偽性副甲状腺機能低下症

Fahr syndrome, characterized by bilateral intracranial calcifications, is a rare but clinically significant complication of chronic calcium-phosphate dysregulation in pseudohypoparathyroidism (PHP). Clinical manifestations frequently do not correlate with the extent of radiological findings, posing diagnostic challenges. An 18-year-old male with longstanding PHP presented with occipital headaches, carpopedal spasms, and depressed mood following more than two weeks of medication non-compliance. Non-contrast computed tomography (CT) of the brain confirmed extensive bilateral calcifications involving the basal ganglia, thalami, dentate nuclei, and subcortical white matter, with supportive findings on magnetic resonance imaging (MRI), including T1 hypointensity, variable T2 signal, and marked blooming artifact on susceptibility-weighted imaging (SWI). Neurological examination was largely unremarkable. Laboratory evaluation revealed hypocalcemia (serum calcium 7.2 mg/dL) with elevated intact parathyroid hormone (137 pg/mL), consistent with end-organ PTH resistance; serum phosphate (4.2 mg/dL) and 25-hydroxyvitamin D (42.4 ng/mL) were within the normal range. Electroencephalography showed no epileptiform activity. Optimization of calcium and calcitriol supplementation, together with symptomatic treatment, resulted in resolution of carpopedal spasms and significant improvement in headaches and mood at 15-day follow-up. This case illustrates the marked clinical-radiological dissociation characteristic of Fahr syndrome. Neurological evaluation or neuroimaging should be considered in PHP patients who develop new neurological or neuropsychiatric symptoms, particularly in the setting of poor biochemical control.

BACKGROUND: Rare bone diseases comprise a heterogeneous group of complex and disabling conditions. Evidence on age-specific hospitalization patterns and in-hospital outcomes across multiple rare bone diseases is limited. METHODS: Population-based cohort study using national hospitalization data (01/2012-12/2021). Among 11,092,151 hospitalizations, 2,875 admissions of children and adults with rare bone diseases were identified via ICD-10 codes (X-linked hypophosphatemia, osteogenesis imperfecta, fibrous dysplasia, achondroplasia, pseudohypoparathyroidism, fibrodysplasia ossificans progressiva) and compared with 14,375 age-, sex-, and patient-complexity-matched hospitalizations from the general population. RESULTS: Hospitalization patterns differed substantially by disease and age. Patients with X-linked hypophosphatemia had an increased risk of emergency admissions in late adulthood, whereas planned admissions were more frequent in early adulthood among patients with achondroplasia and fibrous dysplasia. Malignancies were diagnosed in 22.7% of patients with X-linked hypophosphatemia, and fractures were the leading cause of hospitalization among patients with osteogenesis imperfecta. Across the rare bone diseases, patients had higher all-cause in-hospital mortality compared with matched controls (RR, 2.26; 95% CI, 1.77 to 2.89), longer hospital stays (median difference, 6 days [IQR 3-13 days]), higher risk of ICU admission (RR, 3.08; 95% CI, 2.78 to 3.40), and higher readmission risk (RR, 1.31, 95% CI, 1.15 to 1.49). CONCLUSIONS: The studied rare bone diseases are associated with distinct, disease-specific hospitalization patterns and substantially worse in-hospital outcomes across the lifespan. This underscores the need for tailored preventive strategies and coordinated, long-term care models for patients with rare bone diseases.

Evaluating hand and wrist radiographs is essential in pediatric endocrinology and clinical genetics, particularly for the assessment of suspected skeletal anomalies. In this study, we present Auto-Bone-Caliper, an automated system for the segmentation and length measurement of metacarpal and phalangeal (M&P) bones, trained and evaluated on public datasets comprising both normal and dysmorphic cases. We first introduce InstanceSAM, a two-stage framework that detects and segments all 19 M&P bones in pediatric hand radiographs, achieving Dice scores of 98.7% for normal bones and 95.0% for dysmorphic bones. We further develop and evaluate three methods for bone-length estimation, identifying a k-means-based approach as the most accurate, with relative errors of 2.2% for normal bones and 4.5% for dysmorphic bones. Our automated pipeline, Auto-Bone-Caliper, integrates InstanceSAM with the k-means-based length-estimation method. To enable scale-independent downstream analyses, we derive relative bone-length measures from the automated measurements. Using these relative measures, we statistically compare measurements obtained using Auto-Bone-Caliper on an independent dataset with a healthy reference catalog of normal bone morphologies, observing a high level of agreement (Wasserstein-1 distance = 0.012). Finally, we demonstrate a potential clinical use case of Auto-Bone-Caliper by obtaining relative metacarpophalangeal pattern profiles for three genetic conditions, namely Turner syndrome, achondroplasia, and pseudohypoparathyroidism. Our results highlight the potential of the Auto-Bone-Caliper to streamline and standardize M&P length measurement, providing an objective and reproducible tool suitable for clinical application.

