Genetic spectrum of prenatally diagnosed skeletal dysplasias in a Finnish patient cohort.

OBJECTIVE: This retrospective cohort study aims to describe the genetic spectrum of fetal skeletal dysplasias detected in a Finnish patient cohort and the diagnostic yield of various analysis methods used. METHOD: A total of 121 pregnancies with prenatally suspected or diagnosed skeletal dysplasia were analyzed between 2013 and 2020. Clinical details and findings from genetic testing were collected. RESULTS: Abnormal ultrasound triggered further testing in most cases. However, there were several cases with increased nuchal translucency and/or abnormal risk ratio in the first trimester combined screening as the initial finding. Further genetic testing was performed in 84/121 (69.4%) cases. A genetic diagnosis was confirmed in 36/84 (42.9%) cases. Half of the identified cases could be attributed to a founder mutation specific to the Finnish Disease Heritage, whereas the other half consisted of a variety of other genetic defects. CONCLUSION: In our patient cohort, the overall genetic spectrum of prenatally diagnosed skeletal dysplasias was wide. However, the impact of Finnish founder mutations was considerable, suggesting that the genetic spectrum of skeletal dysplasias may differ significantly between populations. This should be taken into consideration during the diagnostic process especially as initial ultrasound findings may be unspecific and the interpretation of ultrasound features is usually difficult.

Oligogenic Inheritance of Monoallelic TRIP11, FKBP10, NEK1, TBX5, and NBAS Variants Leading to a Phenotype Similar to Odontochondrodysplasia.

Skeletal dysplasias are often well characterized, and only a minority of the cases remain unsolved after a thorough analysis of pathogenic variants in over 400 genes that are presently known to cause monogenic skeletal diseases. Here, we describe an 11-year-old Finnish girl, born to unrelated healthy parents, who had severe short stature and a phenotype similar to odontochondrodysplasia (ODCD), a monogenic skeletal dysplasia caused by biallelic TRIP11 variants. The family had previously lost a fetus due to severe skeletal dysplasia. Exome sequencing and bioinformatic analysis revealed an oligogenic inheritance of a heterozygous nonsense mutation in TRIP11 and four likely pathogenic missense variants in FKBP10, TBX5, NEK1, and NBAS in the index patient. Interestingly, all these genes except TBX5 are known to cause skeletal dysplasia in an autosomal recessive manner. In contrast, the fetus was found homozygous for the TRIP11 mutation, and achondrogenesis type IA diagnosis was, thus, molecularly confirmed, indicating two different skeletal dysplasia forms in the family. To the best of our knowledge, this is the first report of an oligogenic inheritance model of a skeletal dysplasia in a Finnish family. Our findings may have implications for genetic counseling and for understanding the yet unsolved cases of rare skeletal dysplasias.

Positive airway pressure therapy for obstructive sleep apnea in patients with Osteogenesis imperfecta: a prospective pilot study.

BACKGROUND: Obstructive sleep apnea (OSA) is prevalent in individuals with Osteogenesis imperfecta (OI). To date, no study has investigated treatment of OSA in adult individuals with OI using positive airway pressure (PAP). This observational pilot study examined the adherence of adults with OI to treatment of OSA with PAP therapy, and the evolution of self-experienced sleepiness and depression symptoms before and after treatment. METHODS: We included 20 patients, with a mean age of 51 years, who represented varying severity of OI and displayed an apnea and hypopnea index ≥ 5 /sleeping hour as recorded by an overnight polysomnography. PAP therapy was proposed to all patients. Epworth Sleepiness Scale (ESS) questionnaire to evaluate daytime sleepiness, and a validated self-rating depression questionnaire to identify possible depression, were completed prior to PAP therapy and repeated after a minimum of one year. The datasets supporting the conclusions of this article are included within the article. RESULTS: From the 20 patients, 15 initiated PAP therapy, and two patients later interrupted it. The mean PAP follow-up period was 1230 days. At baseline, an abnormally high ESS score was reported by 29% of the respondents, and an abnormally high number of symptoms suggesting depression by 29%. Follow-up questionnaires were completed by 60% of the patients, of whom 83% were adherent to PAP treatment. ESS score and depression symptoms did not decrease significantly with PAP therapy. CONCLUSIONS: Patients with OI accepted well PAP therapy and remained compliant. Sleepiness and depression persisted unaltered despite good PAP adherence. These unexpectedly poor improvements in symptoms by PAP therapy may be due to subjective depression symptoms and the complexity of factors underlying persisting sleepiness in OI. Further research is needed to confirm this novel finding.

Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia.

Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation-positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient-derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation-positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR-Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD-RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia.

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.

Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with "corner fractures".

Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with "corner fractures" (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of "corner fractures". An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extracellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys231Trp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and "corner fracture" appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.

Novel variants in natriuretic peptide receptor 2 in unrelated patients with acromesomelic dysplasia type Maroteaux.

Acromesomelic dysplasia are a heterogeneous group of disorders with variable spectrum and severity of skeletal anomalies in the affected individuals. Acromesomelic dysplasia type Maroteaux (AMDM) is characterized by extreme shortening of the forelimbs and disproportionate short stature. Several homozygous inactivating mutations in NPR2 have been identified in different AMDM patients. We report five novel variants in affected individuals in four different families. These include two nonsense and three missense variants. This study broadens the genotypic spectrum of NPR2 mutations in individuals with AMDM and also describes the intra- and inter-familial phenotypic variability due to NPR2 variants.

Is sleep apnea underdiagnosed in adult patients with osteogenesis imperfecta? -a single-center cross-sectional study.

BACKGROUND: Patients with Osteogenesis imperfecta (OI) suffer from increased bone fracture tendency generally caused by a mutation in genes coding for type I collagen. OI is also characterized by numerous co-morbidities, and recent data from questionnaire studies suggest that these may include increased risk for sleep apnea, a finding that lacks clinical evidence from cohort studies. In this cross-sectional study, 25 adults with OI underwent clinical otorhinolaryngology examination as well as overnight polysomnography to address the question. The participants were aged between 19 and 77 years, and ten of them had mild clinical OI phenotype, seven had a moderately severe phenotype, and eight had a severe phenotype. RESULTS: We found obstructive sleep apnea (apnea hypopnea index ≥5/h) in as many as 52% of the OI patients in the cohort. Unexpectedly, however, no correlation was present between sleep apnea and daytime sleepiness, experienced bodily pain, severity of OI, Mallampati score, or neck circumference. CONCLUSIONS: Seeing that the usual predictors showed no association with occurrence of sleep apnea, we conclude that obstructive sleep apnea may easily be left as an undetected disorder in individuals with OI. Recurrent nocturnal hypoxia due to episodes of apneas can even affect bone metabolism, thereby further aggravating bone fragility in patients with OI.

A Wide Spectrum of Autoimmune Manifestations and Other Symptoms Suggesting Immune Dysregulation in Patients With Cartilage-Hair Hypoplasia.

Background: Mutations in RMRP, encoding a non-coding RNA molecule, underlie cartilage-hair hypoplasia (CHH), a syndromic immunodeficiency with multiple pathogenetic mechanisms and variable phenotype. Allergy and asthma have been reported in the CHH population and some patients suffer from autoimmune (AI) diseases. Objective: We explored AI and allergic manifestations in a large cohort of Finnish patients with CHH and correlated clinical features with laboratory parameters and autoantibodies. Methods: We collected clinical and laboratory data from patient interviews and hospital records. Serum samples were tested for a range of autoantibodies including celiac, anti-cytokine, and anti-21-hydroxylase antibodies. Nasal cytology samples were analyzed with microscopy. Results: The study cohort included 104 patients with genetically confirmed CHH; their median age was 39.2 years (range 0.6-73.6). Clinical autoimmunity was common (11/104, 10.6%) and included conditions previously undescribed in subjects with CHH (narcolepsy, psoriasis, idiopathic thrombocytopenic purpura, and multifocal motor axonal neuropathy). Patients with autoimmunity more often had recurrent pneumonia, sepsis, high immunoglobulin (Ig) E and/or undetectable IgA levels. The mortality rates were higher in subjects with AI diseases ( χ(2)2 = 14.056, p = 0.0002). Several patients demonstrated serum autoantibody positivity without compatible symptoms. We confirmed the high prevalence of asthma (23%) and allergic rhinoconjunctivitis (39%). Gastrointestinal complaints, mostly persistent diarrhea, were also frequently reported (32/104, 31%). Despite the history of allergic rhinitis, no eosinophils were observed in nasal cytology in five tested patients. Conclusions: AI diseases are common in Finnish patients with CHH and are associated with higher mortality, recurrent pneumonia, sepsis, high IgE and/or undetectable IgA levels. Serum positivity for some autoantibodies was not associated with clinical autoimmunity. The high prevalence of persistent diarrhea, asthma, and symptoms of inflammation of nasal mucosa may indicate common pathways of immune dysregulation.

