndrome. We postulate that dolichocephaly and sagittal craniosynostosis may be associated with this condition, and provide a clue to considering IFT81 as the causative gene when deciphering complex ciliopathies.

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. She commenced growth hormone (GH) aged 8 years for short stature and treatment improved linear growth. At age 12 years, she presented with polydipsia, polyuria and vulvovaginitis. She was overweight (BMI SDS +1.43). Diabetes was diagnosed (Blood glucose = 24.2 mmol/L, HbA1c = 121 mmol/mol or 13.2%). She was not acidotic and had negative blood ketones. Autoantibodies typical of type 1 diabetes were negative. She was initially treated with basal bolus insulin regime. GH was discontinued 3 months later due to concerns regarding GH-induced insulin resistance. Off GH, insulin requirements reduced to zero, allowing Metformin monotherapy. However off GH, she reported significant lethargy with static growth and increased weight. Combinations of Metformin with differing insulin regimes did not improve glucose levels. Liraglutide (GLP-1 agonist) and Metformin did not improve glucose levels nor her weight. Liraglutide and Empaglifozin (SGLT-2 inhibitor) therapy used in combination were well tolerated and demonstrated rapid normalisation of blood glucose and improvement in her HbA1c to within target (48 mmol/mol) which was sustained after 6 months of treatment. Conclusions Newer treatments for type 2 diabetes (e. g. GLP-1 agonists or SGLT-2 inhibitors) offer potential treatment options for those with diabetes and PWS when conventional treatments are ineffective.

Post-mortem histology in transient receptor potential cation channel subfamily V member 6 (TRPV6) under-mineralising skeletal dysplasia suggests postnatal skeletal recovery: a case report.

BACKGROUND: The calcium-selective channel TRPV6 (transient receptor potential cation channel subfamily V member 6) is crucial for maternal-fetal calcium transport across the placenta. TRPV6 mutations have recently been associated with an antenatally severe under-mineralising skeletal dysplasia accompanied by postnatal biochemical abnormalities. This is the first post-mortem report in a patient with TRPV6 skeletal dysplasia. CASE PRESENTATION: The female infant had severe antenatal and postnatal skeletal abnormalities by 20 weeks gestation and was ventilator-dependent from birth. These skeletal abnormalities were apparent at an earlier gestational age than in previous reported cases and a more severe clinical course ensued. Biochemical and skeletal abnormalities, including bone density, improved postnatally but cardiac arrest at 4 months of age led to withdrawal of intensive care. Compound heterozygous TRPV6 variants (c.1978G > C p.(Gly660Arg) and c.1528C > T p.(Arg510Ter)) were identified on exome sequencing. Post-mortem identified skeletal abnormalities but no specific abnormalities in other organ systems. No placental pathology was found, multi-organ histological features reflected prolonged intensive care only. Post-mortem macroscopic examination indicated reduced thoracic size and short, pale and pliable ribs. Histological examination identified reduced number of trabeculae in the diaphyses (away from the growth plates), whereas metaphyses showed adequate mineralisation and normal number of trabeculae, but with slightly enlarged reactive chondrocytes, indicating post-natal skeletal growth recovery. Post-mortem radiological findings demonstrated improved bone density, improved rib width, healed fractures, although ribs were still shorter than normal. Long bones (especially humerus and femur) had improved from initial poorly defined metaphyses and reduced bone density to sharply defined metaphyses, prominent growth restart lines in distal diaphyses and bone-in-bone appearance along diaphyses. CONCLUSIONS: This case provide bone histological confirmation that human skeletal development is compromised in the presence of TRPV6 pathogenic variants. Post-mortem findings were consistent with abnormal in utero skeletal mineralisation due to severe calcium deficit from compromised placental calcium transfer, followed by subsequent phenotypic improvement with adequate postnatal calcium availability. Significant skeletal recovery occurs in the early weeks of postnatal life in TRPV6 skeletal dysplasia.

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. Eight patients presented prenatally with short femora, whereas later in childhood their short-spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over-faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi-parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under-recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester.

