Clinical outcomes and medical management of achondroplasia in Japanese children: A retrospective medical record review of clinical data.

Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records-based cohort study (before vosoritide approval) summarized symptoms, complications, monitoring, surgery/interventions, and height with/without GH in Japanese patients with ACH <5 years. Complications were observed in 89.2% of all 37 patients; 75.7% required surgery or intervention. All patients were monitored by magnetic resonance imaging; 73.0% had foramen magnum stenosis, while 54.1% had Achondroplasia Foramen Magnum Score 3 or 4. Of 28 GH-treated patients, 22 initiating at age 3 years were generally taller after 12 months versus 9 non-GH-treated patients. Mean annual growth velocity significantly increased from age 2 to 3 versus 3 to 4 years in GH-treated patients (4.37 vs. 7.23 cm/year; p = 0.0014), but not in non-GH-treated patients (4.94 vs. 4.20 cm/year). The mean height at age 4 years with/without GH was 83.6/79.8 cm. These results improve our understanding of young patients with ACH in Japan and confirm that early diagnosis of ACH and monitoring of complications help facilitate appropriate interventions.

Assessment of body fat mass, anthropometric measurement and cardiometabolic risk in children and adolescents with achondroplasia and hypochondroplasia.

Achondroplasia is a rare skeletal dysplasia characterized by rhizomelic short stature, whose prevalence is about 1 per 25,000 births. For some patients with achondroplasia, excess body weight is one of the major concerns due to an impaired linear growth. Epidemiological studies revealed a premature onset of cardiovascular or cerebrovascular events in achondroplasia. An association between obesity and cardiometabolic risk factors related to cardiovascular events remains unknown in patients with achondroplasia/hypochondroplasia. This cross-sectional study investigated anthropometric measurements, body compositions and cardiometabolic risk factors in pediatric patients with achondroplasia/hypochondroplasia. Thirty-two patients with achondroplasia and ten with hypochondroplasia aged between 1.9 and 18.7 years were enrolled in this study. Half of the participants presented at least one cardiometabolic abnormality. Elevated systolic blood pressure was the most common abnormality. None of the participants developed metabolic syndrome or type 2 diabetes mellitus. Body mass index-standard deviation score and hip/height ratio were strongly correlated with percent body fat assessed by dual energy X-ray absorptiometry although no significant association was found between anthropometric measurements or body fat mass and any cardiometabolic risk factors. No significant difference in body fat mass, as well as body mass index-standard deviation score and hip/height, was found between cardiometabolically normal group and cardiometabolically abnormal groups. These results suggest that not only weight gain and hip/height changes should be monitored but also individual cardiometabolic risk factors should be evaluated to avoid cardiometabolic events in the healthcare management of pediatric patients with achondroplasia/hypochondroplasia.

4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts.

Osteogenesis imperfecta (OI) is a heritable brittle bone disease mainly caused by mutations in the two type I collagen genes. Collagen synthesis is a complex process including trimer formation, glycosylation, secretion, extracellular matrix (ECM) formation, and mineralization. Using OI patient-derived fibroblasts and induced pluripotent stem cells (iPSCs), we investigated the effect of 4-phenylbutyric acid (4-PBA) on collagen synthesis to test its potential as a new treatment for OI. Endoplasmic reticulum (ER) retention of type I collagen was observed by immunofluorescence staining in OI patient-derived fibroblasts with glycine substitution and exon skipping mutations. Liquid chromatography-mass spectrometry analysis revealed excessive glycosylation of secreted type I collagen at the specific sites in OI cells. The misfolding of the type I collagen triple helix in the ECM was demonstrated by the incorporation of heat-dissociated collagen hybridizing peptide in OI cells. Type I collagen was produced excessively by OI fibroblasts with a glycine mutation, but this excessive production was normalized when OI fibroblasts were cultured on control fibroblast-derived ECM. We also found that mineralization was impaired in osteoblasts differentiated from OI iPSCs. In summary, treatment with 4-PBA normalizes the excessive production of type I collagen, reduces ER retention, partially improves misfolding of the type I collagen helix in ECM, and improves osteoblast mineralization. Thus, 4-PBA may improve not only ER retention, but also type I collagen synthesis and mineralization in human cells from OI patients.

