Delayed Bone Age Research Articles

Risk Factors Associated with Incident Vertebral Fractures in Steroid-treated Males with Duchenne Muscular Dystrophy.

Prevention of fractures is an unmet need in glucocorticoid (GC)-treated Duchenne muscular dystrophy. This study explored factors associated with incident vertebral fractures (VFs) to inform future fracture prevention efforts. VFs were evaluated prospectively at study baseline and 12 months on lateral spine radiographs in participants aged 4 to 25 years with Duchenne muscular dystrophy. Clinical factors were analyzed for their association with the change in Spinal Deformity Index (sum of the Genant-defined VF grades from T4 to L4) between baseline and 12 months. Thirty-eight males were evaluated (mean ± SD age at baseline 11.0 ± 3.6 years; mean ± SD GC duration at baseline 4.1 ± 3.1 years; 74% ambulatory). Nine of 38 participants (24%) had 17 incident VFs, of which 3/17 VFs (18%) were moderate/severe. Participants with 12-month incident VF had lower mean ± SD baseline lumbar spine areal bone mineral density Z-scores (-2.9 ± 1.0 vs -1.9 ± 1.1; P = .049) and lower total body less head areal bone mineral density Z-scores (-3.1 ± 1.2 vs -1.6 ± 1.7; P = .036). Multivariable linear regression showed that at least 1 VF at baseline (P < .001), a higher number of antecedent non-VF (P < .001), and greater bone age delay at baseline (P = .027) were significant predictors of an increase in the Spinal Deformity Index from baseline to 12 months. The observation that ≥ 1 prevalent VF and/or non-VF were the strongest predictors of incident VFs at 12 months supports the need for prevention of first fractures in this high-risk setting. Bone age delay, a marker of GC exposure, may assist in the prioritization of patients in efforts to prevent first fractures.

Analysis of children with familial short stature: who should be indicated for genetic testing?

Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤-2 SD in child and his/her shorter parent, excluded secondary short stature, excluded Turner/Prader-Willi syndrome). Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by ACMG guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, four (11%) a variant affecting GH-IGF1 axis, and three (8%) a variant in miscellaneous genes. Lower shorter parent's height (p=0.015) and less delayed bone age (BA) before GH treatment (p=0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent heights <-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, gene variants affecting the growth plate are the most common. Shorter parent's height and bone age are clinical predictors of monogenic FSS.

Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance.

SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age, and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6 x 129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective was to characterize the skeletal phenotype in these mice. Compared to wild type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations, and delayed skeletal development. Because poor survival prevents evaluation of mature knockout mice, we generated a conditional Slc7a7 deletion in mature osteoblasts or mesenchymal cells of the osteo-chondroprogenitor lineage, butno differences in bone architecture were observed. Overall, global Slc7a7 deficiency caused growth failure with low plasma IGF-1 concentrations and delayed skeletal development, but Slc7a7 deficiency in the osteoblastic lineage was not a major contributor to these phenotypes. Future studies utilizing additional tissue-specific Slc7a7 knockout models may help dissect cell autonomous and non-cell autonomous mechanisms underlying phenotypes in LPI.

STUNTING BONE AGE EXAMINATION IN STUNTING CHILDREN IN THE RADIOLOGY INSTALLATION OF SIJUNJUNG HOSPITAL, WEST SUMATRA

Bone age maturity is a key component in evaluating a child's growth. Assessment of bone maturity is determined by measuring "Bone Age", namely an X-ray examination of the left wrist bone. Ossification of trabecular bone occurs in a predictable pattern, so that assessment of bone maturity can be made at several ossification centers and then compared to standard radiographic images for males and females. The results of the radiographs are compared with the individual's chronological age as an indicator of the speed of growth, using the ± SD reference it can be concluded that it is in the late or normal category. Examination of a single X-ray on the representative left hand to assess the center of ossification so as to avoid radiation exposure for radiographic examination of all bones. Assessment of hand radiographic analysis can show a correlation with facial growth during puberty. This research is a qualitative descriptive research method with an observational study, conducted on January 27 2023 at the radiology installation of Sijunjung Hospital with a population of stunted children with a sample of seven stunted children, data collection by examining the left manus anterior posterior projection after that the radiograph results evaluated by a radiologist. The results showed that there were three stunted children who did not experience delays in bone age maturity, namely one boy aged 5 years, one boy aged 11 years and one girl aged 13 years and there were four children who were stunted. delayed bone age maturity, namely one girl aged 10 years, two boys aged 10 years and one boy aged 15 years so that further research needs to be done for the factors causing bone age maturity in stunted children.

