Bio

Bio

CLINICAL FOCUS:
- Pediatric Endocrinology
- Pediatric Diabetes
- Pediatric Bone Health

Clinical Focus

  • Pediatric Endocrinology
  • Pediatric Bone health

Academic Appointments

Administrative Appointments

  • Clinical Associate Professor, Department of Pediatrics, Division of Pediatric Endocrinology (2020 - Present)
  • Co-Director, Bone Health Clinic at Stanford Children's Health (2017 - Present)
  • Clinical Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Stanford School of Medicine, Lucile Packard Children's Hospital (2016 - 2020)
  • Clinical Instructor, Department of Pediatrics, Division of Pediatric Endocrinology, Lucile Packard Children's Hospital, Stanford University (2015 - 2016)
  • Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology, University of Virginia (2013 - 2015)
  • Post Doctoral Associate, Department of Human and Molecular Genetics, Baylor College of Medicine (2012 - 2013)

Honors & Awards

  • New Investigator Award, European Calcified Tissue Society (2013)
  • NRSA (F32), NIH (2012)
  • Research Fellowship Award, Lawson Wilkins Pediatric Endocrine Society (2012)
  • Travel Grant, Pediatric Endocrine Society (2012)
  • Presidential Poster Presentation Award, American Society of Bone and Mineral Research (2011)
  • Travel Grant, Endocrine Society (2011)
  • Grace Lukose Memorial Medal for First position in Surgery, Lady Hardinge Medical College (2003)
  • Acknowledgement for Proficiency in Physiology, Lady Hardinge Medical College (2000)

Boards, Advisory Committees, Professional Organizations

  • Member, Pediatric Endocrine Society Practice Management Committee (2018 - Present)
  • Member, Pediatric Endocrine Society Bone and Mineral Special Interest Group (2017 - Present)
  • Board Certification, American Board of Pediatrics, Pediatric Endocrinology (2013 - Present)
  • Certified Clinical Densitometrist, ISCD (2012 - 2017)
  • Member, American Society of Bone and Mineral Research (2010 - Present)
  • Board Certification, American Board of Pediatrics (2009 - Present)
  • Member, Pediatric Endocrine Society (2009 - Present)

Professional Education

  • Fellowship: Baylor College of Medicine (2012) TX
  • Residency: SUNY Downstate Medical Center Pediatric Residency (2009) NY
  • Internship: SUNY Downstate Medical Center Pediatric Residency (2007) NY
  • Board Certification: American Board of Pediatrics, Pediatric Endocrinology (2013)
  • Board Certification: American Board of Pediatrics, Pediatrics (2009)
  • Fellowship, Baylor College of Medicine/Texas Children's Hospital, Pediatric Endocrinology (2012)
  • Residency, SUNY Downstate School of Medicine, Pediatrics (2009)
  • M.B.B.S., Lady Hardinge Medical College, Medical Education (2005)

Contact

  • Pediatric Endocrinology and Diabetes 300 Pasteur Dr Rm G313 MC 5208 Stanford, CA 94305
    • Tel: (650) 721-1811
    Fax: (650) 725-8375
  • Stanford Childrens Health Specialty Clinic Endocrinology and Diabetes 14601 S Bascom Ave Ste 200 Los Gatos, CA 95032
    • Tel: (408) 356-0524
    Fax: (650) 725-8375
  • Stanford Children's Health Specialty Services Sunnyvale 1195 W Fremont Ave Sunnyvale, CA 94087
    • Tel: (408) 426-5590
    Fax: (408) 426-5590

Teaching

Graduate and Fellowship Programs

  • Pediatric Endocrinology (Fellowship Program)

Publications

All Publications

  • Nitric oxide modulates bone anabolism through regulation of osteoblast glycolysis and differentiation. The Journal of clinical investigation Jin, Z., Kho, J., Dawson, B., Jiang, M., Chen-Evenson, Y., Ali, S., Burrage, L. C., Grover, M., Palmer, D. J., Turner, D. L., Ng, P., Nagamani, S. C., Lee, B. 2020