Alkaline phosphatase in pediatric patients with genu varum caused by vitamin D-deficient rickets.

An elevated serum alkaline phosphatase (ALP) level is one of the markers for the presence of rickets in children, but it is also associated with bone formation. However, its role in diagnosing genu varum in pediatric patients with vitamin D-deficient rickets is still unknown. To clarify the role of the serum ALP level in assessing the severity of genu varum, we retrospectively investigated this issue statistically using data on rickets such as serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, ALP, the level of creatinine as the percentage of the median according to age (%Cr), and the metaphyseal diaphyseal angle (MDA) in the lower extremities as an index of the severity of genu varum. A multiple regression analysis revealed that log ALP and %Cr values were negatively associated with MDA values. The former association was also confirmed by a linear mixed model, while iPTH was positively associated with MDA by path model analysis. To elucidate the association of ALP with MDA in the presence of iPTH, we investigated three-dimensional figures by neural network analysis. This indicated the presence of a biphasic association of ALP with MDA: the first phase increases while the second decreases MDA. The latter phenomenon is considered to be associated with the increase in bone formation due to the mechanical stress loaded on the lower extremities. These findings are important and informative for pediatricians to understand the significance of the serum ALP level in pediatric patients with genu varum caused by vitamin D deficiency.

Parental somatogonadal COL2A1 mosaicism contributes to intrafamilial recurrence in a family with type 2 collagenopathy.

The COL2A1 gene encodes the alpha-1 chain of procollagen type 2. Pathogenic variants in the COL2A1 gene are associated with several different types of skeletal dysplasia collectively known as type 2 collagenopathies. Type 2 collagenopathies have an autosomal dominant inheritance. Some germline or somatogonadal mosaicism cases have been reported. We investigated whether somatogonadal mosaicism occurred in a family with two children suspected of type 2 collagenopathies or related diseases. First, we detected a pathogenic variant in the COL2A1 gene in the two affected children by whole exome sequencing (WES). Next, we performed targeted deep sequencing to their parents without the variant by WES. A low level of COL2A1 mosaicism was revealed in the mother's tissues. We concluded that the mother had somatogonadal mosaicism with the COL2A1 mutation arose in the epiblast, and that the intrafamilial recurrence rate of the disease by the somatogonadal mosaicism was higher than by the germline mosaicism. This report suggests that parental low-level mosaicism should be evaluated in those parents with children carrying de novo germline mutations and the targeted deep sequencing is useful to detect them.

Impact of fracture characteristics and disease-specific complications on health-related quality of life in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a connective tissue disease with bone fragility. Several studies have indicated that physical function in adult OI was correlated to the disease severity, but there have been no reports delineating the impact of the fracture characteristics and disease-specific complications on health-related quality of life (HRQoL). The purpose of this study is to clarify the factors impacted on HRQoL in adult OI patients. We conducted a cross-sectional study between July 2016 and March 2018 and sent a questionnaire regarding HRQoL using Short Form-36 (SF-36) to the OI patients at the age of 20 years or older who had a medical history of the investigators' institutions. The 40 patients completely answered the SF-36. Mental component summary and role/social component summary were unremarkable. Physical component summary (PCS) was significantly associated with z-score for height, teeth abnormality, and cardiopulmonary insufficiency (partial regression coefficient, 3.04, - 9.70, and - 11.35; p, < 0.001, 0.047, and 0.025, respectively). PCS was also significantly lower in the patients who had an initial fracture before the age of 2 years than those without occurrence of fractures until 2 years old (25.80 ± 17.15 versus 44.20 ± 16.54; p = 0.002), or those who had lower extremity fractures more than five times as compared with normal populations. Physical function was decreased in OI patients who had fractures before 2 years old, especially in lower extremity. Appropriate medical managements for cardiopulmonary insufficiency are required not only to maintain physical function but also to decrease mortality.

