Osteopetrorickets: two contradictory patterns-one unifying diagnosis.

A 5-month-old infant with bone findings on x-ray presented an apparent contradiction including findings of both diffusely dense bones and rickets in the context of a history and laboratory investigation that suggested leukemia. Next generation gene panel sequencing revealed a TCIRG1 mutation which is consistent with autosomal recessive osteopetrosis. The paradoxical x-ray findings underscore a recently elucidated mechanism for the pathogenesis of a TCIRG mutation. This case highlights the importance of recognizing this radiographic, seeming contradictory, association in the context of a confusing clinical presentation. Failure to recognize this pattern promptly may lead to a delay in diagnosis, thus potentially permanent organ failure.

Selective rickets from localized advanced maturation-a case report.

An unusual cause of rickets is illustrated by a patient with infantile multisystem inflammatory disease who, by age 2 years and 4 months, developed striking radiographic and clinical rickets restricted to those joints involved by the inflammatory process. The locally increased vascularity from his inflammation led to increased maturation at those sites so rapid as to override the usual enchondral calcification, thus causing a rickets pattern. Other sites, such as the proximal humeri, lacking any inflammation, showed no increased maturation rate and did not manifest local rickets. Rapid local bone maturation may cause localized rickets.

[Rickets and anaemia caused by coeliac disease in a three-year-old girl].

We present a case report of a three-year-old girl of Pakistani origin with coeliac disease. The first symptom was spontaneous fracture of the fibula. Vitamin D deficiency rickets and iron deficiency anaemia were demonstrated. An intestinal biopsy and elevated antibody levels confirmed the coeliac disease. Rickets is a known but rare presentation of coeliac disease, but this case report illustrates, how coeliac disease in children often presents with non-gastrointestinal symptoms. The importance of investigations for malabsorp-tion, if iron deficiency is not easily corrected with sufficient iron supplements, is underlined as well as the importance of screening for coeliac disease.

Cortical Matrix Mineral Density Measured Noninvasively in Pre- and Postmenopausal Women and a Woman With Vitamin D-Dependent Rickets.

Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization, or reduced primary mineralization. Because bone biopsy is invasive, we hypothesized that noninvasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantification of MMD was confined to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization, not porosity. To assess accuracy, 9 cadaveric distal radii were imaged at a voxel size of 82 microns using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland) and compared with VivaCT 40 (µCT) at 19-micron voxel size. Associations between MMD and porosity were studied in 94 healthy vitamin D-replete premenopausal women, 77 postmenopausal women, and in a 27-year-old woman with vitamin D-dependent rickets (VDDR). Microstructure and MMD were quantified using StrAx (StraxCorp, Melbourne, Australia). MMD measured by HR-pQCT and µCT correlated (R = 0.87; p < 0.0001). The precision error for MMD was 2.43%. Cortical porosity and MMD were associated with age (r2 = 0.5 and -0.4, respectively) and correlated inversely in pre- and postmenopausal women (both r2 = 0.9, all p < 0.001). Porosity was higher, and MMD was lower, in post- than in premenopausal women (porosity 40.3% ± 7.0 versus 34.7% ± 3.5, respectively; MMD 65.4% ± 1.8 versus 66.6% ± 1.4, respectively, both p < 0.001). In the woman with VDDR, MMD was 5.6 SD lower and porosity was 5.6 SD higher than the respective trait means in premenopausal women. BMD was reduced (Z-scores femoral neck -4.3 SD, lumbar spine -3.8 SD). Low-radiation HR-pQCT may facilitate noninvasive quantification of bone's MMD and microstructure in health, disease, and during treatment. © 2018 American Society for Bone and Mineral Research.

Multiple unexplained fractures in infants and child physical abuse.

When an infant presents with X-rays showing multiple unexplained fractures in various stages of healing (MUFVSH), the child is usually diagnosed with child abuse based on criteria of the Academy of Pediatrics' Committee on Child Abuse and Neglect (AAPCCAAN). Almost always, the infant is subsequently removed from the home and civil or criminal proceeding commence. It may be that healing infantile rickets or other poorly understood metabolic bone disorders of infancy are responsible for these x-rays. Activated vitamin D is a seco-steroid hormone, whose mechanism of action is genetic regulation. Lack of it can result in musculoskeletal defects known as rickets. Low calcium can also cause rickets. However, it is clear that experts for the state believe that the x-rays in these cases are so definitive as to be pathognomonic for child abuse. Therefore, if the caregivers deny abusing their infants, experts following American Academy of Pediatric's Committee on Child Abuse and Neglect. guidelines are essentially claiming that x-rays showing multiple unexplained fractures in various stages of healing are lie detector tests. However, it is not widely appreciated that the gold standard for the diagnosis of rickets is a bone biopsy, not x-rays, as radiologists miss biopsy proven rickets 80% of the time; that is, 4 out of 5 infants with rickets will have normal x-rays. In this article we provide reports of two cases and their outcomes. We discuss information about healing infantile rickets and an example of common sense medical conclusions in these cases. This information could lead to a significant reduction in the number of innocent parents having their infant removed or sent to prison.