Uncommon clinical features of juvenile primary hypothyroidism

This case study presents an 18-year-old boy with severe short stature and distinct physical features, including facial abnormalities, skeletal deformities, and intellectual impairment. Further investigations revealed hypothyroidism, autoimmune thyroiditis, and delayed bone age. Treatment with levothyroxine replacement therapy was initiated. The study highlights the importance of detection and management of hypothyroidism in individuals with short stature and associated features.

Clinical and Biochemical Characteristics of Untreated Adult Patients With Resistance to Thyroid Hormone Alpha.

Thyroid hormone resistance due to pathogenic variants in thyroid hormone receptor alpha (THRA) is rare and descriptions of patients are sparse. The disorder is probably underdiagnosed as patients may have normal thyroid function tests. Treatment with thyroxine in childhood improves clinical symptoms. However, it is not clear if treatment has beneficial effects if started in adulthood. We investigated 4 previously untreated Caucasian adult first-degree-related patients with the THRA c.788C > T, p.(Ala263Val) variant identified by a gene panel for intellectual disability in the index patient. Clinical data and previous investigations were obtained from medical reports. During childhood and adolescence, short stature, short limbs, metacarpals, and phalanges, and delayed bone age maturation were observed. Delayed motor and language development and decreased intellectual and learning abilities were described. Abdominal adiposity, round face, and increased head circumference were common features. All individuals complained of tiredness, constipation, and low mood. While thyrotropin (TSH) and free thyroxine (FT4) were within the reference range, free triiodothyronine (FT3) was high. FT4/FT3 ratio and reverse T3 were low. Other main features were low hemoglobin and high LDL/HDL ratio. Investigation of 4 first-degree-related adult patients with untreated resistance to thyroid hormone alpha (RTHα) revealed more pronounced phenotype features and hypothyroid symptoms than previously described in patients treated with levothyroxine from childhood or adolescence. The delay in diagnosis is probably due to normal thyroid function tests. We suggest that THRA analysis should be performed in patients with specific clinical features, as treatment in early childhood may improve outcomes.

Delayed puberty: How to approach?

Disorders of puberty can profoundly impact physical and psychosocial well-being. Delayed puberty is the absence of breast development in girls by 13 years of age and absence of testicular growth to at least 4 mL in volume or 2.5 cm in length in boys by 14 years of age. Hypogonadism occurs when there is a disruption in the hypothalamic-pituitary-gonadal axis. Two categories of delayed puberty are: hypergonadotropic (primary) hypogonadism and hypogonadotropic (secondary) hypogonadism. The etiology of delayed puberty varies from relatively benign to life threatening conditions, which may be either congenital or acquired. Constitutional delay of growth and puberty is the commonest cause of delayed puberty, which is a diagnosis of exclusion. There is a notable delay in puberty but eventually progress through normal stages of puberty. History concerns about stature are often present and a familial pattern of inheritance is usually present. Delayed bone age but corresponding to height age helps in diagnosis. Reversible hypogonadotropic hypogonadism may be observed due to associated conditions including chronic malnutrition, systemic disease, untreated hypothyroidism, hyperprolactinemia, anorexia nervosa. Permanent causes include structural damage either to hypothalamic-pituitary axis or linked to the sexual organs of the individual. Complete physical examination should include proper anthropometry, pubertal staging and assessment to look for any signs of chronic illness or stigmata of syndromes. In laboratory analysis, hypogonadotropichypogonadism (pHH) showing low serum testosterone or estradiol and blunted follicle-stimulating hormones (FSH) and luteinizing hormones (LH) levels may be due to abnormalities in the central nervous system. Magnetic resonance imaging is necessary to exclude morphological abnormalities and neoplasia. Low serum testosterone in male patients and low estradiol values in female patients, associated with high serum FSH and LH levels, suggest a diagnosis of hypergonadotropic hypogonadism due to dysfunction of peripheral sex organs. Abnormal growth velocity necessitates assessment of serum thyroid function, prolactin, and insulin like growth factor-1. Karyotyping can reveal a chromosomal abnormality like Turner syndrome or Klinefelter syndrome. Beside reassurance, in cases where the adolescent with CDGP is experiencing psychological difficulties, short courses of sex hormones may be used to allow individuals to catch up with their peers. Definitive treatment for underlying cause is worthy where possible. Long-term hormone replacement therapy is recommended for permanent causes of delayed puberty. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 192