Physical, Mental, and Social Problems of Adolescent and Adult Patients with Achondroplasia.

Patients with achondroplasia (ACH) require various medical interventions throughout the lifetime. Survey of health-related quality of life (HRQoL) in adult ACH patients is essential for the evaluation of treatment outcomes performed during childhood such as growth hormone administration and limb lengthening surgeries, but no study focused on the treatment strategy by analyzing HRQoL of ACH patients. The purpose of this study was to assess whether final height impacted on HRQoL and to evaluate what kinds of medical interventions were positively or negatively associated with HRQoL. We included 184 ACH patients (10-67 years old) who were registered in the patients' associations or who had a medical history of the investigators' institutions, and analyzed HRQoL by using Short Form-36 and patient demographics. Physical component summary (PCS) was significantly lower than the standard values in each age, especially in elderly populations, while mental component summary (MCS) was similar to the standard values. Role/social component summary was deteriorated only in elderly populations. The PCS was improved in the patients who had a height of 140 cm or taller (p < 0.001). The PCS and MCS were strongly associated with the past medical history of spine surgeries (p < 0.001 and p = 0.028, respectively). A treatment strategy would be planned to gain a final height of 140 cm or taller during childhood in combination with growth hormone administration and limb lengthening surgeries. Appropriate medical management for neurological complications of adult ACH patients is required to maintain physical and mental function.

Development of scoliosis in young children with osteogenesis imperfecta undergoing intravenous bisphosphonate therapy.

The purpose of this study was to clarify the prevalence of scoliosis and determine risk factors for the development of scoliosis in young children with osteogenesis imperfecta (OI) who underwent intravenous pamidronate (PAM) therapy. Thirty-four young children with OI who had no scoliosis at the first PAM administration underwent cyclic PAM therapy alone. The medical records and radiographs of these patients were retrospectively reviewed. We examined the relationship between scoliosis (Cobb angle ≥ 10) and type of OI (Sillence classification: types I, III, and IV), physical mobility, Z-scores of bone mineral density in L2-4 of the lumbar spine (L2-4 BMD Z-scores), age of patients at first treatment with PAM, pelvic frontal tilt and leg-length discrepancy. The prevalence of scoliosis was 23.5% in 34 young children with OI who underwent PAM therapy for a mean of 4.2 years. Lower L2-4 BMD Z-scores, the presence of coronal and sagittal vertebral deformities and higher percentage of corrective osteotomy in the lower extremities were significant risk factors for the development of scoliosis. In patients with type III or IV OI, L2-4 BMD Z-scores were significantly lower (p = 0.02) and the percentage of patients who started PAM therapy in early childhood was significantly lower in scoliosis group than in the non-scoliosis group (p = 0.01). Development of scoliosis depends on the severity of OI and has a strong relationship with bone fragility even under PAM therapy. Starting intravenous PAM therapy in infancy or early childhood has a potential to prevent the occurrence and progression of scoliosis associated with bone fragility in young children with severe type III or IV OI.

Functional analysis of monocarboxylate transporter 8 mutations in Japanese Allan-Herndon-Dudley syndrome patients.