Polyostotic Fibrous Dysplasia With and Without McCune-Albright Syndrome-Clinical Features in a Nordic Pediatric Cohort.

OBJECTIVE: Fibrous dysplasia (FD) presents as skeletal lesions in which normal bone is replaced by abnormal fibrous tissue due to mosaic GNAS mutation. McCune-Albright syndrome (MAS) refers to FD combined with skin (café-au-lait) and endocrine manifestations. This study describes the clinical childhood manifestations of polyostotic FD and MAS in a Nordic cohort. PATIENTS AND DESIGN: We retrospectively reviewed a cohort of pediatric patients (n = 16) with polyostotic FD with or without MAS diagnosed and followed in two Nordic Pediatric tertiary clinics between 1996 and 2017. RESULTS: Half of the 16 patients with polyostotic FD presented with MAS. All patients with MAS (n = 8) had café-au-lait spots, and either gonadotropin-independent precocious puberty (PP) (girls; n = 5) or abnormal testicle structure (boys, n = 3). None manifested hyperthyroidism or growth hormone excess. Mild hypophosphatemia was common (11/16), but none had signs of hypophosphatemic rickets. Craniofacial bone involvement was found in 12 patients (75%); in 5 of these, skeletal lesions were limited to craniofacial area. One child with craniofacial disease had lost vision due to optic nerve damage. Eleven (69%) patients had sustained a fracture at FD lesion, over half of them requiring surgical fixation of the fracture, most commonly in the proximal femur. The first symptoms leading to FD/MAS diagnosis included skull/facial asymmetry (n = 4), PP (n = 3), abnormal gait (n = 3), pathologic fracture (n = 3), wide-spread café-au-lait spots (n = 1), headache (n = 1), and vision loss (n = 1). CONCLUSION: Polyostotic FD and MAS remain diagnostic and therapeutic challenges because of the broad clinical spectrum. Recurrent fractures, pain, and even vision loss may impair the quality of life in children with FD.

Fatigue and disturbances of sleep in patients with osteogenesis imperfecta - a cross-sectional questionnaire study.

BACKGROUND: Persisting fatigue has been reported to be a common complaint by individuals with connective tissue disorders, including Osteogenesis imperfecta (OI). This controlled study evaluated in an adult OI population the subjective experience of fatigue, affecting daily life. Sleep disturbances and chronic pain were examined as hypothesized underlying factors. METHODS: This cross-sectional study analyzed the answers of 56 OI patients and 56 matched healthy controls to a questionnaire, designed to evaluate levels of experienced fatigue and bodily pain, as well as the presence or absence of symptoms related to sleep disturbances or sleep apnea. The relationships between fatigue, pain, and sleep disturbances were evaluated with correlation analysis and regression analysis. RESULTS: Fatigue was reported by 96%, and daily pain by 87% of the individuals with OI. Notably, the level of fatigue was similarly experienced by patient respondents and controls. In total, 95% of the patients and 77% of the controls reported one to several sleep disturbance symptoms. These symptoms as well as previously diagnosed sleep apnea were statistically significantly more prevalent in the patient group than in the controls (p < 0.05). Likewise, the experienced bodily pain was statistically highly significantly more severe among the respondents with OI (p < 0.001), and correlated with the reported fatigue. CONCLUSIONS: In comparison with age-matched controls, adults with OI do not differ in experienced fatigue, unlike hypothesized. Therefore, sleep disturbances, which based on the frequency of reported related symptoms and previous sleep apnea diagnoses appear to be common in OI patients, may remain undiagnosed.

Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Gα11 Mutation.

G-protein subunit α-11 (Gα11 ) couples the calcium-sensing receptor (CaSR) to phospholipase C (PLC)-mediated intracellular calcium (Ca2+i ) and mitogen-activated protein kinase (MAPK) signaling, which in the parathyroid glands and kidneys regulates parathyroid hormone release and urinary calcium excretion, respectively. Heterozygous germline loss-of-function Gα11 mutations cause familial hypocalciuric hypercalcemia type 2 (FHH2), for which effective therapies are currently not available. Here, we report a novel heterozygous Gα11 germline mutation, Phe220Ser, which was associated with hypercalcemia in a family with FHH2. Homology modeling showed the wild-type (WT) Phe220 nonpolar residue to form part of a cluster of hydrophobic residues within a highly conserved cleft region of Gα11 , which binds to and activates PLC; and predicted that substitution of Phe220 with the mutant Ser220 polar hydrophilic residue would disrupt PLC-mediated signaling. In vitro studies involving transient transfection of WT and mutant Gα11 proteins into HEK293 cells, which express the CaSR, showed the mutant Ser220 Gα11 protein to impair CaSR-mediated Ca2+i and extracellular signal-regulated kinase 1/2 (ERK) MAPK signaling, consistent with diminished activation of PLC. Furthermore, engineered mutagenesis studies demonstrated that loss of hydrophobicity within the Gα11 cleft region also impaired signaling by PLC. The loss-of-function associated with the Ser220 Gα11 mutant was rectified by treatment of cells with cinacalcet, which is a CaSR-positive allosteric modulator. Furthermore, in vivo administration of cinacalcet to the proband harboring the Phe220Ser Gα11 mutation, normalized serum ionized calcium concentrations. Thus, our studies, which report a novel Gα11 germline mutation (Phe220Ser) in a family with FHH2, reveal the importance of the Gα11 hydrophobic cleft region for CaSR-mediated activation of PLC, and show that allosteric CaSR modulation can rectify the loss-of-function Phe220Ser mutation and ameliorate the hypercalcemia associated with FHH2. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Bisphosphonate Treatment and the Characteristics of Femoral Fractures in Children With Osteogenesis Imperfecta.

Context: The short-term benefits of bisphosphonates (BPs) are evident in the treatment of children with osteogenesis imperfecta (OI), but some concerns related to long-term effects remain. Objective: To elucidate the effect of BPs on characteristics of femoral fractures in children with OI. Design and Setting: Retrospective cohort study at a university hospital. Patients and Main Outcome Measure: The study included 93 patients with OI. We recorded fracture histories and analyzed all femoral fractures for location and fracture type using radiographs obtained at fracture diagnosis. Effects of BPs were evaluated by comparing fracture characteristics in three groups: patients (1) naive to BPs, (2) receiving ongoing BP treatment, and (3) whose treatment was discontinued. Results: In total, 127 femoral fractures occurred in 24 patients. Of the fractures, 63 (50%) occurred in patients naive to BPs, 44 (35%) during BP treatment, and 20 (16%) after treatment discontinuation. Mid or distal shaft fractures were most common (41%), followed by subtrochanteric (33%) and distal (20%) fractures. Almost all fractures were transverse (65%) or oblique (28%). The pattern of femoral fractures was similar in all three BP treatment groups (P = 0.78 for location; P = 0.35 for fracture type) and was not related to cumulative BP dose. Instead, OI type correlated with fracture characteristics, and distal location and transverse configuration were more common in the more severe types III and IV compared with type I OI. Conclusion: Characteristics of femoral fractures in children with OI are affected by OI type but not by BP exposure.

Abnormally High and Heterogeneous Bone Matrix Mineralization After Childhood Solid Organ Transplantation: A Complex Pathology of Low Bone Turnover and Local Defects in Mineralization.

