A Rare Inherited Bone Marrow Failure Syndrome Disclosed by Reanalysis of the Exome Data of a Patient Evaluated for Cytopenia and Dysmorphic Features.

BACKGROUND: Multisystemic findings of inherited bone marrow failure syndromes may cause difficulty in diagnosis. Exome sequencing (ES) helps to define the etiology of rare diseases and reanalysis offers a valuable new diagnostic approach. Herein, we present the clinical and molecular characteristics of a girl who was referred for cytopenia and frequent infections. CASE REPORT: A 5-year-old girl with cytopenia, dysmorphism, short stature, developmental delay, and myopia was referred for genetic counseling. Reanalysis of the ES data revealed a homozygous splice-site variant in the DNAJC21 (NM_001012339.3:c.983+1G>A), causing Shwachman-Diamond Syndrome (SDS). It was shown by the RNA sequencing that exon 7 was skipped, causing an 88-nucleotide deletion. CONCLUSIONS: Precise genetic diagnosis enables genetic counseling and improves patient management by avoiding inappropriate treatment and unnecessary testing. This report would contribute to the clinical and molecular understanding of this rare type of SDS caused by DNAJC21 variants and expand the phenotypic features of this condition.

Two new cases with novel pathogenic variants reflecting the clinical diversity of Schaaf-Yang syndrome.

Schaaf-Yang syndrome (SHFYNG) is a rare pleiotropic disorder, characterized by hypotonia, joint contractures, autism spectrum disorders (ASD), and developmental delay/intellectual disability. Although it shares some common features with Prader-Willi Syndrome, joint contractures, and ASD were more commonly detected in in this syndrome. Recently, it was shown that truncating variants in the paternal allele of the MAGEL2 gene cause SHFYNG. Here, we present two patients diagnosed with SHFYNG syndrome having two different novel truncating variants in the MAGEL2 gene, one paternally inherited and one de novo. One patient had obesity, brachydactyly and dysmorphic features, and the other patient presented with contractures, severe hypotonia and early death. This is the first report of Turkish SHFYNG syndrome cases presented to emphasize the phenotypic diversity of the syndrome.

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features.

Biallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.

Evaluation of growth, puberty, osteoporosis, and the response to long-term bisphosphonate therapy in four patients with osteoporosis-pseudoglioma syndrome.

Osteoporosis-pseudoglioma syndrome (OPPG; MIM #259770) is a rare autosomal recessively inherited disease, characterized by early-onset osteoporosis and congenital blindness, caused by loss-of-function mutations in the LRP5 gene. Beneficial effects of bisphosphonate treatment in patients with OPPG are well known, while follow-up data on growth and pubertal parameters are limited. This article provides clinical follow-up data and long-term bisphosphonate treatment results in four OPPG patients from three unrelated families, ranging between 2.5 and 7 years of age at presentation. Clinical diagnosis was molecularly confirmed in all patients, with four different germline biallelic LRP5 mutations including a novel nonsense variant c.3517C>T (p.(Gln1173*)) in two siblings with marked phenotypic variability. Anthropometric and pubertal data and bone mineral density (BMD) measurements were evaluated retrospectively. Early puberty was observed in two patients. The bisphosphonate treatment duration of patients varied around 4-7 years and improvement in BMD z-scores with bisphosphonate treatment was demonstrated in all patients (z-score changes were +5.6, +4.0, +1.0, and +1.3). Although further research is needed to identify the possible association between early puberty and OPPG, all OPPG patients should be followed up with detailed endocrinological evaluation regarding pubertal status.

Does Genotype-Phenotype Correlation Exist in Vitamin D-Dependent Rickets Type IA: Report of 13 New Cases and Review of the Literature.