    Abstract

    Previous studies have shown that nitric oxide (NO) supplements may prevent bone loss and fractures in preclinical models of estrogen deficiency. However, the mechanisms by which NO modulates bone anabolism remain largely unclear. Argininosuccinate lyase (ASL) is the only mammalian enzyme capable of synthesizing arginine, the sole precursor for nitric oxide synthase (NOS)-dependent NO synthesis. Moreover, ASL is also required for channeling extracellular arginine to NOS for NO production. ASL deficiency (ASLD) is thus a model to study cell-autonomous, NOS-dependent NO deficiency. Here, we report that loss of ASL led to decreased NO production and impairment of osteoblast differentiation. Mechanistically, the bone phenotype was at least in part driven by the loss of NO-mediated activation of the glycolysis pathway in osteoblasts that led to decreased osteoblast differentiation and function. Heterozygous deletion of Caveolin-1, a negative regulator of NO synthesis, restored NO production, osteoblast differentiation, glycolysis, and bone mass in a hypomorphic mouse model of ASLD. The translational significance of these preclinical studies was further reiterated by studies conducted in induced pluripotent stem cells (iPSCs) from an individual with ASLD. Taken together, our findings suggest that ASLD is a unique genetic model for studying NO-dependent osteoblast function and that the NO-glycolysis pathway may be a new target to modulate bone anabolism.

    View details for DOI 10.1172/JCI138935

    View details for PubMedID 33373331

  • Anabolic effects of nitric oxide on osteoblast metabolism revealed by deficiency of argininosuccinate lyase Jin, Z., Kho, J., Dawson, B., Jiang, M., Chen Yuqing, Ali, S., Burrage, L., Grover, M., Palmer, D., Turner, D., Ng, P., Nagamani, S., Lee, B. WILEY. 2020: 19

    View details for Web of Science ID 000593119300052

  • Atraumatic vertebral fractures in two children with Autism Spectrum Disorder Grover, M., Bachrach, L. KARGER. 2020: 29

    View details for Web of Science ID 000544736900038

  • Advances in Diagnosis and Treatment of Pseudovitamin D Deficiency Rickets JOURNAL OF PEDIATRICS Grover, M., Maahs, D. M. 2020; 221: 200

    View details for Web of Science ID 000536007300037

  • Hypercalcemia in Children Using the Ketogenic Diet: A Multicenter Study. The Journal of clinical endocrinology and metabolism Hawkes, C. P., Roy, S. M., Dekelbab, B. n., Frazier, B. n., Grover, M. n., Haidet, J. n., Listman, J. n., Madsen, S. n., Roan, M. n., Rodd, C. n., Sopher, A. n., Tebben, P. n., Levine, M. A. 2020

    Abstract

    The ketogenic diet is associated with progressive skeletal demineralization, hypercalciuria and nephrolithiasis. Acute hypercalcemia has been described as a newly recognized complication of this treatment.To describe the clinical characteristics of acute hypercalcemia in children on the ketogenic diet through analysis of the presentation, response to treatment, and natural history in a large cohort of patients.A multicenter case series was performed including children who developed acute hypercalcemia while treated with the ketogenic diet. Information on clinical presentation, treatment and course of this complication was collated centrally.There were 14 patients (median (range) age 6.3 (0.9 to 18) years) who developed hypercalcemia 2.1 (range 0.2 to 12) years after starting the ketogenic diet. All had low levels of parathyroid hormone and levels of 1,25-dihydroxyvitamin D were low in all except one. Seven (50%) had impaired renal function at presentation. All except the two oldest had low alkaline phosphatase levels for age. Once normocalcemia was achieved, hypercalcemia recurred in only two of these patients over observation of up to 9.8 years. One patient discontinued the ketogenic diet prior to achieving normocalcemia while four more stopped the diet during follow-up after resolution of hypercalcemia.Ketotic hypercalcemia can occur years after starting the ketogenic diet, especially in the setting of renal impairment. The mechanism is unknown, but appears to be due to reduced osteoblast activity and impaired bone formation. We recommend close attention to optimizing bone health in these children, and screening for the development of ketotic hypercalcemia.

