Vitamin D-dependent Rickets Research Articles

CLINICAL CASE OF FAMILIAL HYPOPHOSPHATEMIC RICKETS IN A CHILD

X-linked hypophosphatemic rickets is an inherited disorder caused by mutations in the PHEX gene (phosphate- regulating proteinwith homology to endopeptidases on the X chromosome). Chronic hypophosphatemia leads to impaired bone mineralization, resulting ingrowth retardation, rickets, and damage to other organs and systems, including maxillofacial abnormalities. Clinically, these manifestationsbecome signifi cant when the child begins to walk.The purpose of the study is to describe a clinical case of congenital hypophosphatemic rickets in a child.Material and methods of the study. clinical, biochemical, genetic and imaging examination of the child Results of the study. The article presents a clinical case of a 9-year-old boy, who was adopted after being removed from an unfavorable psychosocial environment and admitted to the Odesa Regional Children’s Clinical Hospital to clarify the diagnosis and treatment tactics.On admission, the mother reported complaints of delayed psychophysical development, memory impairment, psychosocial dysfunction, deformities of the bones of the upper and lower extremities, chest and skull. The examination revealed a decrease in the level of phosphorus in the blood, increased levels of parathyroid hormone and alkaline phosphatase, and signs of osteomalacia in the x-ray. The diff erential diagnosis included vitamin D-dependent rickets, mucopolysaccharidosis, nanism, hyperparathyroidism, and metaphyseal chondrodystrophy. Based on the data obtained, the fi nal diagnosis was made and appropriate treatment was prescribed.Conclusions. The expanded diff erential diagnosis of rickets with rickets-like diseases contributed to the correct clinical diagnosis. Timely pathogenetic treatment reduces renal tubular phosphorus loss, improves mineral metabolism and quality of life. Prescription of growth hormone will reduce the manifestations of nanism.

6874 A Rare Case Of Hereditary 1,25 (OH)2D Resistant Rickets

Abstract Disclosure: G. Umarji: None. F. Thelmo: None. S.A. Jabbour: None. Vitamin D-dependent rickets type 2A (VDDR2A) also known as hereditary 1,25 (OH)2D resistant rickets is due to biallelic loss-of-function mutations in the gene encoding vitamin D receptor on chromosome 12q13.11, thus, it represents a true form of tissue resistance to vitamin D. It is a scarce form of rickets with approximately only 120 cases reported. A 37-year-old male was referred to endocrinology by neurosurgery for evaluation of metabolic bone disease. Seven years ago, he was in a car accident which resulted in a lumbar spine injury causing radiculopathy and severe low back pain leading to lumbar spine decompression/fusion. However, he suffered from nonunion of bones and had to undergo another surgery a year later with recurrent postoperative nonunion of bones. During the operation, the surgeon noticed that his spine seemed demineralized. He had a history of multiple minor fractures in childhood, decreased hearing in left ear for two years, fragile teeth for many years, and some hair loss since age 30. Physical exam showed a height of 1.82 m, weight 89.3 kg with body mass index of 26 kg/m2, broken teeth, no leg bowing and normal stance. Laboratory results showed normal renal function, thyroid function tests and testosterone level, corrected calcium 8.3 mg/dL (8.7-10.2), 25-OH-vitamin D 54 ng/mL (30-100), phosphorus 2.8 mg/dL (2.8-4.1), intact parathyroid hormone 65 pg/mL (15-65), bone-specific alkaline phosphatase 21 mcg/L (4-27), 24-hour urine calcium 156 mg/day (100-300), 24-hour urine phosphorus 1,752 mg/day (390-1,425), FGF-23: 93 RU/mL (44-215) and 1,25 (OH)2D 92 pg/mL (24-81.5). Dual absorptiometry of the lumbar spine and hip showed osteopenia with Z scores of -2.2 and -1.2 respectively. Genetic testing for metabolic bone disease panel showed heterozygous mutation in VDR gene at nucleotide position c.146+9dup associated with autosomal recessive VDDR2A. We present a very rare form of vitamin D resistant rickets. As many patients with VDDR2A are unable to respond to any form of vitamin D, it is suggested that VDDR2 be more appropriately described as hereditary 1,25 (OH)2D resistant rickets (HVDRR), hereditary resistance to 1,25 (OH)2D, or even pseudovitamin D-deficiency type IIA (PDDR IIA). Clinical features include severe rickets, bone pain, hypotonia, dental caries and alopecia. Biochemical features include hypocalcemia, hypophosphatemia, normal to elevated alkaline phosphatase, normal 25(OH)D and importantly, elevated 1,25-(OH)2D levels. Management is with high doses of calcium and vitamin D therapy. While rare, this disease highlights the need for a comprehensive evaluation of metabolic bone diseases and a thorough understanding of calcium and vitamin D metabolism. Presentation: 6/2/2024