Vitamin D-dependent rickets type IA (VDDR-IA) is caused by biallelic mutations in CYP27B1. Data regarding genotype-phenotype correlation in VDDR-IA are scarce. Here, we aimed to investigate clinical/genotypic features and long-term follow-up of 13 new cases with VDDR-IA and genotype-phenotype correlation of reported cases in the literature. Thirteen patients with VDDR-IA were evaluated. Eight patients had reached their final height at the time of the study and, for whom, long-term outcome data were analyzed. Further, all VDDR-IA patients in the literature (n:183) were analyzed and clinical-genetic features were recorded. The median age of diagnosis was 2.55 ± 1.13 (1.0-12) years. Initial diagnoses before referral to our clinic were nutritional rickets (n:7), hypophosphatemic rickets (n:2), and pseudohypoparathyroidism (n:1). All had biochemical evidence suggestive of VDDR-IA; except one with elevated 1,25(OH)2D3 and another with hyperphosphatemia, in whom pseudohypoparathyroidism was excluded with molecular tests. Combined analyses of our cohort and other series in the literature demonstrated that three most common CYP27B1 mutations are p.F443Pfs*24, c.195 + 2T > G, and p.V88Wfs*71. In Turkish population, p.K192E mutation along with the former two is the most common mutations. Comparison of clinical features demonstrated that c.195 + 2T > G mutation causes the most severe and p.K192E mutation causes the least severe phenotype with respect to age and height at presentation and calcitriol requirement. We found a clear genotype-phenotype correlation in VDDR-IA, notably CYP27B1 intronic c.195 + 2T > G mutation causes a more severe phenotype with lower height SDS at presentation and, higher calcitriol requirement, while less severe phenotype occurs in p.K192E mutation.

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age.

Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.

Body mass index at the presentation of premature adrenarche is associated with components of metabolic syndrome at puberty.

The aim of this study was to analyze the relationship between premature adrenarche (PA) and metabolic syndrome (MeS) parameters at presentation and during puberty. This study comprised 47 girls with PA. Age- and puberty-matched 22 healthy girls without PA were the control group. Patients were evaluated at admission (first evaluation) and later in puberty (second evaluation). Anthropometric measurements, lipid levels, and hormonal parameters were studied and oral glucose tolerance test was performed. Indices for insulin resistance (IR) were calculated. The study group was divided in subgroups according to body mass index (BMI) and compared with the control group. The age of the PA group at first evaluation was 8.0 ± 1.1 years; mean height SDS and BMI SDS were 0.4 ± 1.2 and 0.6 ± 0.9, respectively. Age of PA group at the second evaluation was 12.9 ± 2.4 years. Frequency of obesity and overweight was 14.9 and 23.4%. Dyslipidemia ratio was 28.3%. PA group had significantly higher BMI than controls. Mean insulin concentration was higher and mean glucose and FGIR were lower in PA group and also dyslipidemia ratio was 5.3 times higher in PA than controls (p = 0.040). In PA group, overweight/obese subjects had still higher BMI at second evaluation and also higher fasting glucose, insulin, HOMA-IR. However, PA children with exaggerated DHEAS concentrations compared to those without had similar BMI SDS, insulin sensitivity, and secretion indices and lipid profile at second evaluation. BMI SDS at first evaluation was positively correlated with HOMA-IR at puberty; however, there is no correlation between DHEAS at first evaluation and HOMA-IR at puberty.Conclusion: BMI at adrenarche is more important than prepubertal adrogen concentrations such as DHEAS, while predicting the IR in puberty. Long-term follow-up of children supports the observation that PA per se may be related to IR; however, the risk increases with obesity. What is Known: • Premature adrenarche (PA) is receiving more attention as evidence emerges for a relation between early androgen excess and metabolic syndrome. • The onset of the adrenal androgen production before 8 years in girls defined as PA. Pubarche, axillary hair, apocrine body odor, acne are typical phenotypic features of PA. What is New: • Body mass index at adrenarche is an important risk factor for development of insulin resistance in pubertal ages. • Degree of dehydroepiandrosterone sulfate elevation was not shown as a risk factor for insulin resistance.

Two novel mutations in XYLT2 cause spondyloocular syndrome.

We report on two new patients with spondyloocular syndrome. Both patients harbor novel homozygous mutations in the XYLT2 gene. The patients present severe generalized osteoporosis, multiple fractures, short stature, cataract, and mild hearing impairment. XYLT2 mutations have been identified in spondyloocular syndrome, however only five mutations have been reported previously. These two patients with novel mutations extend the phenotypic and genotypic spectrum of spondyloocular syndrome.