Monocarboxylate transporter 8 (MCT8) facilitates T3 uptake into cells. Mutations in MCT8 lead to Allan-Herndon-Dudley syndrome (AHDS), which is characterized by severe psychomotor retardation and abnormal thyroid hormone profile. Nine uncharacterized MCT8 mutations in Japanese patients with severe neurocognitive impairment and elevated serum T3 levels were studied regarding the transport of T3. Human MCT8 (hMCT8) function was studied in wild-type (WT) or mutant hMCT8-transfected human placental choriocarcinoma cells (JEG3) by visualizing the locations of the proteins in the cells, detecting specific proteins, and measuring T3 uptake. We identified 6 missense (p.Arg445Ser, p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, and p.Gly312Arg), 2 frameshift (p.Arg355Profs*64 and p.Tyr550Serfs*17), and 1 deletion (p.Pro561del) mutation(s) in the hMCT8 gene. All patients exhibited clinical characteristics of AHDS with high free T3, low-normal free T4, and normal-elevated TSH levels. All tested mutants were expressed at the protein level, except p.Arg355Profs*64 and p.Tyr550Serfs*17, which were truncated, and were inactive in T3 uptake, excluding p.Arg445Ser and p.Pro561del mutants, compared with WT-hMCT8. Immunocytochemistry revealed plasma membrane localization of p.Arg445Ser and p.Pro561del mutants similar with WT-hMCT8. The other mutants failed to localize in significant amount(s) in the plasma membrane and instead localized in the cytoplasm. These data indicate that p.Arg445Ser and p.Pro561del mutants preserve residual function, whereas p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, p.Gly312Arg, p.Arg355Profs*64, and p.Tyr550Serfs*17 mutants lack function. These findings suggest that the mutations in MCT8 cause loss of function by reducing protein expression, impairing trafficking of protein to plasma membrane, and disrupting substrate channel.

Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D.

Cole-Carpenter syndrome is a rare skeletal dysplasia associated with low-bone mass or an osteogenesis imperfecta (OI)-like syndrome. Only 3 and 6 variants in SEC24D have been reported in patients with Cole-Carpenter syndrome type 2 and autosomal recessive OI, respectively. We describe a 15-year-old Japanese boy with short stature of the short-trunk type and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. These features were consistent with a diagnosis of Cole-Carpenter syndrome. He had low-bone mineral density and basilar impression. Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient. We will report a patient with compound heterozygous variants of SEC24D causing Cole-Carpenter syndrome type 2.

Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan.

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.

Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial.

OBJECTIVE: Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan. DESIGN: Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015. PATIENTS: Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1). MEASUREMENTS: Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development. RESULTS: Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved. CONCLUSION: Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.

Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia.

OBJECTIVE: Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature. DESIGN: This was a longitudinal cohort study. PATIENTS: Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year. MEASUREMENTS: Serum NT-proCNP levels and height were measured. RESULTS: NT-proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT-proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = -0·55). Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P < 0·01, r = 0·72). CONCLUSION: Serum NT-proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients.

Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports.

The C-type natriuretic peptide (CNP)-natriuretic peptide receptor 2 (NPR2) signaling pathway plays an important role in chondrocyte development. Homozygous loss-of-function mutations of the NPR2 gene cause acromesomelic dysplasia, type Maroteaux (AMDM). The aim of this study was to identify and characterize NPR2 loss-of-function mutations in patients with AMDM. The NPR2 gene was sequenced in three Korean patients with AMDM and functional analysis of the mutated proteins was performed in vitro. Five novel NPR2 mutations were found in the three patients: two compound heterozygous mutations [c.1231T>C (Tyr411His) and c.2761C>T (Arg921X) in Patient 1 and c.1663A>T (Lys555X) and c.1711-1G>C (M571VfsX12) in Patient 3] and a homozygous mutation [c.2762G>A (Arg921Gln) in Patient 2]. Serum NT-proCNP concentration was significantly increased in each patient compared to control subjects. Cells transfected with the expression vector of each mutant except those found in Patient 3 showed a negligible or a markedly low cGMP response after treatment with CNP. HA-tagged wild-type (wt) and HA-mutant NPR2 were expressed at comparable levels: there were two bands of ∼130 and ∼120 kDa in wt and Arg921Gln, a single ∼120 kDa band in Tyr411His, and a single ∼110 kDa in the nonsense mutant. With respect to subcellular localization, Arg921Gln as well as wt-NPR2 reached the cell surface, whereas Tyr411His and Arg921X mutants did not. The Tyr411His and Arg921X NPR2 proteins were co-localized with an endoplasmic reticulum (ER) marker and failed to traffic from the ER to the Golgi apparatus. These results are consistent with deglycosylation experiments. Tyr411His and Arg921X NPR2 are complete loss-of-function mutations, whereas Arg921Gln behaves as a receptor for CNP with limited function.

Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth.

UNLABELLED: Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutations in the gene ALPL encoding the tissue nonspecific alkaline phosphatase (TNSALP). There is a broad range of severity in the phenotype of HPP, and the most severe form exhibits perinatal lethality without mineralization of the skeleton. Here, we describe a female infant with perinatal lethal HPP diagnosed in utero. She was treated with a recombinant ALP (asfotase alfa) as an enzyme replacement therapy (ERT), which started from 1 day after birth. She required invasive ventilation immediately upon birth and demonstrated severe hypomineralization of whole body bone. Severe respiratory insufficiency was controlled by intensive respiratory care with high-frequency oscillation ventilation and nitric oxide inhalation and deep sedation just after birth. Bone mineralization improved with treatment; improvements were visible by 3 weeks of age and continued with treatment. Serum calcium levels decreased following treatment, resulting in hypocalcemia and convulsion, and calcium supplementation was required until 3 months of treatment. She was weaned from mechanical ventilation and has now survived more than 1 year. CONCLUSION: This case demonstrates the success of ERT in treating the severest HPP and highlights the importance of early diagnosis and intervention for these patients.

Two Japanese familial cases of Caffey disease with and without the common COL1A1 mutation and normal bone density, and review of the literature.

UNLABELLED: Caffey disease, also known as infantile cortical hyperostosis, is a rare bone disease characterized by acute inflammation with swelling of soft tissues and hyperostosis of the outer cortical surface in early infancy. The common heterozygous mutation of the COL1A1 gene, p.Arg1014Cys, has been reported in patients with Caffey disease. However, its pathogenesis remains to be elucidated, and the reason for the incomplete penetrance and transient course of the disease is still unclear. In the present study, we performed mutation analysis of the COL1A1 and COL1A2 genes and measured bone mineral density in two Japanese familial cases of Caffey disease. The index case and two clinically healthy members of one family carry the common heterozygous mutation; in contrast, no mutation in COL1A1 or COL1A2 was identified in the affected members of the second family. In addition, we found normal bone mineral density in adult patients of both families who have had an episode of cortical hyperostosis regardless of the presence or absence of the common p.Arg1014Cys mutation. CONCLUSION: The results reveal that Caffey disease is genetically heterogeneous and that affected and unaffected adult patients with or without the common COL1A1 mutation have normal bone mineral density.

Association of trabecular bone score and bone mineral apparent density with the severity of bone fragility in children and adolescents with osteogenesis imperfecta: A cross-sectional study.

Osteogenesis imperfecta (OI) is a hereditary skeletal disease characterized by bone fragility. Areal bone mineral density (BMD), evaluated by dual-energy X-ray absorptiometry (DXA), is used to assess bone brittleness. The height-adjusted BMD Z-score (BMDHAZ) is calculated in children and adolescents with OI to reduce the confounding factor of short stature. However, even with the BMDHAZ, severity evaluation in children and adolescents with OI is challenging because certain abnormalities in bone quality cannot be accurately assessed by BMD analysis. The trabecular bone scores (TBS) and bone mineral apparent density (BMAD), which represent the structural integrity of bone and bone-size-associated BMD, respectively, are associated with fracture risk. Recently, age- and sex-specific reference ranges have been reported, enabling the calculation of Z-scores for children. To evaluate which density measurements show the highest correlation with fracture risk, we analyzed the associations between the Z-scores of TBS, BMAD, and BMDHAZ, fracture rate, and genetic variants. We retrospectively reviewed 42 participants with OI aged 5 to 20 years who underwent DXA. COL1A1/2 pathogenic variants were detected in 41 of the 42 participants. In participants with nonsense and frameshift variants (n = 17) resulting in haploinsufficiency and mild phenotype, the TBS Z-score was negatively correlated with fracture rate (FR) (r = -0.50, p = 0.042). In participants with glycine substitution (n = 9) causing the severe phenotype, the BMAD Z-scores were negatively correlated with FR (r = -0.74, p = 0.022). No correlation between the BMDHAZ and FR was observed in both groups. These findings suggest that the TBS and BMAD are useful in assessing children and adolescents with OI with specific genetic variants.

