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.

Parietal aplasia and hypophosphatasia in a child harboring a novel mutation in RUNX2 and a likely pathogenic variant in TNSALP.

Cleidocranial dysplasia is a dominantly inherited skeletal dysplasia resulting from inherited or spontaneous mutations of Runt-related transcription factor 2 gene (RUNX2). It represents a clinical continuum typically characterized by wide calvarial sutures, clavicular hypoplasia and dental abnormalities. CDD has been rarely associated with skeletal and biochemical features that mimic hypophosphatasia. We report clinical, biochemical and molecular profile of a 3-year-old female with CCD, presented in utero with large cranial defects. She displayed severe parietal dysplasia, wide cranial sutures, clavicular abnormalities and biochemical features of hypophospatasia (HHP). She was preliminary diagnosed with benign perinatal HHP, harboring a likely pathogenic heterozygous TNSALP variant (p.Ser181Leu) inherited by the mother, who also displayed low levels of ALP. Asfotase alfa was introduced for a six-month-period with rather positive impact on cranial ossification. Nevertheless, focal skeletal disease (cranium and clavicles) and absence of clinical symptoms in the mother, carrier of the same genetic variant, posed diagnosis into question and further genetic analysis detected the novel spontaneous frameshift mutation c.1191delC (p.Phe398Leufs*86) in RUNX2 gene, establishing the CCD diagnosis. Although genotype-phenotype correlations are difficult, p.Phe398Leufs*86 appears to be associated with a severe cranial phenotype and absence of parietal bones, similarly to other adjacent frameshift/splicing mutations. The TNSALP variant (p.Ser181Leu) may contributed to patient's final phenotype, as well as to maternal low ALP levels. However, since low ALP levels have been also reported in few CCD patients with no alterations in TNSALP gene, studies to elucidate RUNX2 and TNSALP interactions could shed more light on differential diagnosis between CCD and HHP, CCD appropriate therapy and genetic counselling. ACCESSION NUMBER: (SUB8185506).

Autosomal Recessive Osteogenesis Imperfecta Caused by a Novel Homozygous COL1A2 Mutation.

Osteogenesis imperfecta (OI) is a skeletal dysplasia characterized by brittle bones and extraskeletal manifestations. The disease phenotype varies greatly. Most commonly, OI arises from monoallelic mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2 and is inherited as an autosomal dominant trait. Here, we describe a consanguineous family with autosomal recessive OI caused by a novel homozygous glycine substitution in COL1A2, NM_000089.3: c.604G>A, p.(Gly202Ser), detected by whole-genome sequencing. The index patient is a 31-year-old Greek woman with severe skeletal fragility. She had mild short stature, low bone mineral density of the lumbar spine and blue sclerae. She had sustained multiple long bone and vertebral fractures since childhood and had been treated with bisphosphonates for several years. She also had an affected sister with similar clinical manifestations. Interestingly, the parents and one sister, all carriers of the COL1A2 glycine mutation, did not have manifestations of OI. In summary, we report on autosomal recessive OI caused by a homozygous glycine-to-serine substitution in COL1A2, leading to severe skeletal fragility. The mutation carriers lacked OI manifestations. This family further expands the complex genetic spectrum of OI and underscores the importance of genetic evaluation for correct genetic counselling.

Long-term follow-up of a child with Klinefelter syndrome and achondroplasia from infancy to 16 years.

BACKGROUND: Achondroplasia (ACH), an autosomal dominant skeletal dysplasia, occurs in approximately 1:20,000 births. On the other hand, 47,XXY aneuploidy (Klinefelter syndrome [KS]) is the most common sex chromosome disorder, with a prevalence of approximately 1:600 males. To the best of our knowledge, only five cases of patients presenting both ACH and KS have been reported to date in the international literature. However, none of these cases has been longitudinally followed during the entire childhood. CASE PRESENTATION: We report a male patient with ACH and KS, diagnosed in early infancy because of his typical phenotype of ACH. The diagnosis was confirmed by molecular analysis revealing a de novo heterozygous 1138 G-to-A mutation of the FGFR3 gene. During his first assessment, a karyotype was performed, which also revealed coexistence of KS. He was followed by our pediatric endocrinology team until the age of 16 years, then he was gradually transferred to adult endocrine care. CONCLUSIONS: This is the first reported case with both conditions that was diagnosed in infancy and was longitudinally followed by a pediatric endocrinology team regularly, from infancy to late adolescence. With a typical phenotype of ACH, it is striking and noteworthy that he did not develop the classical endocrine complications of a child with KS, neither did he necessitate testosterone supplementation during his pubertal development, due to his normal virilization and testosterone levels.

Body composition and lung function in children with cystic fibrosis and meconium ileus.

The aim of this study was to explore whether history of meconium ileus (MI) at birth in children and adolescents with cystic fibrosis (CF) adversely affects body composition and lung function in later life. Data of children and adolescents with CF who underwent spirometry and DXA as part of their routine care were analyzed. Associations between MI (explanatory variable) and areal bone mineral density (total body less head-TBLH aBMD), lean tissue mass (LTM), and fat mass (FM) (outcomes) were assessed using general linear models. Potential relationships of TBLH aBMD, LTM, and FM with FEV1 (additional outcome) were also explored. One hundred and one subjects with CF (mean age 14 ± 3 years) were included, 19 (18.8%) of whom had history of MI. Negative associations were demonstrated between history of MI and FEV1 (P = 0.04), TBLH aBMD (P = 0.03), and FM (P < 0.01) but not between history of MI and LTM (P = 0.07) after adjustment for other variables. Lung function was positively associated with TBLH aBMD (P < 0.01) and LTM (P = 0.02) but not with FM (P = 0.20). CONCLUSION: Among children and adolescents with CF, those with history of MI have lower bone mineral density, FM, and lung function. What is Known: • Among children and adolescents with cystic fibrosis, those with history of meconium ileus in the neonatal period are at risk of having lower body mass index percentile and FEV 1 percent predicted. What is New: • Children and adolescents with cystic fibrosis and history of meconium ileus have decreased bone mineral density and fat mass compared to patients without such history. • Lower lung function in children with MI coexists with suboptimal bone mineral density.