    View details for DOI 10.1210/clinem/dgaa759

    View details for PubMedID 33124662

  • 50 Years Ago in TheJournalofPediatrics: Advances in Diagnosis and Treatment of Pseudovitamin D Deficiency Rickets. The Journal of pediatrics Grover, M. n., Maahs, D. M. 2020; 221: 200

    View details for DOI 10.1016/j.jpeds.2019.12.030

    View details for PubMedID 32446481

  • High Incidence of electrolyte abnormalities despite low first dose of Zoledronic acid Grover, M., Bachrach, L. WILEY. 2019: 130

    View details for Web of Science ID 000508614700380

  • Argininosuccinate lyase deficiency as a model to study nitric oxide function in Bone Jin, Z., Kho, J., Dawson, B., Grover, M., Jiang, M., Chen, Y., Lee, B. WILEY. 2018: 44

    View details for Web of Science ID 000450475400135

  • Team Approach: Bone Health in Children and Adolescents. JBJS reviews Kraus, E., Bachrach, L. K., Grover, M. 2018

    View details for PubMedID 30325758

  • Treatment of Adolescent Osteoporosis A practical approach to adolescent bone health Grover, M., Bachrach, L. 2018
  • The Impact of Frequency and Tone of Parent-Youth Communication on Type 1 Diabetes Management. Diabetes therapy DeBoer, M. D., Valdez, R., Chernavvsky, D. R., Grover, M., Burt Solorzano, C., Herbert, K., Patek, S. 2017; 8 (3): 625-636

    Abstract

    The purpose of this study is to assess the impact of frequency and tone of parent-youth communication on glycemic control as measured by the Family Communication Inventory (FCI). Adolescence provides a unique set of diabetes management challenges, including suboptimal glycemic control. Continued parental involvement in diabetes management is associated with improved HbA1c outcomes; however, diabetes-related conflict within the family can have adverse effects. Although it is clear that communication plays an important role in diabetes outcomes, the specific impact of frequency and tone of such communication is largely understudied.A total of 110 youths with type 1 diabetes and their parents completed questionnaires assessing diabetes-related adherence, family conflict, and family communication (i.e., frequency and tone) during a routine clinic visit. Routine testing of HbA1c was performed.Youth- and parent-reported frequency of communication were unrelated to HbA1c. Instead, greater discrepancies between parents and children on reported frequency of communication (most commonly parents reporting frequent and youth reporting less frequent communication) corresponded with poorer glycemic control and increased family conflict. More positive tone of communication as rated by youth was associated with lower HbA1c.Diabetes-related communication is more complex than conveyed simply by how often children and their parents communicate. Tone of communication and discrepancies in a family's perception of the frequency of communication were better than frequency as predictors of glycemic control. The FCI appears to capture the frequency and tone of diabetes-related communication, though larger-scale studies are warranted to inform future use of this scale.

    View details for DOI 10.1007/s13300-017-0259-2

    View details for PubMedID 28405895

    View details for PubMedCentralID PMC5446384

  • Osteoporosis in Children with Chronic Illnesses: Diagnosis, Monitoring, and Treatment. Current osteoporosis reports Grover, M. n., Bachrach, L. K. 2017

    Abstract

    Osteoporosis is an under-recognized complication of chronic illness in childhood. This review will summarize recent literature addressing the risk factors, evaluation, and treatment for early bone fragility.Criteria for the diagnosis of pediatric osteoporosis include the presence of low trauma vertebral fractures alone or the combination of low bone mineral density and several long bone fractures. Monitoring for bone health may include screening for vertebral fractures that are common but often asymptomatic. Pharmacologic agents should be offered to those with fragility fractures especially when spontaneous recovery is unlikely. Controversies persist about the optimal bisphosphonate agent, dose, and duration. Newer osteoporosis drugs have not yet been adequately tested in pediatrics, though clinical trials are underway. The prevalence of osteoporosis is increased in children with chronic illness. To reduce the frequency of fragility fractures requires increased attention to risk factors, early intervention, and additional research to optimize therapy and potentially prevent their occurrence.

    View details for PubMedID 28620868

  • Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton MOLECULAR GENETICS AND METABOLISM Chen, S., Grover, M., Sibai, T., Black, J., Rianon, N., Rajagopal, A., Munivez, E., Bertin, T., Dawson, B., Chen, Y., Jiang, M., Lee, B., Yang, T., Bae, Y. 2015; 115 (1): 53-60

    Abstract

    Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development.