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development.

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11ß-hydroxylase, 3ß-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.

Phenotype-Genotype Correlations of GH1 Gene Variants in Patients with Isolated Growth Hormone Deficiency or Multiple Pituitary Hormone Deficiency.

INTRODUCTION: Genetic forms of growth hormone deficiency (GHD) may occur as isolated GHD (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to present the clinical and molecular characteristics of patients with IGHD/MPHD due to the GH1 gene variants. METHODS: A gene panel accommodating 25 genes associated with MPHD and short stature was used to search for small sequence variants. Multiplex ligation-dependent probe amplification was performed in patients with normal panel results to investigate gross deletion/duplications. Segregation in the family was performed by Sanger sequencing. RESULTS: The GH1 gene variants were detected in 5 patients from four unrelated families. One patient had IGHD IA due to homozygous whole GH1 gene deletion and one had IGHD IB due to novel homozygous c.162C>G/p.(Tyr54*) variant. Two patients from a family had previously reported heterozygous c.291+1G>A/p.(?) variant in which clinical and genetic characteristics were compatible with IGHD II accompanying MPHD. One patient had clinical and laboratory characteristics of IGHD II with MPHD but the heterozygous c.468 C>T/p.(R160W) variant had conflicting results about the relationship with the phenotype. CONCLUSION: Expanding our knowledge of the spectrum of GH1 gene variants by apprehending clinical and molecular data of more cases, helps to identify the genotype-phenotype correlation of IGHD/MPHD and the GH1 gene variants. These patients must be regularly followed up for the occurrence of additional pituitary hormone deficiencies.

A Novel RNPC3 Gene Variant Expands the Phenotype in Patients with Congenital Hypopituitarism and Neuropathy.

INTRODUCTION: Pathogenic biallelic RNPC3 variants cause congenital hypopituitarism (CH) with congenital cataracts, neuropathy, developmental delay/intellectual disability, primary ovarian insufficiency, and pituitary hypoplasia. Here, we aimed to evaluate the clinical and molecular characteristics of 2 patients with CH and neuropathy. MATERIALS AND METHODS: Proband was evaluated by clinical, laboratory, and radiological exams, followed by exome sequencing (ES). Clinical investigation of an affected sibling and variant segregation in the family was performed by Sanger sequencing. A three-dimensional protein model study was conducted to predict the effect of the variant on the function of the RNPC3 peptide. RESULTS: Proband was a 16-month-old girl who was referred for the evaluation of failure to thrive. Her height, weight, and head circumference were 55.8 cm (-7.6 SDS), 6.5 kg (-3.6 SDS), and 41.8 cm (-3.82), respectively. She had a developmental delay and intellectual disability. Central hypothyroidism, growth hormone, and prolactin deficiencies were identified, and MRI revealed pituitary hypoplasia. Electroneuromyography performed for the gait abnormality revealed peripheral neuropathy. A homozygous novel variant c.484C>T/p.(Pro162Ser) in the RNPC3 was detected in the ES. Her brother had the same genotype, and he similarly had pituitary hormone deficiencies with polyneuropathy. CONCLUSION: Expanding our knowledge of the spectrum of RNPC3 variants, and apprehending clinical and molecular data of additional cases, is decisive for accurate diagnosis and genetic counseling.

Long-Term Endocrinologic Follow-Up of Children with Brain Tumors and Comparison of Growth Hormone Therapy Outcomes: A SingleCenter Experience.