Bone health assessment of food allergic children on restrictive diets: a practical guide.

BACKGROUND: Food allergy in childhood is on the rise globally and is managed with avoidance diets; recent case reports of food allergic children with nutritional rickets in the literature highlight the importance of close monitoring of bone health in this population. METHODS: There is no consensus as yet with regard to bone health evaluation in food allergic children; therefore, extensive literature search was performed and the existing evidence is presented, along with a relevant algorithm. RESULTS: Children allergic to cow's milk protein or presenting with allergy in more than three food items, as well as patients with severe allergic phenotypes or comorbidities known to affect the skeleton, seem to be at risk of metabolic bone disorders. As a practical guide, suspicious cases can be investigated with basic bone profile, whereas more severe cases (persistent bone pain and fractures) may undergo advanced bone health assessment, with bone mineral density (BMD) and metabolic bone markers' evaluation. Of note, these diagnostic steps call for further studies in the field of food allergy, as they are not performed as a routine. Evidence is accumulating with regard to vitamin D deficiency, osteopenia and imbalanced bone metabolism in those food allergic children who show poor dietary compliance or have inadequate medical supervision. CONCLUSIONS: Ensuring optimal bone accrual in a food allergic child is an important task for the clinician and requires close monitoring of the restrictive diet and prompt therapeutic intervention, in an effort to avoid rickets or osteopenia.

Bone health evaluation of children and adolescents with homozygous ß-thalassemia: implications for practice.

OBJECTIVE: Bone tissue is adversely affected in patients with homozygous ß-thalassemia. The aim of this study was to find warning signs of bone loss in young patients with ß-thalassemia and allow prompt therapeutic interventions. METHODS: Thirty-eight patients were studied, 20 boys and 18 girls, aged 5 to 18 years (median = 14.13 y), on regular transfusions and chelation treatments. Their bone mineral density (BMD) was measured with dual x-ray absorptiometry. The recorded parameters were weight, height, bone age (BA), transfusion adequacy (mean fetal hemoglobin value), and chelation efficacy (mean ferritin value, compliance). Tanner stage was also evaluated: 8 prepubertal subjects (stage 1), 18 peripubertal subjects (stages 2 and 3), and 12 postpubertal patients (stages 4 and 5). Blood and urine samples were collected for biochemical analysis. RESULTS: Mean BMD z score was -1.56 ± 1.25. Thirteen patients had normal BMD (z score >-1), 17 patients had low BMD (z score: -1 up to -2.4), and 8 patients had very low BMD (z score <-2.5). Low BMD was observed in patients older than 12 years and was associated with short stature (r = 0.33, P = 0.04), delayed BA (r = 0.61, P = 0.01), and increased bone formation markers. There was no correlation of BMD z score with sex, fetal hemoglobin value, ferritin, and compliance. Regarding Tanner stage, it was associated strongly with short stature (r = 0.57, P = 0.01), ferritin (r = -0.38, P = 0.02), and compliance (r = 0.58, P = 0.01). CONCLUSIONS: [corrected] The decline in BMD may start early, even in the well-transfused patients. This study targets the young patients who are mostly at the risk for bone loss, that is short adolescents with delayed BA. Their prompt recognition in everyday practice is important, as they will need close monitoring of their BMD and metabolic bone profile. In addition, therapeutic interventions, such as adequate calcium intake and sunlight exposure, weight-bearing exercise and, in cases of vitamin D insufficiency, proper supplementation could be suggested.

Effects of L-phenylalanine on acetylcholinesterase and Na+,K+-ATPase activities in suckling rat frontal cortex, hippocampus and hypothalamus.

The effect of different L-phenylalanine (Phe) concentrations (0.12-12.1 mM) on acetylcholinesterase (AChE), (Na+,K+)-ATPase and Mg2+-ATPase activities was evaluated in homogenates of suckling rat frontal cortex, hippocampus and hypothalamus. Phe, at high concentrations, reduced AChE activity in frontal cortex and hippocampus by 18%-20%. On the contrary, the enzyme activity was unaltered in the hypothalamus. Na+,K+-ATPase was stimulated by high levels of the amino acid, both in the frontal cortex and the hypothalamus by 60%, whereas it was inhibited in the hippocampus by 40%. Mg2+-ATPase was not influenced by Phe. It is suggested that: a) In the frontal cortex, the improper acetylcholine (ACh) release, due to AChE inhibition by Phe, combined with the stimulation of Na+,K+-ATPase, possibly explain tremor and the hyperkinetic behaviour in patients with classical phenylketonuria (PKU). b) In the hippocampus, inhibition of AChE by Phe could lead to problems in memory, while Na+,K+-ATPase inhibition by Phe may induce metabolic disorders and electrical instability of the synaptosomal membrane. c) In the hypothalamus, the behavioral problems in PKU "off diet" may be related to noradrenaline (NA) levels, which are probably correlated with the modulated Na+,K+-ATPase by Phe.