    View details for DOI 10.1016/j.ymgme.2015.02.006

    View details for PubMedID 25779879

  • Case report: long-term follow-up of a 45,X male with SHOX haploinsufficiency. Journal of pediatric endocrinology & metabolism : JPEM Grover, M. n., French, S. n., Yazdani, P. n. 2015; 28 (7-8): 937?41

    Abstract

    The 45,X disorder of sexual differentiation (DSD) is a rare disorder. We report long-term follow-up of a 5-year-old African-American male whose evaluation for short stature revealed a karyotype of 45,X der(X)t(X;Y)(p22.3;p11.2)(SRY+). Presence of the SRY (sex-determining region Y) gene resulted in his male development. His chromosome abnormality also resulted in a deletion of the SHOX (short stature homeobox-containing) gene, which partly contributed to his short stature and skeletal features. He underwent normal spontaneous pubertal development, but his final height remained compromised due to advanced bone age, non-optimal response to recombinant human growth hormone (rhGH) treatment during the period of compliance and ultimately non-compliance with rhGH therapy. To our knowledge, this is the first case report describing long-term follow-up of a 45,X male DSD which highlights the similarities and differences from Turner syndrome females.

    View details for DOI 10.1515/jpem-2014-0388

    View details for PubMedID 25781530

  • SERPINF1 as a Cause of Osteogenesis Imperfecta Type VI OSTEOGENESIS IMPERFECTA: A TRANSLATIONAL APPROACH TO BRITTLE BONE DISEASE Joeng, K., Grover, M., Rajagopal, A., Lee, B. H., Shapiro 2014: 167?72

    View details for DOI 10.1016/B978-0-12-397165-4.00017-4

    View details for Web of Science ID 000326245700019

  • Osteogenesis Imperfecta Without Features of Type V Caused by a Mutation in the IFITM5 Gene JOURNAL OF BONE AND MINERAL RESEARCH Grover, M., Campeau, P. M., Lietman, C. D., Lu, J. T., Gibbs, R. A., Schlesinger, A. E., Lee, B. H. 2013; 28 (11): 2333-2337

    Abstract

    Osteogenesis imperfecta (OI) is typically caused by mutations in type 1 collagen genes, but in recent years new recessive and dominant forms caused by mutations in a plethora of different genes have been characterized. OI type V is a dominant form caused by the recurrent (c.-14C?>?T) mutation in the 5'UTR of the IFITM5 gene. The mutation adds five residues to the N-terminus of the IFITM5, but the pathophysiology of the disease remains to be elucidated. Typical clinical features present in the majority of OI type V patients include interosseous membrane calcification between the radius and ulna and between the tibia and fibula, radial head dislocation, and significant hyperplastic callus formation at the site of fractures. We report a 5-year-old child with clinical features of OI type III or severe OI type IV (characteristic facies, gray sclerae, typical fractures) and absence of classical features of OI type V with a de novo recurrent IFITM5 mutation (c.-14C?>?T), now typical of OI type V. This highlights the variability of OI caused by IFITM5 mutations and suggests screening for mutations in this gene in most cases of OI where type 1 collagen mutations are absent.

    View details for DOI 10.1002/jbmr.1983

    View details for Web of Science ID 000326024000011

    View details for PubMedID 23674381

  • Next-generation sequencing for disorders of low and high bone mineral density OSTEOPOROSIS INTERNATIONAL Sule, G., Campeau, P. M., Zhang, V. W., Nagamani, S. C., Dawson, B. C., Grover, M., Bacino, C. A., Sutton, V. R., Brunetti-Pierri, N., Lu, J. T., Lemire, E., Gibbs, R. A., Cohn, D. H., Cui, H., Wong, L., Lee, B. H. 2013; 24 (8): 2253-2259

    Abstract

    To achieve an efficient molecular diagnosis of osteogenesis imperfecta (OI), Ehlers-Danlos syndrome (EDS), and osteopetrosis (OPT), we designed a next-generation sequencing (NGS) platform to sequence 34 genes. We validated this platform on known cases and have successfully identified the causative mutation in most patients without a prior molecular diagnosis.Osteogenesis imperfecta, Ehlers-Danlos syndrome, and osteopetrosis are collectively common inherited skeletal diseases. Evaluation of subjects with these conditions often includes molecular testing which has important counseling and therapeutic and sometimes legal implications. Since several different genes have been implicated in these conditions, Sanger sequencing of each gene can be a prohibitively expensive and time-consuming way to reach a molecular diagnosis.In order to circumvent these problems, we have designed and tested a NGS platform that would allow simultaneous sequencing on a single diagnostic platform of different genes implicated in OI, OPT, EDS, and other inherited conditions, leading to low or high bone mineral density. We used a liquid-phase probe library that captures 602 exons (~100 kb) of 34 selected genes and have applied it to test clinical samples from patients with bone disorders.NGS of the captured exons by Illumina HiSeq 2000 resulted in an average coverage of over 900X. The platform was successfully validated by identifying mutations in six patients with known mutations. Moreover, in four patients with OI or OPT without a prior molecular diagnosis, the assay was able to detect the causative mutations.In conclusion, our NGS panel provides a fast and accurate method to arrive at a molecular diagnosis in most patients with inherited high or low bone mineral density disorders.