Severe congenital neutropenia type 4 with early-onset inflammatory bowel disease attributed to a G6PC3 variant (not previously associated with disease): A case report and a literature review

Severe congenital neutropenia type 4 is an extremely rare autosomal recessive disorder due to biallelic loss-of-function mutations affecting the glucose-6-phosphatase catalytic subunit 3 (G6PC3). It encompasses a complex heterogeneous spectrum of clinical presentations with many extra-hematological complications. In this report, we present a case of a 6-year-old Mediterranean female patient with repeated admissions due to recurrent infections, arthritis and chronic diarrhea. Thorough investigations reveled significant neutropenia, thrombocytosis, hepatosplenomegaly, delayed bone age, and Crohn's disease. Whole exome sequencing showed an extremely rare homozygous frameshift mutation affecting the penultimate exon (c.765_766del/ p.Ala257CysfsTer129); the mutation was not associated with disease previously. The patient's symptoms were controlled using antibiotics, steroids, granulocyte colony stimulating factor and infliximab. Although the latter showed marked control of both the recurrent arthritis and the inflammatory bowel disease symptoms, this was unfortunately short lived and required dose escalation and more frequent infusions.

Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome.

Objective: Wiedemann-Steiner syndrome (WSS) is a rare autosomal dominant disorder caused by deleterious heterozygous variants of the KMT2A gene. This study aims to describe the phenotypic and genotypic features of Chinese WSS patients, and assess therapeutic effects of recombinant human growth hormone (rhGH). Methods: Eleven Chinese children with WSS were enrolled in our cohort. Their clinical, imaging, biochemical and molecular findings were analyzed retrospectively. Moreover, the phenotypic features of 41 previously reported Chinese WSS patients were reviewed and included in our analysis. Results: In our cohort, the 11 WSS patients presented with classic clinical manifestations, but with different frequencies. The most common clinical features were short stature (90.9%) and developmental delay (90.9%), followed by intellectual disability (72.7%). The most frequent imaging features were patent ductus arteriosus (57.1%) and patent foramen ovale (42.9%) in cardiovascular system, and abnormal corpus callosum (50.0%) in the brain. In the set comprising 52 Chinese WSS patients, the most common clinical and imaging manifestations were developmental delay (84.6%), intellectual disability (84.6%), short stature (80.8%) and delayed bone age (68.0%), respectively. Eleven different variants, including three known and eight novel variants, of the KMT2A gene were identified in our 11 WSS patients without a hotspot variant. Two patients were treated with rhGH and yielded satisfactory height gains, but one developed acceleration of bone age. Conclusion: Our study adds 11 new patients with WSS, reveals different clinical characteristics in Chinese WSS patients, and extends the mutational spectrum of the KMT2A gene. Our study also shares the therapeutic effects of rhGH in two WSS patients without GH deficiency.

Origins of SOPH syndrome: A study of 93 Yakut patients with review of C-terminal phenotype.

Since the first report of SOPH syndrome among the Yakut population in 2010, new clinical data of SOPH-like conditions continue to appear. We expand the phenotypic spectrum of SOPH syndrome and perform a comparative analysis of Yakut SOPH patients' clinical data with SOPH-like conditions reported in the world scientific literature to form a foundation for NBAS pathogenesis discussion. Clinical data from the genetic records of 93 patients with SOPH syndrome and global survey data on patients with pathogenic variants of the C-terminal in the NBAS gene were collected. A detailed phenotype description of patients is presented with a total number of 111 individuals. Underweight below the fifth centile and prone to delayed bone age in Yakut SOPH patients are retrospectively observed. We outline the short stature with optic atrophy as the leading phenotyping trait for C-terminal NBAS patients. The pathophysiology and patients management of SOPH-like conditions are discussed.