A family with brachydactyly mental retardation syndrome with a missense variant in HDAC4.

Brachydactyly mental retardation syndrome (BDMR) or chromosome 2q37 deletion syndrome is a genetic disorder caused by 2q37 deletion or haploinsufficiency of histone deacetylase 4 (HDAC4). The HDAC4 gene is responsible for major BDMR phenotypes. The symptoms of BDMR include mild-to-moderate intellectual disability, seizures, autism spectrum disorder, short stature, obesity, and facial dysmorphism. Here, we report a family (n = 5) with BDMR who had a missense variant of HDAC4. Four affected individuals [5-yr-old girl (index case); 15- and 3-yr-old siblings; and father] had mild intellectual disability, three of the four affected individuals had short stature and mild cardiac anomalies, and two of the four affected individuals had hypothyroidism. Whole-exome sequencing and analyses of the index case and her family revealed an allelic variant in the HDAC4 gene (NM_001378414.1:c.2204G>A:p. Arg735Gln). A healthy family member (mother) did not have the missense variant. To our knowledge, this is the first report of a missense variation in HDAC4 that is associated with BDMR.

Pediatric aspects of skeletal dysplasia.

Skeletal dysplasia is a disorder of skeletal development characterized by abnormality in shape, length, a number and mineral density of the bone. Skeletal dysplasia is often associated with manifestation of other organs such as lung, brain and sensory systems. Skeletal dysplasias or dysostosis are classified with more than 400 different names. Enchondral bone formation is a coordinated event of chondrocyte proliferation, differentiation and exchange of terminally maturated chondrocyte with bone. Impaired enchondral bone formation will lead to skeletal dysplasia, especially associated with short long bones. Appropriate bone volume and mineral density are achieved by balance of bone formation and bone resorption and mineralization. The gene encoding fibroblast growth factor receptor 3 is responsible for achondroplasia, representative skeletal dysplasia with short stature. The treatment with growth hormone is approved for achondroplasia in Japan. Osteogenesis imperfecta is characterized by low bone mineral density and fragile bone. Data on the beneficial effect of bisphosphonate for osteogenesis imperfecta are accumulating. Osteopetrosis has high bone mineral density, but sometimes show bone fragility. In Japan as well as other countries, pediatrician treat larger numbers of patients with skeletal dysplasia with short stature and fragile bones compared to 20 years ago.

Inconvenience and adaptation in Japanese adult achondroplasia and hypochondroplasia: A cross-sectional study.

The health-related quality of life is reduced in patients with achondroplasia (ACH) and hypochondroplasia (HCH); however, the detailed inconveniences in the daily living and individual adaptations have not been elucidated. This study aimed to evaluate the inconvenience and adaptation in patients with ACH/HCH. A cross-sectional study was conducted in patients with ACH/HCH aged 20 yr or older. Questionnaires were sent to 567 patients (described 86) with a medical history at the co-authors' institutions or who were registered at the patients' association with ACH in Japan. The questionnaire included a free description format for the inconveniences and adaptations in daily living; a content analysis was performed. The recorded inconveniences included 148 physical, 84 mental, and 52 social problems. Patients who underwent spine surgery had significantly more recorded physical problems than those who did not (p < 0.05). Pain and numbness were significantly higher in patients aged ≥ 50 yr (p < 0.05). The 160 and 1 adaptations were for physical and social problems, respectively. No patient adaptation was found for mental health problems. Individual adaptations by ACH/HCH patients can improve only some aspects of physical and social problems. Multilateral social support is needed to resolve patients' issues.