A toddler with severe vitamin D-dependent rickets type 1A (VDDR1A), hungry bone syndrome, and severe RSV infection: presentation and therapeutic challenges.

Vitamin D-dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder due to mutations in the CYP27B1 gene which result in inability to generate 1,25(OH)2D. An 18-month-old boy with VDDR1A presented with hypotonia and respiratory distress. He had been diagnosed 2 months earlier, having been evaluated for stunted growth, hypotonia, and delayed developmental milestones. He was stabilized with oxygen and bronchodilators for his bronchiolitis and high doses of alfacalcidol, calcium, and phosphate supplements for his hungry bone syndrome. Of note, the patient sustained upper limb fractures after a fall from his bed during admission. Overall, he had a protracted disease course; however, his bone profile gradually improved and he steadily recovered. VDDR1A causes failure to thrive, hypotonia, and increased fracture risk and may complicate the clinical course of lower respiratory tract infections. Furthermore, management of hungry bone syndrome requires supraphysiologic doses of vitamin D metabolites and calcium.

The Role of Intestinal Cytochrome P450s in Vitamin D Metabolism.

Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3 controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. Cytochrome P450 (CYP) 24A1 is a catabolic enzyme expressed in the kidneys. Interestingly, a recently identified mutation in another CYP enzyme, CYP3A4 (gain-of-function), caused type III vitamin D-dependent rickets. CYP3A are also expressed in the intestine, but their hydroxylation activities towards vitamin D substrates are unknown. We evaluated CYP3A or CYP24A1 activities on vitamin D action in cultured cells. In addition, we examined the expression level and regulation of CYP enzymes in intestines from mice. The expression of CYP3A or CYP24A1 significantly reduced 1,25(OH)2D3-VDRE activity. Moreover, in mice, Cyp24a1 mRNA was significantly induced by 1,25(OH)2D3 in the intestine, but a mature form (approximately 55 kDa protein) was also expressed in mitochondria and induced by 1,25(OH)2D3, and this mitochondrial enzyme appears to hydroxylate 25OHD3 to 24,25(OH)2D3. Thus, CYP3A or CYP24A1 could locally attenuate 25OHD3 or 1,25(OH)2D3 action, and we suggest the small intestine is both a vitamin D target tissue, as well as a newly recognized vitamin D-metabolizing tissue.

CYP4A22 loss-of-function causes a new type of vitamin D-dependent rickets (VDDR1C).

Vitamin D-dependent rickets (VDDR) is a group of genetic disorders characterized by early-onset rickets due to deficiency of active vitamin D or a failure to respond to activated vitamin D. VDDR is divided into several subtypes according to the corresponding causative genes. Here we described a new type of autosomal dominant VDDR in a Chinese pedigree. The proband and his mother had severe bone malformations, dentin abnormalities, and lower serum 25 hydroxyvitamin D3 (25[OH]D3) and phosphate levels. The proband slightly responded to a high dose of vitamin D3 instead of a daily low dose of vitamin D3. Whole-exome sequencing, bioinformatic analysis, PCR, and Sanger sequencing identified a nonsense mutation in CYP4A22 (c.900delG). The overexpressed wild-type CYP4A22 mainly localized in endoplasmic reticulum and Golgi apparatus, and synthesized 25(OH)D3 in HepG2 cells. The overexpressed CYP4A22 mutant increased the expression of CYP2R1 and produced little 25(OH)D3 with vitamin D3 supplementation, which was reduced by CYP2R1 siRNA treatment. We concluded that CYP4A22 functions as a new kind of 25-hydroxylases for vitamin D3. Loss-of-function mutations in CYP4A22 lead to a new type of VDDR type 1 (VDDR1C). CYP2R1 and CYP4A22 may have some genetic compensation responding to nonsense-mediated mRNA decay effect of each other.