Literature review, report, and analysis of genotype and clinical phenotype of a rare case of ulnar-mammary syndrome.

The clinical characteristics of Ulnar-mammary syndrome (UMS) caused by mutations in TBX3 (T-Box transcription factor 3) were studied and the correlation between genotype and clinical phenotype were analyzed to improve awareness and early diagnosis of the disease. The clinical data of a boy aged 13 years and 5 months with left forearm deformity and growth retardation as the main features were analyzed. Genomic exon detection was performed, and the results were verified by Sanger sequencing. Simultaneously, we performed literature review to analyze the correlation between clinical phenotypes and genotypes. The clinical manifestations in the child were short stature, ulnar hypoplasia of the forearm, hypohidrosis, retracted nipple, micropenis, and cryptorchidism. Laboratory examination revealed hyperthyroidism, growth hormone deficiency, and hypogonadotropic hypogonadism. Imaging results displayed delayed bone age, small pituitary gland, and persistence of Rathke's cleft cyst. The results of the exome sequencing revealed the deletion of AGA at positions 1121-1,124 of TBX3, which resulted in a frameshift mutation (c.1121-1124del AGAG; pGlu374fs). According to the American College of Medical Genetics (ACMG) assessment, the mutation is a pathogenic variant. A definitive diagnosis of UMS was made on the basis of the clinical phenotype of the patient. The Chinese and English literature were reviewed to analyze the correlation between TBX3 genotype and clinical phenotype. UMS is a rare hereditary disease caused by mutations in TBX3. There is significant clinical heterogeneity associated with the variants of this gene. To our knowledge, this mutation site in TBX3 has been reported for the first time, thereby expanding the mutation spectrum of this gene.

A Rare association of Mauriac syndrome and Van-Wyk Grumbach syndrome found in a young Saudi girl with poorly controlled type 1 Diabetes and Hypothyroidism: A Case Report and Brief literature review

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insufficient insulin production of the pancreatic beta-cells. Patients with T1DM will have a higher risk of other autoimmune disorders like celiac and thyroid diseases. Hypothyroidism is the failure of the thyroid gland to secrete an adequate amount of thyroxine, which is required for physical growth, brain development, and cellular metabolism. Most studies reported that children with T1DM have a higher incidence of hypothyroidism than normal children, with 9.6% having hypothyroidism and 19% having positive anti-TPO antibodies. Hypothyroidism will aggravate the condition in a child with T1DM and vice versa. Uncontrolled diabetes for a long time might increase insulin resistance due to complete depression of the hypothalamus-pituitary thyroid axis. A rare complication of poorly controlled T1DM is Mauriac syndrome, characterized by elevated liver enzymes, hyperlipidemia, cushingoid features, growth retardation, and hepatomegaly due to glycogenic hepatopathy. Van Wyk–Grumbach syndrome is also a rare complication of long-standing, untreated hypothyroidism, manifested by breast development, multicystic ovary, uterine bleeding associated with lack of pubic and axillary hair growth, and delayed bone age. Here, we report a case with two rare complications of Mauriac syndrome and Van Wyk–Grumbach syndrome in a child with hypothyroidism and poorly controlled T1DM.

Differences in the clinical picture at the onset of diagnosis of severe autoimmune hypothyroidism in children depending on the time of diagnosis: before or during the SARS-CoV-2 pandemic.