Chronic renal, liver, and heart failure in children associates with multiple skeletal complications. Increased fracture incidence often persists after transplantation and could be related to alterations in bone material properties. In the present cohort study we evaluated bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging (qBEI) in 23 pediatric solid organ allograft recipients with suspected osteoporosis. We measured BMDD in the entire cross-sectional area of transiliac bone biopsies obtained from kidney (n = 9), liver (n = 9), and heart (n = 5) transplant recipients (aged 7.6 to 19.7 years; 6.0 ± 5.6 years posttransplantation, patients with a history of clinical fractures: n = 14). The BMDD findings were compared with age-appropriate references and with a previously presented cohort of children with chronic kidney disease on dialysis (CKD5D, n = 18). Furthermore, we related the BMDD parameters with patients' clinical and bone histomorphometric outcomes. Compared to healthy children, qBEI results for cancellous and cortical bone in transplant recipients revealed an increase in the most frequently occurring calcium concentration (+2.9%, p = 0.001; +3.5%, p = 0.014), in the portion of fully mineralized bone (fivefold; 10-fold, both p < 0.0001) and in heterogeneity of mineralization (+26,5% and +27.8%, both p < 0.0001), respectively. Moreover, the BMDD parameters were nonsignificantly distinct from CKD5D cohort except that the heterogeneity in mineralization was higher posttransplantation. There was a strong inverse correlation between the average calcium content of the bone matrix and patients' biochemical ALP levels, histomorphometric indices of bone formation and resorption. The abnormally high bone matrix mineralization in transplant recipients, consistent with serum and histomorphometric outcomes, suggests a history of low bone turnover with accumulation of fully mineralized bone packets. Additionally, the increased heterogeneity of mineralization suggests local alterations in mineralization kinetics, which may be linked to dysfunctional osteocytes that were recently shown to accumulate within the bone matrix during organ failure and concomitant glucocorticoid and immunosuppressive medication. © 2017 American Society for Bone and Mineral Research.

Timing of dental development in osteogenesis imperfecta patients with and without bisphosphonate treatment.

Bisphosphonates have established their role as medical therapy for pediatric osteogenesis imperfecta (OI) patients. Since bisphosphonates have also been shown to delay tooth development in animal models, we aimed to assess whether the medication has a similar effect on children with OI. In this cross-sectional study, bisphosphonate-treated OI patients of whom dental panoramic tomograph was taken between 3 and 16years of age formed the study group. The patients, 22 in total, had been treated with pamidronate, zoledronic acid or risedronate for at least one year before the radiography. Developmental stage of the permanent teeth, resorption of the deciduous teeth, and number of the erupted permanent teeth were radiographically assessed in the left mandibular quadrant. Dental panoramic tomographs of 50 OI patients, naïve to bisphosphonates, and of 50 healthy individuals of the same age were used as controls. The dental development was statistically significantly accelerated in the OI group naïve to bisphosphonates showing median advancement of dental age by 0.63years from chronological age and median increase in the number of erupted teeth by 0.31 as compared to Finnish norms. Bisphosphonate-treated OI patients displayed, however, age-appropriate dental development. The OI patients not treated with bisphosphonates also showed statistically significantly faster resorption of the deciduous teeth than the treated ones, and displayed an altered interrelationship between the resorption stage of an individual primary tooth and the developmental stage of the succedaneous permanent tooth, unlike the OI patients treated with bisphosphonate. No correlation between either cumulative bisphosphonate dose or between treatment length and any measured component of the dental development was found. To conclude, OI itself was found to lead to advanced dental development. Bisphosphonate treatment had a delaying effect in all the three aspects studied, resulting in a rate of dental development indistinguishable from normal.

Skeletal Characteristics of WNT1 Osteoporosis in Children and Young Adults.

WNT proteins comprise a 19-member glycoprotein family that act in several developmental and regenerative processes. In bone, WNT proteins regulate osteoblast differentiation and maintain bone health by activating the canonical WNT/ß-catenin pathway. We reported a heterozygous missense mutation c.652T>G (p.C218G) in WNT1 exon 4 as the cause for severe early-onset, autosomal dominant osteoporosis. The initial study concerned a large Finnish family with 10 affected adults. Here we report clinical findings of the WNT1 osteoporosis in 8 children and young adults (median age 14 years; range 10 to 30 years) in two families, all with the p.C218G mutation in WNT1. Clinical assessments showed no apparent dysmorphia or features similar to typical osteogenesis imperfecta (OI). Biochemistry revealed no changes in parameters of calcium metabolism and bone turnover markers. Fracture frequencies varied, but all subjects had sustained at least one fracture and 4 had a pathological fracture history. Plain radiographs showed osteopenic appearance, loss in vertebral height, and thin diaphyses of the long bones. Bone densitometry showed the BMD to be below normal median in all subjects and the bone mass deficit seemed to be more severe in older participants. Bone histomorphometry revealed a low turnover osteoporosis in 2 subjects at ages 14 and 16 years. These findings are congruent with earlier findings in adult patients and indicate that WNT1 osteoporosis causes significant skeletal changes already in early childhood and impairs bone mass gain during pubertal years. Genetic testing of children or close relatives of affected individuals is recommended for appropriate preventive measures. © 2016 American Society for Bone and Mineral Research.