Siblings with vitamin D-dependent rickets type 1A: Importance of genetic testing and a review of genotype-phenotype correlations.

Vitamin D-dependent rickets type 1A (VDDR1A) is a rare condition caused by biallelic pathogenic variants in CYP27B1, which encodes 25-hydroxyvitamin D3-1-α-hydroxylase. Inadequate activity of this enzyme results in deficient 1α-hydroxylation of inactive 25-hydroxyvitamin D to biologically active 1,25-dihydroxyvitamin D, with consequent adverse effects on calcium and phosphate metabolism. A female child was clinically diagnosed at 18 months old with hypophosphatemic rickets based on phenotype and biochemical testing, with neither parent affected. A subsequent affected male sibling led to the reconsideration of the diagnosis. Exome sequencing showed a homozygous CYP27B1 c.1040T>A (p.Ile347Asn) variant for both children. No variants were found in genes associated with hypophosphatemic rickets. A review of published cases of VDDR1A with homozygous CYP27B1 variants indicates variable clinical presentation, lack of genotype-phenotype correlation, and low serum phosphate at diagnosis in most cases. These findings emphasize the clinical importance of molecular testing as part of the diagnostic evaluation for cases of non-nutritional rickets.

A Rare Case of Neuronal Ceroid Lipofuscinosis-Type 1 (NCL-1) with Vitamin D-Dependent Rickets-Type 1 (VDDR-1), Complex 1 Mitochondrial Deficiency, and Mixed Variant-Checkerboard and Phylloid Type of Pigmentary Mosaicism.

Introduction Neuronal ceroid lipofuscinosis-type 1 (NCL-1) is a neurodegenerative lysosomal storage disorder. Vitamin D-dependent rickets type 1 (VDDR-1) is a rare cause of refractory rickets. Here, we report an unusual association of NCL-1 with VDDR-1. Case A 3-year-old boy presented with a history of seizures from 45 days of life, delayed development, and loss of attained milestones at 20 months of age, along with progressive vision impairment since 1 year. Examination showed a failure to thrive, microcephaly, rachitic rosary, checkerboard and phylloid type of pigmentary mosaicism, fundus showed disc pallor with generalized narrowing of arterioles, bilateral retinitis pigmentosa, spasticity and dystonia, brisk reflexes, extensor plantar, and left choreoathetoid movements. Investigations showed hypocalcemia (7.8 mg/dL), normal phosphorus (3.9 mg/dL), elevated alkaline phosphatase (508.8 U/L), elevated parathyroid hormone (513.35 pg/mL), low 1,25-dihydroxy-vitamin D (9.93 pg/mL), and normal renal function. The child had metabolic acidosis, elevated ammonia (403.9 micromol/L), lactate (95 mg/dL, normal range 4.5-19.8 mg/dL), and creatine phosphokinase (432 U/L) level, and normal tandem mass spectroscopy. X-ray wrist showed healing vitamin deficiency rickets. Abnormal electroencephalogram was suggestive of low voltage activity. Magnetic resonance imaging brain showed gross cerebral and cerebellar atrophy. A muscle biopsy showed scattered atrophic fibers and several ultrastructural granular osmiophilic deposits and some mitochondrial aggregates of varying size were observed. Mitochondrial respiratory chain enzyme assay exhibited complex-1 deficiency (activity < 30%). Genetic analysis showed two pathogenic mutations: homozygous nonsynonymous variation c.674T > C in exon 7 of the PPT1 gene and a homozygous frameshift variation c.1178_1179delAA in exon 7 of CYP27B1 confirming the diagnosis of NCL-1 with VDDR-1. The child was treated with a low protein diet, levetiracetam, clonazepam, trihexyphenidyl, haloperidol, calcium supplement, calcitriol, and sodium benzoate; some improvement in clinical and biochemical parameters was noted on follow-up. Conclusion This is a novel association of NCL-1 with VDDR-1 associated with complex-1 mitochondrial deficiency which has previously not been reported in the literature.