There are few data about effects of COVID-19 on thyroid disease presentation in children, due to difficulties in healthcare services access. To assess the differences in hypothyroidism presentation before and during the COVID-19 pandemic. All paediatric patients with autoimmune hypothyroidism (AIT) diagnosed from January 2017 to December 2022 were analysed. A total of 150 subjects were enrolled (94 in before and 56 during the pandemic period). Severe AIT was detected in 7.4% before and 12.5% during the pandemic. Age at the onset in the pre-pandemic period was lower ( p = 0.04). Diagnosis delay (time elapsed from onset of symptoms and diagnosis) was significantly different between the before and during the pandemic groups ( p = 0.02). In the pre-pandemic period the TSH value was 447.7 ±59.1, and it was 713.7 ±104.4 mUI/l during the pandemic ( p = 0.04), whereas mean fT4 values were 2.66 ±0.34 and 0.58 ±0.08 ng/l, respectively ( p = 0.0002). Significantly greater thyroid volume and bone age delay SDS were observed during the pandemic ( p = 0.04). Neurological symptoms were mostly observed during the pandemic, especially slow speech and impaired school performance. A higher rate of severe AIT was observed during the pandemic period, mostly related to difficulties in access to healthcare services. The diagnosis delay led to a more severe biochemical thyroid hormone profile, goitre, and more frequent presence of bone age delay and neurological symptoms at the onset. Recognizing hypothyroidism and recalling symptoms in child-hood, even if often non-specific, is fundamental for avoiding diagnosis delay.

Effect of Growth Hormone Therapy in Indian Children with Short StatureA Retrospective Study

Introduction: The causes for short stature are multifactorial. The recombinant Growth Hormone (rGH) is used worldwide for its treatment however there is paucity of data on use of growth hormone in Indian Children. Aim: To study the effect of rGH in Indian children with short stature who were enrolled under ESIC scheme. Materials and Methods: This was a retrospective observational study. Subjects who had short stature (≤2SD) and diagnosed to have Growth Hormone Deficiency (GHD) by stimulation test and other causes for which growth hormone was indicated were enrolled. All subjects received treatment at ESI PGIMSR Basaidarapur, New Delhi, India, from July 2016 to July 2020, without discontinuation for more than one week. The data regarding gain in height was collected at the end of first year and then at the end of second year. Height velocity and change in Height SD were calculated (Mean±Standard Deviations). The associations and correlations were calculated by Spearman correlation test. Results: This study included data of 27 children (19 male and 8 female) with short stature. The mean age at treatment initiation was 9.85 years±3.04. The most common aetiology for which growth hormone was started was Idiopathic GHD (IGHD) seen in (15/27) 55.5% followed by Multiple Pituitary Hormone Deficiency (MPHD) 18.5% (5/27). The mean height and height SD at baseline was 111.76 cm ±17.40 and -3.85±1.19 (-6.0 to -1.5), respectively. The mean bone age delay (chronological age-bone age difference) was 40.96±25.58 months. The height velocity response was maximum during the first year of treatment (8.74±2.59 cm), declining to 8.13±2.30 cm in the second year. Correlation of the treatment response with age at treatment initiation, bone age delay and MPH was not significant. Conclusion: It was found that the growth velocity was significantly increased after one year of treatment. The study provides long term follow-up and response to rGH Treatment (rGHT) in Indian children enrolled under ESIC scheme however prospective studies with large sample size and longer follow-up duration which can report final height outcomes are needed.

Orthopaedic Diagnoses in the Black Pediatric Population.

The Black pediatric population is one that has been historically underserved and continues to have unmet needs. Factors including lack of diversity in orthopaedic studies and in historical standards, such as bone age, may inadvertently lead to inferior care. There are certain conditions in this population for which the practicing orthopaedic surgeon should have a higher degree of suspicion, including slipped capital femoral epiphysis, Blount disease, and postaxial polydactyly. Systemic diseases with higher rates in this population have orthopaedic manifestations, including sickle cell disease, vitamin D deficiency, and obesity. Racial discrepancies in access to prenatal care can have orthopaedic consequences for babies, especially cerebral palsy and myelodysplasia. Racial discrepancy exists in evaluation for nonaccidental trauma. Increased awareness of these issues better prepares practitioners to provide equitable care.