OBJECTIVE: Brain tumors in childhood carry a high risk for endocrine disorders due to the direct effects of the tumor and/or surgery and radiotherapy. Somatotropes are vulnerable to pressure and radiotherapy; therefore, growth hormone deficiency is one of the most frequent abnormalities. This study aimed to evaluate endocrine disorders and recombinant growth hormone treatment outcomes in brain tumor survivors. MATERIALS AND METHODS: In this study, 65 (27 female) patients were classified into 3 groups as craniopharyngioma (n = 29), medulloblastoma (n = 17), and others (n = 19). "Others" group included astrocytoma, ependymoma, germinoma, pineoblastoma, and meningioma patients. Anthropometric data and endocrine parameters of patients and their growth outcome with/without recombinant growth hormone therapy were collected from medical records, retrospectively. RESULTS: Mean age at the first endocrinological evaluation was 8.7 ± 3.6 years (range: 1.0- 17.1 years). Height, weight, and body mass index standard deviation score, mean ± standard deviation (median) values were -1.7 ± 1.7 (-1.5), -0.8 ± 1.9 (-0.8), and 0.2 ± 1.5 (0.4), respectively. Hypothyroidism (central 86.9%, primary 13.1%) was detected during follow-up in 81.5% of patients. Primary hypothyroidism in medulloblastoma (29.4%) was significantly higher compared to other groups (P = .002). The frequency of hypogonadotropic hypogonadism, central adrenal insufficiency, and diabetes insipidus was significantly high in the craniopharyngioma cases. CONCLUSION: In our study, endocrine disorders other than growth hormone deficiency were also frequently observed. In craniopharyngioma cases, the response to recombinant growth hormone therapy was satisfactory. However, there was no improvement in height prognosis during recombinant growth hormone therapy in medulloblastoma patients. A multidisciplinary approach to the care of these patients, referral for endocrine complications, and guidelines on when recombinant growth hormone therapy is required.

Challenges in the Management of a 7-Year-Old Child with Thyrotropin-Secreting Pituitary Adenoma and the Review of the Literature.

INTRODUCTION: Thyrotropin-producing pituitary adenoma (TSHoma) is a very rare disease, representing less than 1% of the pituitary tumours and presenting with elevated thyroid hormones and normal/high TSH concentrations. CASE PRESENTATION: A 7-year-old boy with nervousness was referred by his psychiatrist for elevated free T4, T3, and TSH levels. Initial evaluation revealed an elevated α-subunit. Pituitary magnetic resonance imaging (MRI) demonstrated a macroadenoma. The patient underwent a trans-sphenoidal tumour resection (TSS) which showed positive immunohistochemical staining for TSH, growth hormone, and prolactin in tumoral tissue. Euthyroidism was achieved for 1 year after TSS, then recurrence of tumour with elevated TSH and thyroid hormone levels necessitated a re-operation with TSS followed by gamma-knife radiosurgery. The euthyroid state was achieved and lasted for 2.5 years this time, but due to the recurrence, medical treatment had been commenced with cabergoline and octreotide. Euthyroidism was maintained for the last 4 years on monthly octreotide treatment. A repeat MRI demonstrated no pituitary mass, but a mass in the sphenoidal sinus had been detected. Removal of this mass by surgery did not achieve euthyroidism. 68Ga-DOTA-TATE positron emission tomography/computed tomography showed residual tissue extending from the pituitary region to the sphenoid sinus. The patient's bone age was advanced by 2 years at diagnosis which became 4 years in 1 year after the diagnosis and remained so throughout follow-up, leading to a final height of -3.3 SDS below his target height at the age of 16 years. CONCLUSION: The diagnosis, treatment, and follow-up of TSHomas are challenging, and short stature due to accelerated bone maturation is a complication of paediatric TSHomas.

PROKR2 Mutations in Patients with Short Stature Who Have Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiency

Objective: Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of pituitary hormone deficiencies, suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in gonadotropin releasing hormone-expressing neuron development. Here, we present the clinical and molecular findings of four patients with PROKR2 mutations. Methods: Next-generation targeted sequencing was used to screen 25 genes in 59 unrelated patients with multiple pituitary hormone deficiency (MPHD), isolated growth hormone (GH) deficiency, or idiopathic short stature. Results: Two different, very rare PROKR2 missense alterations classified as pathogenic (NM_144773.4:c.518T>G; NP_658986.1:p. (Leu173Arg)) and likely pathogenic (NM_144773.4:c.254G>A; NP_658986.1:p.(Arg85His)) were identified in four patients in heterozygous form. Patient 1 and Patient 2 presented with short stature and were diagnosed as GH deficiency. Patient 3 and Patient 4 presented with central hypothyroidism and cryptorchidism and were diagnosed as MPHD. No other pathogenic alterations were detected in the remaining 24 genes related to short stature, MPHD, and hypogonadotropic hypogonadism. Segregation analysis revealed asymptomatic or mildly affected carriers in the families. Conclusion: PROKR2 dominance should be kept in mind as a very rare cause of GH deficiency and MPHD. Expressional variation or lack of penetrance may imply oligogenic inheritance or other environmental modifiers in individuals who are heterozygous carriers.