Compound Heterozygous Variants of CYP27B1 Causing Autosomal Recessive Vitamin D-Dependent Rickets Type 1A in an Indian Child

Background: Vitamin D-dependent rickets Type 1A (VDDR-1A) is a rare cause of rickets occurring due to variants of CYP27B1 responsible for encoding enzyme 1ά hydroxylase. Clinical Description: We report a 17-months-old girl who presented to us with clinical and radiological features of rickets. The biochemistry investigations suggestive of low calcium, low phosphorous, markedly elevated alkaline phosphatase and parathyroid hormone, high-normal 25 hydroxy Vitamin D level and inappropriately normal 1,25 dihydroxy Vitamin D levels, and no response to oral calcium and Vitamin D supplementation, prompted the diagnosis of VDDR-1A, which was proven genetically with a novel compound heterozygous variant. Management and Outcome: She was treated with oral calcitriol 1.5 μg/day and oral elemental calcium at 500 mg/day; after which at the 3-month follow-up, improvement in clinical, biochemical, and radiological features was observed. Conclusion: Following a clinical diagnosis of VDDR, genetic analysis is preferable to identify the variant and hence understand the genotype–phenotype correlation.

Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets

Hypophosphatemic rickets, which is often hereditary, is still under- or misdiagnosed in both children and adults, denying these individuals access to optimal management and genetic counseling. There have been recent calls to compile real-world data and share best practice on these rare conditions to guide clinical decision-making. Here we present eight clinical vignettes of patients with hypophosphatemic rickets encountered in our tertiary pediatric endocrinology practice. We describe the clinical features, genetics, and management of four cases of X-linked hypophosphatemia (PHEX mutations), one each of autosomal recessive hypophosphatemic rickets (DMP1 mutation) and autosomal recessive vitamin D-dependent rickets type 1A (CYP27B1 mutation), and two cases of distal renal tubular acidosis with FOXI1 mutation-associated hypophosphatemic rickets. Our cases prompt consideration of the (i) frequent misdiagnosis of hypophosphatemic rickets in clinical practice and the importance of comprehensive genetic testing; (ii) variable expressivity of the causative mutations; and (iii) a lack of responsiveness and/or compliance to conventional therapy and the value of burosumab in modern management, provided access is equitable. These cases highlight common real-world themes and challenges to managing patients presenting with these diverse conditions, especially the burden of disease hidden by misdiagnosis. In sharing these cases, we hope to raise awareness of these conditions, promote best practice in genetic diagnosis and management, and further advocate for reimbursement equity for the best available therapies.

Clinical characteristics and long-term management for patients with vitamin D-dependent rickets type II: a retrospective study at a single center in Saudi Arabia.

Hereditary Vitamin D-dependent rickets type II (HVDDR-type II) is a rare autosomal recessive disorder caused by molecular variation in the gene encoding the vitamin D receptor (VDR). This study aims to evaluate phenotype and genotype characteristics and long-term follow-up of the largest group of patients with (HVDDR-type II) in Saudi Arabia. We conducted a retrospective chart review to collect the clinical, biochemical, and genetic data for all HVDDR-type II patients currently receiving treatment at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. A total of 42 patients, 57.1% female, and 42.9% male were included in the study. Seven patients were treated with high doses of oral calcium, while 35 patients were treated with IV calcium infusion. The median age at presentation was 15.5 months. Alopecia was found in 97.6%, 21.4% presented with bowing legs, 14.3% with delayed walking, 9.5% with seizure, and 2.4% presented with respiratory failure, while a family history of the disease was positive in 71.4% of total patients. Molecular genetic testing of the VDR gene in our cohort identified six different gene variants c.885 C>A (p.Tyr295Ter), c.88 C>T (p.Arg30Ter), c.1036G>A (p.Val346Met), c.820C>T (p.Arg274Cys), c.803 T>C (p.Ile268Thr), and c.2T>G (p.Met1?). We are describing the largest cohort of patients with HVDDR-type II, their clinical biochemical findings, and the most prevalent genetic variants in our population.

Vitamin D Dependent Rickets Type 1a as a Rare Cause of Rickets: Case Report and Literature Review

Aim: The purpose of this paper is to describe one example of type Ia, vitamin D-dependent rickets. Methods: A diagnosis has been made based on physical examination, laboratory results, and radiographic examination. A positive gentic mutation has also been used to corroborate the diagnosis. Results: Here, we present a case of a 2-year-old Saudi girl who exhibits delayed motor development and valgus deformity of the feet together with biochemical and radiographic signs of vitamin D abnormalities. She was initially treated at a peripheral hospital for rickets as Vitamin D deficiency and given cholecalciferol for six months; however, there was little improvement. Later, she was referred to us, and we performed a genetic study that revealed a positive gentic mutation at CYP27B1, confirming the diagnosis of Vitamin D dependent Rickets 1a, and Calcitriol treatment followed. Within 4 weeks, the patient exhibits significant recovery, and both PTH and alkaline phosphatase levels return to normal. After three months of calcitriol treatment, clinical and radiological proof of the improvement was observed. Conclusions: In this research, we raise the knowledge that rickets is not always caused by vitamin deficiency and that early presentations should increase awareness of inherited causes of rickets such VDDR1a that do not react to cholecalciferol and gentic investigation is helpful in such cases.