Tanner–Whitehouse skeletal maturity score derived from ultrasound images to evaluate bone age

ObjectiveThe complexity of radiographic Tanner–Whitehouse method makes it less acceptable by radiologists and endocrinologists to assess bone age. Conventional ultrasound could be used to measure the ratio of the height of the ossification center to the epiphysis of the bone to evaluate maturity of bone. The purpose of this study is to obtain radiographic TW3 skeletal maturity score with ultrasound images.MethodsIn this prospective diagnostic study, participants aged between 1 and 18 years undergoing radiography for bone age evaluation were evaluated from April 2019 to November 2021. Ultrasonic skeletal maturity scores of participants were transformed into radiographic skeletal maturity scores with the fitted formulas established in this study. Diagnostic performances of the transformed scores to diagnose advanced or delayed bone age were confirmed. Ultrasound images of 50 participants in the validation group were re-evaluated to confirm inter-rater reliability.ResultsA total of 442 participants (median age, 9.5 years [interquartile range, 7.8–11.1 years]; 185 boys) were enrolled. Ultrasound determination of bone age had a sensitivity of 97% (34/35, 95% CI: 83, 99) and a specificity of 98% (106/108, 95% CI: 93, 99) to diagnose advanced or delayed bone age. The intra-class correlation coefficient for inter-rater reliability was 0.993 [95% CI: 0.988, 0.996], p < 0.0001.ConclusionsRadiographic Tanner–Whitehouse skeletal maturity score could be obtained from ultrasound images in a simple, fast, accurate, and radiation-free manner.Key Points• The fitting formulas between radiographic TW3 skeletal maturity score and ultrasonic skeletal maturity score were developed.• Through measurement of ossification ratios of bones with ultrasound, TW3 skeletal maturity score was obtained in a simple, fast, and radiation-free manner.

Risk factors associated with prevalent vertebral fractures in Duchenne muscular dystrophy.

Fragility fractures are frequent in DMD. The purpose of this study was to identify clinical factors associated with prevalent vertebral fractures (VF) in boys, teens/young adults with Duchenne muscular dystrophy (DMD). This was a cross-sectional study of males aged 4-25years with DMD. VF were evaluated using the modified Genant semi-quantitative method on T4-L4 lateral spine radiographs. Areal bone mineral density (aBMD) was measured at the lumbar spine (LS) and used to estimate volumetric BMD (vBMD). Clinical factors were analyzed for their association with the Spinal Deformity Index (SDI, the sum of the Genant grades). Sixty participants were enrolled (mean age 11.5years, range 5.4-19.5). Nineteen participants (32%) had a total of 67 VF; 23/67 VF (34%) were moderate or severe. Participants with VF were shorter (mean height Z-score ± standard deviation: - 3.1 ± 1.4 vs. - 1.8 ± 1.4, p = 0.001), had longer glucocorticoid exposure (mean duration 6.0 ± 3.3 vs. 3.9 ± 3.3years, p = 0.027), greater bone age (BA) delay (mean BA to chronological age difference - 3.2 ± 3.4 vs. - 1.3 ± 1.2years, p = 0.035), and lower LSaBMD Z-scores (mean - 3.0 ± 1.0 vs. - 2.2 ± 1.2, p = 0.023). There was no difference in LSvBMD Z-scores. Multivariable Poisson regression showed that every 0.1mg/kg/day increment in average glucocorticoid daily dose was associated with a 1.4-fold SDI increase (95% confidence interval: 1.1-1.7, p = 0.013). Greater BA delay (p < 0.001), higher weight Z-score (p = 0.004), decreased height Z-score (p = 0.025), and lower LSvBMD Z-score (p = 0.025) were also associated with SDI increase. Readily measurable clinical variables were associated with prevalent VF in males with glucocorticoid-treated DMD. These variables may be useful to identify candidates for primary osteoporosis prevention after glucocorticoid initiation.

