Evaluation of diagnostic potential of CD38 in rickets.

BACKGROUND: Rickets occurs in infants and children (aged 2 months to 3 years), compromising their skeletal development and damaging nervous, hematopoietic, immune, and other system functions. This study aimed to explore the significance of CD38 in rickets. METHODS: The microarray dataset GSE22523 was analyzed to obtain differentially expressed genes in rickets patients. A total of 36 rickets patients and healthy controls were recruited for the study, and their blood samples were collected, followed by detecting mRNA levels of CD38 using quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, the significance of CD38 in rickets patients was analyzed by receiver operating characteristic (ROC) analysis, while the correlation between CD38 and 25-hydroxy-vitamin D (25OHD)/parathyroid hormone (PTH) was analyzed with Pearson's correlation. RESULTS: Results showed that CD38 mRNA levels and PTH contents were significantly increased in the rickets patients while 25OHD contents were decreased. Correlation analysis indicated that CD38 was positively correlated with PTH and negatively correlated with 25OHD in both serum and plasma samples of rickets patients. Moreover, ROC analysis showed that serum CD38 was 0.9005 (95 % CI: 0.8313-0.9696), and the AUCs of plasma CD38 was 0.7215 (95 % CI: 0.6031-0.8398) in differentiating rickets patients from healthy persons, advocating serum CD38 had better diagnostic value. CONCLUSION: CD38 mRNA levels were upregulated in rickets patients and closely correlated with PTH and 25OHD contents, indicating CD38 might be a diagnostic marker of rickets patients. Further research on the diagnostic utility of CD38 is necessary for the diagnosis and treatment of ricketsin rickets in the future.

Pediatric Renal Rickets at a Tertiary Center.

We report clinical and etiological profile of 19 children (10 males) with renal rickets managed in the years 2021-2022. Median (IQR) age of presentation was 60 (18-96) months. The commonest cause was renal tubular acidosis (n=8). Genetic analysis revealed the diagnosis in 83% subjects (5 out of 6 tested).

Treatment of vitamin D deficiency in children.

INTRODUCTION: Vitamin D deficiency affects from 10% to 50% in various pediatric population groups and causes life-threatening hypocalcemia in infants, crippling rickets in infants and children, and increased risk of subsequent adult metabolic and neurologic problems. AREAS COVERED: An English language literature search of PubMed was performed since 1940 as were the authors' personal literature collections. References identified in the reviewed literature are considered. DIAGNOSIS: The diagnosis of vitamin D deficiency is based on serum 25-hydroxyvitamin D levels. Clinical features of rickets include bone deformities and elevated alkaline phosphatase. Most children and adolescents who are biochemically vitamin D deficient do not have specific symptoms or signs of deficiency. PREVENTION: Prevention of vitamin D deficiency is via exposure to sunshine, food and beverage fortification, and dietary supplementation. TREATMENT: Effective treatment of vitamin D deficiency is via oral or injectable administration of vitamin D. Dosing and duration of vitamin D therapy have been described for healthy children and for children with underlying medical conditions, but recommendations vary. EXPERT OPINION: Further investigation is needed to determine long-term non-skeletal effects of childhood vitamin D deficiency, benefits of supplementation in asymptomatic individuals with biochemical vitamin D deficiency, and appropriate screening for vitamin D deficiency in asymptomatic children and adolescents.

Vitamin D deficiency rickets in a toddler.

ABSTRACT: Nutritional rickets is the failure of normal bone formation in children, caused by vitamin D deficiency, low calcium intake, or a combination of both. In the United States, prolonged breastfeeding without vitamin D supplementation is a major risk factor. Increasing awareness of the rationale for and importance of vitamin D supplements for all breastfed infants and children should reduce the incidence of vitamin D deficiency rickets and prevent bone deformity.

Nutritional rickets masquerading as spinal muscular atrophy type III.

Muscle atrophy, weakness, and loss of ambulation in the pediatric population are signs of progressive neuromuscular diseases. Rapid identification of such diseases is important to prevent further progression. In pediatric neurology, it is well understood to include neuromuscular disorders in the differential for such presentations. We report a case of severe nutritional rickets that mimicked the presentation of spinal muscular atrophy type III and discuss the importance of including rickets in the differential for muscle atrophy and loss of ambulation. A 33-month-old African American boy with several months of gait abnormality was referred to outpatient neurology. The initial diagnostic evaluation focused primarily on neuromuscular disorders, specifically SMA type III, given the absence of reflexes on examination and the history of prior ambulation. After an unfruitful genetic workup, it was elucidated that the child had very poor dietary intake and minimal sun exposure causing nutritional rickets that improved with intervention.

Nutritional rickets presenting with developmental regression: a rare presentation of rickets.

Rickets is a disorder of defective mineralisation of the growth plate. Vitamin D deficiency remains the leading cause of nutritional rickets worldwide.We present the case of a 3.5-year-old breastfed boy who presented with dental abscess when a history of developmental regression was noted. Clinical assessment revealed hypotonia, poor growth and stunting. Biochemistry identified hypocalcaemia (1.63mmol/L, [normal range (NR) 2.2-2.7mmol/L]), severe vitamin D deficiency (25hydroxyvitamin D 5.3nmol/L, [NR > 50nmol/L]) with secondary hyperparathyroidism (Parathormone 159pmol/L, [NR 1.6-7.5pmol/L]) and rickets on radiographs. Growth failure screening suggested hypopituitarism with central hypothyroidism and low IGF1 at baseline, however, dynamic tests confirmed normal axis. Management included nasogastric nutritional rehabilitation, cholecalciferol and calcium supplementation and physiotherapy. A good biochemical response in all parameters was observed within 3 weeks and reversal of developmental regression by 3 months from treatment. Developmental regression as a presentation of nutritional rickets is rare and requires a high index of suspicion.

Feline precision medicine using whole-exome sequencing identifies a novel frameshift mutation for vitamin D-dependent rickets type 2.

OBJECTIVES: A 14-week-old female domestic longhair kitten presented with shifting lameness and disproportionately smaller size compared with a co-housed littermate. METHODS: Hematology and serum biochemical testing were conducted to investigate causes for delayed growth, and radiographs of the appendicular skeleton were obtained. RESULTS: The afflicted kitten had marked hypocalcemia, mild hypophosphatemia and substantial elevations in alkaline phosphatase activity, as well as pathognomonic radiographic findings consistent with rickets. Skeletal changes and hypocalcemia prompted testing of concentrations of parathyroid hormone (PTH) and vitamin D metabolites. Endocrine testing demonstrated significant increases in serum concentrations of PTH and 1,25-dihydroxycholecalciferol (calcitriol), supporting a diagnosis of vitamin D-dependent rickets type 2. Provision of analgesia, supraphysiologic doses of calcitriol and calcium carbonate supplementation achieved normalization of the serum calcium concentration and restoration of normal growth, although some skeletal abnormalities persisted. Once skeletally mature, ongoing calcitriol supplementation was not required. Whole-exome sequencing (WES) was conducted to identify the underlying DNA variant. A cytosine deletion at cat chromosome position B4:76777621 in VDR (ENSFCAT00000029466:c.106delC) was identified and predicted to cause a stop codon in exon 2 (p.Arg36Glufs*18), disrupting >90% of the receptor. The variant was unique and homozygous in this patient and absent in the sibling and approximately 400 other cats for which whole-genome and whole-exome data were available. CONCLUSIONS AND RELEVANCE: A unique, heritable form of rickets was diagnosed in a domestic longhair cat. WES identified a novel frameshift mutation affecting the gene coding for the vitamin D3 receptor, determining the likely causal genetic variant. Precision medicine techniques, including whole-exome and whole-genome sequencing, can be a standard of care in cats to identify disease etiologies, and to target therapeutics and personalize treatment.

Assessing diagnostic certainty for scurvy and rickets in human skeletal remains.

OBJECTIVES: Identifying scurvy and rickets has important implications for understanding adaptations and variability among past communities, and bioarchaeologists now regularly evaluate these conditions. Due to the increased number of studies, cases with less clear-cut lesions and variable preservation are now frequently reported. Despite an improved understanding of the biological mechanisms for disease expression, there is a lack of consensus on the language used to express diagnostic certainty, limiting comparability. This article aims to address these issues and provide recommendations on more consistent diagnostic terminology using widely accepted diagnostic methodology based on biological mechanisms. MATERIALS AND METHODS: We review diagnostic terms used in bioarchaeology by considering published cases of rickets, scurvy and co-occurrence alongside M.B.B.'s past project notes. We also consider differences in the diagnosis of rickets and scurvy in living and archeological individuals. RESULTS: We provide recommendations on a framework that can be used to show diagnostic certainty in cases of rickets, scurvy, and co-occurrence. Core lesions of rickets and scurvy are used alongside a limited lexicon of diagnostic terminology based on the Istanbul protocol. DISCUSSION: It is not the number of lesions that determines whether an individual is assigned to a particular diagnosis category, but rather the range and expression of lesions present. Avoiding a "tick-list" approach to core lesions of these diseases will be critical to ensure that identifying rickets and scurvy continues to contribute to understanding adaptations and variability among past communities. The framework allows more consistency in diagnostic certainty, facilitating greater comparability in research.

Severe hypophosphataemia can be an early sign of osteopetrorickets: a case report.

Osteopetrorickets is a rare complication of autosomal recessive ("malignant") osteopetrosis. Its prompt diagnosis is essential, because early suspicion of infantile osteopetrosis enables treatment with human stem cell transplantation, depending on the gene involved. It is important to identify not only the characteristic radiological changes of rickets, but also the coexistence of increased bone density, so as not to miss this very rare entity. Herein, a brief case report is presented.

Investigating the "scapula sign" as an indicator of rickets.

OBJECTIVE: In 1971, Weiss identified a "scapula sign" comprising a defect at the inferior angle of the scapula in juveniles with vitamin D deficiency rickets, but this has been little studied since. This study aimed to explore pathological variation of this defect in juveniles with other skeletal manifestations of vitamin D deficiency rickets. MATERIALS AND METHODS: 527 juveniles, aged from birth to 12 years, from two post-medieval British assemblages were macroscopically evaluated to document the range of pathological changes at the inferior angle. Scapula maximum lengths were recorded and supplementary radiographs were assessed. RESULTS: Blunting, flattening or squaring of the inferior angle occurred in 34 of 155 (22%) juveniles with other indicators of rickets and occurred frequently in cases of severe active rickets. Coarsening of the border and cupping deformities were identified radiographically, as well as residual defects in healed cases. Scapula lengths in juveniles with active rickets did not consistently deviate from those expected in any age group. CONCLUSIONS: The scapula sign is identifiable in some children with rickets. Differential diagnoses of scapula defects are important but the socio-cultural and environmental context of this sample suggests a link to vitamin D deficiency. SIGNIFICANCE: This finding expands the range of pathological changes known to occur in rickets, helping to improve recognition of this condition in past groups. LIMITATIONS: Small sample sizes prevented observation of the defect in adolescents with rickets. Defects can affect the positioning of standardised scapula length measures, complicating assessments of growth impacts. SUGGESTIONS FOR FUTURE RESEARCH: Continued research into the range of skeletal changes that can develop in vitamin D deficiency to improve the identification of this deficiency in past groups.

Refractory Rickets.

Nutritional rickets, caused by vitamin D and/or calcium deficiency is by far the most common cause of rickets. In resource-limited settings, it is therefore not uncommon to treat rickets with vitamin D and calcium. If rickets fails to heal and/or if there is a family history of rickets, then refractory rickets should be considered as a differential diagnosis. Chronic low serum phosphate is the pathological hallmark of all forms of rickets as its low concentration in extracellular space leads to the failure of apoptosis of hypertrophic chondrocytes leading to defective mineralisation of the growth plate. Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) control serum phosphate concentration by facilitating the excretion of phosphate in the urine through their action on the proximal renal tubules. An increase in PTH, as seen in nutritional rickets and genetic disorders of vitamin D-dependent rickets (VDDRs), leads to chronic low serum phosphate, causing rickets. Genetic conditions leading to an increase in FGF23 concentration cause chronic low serum phosphate concentration and rickets. Genetic conditions and syndromes associated with proximal renal tubulopathies can also lead to chronic low serum phosphate concentration by excess phosphate leak in urine, causing rickets.In this review, authors discuss an approach to the differential diagnosis and management of refractory rickets.

Approach to nutritional rickets.

Rickets is the disease of a growing skeleton and results from impaired apoptosis of hypertrophic chondrocytes and mineralization of the growth plate. Nutritionally induced rickets, secondary to vitamin D and/or calcium deficiency, remains a major global problem. In this review, we discuss pathogenesis, clinical signs, investigation and management of nutritional rickets.

Forgotten and found: A case of childhood rickets in the 19th-century settler village of Heuvelton, New York.

OBJECTIVE: To evaluate pathological lesions suggesting the presence of rickets and to place the diagnosis into bioarchaeological and historical context. MATERIALS: The remains of a 3-year ± 12-month-old child discovered during a rescue excavation in Heuvelton, New York. METHODS: We examined the individual macroscopically and conducted a differential diagnosis following established protocols in the palaeopathological literature. RESULTS: Bony change on the orbits, mandible, ribs, clavicles, left scapula, humerii, radii, ulnae, femora, tibiae, fibulae (e.g., porosity, diaphyseal thickening, flaring, bowing), and dental lesions were recorded. CONCLUSIONS: We demonstrate that the child likely presented with vitamin D deficiency rickets during crawling and as they learned to walk. SIGNIFICANCE: This example offers an important contribution to the bioarchaeological literature, as few cases of rickets have been recorded in rural North America using updated diagnostic criteria and little is known of the health and lifeways of early settlers in 19th-century upstate New York. LIMITATIONS: It is not possible to ascertain the precise aetiology of this child's rachitic state and to compare this individual with others in the population. SUGGESTIONS FOR FURTHER RESEARCH: Examination (and re-assessment) of other North and South American skeletal assemblages for signs of vitamin D deficiency rickets following current bioarchaeological standards.

Clinical spectrum and diagnostic challenges of vitamin D dependent rickets type 1A (VDDR1A) caused by CYP27B1 mutation in resource limited countries.

OBJECTIVES: Vitamin D dependent rickets type 1A (VDDR1A) is a rare autosomal recessive condition due to inactivating mutation of CYP27B1. It mimics clinically, biochemically and rediologically to nutritional and hypophosphatemic rickets. In developing countries like Pakistan, VDDR1A is often misdiagnosed as nutritional rickets or hypophosphatemic rickets due lack of free access to 1,25 (OH) 2 D level and genetic testing. This study was aimed to determine the clinical spectrum and diagnostic challenges of VDDR1A due to CYP27B1 mutation in developing countries. METHODS: Retrospective review of all cases of VDDR1A due to CYP27B1 mutation over a period of two years presenting in the Pediatric Endocrine clinic of Hameed Latif Hospital, Lahore, Pakistan. RESULTS: Six cases of VDDR1A (4 males) were identified. Mean age of clinical manifestation was 14 (9-24) months. Mean age of presentation to endocrine department was 5.5 (1.5-11.8) years. Growth failure and bony deformities were the most common presentation (n=6), followed by repeated diarrheas and abdominal distension (n=3) and recurrent fractures (n=1). All cases shared same biochemical profile of low/normal calcium, hypophosphatemia, raised alkaline phosphatase, raised PTH, normal/high 25(OH)D and tubular reabsorption of phosphate (TRP) <85%. Patients treated with calcitriol showed rapid healing as compared to those treated with 1-alfacalcidol. CONCLUSIONS: We should have a high index of suspicion of VDDR1A in rickets not responding to cholecalciferol therapy.

Pitfalls in the Diagnosis of Primary Hyperparathyroidism in a Sudanese Adolescent Boy; a case disguised as rickets.

BACKGROUND: Juvenile primary hyperparathyroidism (PHPT) is a rare endocrine disease. Its diagnosis might be masked by clinical, biochemical, and radiological features of rickets. CASE PRESENTATION: A 12-year-old Sudanese boy presented with progressive lower limbs deformity and difficulty in walking for six months. It was associated with fatigability, poor appetite, and generalized bone pain. On examination, he was thin, disproportionately short and pubertal, and had bilateral genu valgum deformity. X-rays showed osteopenia and signs of rickets. Biochemical workup revealed mildly elevated serum calcium, low phosphate, high alkaline phosphatase, and high parathyroid hormone with low 25-hydroxy vitamin D3. Celiac screening, liver function test and renal profile were normal. Serum calcium rose dramatically after vitamin D therapy. Genetic testing was negative for CYP2R1 and MEN1 genes. Ultrasound neck showed left inferior parathyroid adenoma which was surgically excised. Histopathology confirmed the diagnosis of parathyroid adenoma. Postoperatively, he had hypocalcemia which was treated with calcium and alfacalcidol. Corrective surgery is planned for the genu valgum deformity which markedly improved after parathyroidectomy. CONCLUSION: Although PHPT is extremely rare in the young population, it should be considered in patients with rickets and elevated serum calcium at baseline or after initiating vitamin D therapy.