Decline in the Age of Menarche in Istanbul Schoolgirls Over the Last 12 Years

Objective: Menarche is the endpoint of a sequence of maturational events of female puberty. The timing of menarche is a strongly heritable trait. However, secular trends suggest that lifestyle and environmental factors are important. To assess the trend in age at menarche (AAM), and its associated factors in Istanbul over the last 12 years. Methods: A cross-sectional study was carried out between March and April 2022 on schoolgirls aged 9-18 years. A predesigned and self-administered questionnaire was filled out anonymously by the students. The data of AAM was included in the statistical analysis if the time of AAM is remembered in both months and years. A probit model was used to calculate the median AAM. The findings were compared with those from a study performed 12 years ago in the same region of Istanbul. Results: Among 9000 girls to whom the questionnaire was distributed, 1749 (19.5%) responded. The median AAM of 1374 girls whose AAM information was considered valid was 12.04 years (95% confidence interval: 12.01-12.13), 0.7 years lower than was reported 12 years ago (p<0.0001). AAM was correlated positively with maternal AAM, and negatively with body mass index (BMI) standard deviation score and maternal educational status (p<0.0001, p<0.0001 and p=0.002), respectively. There was no correlation between the AAM and birth weight. Girls with BMI percentile ≥85% (n=251) had earlier menarche than the ones with BMI percentile <85% (n=1072) (11.5 vs. 12.1 years, p<0.0001). Among the mother-daughter pairs (n=1162), AAM of girls was 0.91 years (median 0.94 years) earlier than their mothers. Conclusion: The present study demonstrates a significant downward trend in the menarcheal age in Istanbul over the last twelve years. These findings support a strong contribution from genetic factors and BMI on AAM.

Venous thrombosis in a pseudohypoparathyroidism patient with a novel GNAS frameshift mutation and complete resolution of vascular calcifications with acetazolamide treatment.

Introduction Pseudohypoparathyroidism type IA (PHP1A) is characterized by end-organ resistance to multiple hormones and Albright's hereditary osteodystrophy (AHO). PHP1A is caused by inactivating mutations of the GNAS gene encoding the α-subunit of the stimulatory G protein (Gsα). In line with the underlying genetic defect, impaired inhibition of platelet aggregation has been demonstrated in some patients. However, no PHP1A case with thrombotic events has been described. Also, PHP1A cases typically have subcutaneous ossifications, but soft tissue calcifications are another common finding. Treatment options for those and other non-hormonal features of PHP1A are limited. Case Presentation A female patient presented with short stature, fatigue, and exercise-induced carpopedal spasms at age 117/12 years. Diagnosis of PHP1A was made based on hypocalcemia, hyperphosphatemia, elevated serum PTH, and AHO features, including short stature and brachydactyly. A novel frameshift variant was detected in the last exon of GNAS (c.1065_1068delGCGT, p.R356Tfs*47), showing complete loss of baseline and receptor-stimulated activity in transfected cells. The patient developed venous thrombosis and vascular and subcutaneous calcifications on both forearms after venous puncture on the right and extravasation of calcium gluconate during treatment on the left. The thrombosis and calcifications completely resolved following treatment with low molecular weight heparin and acetazolamide for 5 and 8 months, respectively. Conclusions This case represents the first PHP1A patient displaying thrombosis and the first successful use of acetazolamide for PHP1A-associated soft tissue calcifications, thus providing new insights into the treatment of non-endocrinological features in this disease.