PSAT224 Endocrine Manifestations in Diamond Blackfan Anemia

Abstract Introduction Diamond Blackfan anemia (DBA) is a form of pure red cell aplasia characterized by erythroid hypoplasia, congenital deformities, and increased risk of malignancy. It is typically diagnosed in first year of life. Treatments include chronic corticosteroids and frequent blood transfusions, which can result in significant endocrine complications. Case Presentation A 39 year-old African American male with DBA presented to the hospital with decompensated heart failure secondary to hemosiderosis, with ferritin level of 14,054 ng/ml (22-322). He complained of muscle cramps and weakness but denied paresthesias. He was diagnosed with DBA at 1 month of age, which required blood transfusions every 2 weeks and dual chelation therapy. He had previously tried corticosteroids for 6 months with poor response. Endocrine service was consulted to manage his multiple endocrine issues. He was diagnosed with primary hypothyroidism at age 1 and was on levothyroxine 175 mcg daily. At age 19, he was diagnosed with hypogonadotropic hypogonadism and was on testosterone cypionate 200 mg weekly. He received growth hormone injections from age 19 to 21 due to his delayed bone age and short stature. At age 23, he was diagnosed with adrenal insufficiency due to pituitary iron overload and was on prednisone 2.5mg daily. Physical exam was remarkable for short stature with height 152 cm, weight 46.4 kg, BMI 21.9 kg/m2, blood pressure 90/54 mm Hg and heart rate 93 bpm. He had positive Chvostek sign, pedal edema, jugular venous distension and bilateral lung crackles. There were no skeletal deformities, no hyper-pigmented skin, no surgical neck scars, negative Trousseau sign, and normal deep tendon reflexes. His lab work up was remarkable for TSH 80 mcIU/ml (0.4-4.7) and HbA1c in the prediabetes range. He had ionized calcium 3.1 mg/dl (4.5-5.2), phosphorus 6.9 mg/dl (2.4-5.1), PTH 27 pg/ml (11.1-79.5), eGFR &amp;gt;90 ml/min/m2 (&amp;gt;90), and 25-hydroxy vitamin 19.7 ng/ml (25-80), therefore he was newly diagnosed with primary hypoparathyroidism, most likely attributed to iron infiltration of the parathyroid glands. He was started on calcium carbonate 500 mg BID, calcitriol 0.5 mcg daily, sevelamer 2400 mg TID and ergocalciferol 50,000 IU/week with variable compliance. He was subsequently approved for teriparatide, as a substitute for Natpara (parathyroid hormone). Unfortunately, he expired before he could receive teriparatide. Discussion Endocrine complications in DBA are common with a prevalence in the American DBA registry of 53% having one or more endocrinopathy. These complications are related to long-term corticosteroid treatment or iron related deposition from transfusions. Our patient had transfusion related endocrinopathies including newly diagnosed primary hypoparathyroidism and history of hypopituitarism with resultant hypogonadism, adrenal insufficiency and growth hormone deficiency. Given the frequency of endocrine complications associated with DBA treatment, it is important to screen for these conditions starting in childhood. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PMON37 Diabetes and Hypopituitarism Secondary to Iron Overload in a Patient with Pure Red Cell Aplasia

Abstract Background Pure red cell aplasia is a rare bone marrow disorder that results in decline in red blood cell production by the bone marrow. Treatment involves multiple blood transfusions to keep up the red blood cell count, which can lead to iron overload. Hypopituitarism is a condition, where two or more pituitary hormones are deficient. Here we present a case of diabetes and hypopituitarism secondary to iron overload from blood transfusions. Clinical Case A 19 year male with pure red cell aplasia was admitted for anemia and was noted to have short stature with growth percentile at 0.36% with predicted MPH estimated to be 180.5 cm. He was Tanner stage 2 on exam and work-up showed IGF1 128 (n 281-510 ng/mL), Testosterone of &amp;lt;1 (n 250-1100 ng/dL), LH 1.1 (n 1-10 mIU/mL), FSH 1.5 (n 1-10 mIU/mL), delayed bone age of 15 years consistent with delayed puberty and hypogonadotropic hypogonadism so he was initiated on 50 mg IM Testosterone monthly. After 1 month, he presented to the hospital again for mild DKA secondary to high dose steroids as part of treatment for his underlying medical condition and also pancreatic dysfunction given history of regular transfusions and iron overload. Initial Fructosamine level was 438 equivalent to HgbA1c of ∼10-11%. He was started on SQ insulin regimen with both long- and short-acting insulin and 50 mcg Levothyroxine as thyroid levels checked during admission showed hypothyroid state, thus, meeting diagnostic criteria for hypopituitarism. Brain MRI was obtained which was negative for mass or lesions, however abdominal MRI showed very high level iron overload on liver, spleen and pancreas. Steroids were weaned and insulin regimen was adjusted on a regular interval according to his blood glucose levels, however, he was not able to wean off insulin even after steroids were discontinued and was transitioned to 70/30 regimen for ease of management with normalization of Fructosamine levels. His testosterone was eventually increased up to 200 mg and was transitioned to daily topical Androgel and currently increasing dose gradually. His most recent testosterone level was 38 ng/dL with goal range of 400-600 ng/dL. His thyroid levels continued to be stable on current dose. He had passed the ACTH stimulation test ∼4-6 weeks after discontinuation of steroids and decided not to pursue growth hormone therapy. Conclusion Patients who receive regular blood transfusions are at risk of iron overload, which can affect multiple organs including the pancreas and pituitary gland. This can subsequently lead to insulin-dependent diabetes and hypopituitarism, which should bring awareness of regular assessment of diabetes and pituitary function starting early in life. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