A case of vitamin-D dependent type-1A rickets

Abstract Rickets is a disease of growing bones characterized by softening of bones as a result of defective mineralization of cartilage in the epiphyseal growth plate. The predominant cause is a deficiency or impaired metabolism of vitamin D. Some forms of rickets do not respond to regular doses of cholecalciferol, which leads to suspicion of vitamin D-dependent rickets (VDDR). VDDR is of two types: type I is due to defective renal tubular 25-hydroxyvitamin D 1-α hydroxylase, and type II is due to end-organ resistance to the active metabolite of vitamin D. Here, we describe a child with seizures and calcipenic rickets with biochemical profile suggestive of VDDR type 1 worsened by phenytoin which responded completely to calcium and calcitriol supplementation. Whole exome sequencing revealed a heterozygous missense mutation in exon 7 of the TRPV4 gene (chromosome 12,c.1292C&gt;A), whereas no mutations in CYP2R1, CYP27B1, VDR, and CYP3A4 were detected.

A severe presentation of vitamin D-dependent hypocalcemic rickets associated with hypophosphatemia.

A severe presentation of vitamin D-dependent hypocalcemic rickets associated with hypophosphatemia.

A severe presentation of vitamin D-dependent hypocalcemic rickets associated with hypophosphatemia

A severe presentation of vitamin D-dependent hypocalcemic rickets associated with hypophosphatemia

Approach to Rickets: Is It Calciopenic or Phosphopenic?

Rickets is a childhood disorder of decreased mineralization of bone tissue. It is either calciopenic or phosphopenic, according to the deficient mineral. Calcium, phosphate, and vitamin D metabolism should be known to understand the pathophysiology of rickets. A deficiency of calcium or vitamin D can be caused by several conditions. These conditions lead to defective osteoid mineralization, impaired chondrocyte differentiation, and apoptosis in the growth plate, resulting in clinical and radiological findings of rickets. Rickets developing as a result of vitamin D deficiency is the most frequently encountered form. Vitamin D-dependent rickets classification is made according to genetic abnormalities of enzymes that are involved in vitamin D metabolism. Phosphopenic rickets is divided mainly into 2 categories that are FGF23 related or not. A systemic approach that includes a detailed history, physical examination, and laboratory evaluation is required when performing a diagnostic evaluation. Vitamin D and calcium supplementation should be used to treat nutritional rickets. To prevent rickets and its morbidities, vitamin D prophylaxis in the newborn period is suggested. High dose of vitamin D3, 1.25(OH)2D, and calcium are treatment choices in vitamin D-dependent rickets according to its subgroup. If conventional treatment consisting of phosphate and calcitriol is ineffective in the treatment of phosphopenic rickets, Burosumab is the new treatment option.