BACKGROUND: The presence of multiple rare Mendelian disorders in a single patient may mask clinical recognition when phenotypes overlap. We describe a patient with longstanding myotonia congenita due to a CLCN1 variant in whom an incidental discovery of severe hypocalcemia led to the diagnosis of GNAS-related pseudohypoparathyroidism (PHP). Exome reanalysis also identified an incidental homozygous pathogenic CYP1B1 variant associated with autosomal recessive glaucoma. CASE PRESENTATION: A 23-year-old man born to consanguineous parents was referred for management of chronic myotonia congenita, manifested by delayed motor milestones, frequent falls, contractures, and muscle hypertrophy. Electrophysiological assessment demonstrated myotonic discharges, and whole-exome sequencing (WES) identified a homozygous CLCN1 splice-site variant (NM_000083.3:c.1167-10T>C) known to cause myotonia congenita. During subsequent evaluation, he was found to have severe hypocalcemia, hyperphosphatemia, markedly elevated parathyroid hormone, basal ganglia and dentate calcifications, brachydactyly, subcutaneous calcifications, and mild hypothyroidism, raising suspicion for PHP. GENETIC AND OPHTHALMOLOGIC FINDINGS: Reanalysis of WES data demonstrated a heterozygous frameshift GNAS variant (NM_080425.4:c.2494_2497delCTGA) and a homozygous CYP1B1 variant (NM_000104.4:c.182G>A; p.Gly61Glu) in addition to the CLCN1 defect. Sanger sequencing confirmed all three variants. The CYP1B1 finding prompted glaucoma-specialist evaluation. Visual acuity was 20/22 in the right eye and 20/25 in the left eye; intraocular pressures were 8 and 12 mmHg, respectively. The corneas were clear, cup-to-disc ratios were 0.4 and 0.5, and average retinal nerve fiber layer thicknesses were 74 and 75 µm. No definite glaucomatous damage was identified, and the patient was classified as a glaucoma suspect. After treatment with calcium, calcitriol, and ergocalciferol, serum calcium improved, parathyroid hormone levels declined, creatine kinase normalized, and the patient reported improved muscle stiffness and function. CONCLUSION: This case demonstrates two clinically expressed Mendelian disorders together with a third actionable molecular finding. It highlights the importance of careful phenotyping, molecular testing, and cautious genotype-phenotype interpretation, particularly in consanguineous populations.

Recent classification of skeletal dysplasias has reclassified disorders according to their underlying pathophysiologic mechanisms. The latest nosology of skeletal dysplasias introduced a new pathogenic category termed "skeletal disorders of the parathyroid hormone (PTH) signaling cascade." The group encompasses genetic defects associated with abnormal signaling of PTH, PTH-related protein (PTHrP) encoded by the PTHLH (PTH-like hormone) gene, and their common receptor termed parathyroid hormone 1 receptor (PTH1R). PTH1R is a guanine nucleotide-binding protein (G protein)-coupled receptor; and thus, defects of the a-subunit of stimulatory G protein (Gsα) and its downstream effectors cause disorders that overlap with those of the PTH signaling cascade. PTH and PTHrP have both catabolic and anabolic effects on bone metabolism, while PTHrP inhibits maturation of chondrocytes. Therefore, increased signaling of the cascade includes osteolysis that may be accompanied by focal osteosclerosis and/or delayed ossification of the growth plate or metaphyseal dysplasia. Partial loss of signaling can present as type E brachydactyly due to premature maturation of the growth plate of short tubular bones, typically exemplified by pseudohypoparathyroidism. Total loss of signaling leads to osteosclerosis and significantly accelerated bone maturation seen in a lethal sclerosing bone dysplasia termed Blomstrand dysplasia.