RF34 | PMON19 Biallelic Variants in the INHA Gene Are the Cause of Gonadal Dysgenesis, Primary Amenorrhea and Absence of Puberty in the Setting of Hypergonadotropic Hypogonadism

Abstract Background Hypergonadotropic hypogonadism can be caused by congenital or acquired causes. These can range from chromosomal abnormalities, enzymatic defects or mutations that cause gonadotropin resistance, trauma, chemotherapy, infections etc. It is uncommon in females other than in Turner syndrome and not all the genetic etiologies are known. Clinical Case A 15 10/12 year old female with primary amenorrhea and absent pubertal development presented with FSH and LH levels of 35.24 mIU/mL and 14.38 mIU/mL, respectively and non-pubertal estradiol levels of 4 pg/mL consistent with hypergonadotropic hypogonadism. Her evaluation showed a normal 46,XX female karyotype and no evidence of hyperandrogenism or thyroid dysfunction. Ultrasound showed no evidence of ovaries and a rudimentary uterus measuring 0.9 cm×1.4 cm×1.2 cm with a delayed bone age of 12 years. Family history was positive for mother having delayed puberty with menarche at 16.5 years of age. Patient was started on hormone replacement therapy with transdermal estrogen. Four months after treatment she developed breast buds and vaginal discharge. After 1.5 years, the uterus measurements were 5.7 cm x3.7 cm x2.2 cm although no ovarian tissue or follicles were identified on MRI. Her biochemical profile also showed decreases in FSH (3.48 mIU/mL) and LH (0.99 mIU/mL) and an increase in estradiol (38pg/mL). Exome sequencing was performed and revealed biallelic missense variants c.766C&amp;gt;T, p.(Pro256Ser) and c.1036G&amp;gt;C p.(Gly346Arg) in exon 2 of the INHA (NM_002191) gene. Both variants are rare in the human population, seen in a heterozygous state with a global allele frequency (gnomADv2.1) of 0 and 0.00002790 (rs780833794), respectively, and predicted to be damaging by bioinformatic tools. INHA, a member of the transforming growth factor-β (TGF-β) superfamily, encodes the alpha subunit of glycoprotein hormones inhibin A and B. Studies in animal models indicate that inhibin A negatively regulates follicle stimulating hormone (FSH) secretion by suppressing FSHR expression and plays a crucial role in ovarian steroid hormone production, follicular development, proliferation and apoptosis of granulosa cells, and oocyte maturation. Heterozygous pathogenic variants in the INHA gene have been reported in patients with primary ovarian insufficiency (POI) and secondary amenorrhea1, while our patient with biallelic variants in INHA is affected by gonadal dysgenesis, primary amenorrhea, absence of puberty, a more severe POI phenotype. Conclusion To our knowledge, this is the first case of biallelic mutations in INHA gene leading to a severe phenotype (gonadal dysgenesis, primary amenorrhea and absence of puberty) compared to heterozygous mutations that lead to POI with secondary amenorrhea. 1