Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by the excessive secretion of parathyroid hormone (PTH), resulting in significant hypercalcemia and skeletal complications. In the context of chronic kidney disease (CKD), neglected PHPT can progress to a biochemical profile resembling tertiary hyperparathyroidism (THPT), further complicating diagnosis, especially when concomitant genetic skeletal disorders (GSD) exist. We present a rare and complex case of a 63-year-old woman with stage 3 CKD who presented with recurrent pathological fractures, severe hypercalcemia, and extensive osteolytic bone lesions in both femurs. The patient's clinical picture was complicated by notable skeletal anomalies, including short stature, brachydactyly, and hypoplastic metatarsals. Elevated serum calcium, markedly increased PTH levels, hypercalciuria, hyperphosphaturia, and parathyroid imaging, confirmed previously untreated PHPT resulting in a THPT-like biochemical profile in the setting of CKD. The patient ultimately underwent surgical fixation for bilateral lower limb fractures, followed by a simple parathyroidectomy, achieving symptomatic relief and metabolic stabilization. A genetic investigation, prompted by distinctive skeletal features, uncovered a frameshift mutation in the growth differentiation factor 5 (GDF5) gene indicative of brachydactyly type C, a rare form of GSD. This case highlights the complexity in differentiating PHPT from other causes of hyperparathyroidism in the setting of CKD, particularly when concurrent skeletal dysplasia is present. The thorough clinical, biochemical, imaging, and genetic assessments were pivotal in reaching an accurate diagnosis and guiding appropriate surgical management.

Brachydactyly is a common feature of congenital hand anomalies characterized by shortening of the phalanges and/or metacarpals. Mutation of growth differentiation factor-5 (GDF5) may result in loss of appearance and function in brachydactyly type C (BDC). Herein, we describe an 11 year-old Chinese BDC patient with significant shortening of the 1st, 2nd, 3rd, and 5th digits. Notably, according to the analysis of metacarpophalangeal pattern profiles, we do not think the 4th digit appears unaffected as usual. In this patient a novel heterozygous frameshift mutation was identified (c.349delG) causing termination of translation after translating six amino acids from codon 117 (p.A117fs*6). This mutation is located in the propeptide region of GDF5, causing GDF5 haploinsufficiency in BDC. Considering our results expanding the genetic spectrum of BDC-causing mutations, further molecular analysis to diagnose and reclassify isolated brachydactyly on the basis of genotype rather than phenotype is warranted.

Brachydactyly (BD) type C is a rare form of familial BD caused by GDF5 mutations. Some of the affected children have severe clinodactyly requiring surgery. The literature is limited to case reports. The current retrospective study included 15 Saudi Arabian families with 42 affected children seen by the author for 25 years. A total of 23 digits (in 23 hands) underwent surgical correction of clinodactyly using a closing wedge osteotomy. The current study reports on the genetics, clinical presentation, radiological features, and midterm outcome of surgery. Genetic analysis was done in 6 families and confirmed the presence of 2 novel missense mutations (p.Met173Val in 3 families and p.Thr203Asn in 3 families) in the GDF5 gene. All cases in the study group demonstrated the classical clinical and radiographic features of BD type C. However, only 1 hand showed all the features of angel-shaped bony defect. The clinodactyly defect was mostly observed in the index or middle fingers. Surgery for the clinodactyly defect was only done if there was finger overlap. Closing wedge osteotomy was done in a total of 23 digits with a satisfactory outcome. This study represents the largest reported series of children undergoing surgery for correction of BD type C clinodactyly with a uniform technique performed by a single surgeon. The closing wedge osteotomy used resulted in good midterm outcomes, although long-term follow-up is lacking.

Different mutations in the Growth/Differentiation Factor 5 gene (GDF5) have been associated with varying types of skeletal dysplasia, including Grebe type chondrodysplasia (GTC), Hunter-Thompson syndrome, Du Pan Syndrome and Brachydactyly type C (BDC). Heterozygous pathogenic mutations exert milder effects, whereas homozygous mutations are known to manifest more severe phenotypes. In this study, we report a GDF5 frameshift mutation (c.404delC) segregating over six generations in an extended consanguineous Pakistani family. The family confirmed that both GTC and BDC are part of the GDF5 mutational spectrum, with severe GTC associated with homozygosity, and with a wide phenotypic variability among heterozygous carriers, ranging from unaffected non-penetrant carriers, to classical BDC and to novel unclassified types of brachydactylies.

Brachydactyly is a bone development abnormality presenting with variable phenotypes and different transmission patterns. Mutations in GDF5 (Growth and Differentiation Factor 5, MIM *601146) account for a significant amount of cases. Here, we report on a three-generation family, where the proband and the grandfather have an isolated brachydactyly with features of both type A1 (MIM #112500) and type C (MIM #113100), while the mother shows only subtle hand phenotype signs. Whole Exome Sequencing (WES) was performed on the two affected individuals. An in-depth analysis of GDF5 genotype-phenotype correlations was performed through literature reviewing and retrieving information from several databases to elucidate GDF5-related molecular pathogenic mechanisms. WES analysis disclosed a pathogenic variant in GDF5 (NM_000557.5:c.157dup; NP_000548.2:p.Leu53Profs*41; rs778834209), segregating with the phenotype. The frameshift variant was previously associated with Brachydactyly type C (MIM #113100), in heterozygosity, and with the severe Grebe type chondrodysplasia (MIM #200700), in homozygosity. In-depth analysis of literature and databases allowed to retrieve GDF5 mutations and correlations to phenotypes. We disclosed the association of 49 GDF5 pathogenic mutations with eight phenotypes, with both autosomal dominant and recessive transmission patterns. Clinical presentations ranged from severe defects of limb morphogenesis to mild redundant ossification. We suggest that such clinical gradient can be linked to a continuum of GDF5-activity variation, with loss of GDF5 activity underlying bone development defects, and gain of function causing disorders with excessive bone formation. Our analysis of GDF5 pathogenicity mechanisms furtherly supports that mutation and zygosity backgrounds resulting in the same level of GDF5 activity may lead to similar phenotypes. This information can aid in interpreting the potential pathogenic effect of new variants and in supporting an appropriate genetic counseling.