Influence of radiographic examination findings on recommendations made during routine clinical re-evaluation of dogs with uncomplicated tibial plateau leveling osteotomy.

OBJECTIVE: To determine the influence of follow-up radiographic examination on recommendations made during routine clinical re-evaluation of dogs that had undergone uncomplicated tibial plateau leveling osteotomy (TPLO). STUDY DESIGN: Retrospective multi-institutional case series. ANIMALS: Client-owned dogs (N = 1010) that underwent uncomplicated TPLO. METHODS: Records from 11 institutions were searched for dogs that had been treated with unilateral TPLO and had no history of postoperative complications before their routine follow-up examination. The frequency of change in further clinical recommendations resulting from client- or clinician-voiced concerns or radiographic abnormalities was investigated. RESULTS: Follow-up evaluation was performed at a median of 6 (range, 4-15) weeks after TPLO. Radiographic examination findings contributed to a change in recommendations in 4.15% (38/915) of dogs presented without client concerns and without abnormalities at orthopedic examination. Abnormal radiographic findings alone influenced the management of 3.76% (38/1010) of dogs. An association was detected between clinical features and radiological findings leading to a change in recommendations (P < .0001). Administration of analgesia at the time of follow-up was associated with radiographic abnormalities (P = .017) and change in postoperative plans (P = .0007). CONCLUSION: Radiographic examination findings at follow-up did not influence the management of most dogs with uncomplicated TPLO. CLINICAL SIGNIFICANCE: Radiographic examination findings are unlikely to influence the treatment of dogs that seem to be recovering uneventfully from an uncomplicated TPLO without concerns from clients, analgesia, or abnormal findings on thorough orthopedic examination by a surgical specialist, at the time of the planned clinical re-evaluation.

Expanding the phenome and variome of skeletal dysplasia.

PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS: Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis.

We report two patients of east African ancestry with the same novel homozygous variant in the parathyroid hormone receptor type 1 (PTH1R). Both patients shared skeletal features including brachydactyly, extensive metacarpal pseudoepiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, deficient sacral ossification, suggestive of Eiken syndrome. Strikingly, both patients exhibited clinically manifest parathyroid hormone (PTH) resistance with hypocalcaemia and elevated serum phosphate levels. These laboratory and clinical abnormalities initially suggested pseudohypoparathyroidism, which is typically associated with GNAS abnormalities. In both patients, however, a homozygous novel PTH1R variant was identified (c.710 T > A; p.IIe237Asn, p.I237N) that is located in the second transmembrane helical domain. Previously, others have reported a patient with a nearby PTH1R mutation (D241E) who presented with similar clinical features, e.g. delayed bone mineralization as well as clinical PTH resistance. Functional analysis of the effects of both novel PTH1R variants (I237N- and D241E-PTH1R) in HEK293 reporter cells transfected with plasmid DNA encoding the wild-type or mutant PTH1Rs demonstrated increased basal cAMP signalling for both variants, with relative blunting of responses to both PTH and PTH-related peptide (PTHrP) ligands. The clinical presentation of PTH resistance and delayed bone mineralization combined with the functional properties of the mutant PTH1Rs suggest that this form of Eiken syndrome results from alterations in PTH1R-mediated signalling in response to both canonical ligands, PTH and PTHrP.

Eiken syndrome is an extremely rare genetic disorder of skeletal development, previously reported in only 7 people in the medical literature. It is due to alterations in the gene for the parathyroid hormone receptor type 1 (PTH1R). This receptor can bind two different hormones; parathyroid hormone (PTH), which is the body's main regulator of the level of calcium in the blood, and parathyroid hormone related peptide (PTHrP), a smaller hormone that regulates bone development. We report two new cases of Eiken syndrome sharing the exact same change in the PTH1R gene. This genetic change has not been previously reported. The patients had many of the typical findings in the skeleton reported in previous cases of Eiken syndrome, but with some variation in the features. However, unlike any previously reported people with Eiken syndrome, the two patients we describe had low levels of calcium in the blood causing significant symptoms. Low calcium has been reported in some cases of Eiken syndrome before, but this has been mild and not associated with symptoms. We wanted to explore how this new mutation affects the function of the PTH receptor, particularly how it might affect the signals generated when the receptor binds to its two different hormones, PTH and PTHrP. We did this by genetically reprogramming a cell line with the new mutation, and then testing those cells' responses to stimulation by the two hormones. We showed that the altered receptor appears to be unable to bind both hormones in a stable fashion, explaining why the patients showed changes both in the skeleton (due mostly to altered PTHrP signalling) and in the blood level of calcium (mostly due to altered PTH signalling).

Ambulatory intravenous ceftriaxone in paediatric A&E: a useful alternative to hospital admission?

BACKGROUND: Treatment of children with intravenous ceftriaxone on an ambulatory basis is described. This allows a child to remain at home, but also be reviewed regularly when attending the Emergency Department for antibiotics. METHODS: Indications for, and length of, treatment and laboratory parameters were recorded. Also, a survey of children's parents was undertaken to ascertain opinions regarding ambulatory treatment. RESULTS: 36 patients were treated with ambulatory ceftriaxone over 4 months. Indications included fever without focus, tonsillitis, periorbital cellulitis, urinary tract infection, petechial rash and lymphadenitis. Median duration of treatment was 2.3 days. There was no occult bacteraemia but five positive urine cultures. There was one failure of treatment with subsequent admission for alternative intravenous antibiotics. CONCLUSIONS: Parental opinion favours ambulatory treatment, with 94% of parents acknowledging they would choose it again in similar circumstances. Cost analysis favours ambulatory treatment based on predicted costs of a similar length of inpatient stay.

Costello syndrome and hyperinsulinemic hypoglycemia.

Costello syndrome is characterized by mental retardation, loose skin, coarse facies, skeletal abnormalities, cardiovascular abnormalities (congenital heart defects, cardiomyopathy, rhythm disturbances), and predisposition to neoplasia. Endocrine abnormalities including growth hormone deficiency, adrenal insufficiency, glucose intolerance, parathyroid adenoma with hyperprolactinemia and hypoglycemia have been described. Hypoglycemia has been documented due to growth hormone and cortisol deficiency. We report on two patients with Costello syndrome and persistent hyperinsulinemic hypoglycemia and review the endocrine manifestations of Costello syndrome. Both patients required diazoxide therapy to stop the unregulated insulin secretion and maintain normoglycemia. The mechanism of persistent hyperinsulinism in patients with Costello syndrome is unclear.