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. Skeletal survey showed generalized marked undermineralization, hypoplastic fractured ribs, metaphyseal fractures, and extensive periosteal reaction along femoral, tibial, and humeral diaphyses. Parathyroid hormone (PTH) elevation (53.4-101 pmol/L) initially suggested PTH signaling disorders. Progressively, biochemical normalization with radiological mineralization suggested recovery from in utero pathophysiology. Genomic testing was undertaken and in silico protein modeling of variants. No abnormalities in antenatal CGH array or UPD14 testing. Postnatal molecular genetic analysis found no causative variants in CASR, GNA11, APS21, or a 336 gene skeletal dysplasia panel investigated by whole exome sequencing. Trio exome analysis identified compound heterozygous TRPV6 likely pathogenic variants: novel maternally inherited missense variant, c.1978G > C p.(Gly660Arg), and paternally inherited nonsense variant, c.1528C > T p.(Arg510Ter), confirming recessive inheritance. p.(Gly660Arg) generates a large side chain protruding from the C-terminal hook into the interface with the adjacent TRPV6 subunit. In silico protein modeling suggests steric clashes between interface residues, decreased C-terminal hook, and TRPV6 tetramer stability. The p.(Gly660Arg) variant is predicted to result in profound loss of TRPV6 activity. This first case of a novel dysplasia features severe but improving perinatal abnormalities. The TRPV6 compound heterozygous variants appear likely to interfere with fetoplacental calcium transfer crucial for in utero skeletal development. Astute clinical interpretation of evolving perinatal abnormalities remains valuable in complex calcium and bone pathophysiology and informs exome sequencing interpretation.

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. There are a handful of reports of pubertal delay, infertility and cryptorchidism in Lowe syndrome. Biochemistry aged 72 h: testosterone 6.4 nmol/L, LH <0.5 IU/L and FSH <0.5 IU/L. Gonadotropin-releasing hormone stimulation test identified significantly raised baseline LH = 45.4 IU/L (contrasts with earlier undetectable LH), with a 20% increase on stimulation, while baseline FSH = 4.3 IU/L with no increase on stimulation. Day 14 HCG stimulation test produced an acceptable 50% increase in testosterone. The constellation of further abnormalities suggested Lowe syndrome: hypotonia, bilateral cataracts (surgical extraction and intraocular lens implantation) and renal tubular acidosis (microscopic haematuria, hypercalciuria, proteinuria, generalised aminoaciduria, hypophosphataemia and metabolic acidosis). DNA sequencing identified de novo hemizygous frameshift mutation OCRL c.2409_2410delCT in exon 22. Interpretation of initial and repeat GnRH and HCG testing indicates the likelihood of testicular failure. Partial testicular descent occurred but left orchidopexy was required. Improving long-term gonadal function in Lowe syndrome assumes increased importance for current cohorts as advances in renal replacement therapy have greatly improved life expectancy. Noting HPG axis abnormalities in Lowe syndrome in infancy can identify cases requiring increased surveillance of pubertal progress for earlier detection and management. LEARNING POINTS: Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.Early testing of the HPG axis in patients with Lowe syndrome may help predict gonadal abnormalities from a younger age, which will enhance the overall case management into adolescence.

Diagnostic and management challenges from childhood, puberty through to transition in severe insulin resistance due to insulin receptor mutations.

Two Caucasian girls, both of normal weight and body mass indices, were diagnosed with type A insulin resistance (IR) in childhood. Case 1 presented with premature adrenarche aged 7 years, then by age 12 years had hirsutism, acne, acanthosis nigricans, and asymptomatic diabetes. Subsequent investigation revealed raised adiponectin (15.3 mg/L) and heterozygous p.Pro1205Leu mutation in the INSR gene encoding the insulin receptor. She experienced postprandial hypoglycaemia on metformin; acarbose was trialled and discontinued aged 16 years, as she became normoglycaemic. Hirsutism was treated with topical eflornithine, oral spironolactone and flutamide, and laser therapy. Unfortunately, diabetes reemerged in young adulthood with obesity. Case 2: during an emergency admission for acute abdominal pain aged 11 years, hyperglycaemia was noted which led to further investigation. An oral glucose tolerance test showed diabetes and ultrasound showed polycystic ovaries. Further investigations revealed raised adiponectin (18 mg/L) and compound heterozygous mutations in the INSR gene: p.Pro1263Ala and p.Ser748Leu (latter probable normal variant). She was treated with metformin and experienced postprandial hypoglycaemia. Symptoms of hyperandrogenism were controlled by flutamide. She maintained a healthy weight and reassessment at young adulthood showed resolution of diabetes. Type A IR may present in childhood with overlapping features of common endocrine entities such as premature adrenarche and polycystic ovarian syndrome. Patients with abnormal glucose tolerance yet normal weight merit screening with adiponectin; raised adiponectin levels prompt insulin receptor mutational analysis. Postprandial hypoglycaemia is characteristic. Management includes optimization of glycaemic control with oral hypoglycaemic agents and maintenance of healthy weight, and controlling the effects of hyperandrogenism.