    View details for DOI 10.1007/s00198-013-2290-0

    View details for Web of Science ID 000321655500012

    View details for PubMedID 23443412

  • Phenotypic Variability of Osteogenesis Imperfecta Type V Caused by an IFITM5 Mutation JOURNAL OF BONE AND MINERAL RESEARCH Shapiro, J. R., Lietman, C., Grover, M., Lu, J. T., Nagamani, S. C., Dawson, B. C., Baldridge, D. M., Bainbridge, M. N., Cohn, D. H., Blazo, M., Roberts, T. T., Brennen, F., Wu, Y., Gibbs, R. A., Melvin, P., Campeau, P. M., Lee, B. H. 2013; 28 (7): 1523-1530

    Abstract

    In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5' untranslated region (5'UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.-14C?>?T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.

    View details for DOI 10.1002/jbmr.1891

    View details for Web of Science ID 000320561900003

    View details for PubMedID 23408678

  • WNT1 Mutations in Early-Onset Osteoporosis and Osteogenesis Imperfecta NEW ENGLAND JOURNAL OF MEDICINE Laine, C. M., Joeng, K. S., Campeau, P. M., Kiviranta, R., Tarkkonen, K., Grover, M., Lu, J. T., Pekkinen, M., Wessman, M., Heino, T. J., Nieminen-Pihala, V., Aronen, M., Laine, T., Kroger, H., Cole, W. G., Lehesjoki, A., Nevarez, L., Krakow, D., Curry, C. J., Cohn, D. H., Gibbs, R. A., Lee, B. H., Makitie, O. 2013; 368 (19): 1809-1816

    Abstract

    This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T?G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C?A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.

    View details for DOI 10.1056/NEJMbr1215458

    View details for Web of Science ID 000318540000009

    View details for PubMedID 23656646

  • Human fetal and neonatal bone development Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism Yang, T., Grover, M., Joeng, K. S., Lee, B. 2013
  • Assessment of Bone Mineral Status in Children With Marfan Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Grover, M., Brunetti-Pierri, N., Belmont, J., Phan, K., Tran, A., Shypailo, R. J., Ellis, K. J., Lee, B. H. 2012; 158A (9): 2221-2224

    Abstract

    Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with skeletal involvement. It is caused by mutations in fibrillin1 (FBN1) gene resulting in activation of TGF-?, which developmentally regulates bone mass and matrix properties. There is no consensus regarding bone mineralization in children with MFS. Using dual-energy X-ray absorptiometry (DXA), we evaluated bone mineralization in 20 children with MFS unselected for bone problems. z-Scores were calculated based on age, gender, height, and ethnicity matched controls. Mean whole body bone mineral content (BMC) z-score was 0.26±1.42 (P=0.41). Mean bone mineral density (BMD) z-score for whole body was -0.34±1.4 (P=0.29) and lumbar spine was reduced at -0.55±1.34 (P=0.017). On further adjusting for stature, which is usually higher in MFS, mean BMC z-score was reduced at -0.677±1.37 (P=0.04), mean BMD z-score for whole body was -0.82±1.55 (P=0.002) and for lumbar spine was -0.83±1.32 (P=0.001). An increased risk of osteoporosis in MFS is controversial. DXA has limitations in large skeletons because it tends to overestimate BMD and BMC. By adjusting results for height, age, gender, and ethnicity, we found that MFS patients have significantly lower BMC and BMD in whole body and lumbar spine. Evaluation of diet, exercise, vitamin D status, and bone turnover markers will help gain insight into pathogenesis of the reduced bone mass. Further, larger longitudinal studies are required to evaluate the natural history, incidence of fractures, and effects of pharmacological therapy.