Radiology of Osteogenesis Imperfecta, Rickets and Other Bony Fragility States.

This section gives an overview of radiological findings in bony fragility states, with a special focus on osteogenesis imperfecta (OI) and rickets. Conventional radiological assessment of bone density is inaccurate and imprecise and only reliably detects severe osteopaenia. However, other aspects of bone structure and morphology can be assessed, and it is possible to distinguish between osteopaenic and osteomalacic states. OI is a heterogeneous group of disorders of type 1 collagen formation and processing that are characterised by varying degrees of bony fragility, with presentations varying from perinatal lethality to asymptomatic. Radiological diagnosis of severe forms is usually straightforward, but that of milder disease may be challenging because specific features are often absent. However, a multidisciplinary approach is usually successful. Features of OI, including Wormian bones, skull base deformities, vertebral involvement and long bone fractures and deformities, are reviewed in this section. Rickets is best defined as a disorder of the growth plate characterised by the impaired apoptosis of hypertrophied chondrocytes. Vitamin D deficiency is a common cause of rickets. The patho-anatomical basis of radiological findings in rickets is reviewed and illustrated. Rickets is frequently accompanied by hyperparathyroidism and osteomalacia. Rickets used to be classified as calciopaenic or phosphopaenic but is now referred to as parathyroid hormone or fibroblast growth factor 23 mediated, respectively [1]. The radiological features of the two forms are reviewed.

Rickets or abuse? A histologic comparison of rickets and child abuse-related fractures.

PURPOSE: The bone changes of vitamin D deficiency rickets have been invoked as an alternate explanation for child-abuse related fractures identified through medical imaging. The lack of modern histopathologic comparisons between these two entities limits the abilities of the forensic pathologist to address this differential diagnosis, both in their autopsy reports and on the witness stand. METHODS: We report a comparison of the histologic appearance of the bones in a two year old child with vitamin D deficiency rickets with fractures occurring in three young children with child abuse. RESULTS: In the case of rickets, there was marked architectural disorganization of endochondral ossification at the costochondral junctions and growth plates of long bones. The child abuse-related fractures showed osteochondral callus at different stages of healing, either centered on a discrete fracture line or at metaphyses (e.g. classical metaphyseal lesions). In many instances, the healing fractures disrupted the line of endochondral ossification. In none of the child abuse-related fractures was there any similarity to the histologic appearance of rickets. CONCLUSION: The maturation disturbance in the growth plate that occurs in rickets is a distinctive entity that cannot be confused histologically with healing fractures, including the classical metaphyseal lesion.

A head within a head sign: a manifestation of healing nutritional rickets.

The epiphyseal perichondrium is calcified during the rachitic healing process and visible radiologically as 'a head within a head' around the proximal femoral epiphysis in young children. Seen in isolation, these radiographs can pose diagnostic dilemmas.

Radiographic changes in nutritional ricket hips in children in response to treatment.

PURPOSE: To review radiographic changes in the proximal femurs of children of different ages during the course of treatment for nutritional rickets. METHODS: Pelvic radiographs of 161 children aged ≤ 13 years with nutritional rickets were retrospectively reviewed. Patients were treated with dietary counselling and vitamin D and calcium supplementation. Patients were followed up at week 3 and thereafter at a 2-month interval until ulnar convexity was achieved. Sequential radiographs of the hips in children of different ages were reviewed for each growth plate in terms of (1) the direction of growth, (2) active areas, (3) contribution of growth, and (4) the structure of the epiphysis. Radiographs were superimposed for comparison by matching the triradiate cartilage and the ischial portion of the obturator foramen. RESULTS: The direction of growth of the growth plates was from the physeal plate that is the longitudinal growth plate of the neck (LGP), the femoral neck isthmus (FNI), and the trochanteric growth plate (TGP) to the diaphyseal region, and from the perichondrium to the ossification centre in the proximal femoral epiphysis. Before the age of one year, the growth zone of the proximal femur was homogenous, with no differentiation between the LGP, FNI, and TGP. By the age of 2 years, the differentiation was more clearly established; the FNI was usually smaller than the TGP and LGP. By the age of 3 years, the FNI became prominent and the TGP remained small. By the age of 4 years, the ossification centre of the greater trochanter appeared, and the LGP extended medially as a medial overhang (MOH). During the children's growth, the LGP, FNI, or TGP remained active to a variable extent and were distinct until the age of 6 years. Gradually, the periphery of the LGP became less active than the centre of the LGP and gave rise to the 'eye sign'. The MOH generally ceased to be active beyond the age 9 years. By the age of 12 years, the TGP and FNI were minimally active and only the centre of the LGP remained active. CONCLUSION: The mineralisation process of healing rickets provides a useful biological marker for patterns of growth. Knowledge of the quantitative contribution of various growth plates of the proximal femur in childhood may increase the understanding of the pathomechanism of hip deformations.

High incidence of rickets in extremely low birth weight infants with severe parenteral nutrition-associated cholestasis and bronchopulmonary dysplasia.

Risk factors for rickets of prematurity have not been re-examined since introduction of high mineral formula, particularly in ELBW infants. We analyzed the incidence and the risk factors of rickets in extremely low birth weight (ELBW) infants. As a retrospective case-control study from 2004 to 2008, risk factors were analyzed in 24 patients with rickets versus 31 patients without. The frequency of rickets in ELBW infants was 24/55 (44%). Infants with rickets were diagnosed at 48.2 ± 16.1 days of age, and improved by 85.3 ± 25.3 days. By radiologic evaluation, 29% were grade 1 rickets, 58% grade 2 and 13% grade 3. In univariate analysis, infants with rickets had significantly higher incidence of patent ductus arteriosus, parenteral nutrition associated cholestasis (PNAC), severe PNAC and moderate/severe bronchopulmonary dysplasia (BPD). In multiple regression analysis, after adjustment for gestation and birth weight, rickets significantly correlated with severe PNAC and with moderate/severe BPD. Serum peak alkaline phosphatase levels were significantly elevated in rickets (P < 0.001). In ELBW infants, the incidence of rickets of prematurity remains high and the incidence of severe PNAC and moderate/severe BPD was significantly increased 18 and 3 times, respectively.

Enzyme-replacement therapy in life-threatening hypophosphatasia.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

[Rickets in a child]. / Beinkrom hja barni.

Vitamin D is necessary for normal bone growth. Deficiency of vitamin D can lead to rickets in children and osteomalacia in adults. It is difficult to reach the recommended daily dose of vitamin D in children without cod liver oil or other vitamin D supplementation. Several cases of rickets have been diagnosed in Iceland the past few years. Studies suggest a worldwide increase in the prevalence of the disorder. We report on a girl who was diagnosed with rickets at the age of 27 months. She received inadequate amounts of vitamin D supplementation in the form of AD drops and cod liver oil. Because of food allergy she was on a restricted diet which limited her intake of dietary vitamin D. After diagnosis, she received a high-dose vitamin D therapy (Stoss therapy) which corrected the deficiency. Key words: rickets, food allergy, vitamin D.

Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Despite increased urinary calcium excretion, HHRH is typically not associated with kidney stones prior to treatment. However, here we describe two sisters, who displayed nephrolithiasis or nephrocalcinosis upon presentation. The index patient, II-4, presented with short stature, bone pain, and knee X-rays suggestive of mild rickets at age 8.5 years. Laboratory evaluation showed hypophosphatemia, elevated 1,25(OH) (2) vitamin D levels, and hypercalciuria, later also developing vitamin D deficiency. Her sister, II-6, had a low normal serum phosphorous level, biochemically vitamin D deficiency and no evidence for osteomalacia, but had undergone left nephro-ureterectomy at age 17 because of ureteral stricture secondary to renal calculi. Nucleotide sequence analysis of DNA from II-4 and II-6 revealed a homozygous missense mutation c.586G>A (p.G196R) in SLC34A3/NaPi-IIc. Ultrasonographic examinations prior to treatment showed grade I nephrocalcinosis for II-4, while II-6 had grade I-II nephrocalcinosis in her remaining kidney. Four siblings and the mother were heterozygous carriers of the mutation, but showed no biochemical abnormalities. With oral phosphate supplements, hypophosphatemia and hypercalciuria improved in both homozygous individuals. Renal calcifications that are presumably due to increased urinary calcium excretion can be the presenting finding in homozygous carriers of G196R in SLC34A3/NaPi-IIc, and some or all laboratory features of HHRH may be masked by vitamin D deficiency.

High dose calcitriol in osteopetrorickets.

Osteopetrorickets is a rare autosomal recessive disorder of osteoclast function characterized by abnormally dense bone and failure of resorption of calcified cartilage. Rickets is a paradoxical complication of osteopetrosis, resulting from the inability of the osteoclasts to maintain a normal calcium-phosphorus balance in the extracellular fluid. We report a patient with an unusual case of infantile osteopetro-rickets who was admitted with anterior fontanel bulging and was treated with haploidentical bone marrow transplantation.

Guided growth for pathological physes: radiographic improvement during realignment.

BACKGROUND: Children with rickets are prone to having deformities of the lower extremities that are bilateral and often symmetrical. Although initially attributed to pathological or "sick" physes, the deformities are eventually seen in the metaphyses and diaphyses of the long bones; if left untreated, they may result in bone pain and stress fractures. The orthopaedists' role in managing these children is to correct and maintain alignment. Alternatively, we have exploited the use of hemiepiphysiodesis or guided growth, using staples or, more recently, the 8-plate (Orthofix, Verona, Italy). While gradually normalizing the mechanical axis, we have noted improvement in the appearance and width of all of the ipsilateral physes, not only at the knee but at the hip and ankle as well. This report summarizes our observations of the effects on the pathological physes in a group of patients with rickets who were preferentially treated with guided growth, often starting at a young age. METHOD: This retrospective review approved by an institutional review board included 14 children with rickets, including 10 treated with staples and 4 with 8-plates, who collectively underwent a total of 68 hemiepiphysiodeses (guided growth) and 35 osteotomies. Each was under appropriate medical management during the entire course of treatment, before and after surgery. We measured the mechanical axis deviation and anatomic angles of the femur and proximal tibia, noting the width and appearance of their physes at the hips, knees, and ankles preoperatively and upon correction of the axis. RESULTS: Of the 10 stapled patients, we noted 24 (45%) of 53 migrations and 41% rebound deformity. Four patients with 15 deformities that corrected with 8-plates experienced no hardware migration; for them, it is too early to comment on rebound deformity. While gradually correcting the mechanical axis, we have noted improvement in the appearance and width, not only of the pan-genu physes but also of remote physes at the hip and ankle. We suspect that the improved quality of the physes reflects not only the normalization of the mechanical axis but also the corresponding resolution of the waddling (varus) or circumduction (valgus) gait pattern. CONCLUSION: We recommend early intervention, via guided growth, to restore and preserve a neutral axis so that the child can enjoy a normal lifestyle while maximizing the growth potential of his or her physes, not only of the knees but the hips and ankles as well. We believe that by correcting and maintaining alignment, secondary bony deformities may be ameliorated and osteotomies for angular correction deferred if not avoided altogether. LEVEL OF EVIDENCE: IV (retrospective clinical series).

Ectopic thymic parathyroid adenoma and vitamin D deficiency rickets: a 5-year-follow-up case report and review of literature.

Sixteen patients with primary hyperparathyroidism presenting as rickets have so far been reported in the English literature. However, no report of an ectopic thymic parathyroid adenoma presenting as rickets has been published. We report a 14-year-old Caucasian American, wheelchair-ridden male who presented with signs and symptoms suggestive of vitamin D deficiency rickets subsequently confirmed by laboratory and radiological findings. Following the intramuscular administration of 125,000 U ergocalciferol (vitamin D2), he developed hypercalcemia with persistently elevated parathyroid hormone (PTH) levels suggestive of primary hyperparathyroidism. Sestamibi scan demonstrated significant uptake in the superior chest, without uptake at the normal parathyroid glands location. Surgical exploration revealed normal parathyroid glands and a thymic mass, which was removed and confirmed by pathology to be a parathyroid adenoma. With subsequent oral ergocalciferol solution and calcium carbonate therapies, the patient's symptoms resolved, blood chemistries normalized, and radiological evidence of rickets significantly improved. To our knowledge, this is the first case of an ectopic thymic parathyroid adenoma in a patient presenting with rickets. Our patient demonstrates that hyperparathyroidism-induced hypercalcemia may be masked by severe vitamin D deficiency. Prolonged treatment with ergocalciferol after removal of the parathyroid adenoma was necessary to normalize iPTH and replenish vitamin D store.