Vitamin D-dependent Rickets Type II

The work aimed to present one case with vitamin D-dependent rickets type II, treated at Nasser Hospital – in the Gaza Strip. The patient was 3 years old with a body weight of 8.5 kg and a height of 90 CM. Skin color was cyanotic, but skin moisture was dry. Body temperature was 39 C from axillary; Turgor was warm and rough. The texture of vascularity was ecchymosis. The patient was on NGT and ETT and had alopecia in their hair. His Nails color was pale but was clubbing in shape. Deformity in the head and face; his eyes are symmetrical, but he is blind with corneal opacities bilateral, about ears are symmetrical auricles and gross hearing acuity. Mouth mucous membrane was moist but had ulcers and infection; teeth were missing, and tongues cyanotic and cracked. He has dysphagia, dyspepsia and hoarseness of voice. Full range of motion of the neck. Carotid pulsation rate 160 b/min symmetrical and bounding, cervical lymph nodes are enlarged and tender. Respiratory rate 40 b/min, barrel chest and abnormal breathing pattern. The patient complained of productive cough, on percussion, lung sound was dullness, but in auscultation, bilateral wheezy; apical heart rate was 140 b/min regular and strong. His blood pressure was 130/83 mm Hg. Capillary refill was 3 seconds. Normal heart sounds. The abdomen was soft and relaxed but distended. A genitalia was normal, About range of motion was limited and flaccid motor response.M. Aker 3 years old of cons. marriage 1st cousin, the second order of birth; the chief complaint was Rickets Type 2, which is badly responding to vit D. The Personal history of this disease was discovered when he was two months old with a history of sibling died at the age of 4 years (his sister), at birth. The patient was normal without any symptoms, and at the age of two months, he started the symptoms; 1st one was hair loss with fragile bone. With investigation, there is Vit D deficiency, so calcium supplement and Vit D were given; at the age of one year, the condition worsened, and bones were more fragile with bowing of legs, so doctors advised increasing the dose of Vit D and calcium with calciless treatment, but the immune system suppressed, and he got a lot of chest infections, so hospital admission many times with intravenous antibiotics, sometimes he was intubated on Mechanical ventilation in pediatric (I c u ), on 2 years, he was Oxygen-dependent then later he developed Respiratory Failure, at 3 year pt. was complaining severe chest infection and was intubated on Mechanical ventilation; unfortunately the child died at the age of 3 years.

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

A 14-week-old female domestic longhair kitten presented with shifting lameness and disproportionately smaller size compared with a co-housed littermate. Hematology and serum biochemical testing were conducted to investigate causes for delayed growth, and radiographs of the appendicular skeleton were obtained. 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. 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.

Hereditary dentin defects with systemic diseases.

This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms. References on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared. Over 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D-dependent rickets, familial tumoral calcinosis, Ehlers-Danlos syndrome, Schimke immuno-osseous dysplasia, hypophosphatasia, Elsahy-Waters syndrome, Singleton-Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation. Some specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.

A Pair of Siblings with Vitamin D Dependent Rickets (VDDR) Type 1A: More Than Dairy and Sunshine

Vitamin D-dependent rickets (VDDR) type 1A, owing to 1-alpha-hydroxylase deficiency, albeit rare, is an important diagnosis to consider in children with rickets not responding to conventional doses vitamin D and calcium. In this case report, we describe two siblings who presented with multiple fractures since childhood. A low 1,25-dihydroxyvitamin D (1,25(OH)2D) despite a sufficient 25-hydroxyvitamin D (25OHD) level was suggestive of 1-alpha-hydroxylase deficiency. Genetic testing confirmed a mutation in the CYP27B1 gene on chromosome 12q13.3, which produces 1-alpha-hydroxylase. The inability to convert 25OHD to 1,25 (OH)2D leads to hypocalcemia and severe rickets. Treatment requires a pharmacologic dose of activated hydroxylated vitamin D and adequate calcium intake. Rare forms of hereditary rickets should be suspected in severe rickets. Early recognition of VDDR type 1A is imperative to ensure adequate healing of rickets during childhood. Establishing a diagnosis also helps to ensure compliance with the high doses of active vitamin D metabolite required in this condition.

Vitamin D dependent rickets type 2: a case-based review of patient with alopecia and rickets

Vitamin D dependent rickets (VDDR) type 2 is a very rare hereditary disease which has an autosomal recessive mode of inheritance. Patients with VDDR type 2 have a mutation in the gene encoding for vitamin D receptor on chromosome 12q12-q14, thus averting normal physiological action of 1,25 vitamin D. It's presents with the developmental delay in motor domain with features of rickets usually in the first year of life. Alopecia totalis has a frequent association with the disease. We are reporting a case of a 5-year-old boy who has a history of difficulty walking since 2 year of life, with a gradually progressive motor weakness course. Patients have a history of alopecia since 2 months of age, which progressed to alopecia totalis. On investigation, serum calcium was 7.2 mg/dl with a very high alkaline phosphate level of 1065 IU/ML with a normal vitamin D level was reported. The initial treatment started with IV calcium followed by 1000mg of oral calcium, along with a high dose of calcitriol. The patient was under periodic follow-up showing improvement in biochemical parameters. We reviewed literature of seven patient out of which 5 patients had alopecia and found 2 patients had enamel hypoplasia and all had features of rickets.