    View details for DOI 10.1002/ajmg.a.35540

    View details for Web of Science ID 000310068700018

    View details for PubMedID 22887731

  • Decreased bone mineralization in children with Noonan syndrome: another consequence of dysregulated RAS MAPKinase pathway? Molecular genetics and metabolism Choudhry, K. S., Grover, M., Tran, A. A., O'Brian Smith, E., Ellis, K. J., Lee, B. H. 2012; 106 (2): 237-240

    Abstract

    Noonan syndrome (NS) is a disorder of RAS- mitogen activated protein kinase (MAPK) pathway with clinical features of skeletal dysplasia. This pathway is essential for regulation of cell differentiation and growth including bone homeostasis. Currently, limited information exists regarding bone mineralization in NS.Using dual-energy X-ray absorptiometry (DXA), bone mineralization was evaluated in 12 subjects (mean age 8.7 years) with clinical features of NS. All subjects underwent genetic testing which showed mutations in PTPN11 gene (N=8) and SOS1 gene (N=1). In a subgroup of subjects with low bone mass, indices of calcium-phosphate metabolism and bone turnover were obtained.50% of subjects had low bone mass as measured by DXA. Z-scores for bone mineral content (BMC) were calculated based on age, gender, height, and ethnicity. Mean BMC z-score was marginally decreased at -0.89 {95% CI -2.01 to 0.23; p=0.1}. Mean total body bone mineral density (BMD) z-score was significantly reduced at -1.87 {95% CI -2.73 to -1.0; p=0.001}. Mean height percentile was close to - 2 SD for this cohort, thus total body BMD z-scores were recalculated, adjusting for height age. Adjusted mean total body BMD z-score was less reduced but still significant at -0.82 {95% CI -1.39 to -0.25; p=0.009}. Biochemical evaluation for bone turnover was unremarkable except serum IGF-I and IGF-BP3 levels which were low-normal for age.Children with NS have a significantly lower total body BMD compared to age, gender, ethnicity and height matched controls. In addition, total BMC appears to trend lower in children with NS compared to controls. We conclude that the metabolic bone disease present resulted from a subtle variation in the interplay of osteoclast and osteoblast activity, without clear abnormalities being defined in the metabolism of either. Clinical significance of this finding needs to be validated by larger longitudinal studies. Also, histomorphometric analysis of bone tissue from NS patients and mouse model of NS may further elucidate the relationship between the RAS-MAPK pathway and skeletal homeostasis.

    View details for DOI 10.1016/j.ymgme.2012.04.003

    View details for PubMedID 22551697

  • Autoimmune polyglandular syndrome Type 3 and growth hormone deficiency PEDIATRIC DIABETES Quintos, J. B., Grover, M., Boney, C. M., Salas, M. 2010; 11 (6): 438-442

    Abstract

    The simultaneous occurrence of prepubertal Graves' disease, type 1 Diabetes Mellitus (DM), and Growth hormone deficiency (GHD) is uncommon. GHD has been reported in Autoimmune Polyglandular Syndrome (APS) Type 1 and Type 2 but not in APS Type 3. We report a 3-yr-old boy who presented simultaneously with type 1 DM and Graves' disease. After he developed urticarial rash to Propylthiouracil and Methimazole with persistent thyrotoxicosis, he received 8 millicuries of (131)I at 5 yr of age. We diagnosed GHD at age 8 yr 8 months because of growth deceleration (from 95 to 25%) and abnormal growth rate (3 cm/yr) despite euthyroidism, fair glycemic control, and normal weight gain. Both insulin-like growth factor (IGF) 1 (90 ng/mL; normal 113-261 ng/mL) and IGFBP3 (1.3 mcg/mL; normal 2.1-4.2 mcg/mL) levels were low and peak growth hormone level measured by RIA was 5.2 ng/mL after L-Dopa and insulin tolerance test. The rest of his pituitary functions and magnetic resonance imaging of the pituitary gland were normal. Growth hormone treatment (0.3 mg/kg/wk) was administered at 8 yr 9 months until near final adult height (FAH). Near FAH (172 cm) was close to midparental target height of 180 cm. GHD may be a component of all APS even though it is rare. Growth in treated children with Graves' disease should be followed closely as catch down growth below genetic height potential may be a harbinger of underlying GHD.

    View details for DOI 10.1111/j.1399-5448.2009.00622.x

    View details for Web of Science ID 000281285600011

    View details for PubMedID 19968812

Footer Links:

Stanford Medicine Resources: