Usefulness of fetal autopsy in the diagnosis of blomstrand chondrodysplasia: a report of three cases

Beena, Suresh; Murlidhar, Lata; Seshadri, Suresh; Jagadeesh, Sujatha; Suresh, Indrani

doi:10.1080/14767058.2016.1199675

Cited by 2 publications

(7 citation statements)

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“…Furthermore, the region flanked between 435 and 459 is the helix motif of the domain that is important for solubility and interactions (Uniprot Alignment Tools; https://www.uniprot.org/align). It is disclosed as ultrarare in populations, in dbSNP (1 heterozygous in 120908 ExAC population, and none in gnomAD) 9 . In silico prediction tools rate the variant as potentially damaging (SIFT: 0.004, MutationTaster: 0.81, PolyPhen2: 1, MetaLR: 0.52, REVEL: 0.64, DANN: 0.99, and PROVEAN: −11.03, −12.73).…”

Section: Resultsmentioning

confidence: 99%

“…(1 heterozygous in 120908 ExAC population, and none in gnomAD). 9 In silico prediction tools rate the variant as potentially damaging (SIFT: 1). Details on the palate are scarce in previously reported BOCD cases; only one case was reported to have an intact palate.…”

Section: Molecular Test Resultsmentioning

confidence: 99%

“…The skeletal phenotype comprises generalized osteosclerosis, laryngeal and hyoid ossification, narrow and thick clavicles, short and thickened ribs, short and dense vertebral bodies, ovoid ilia, severe micromelia, dumbbell‐like appearance of tubular bones, and advanced ossification of carpal/tarsal bones (Table 1). The most remarkable skeletal finding of BOCD is the advanced bone and laryngeal cartilage maturation 2,5,9,19,20 . It is caused by biallelic inactivating variants in parathormone (PTH) receptor 1, resulting in a decreased response to PTH, altered enchondral bone formation, and accelerated cartilage apoptosis 19 .…”

Section: Discussionmentioning

confidence: 99%

“…Since the first report on a Finnish female newborn who died suddenly after birth described by Blomstrand et al. in 1985, only 17 cases have been reported to date, based on the radiological or histopathological evaluation after stillbirth or neonatal death 2,4–10 . BOCD is caused by biallelic loss‐of‐function variants in PTH1R.…”

Section: Introductionmentioning

confidence: 99%

“…Since the first report on a Finnish female newborn who died suddenly after birth described by Blomstrand et al in 1985, only 17 cases have been reported to date, based on the radiological or histopathological evaluation after stillbirth or neonatal death. 2,[4][5][6][7][8][9][10] BOCD is caused by biallelic loss-of-function variants in PTH1R. 3,11 It is allelic with Eiken syndrome, and Jansen type metaphyseal chondrodysplasia, caused by truncating mutations in the C-terminal cytoplasmic tail and activating PTH1R mutations, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal ultrasonographic features in Blomstrand osteochondrodysplasia: Antenatal case series confirmed by postmortem radiology and molecular diagnosis

et al. 2022

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Objective: Blomstrand osteochondrodysplasia (BOCD, MIM #215045) is an ultrarare lethal skeletal dysplasia (LSD) perinatally, characterized by extremely advanced bone maturation, generalized osteosclerosis, and severe tetramicromelia caused by biallelic loss-of-function mutations in the parathyroid hormone receptor-1 gene (PTHR1). We aim to describe prenatal ultrasonographic features in a retrospective fetal case series of BOCD and emphasize the importance of multidisciplinary antenatal evaluation of LSDs to improve the differential diagnosis. Method: Prenatal ultrasound findings of five fetal cases diagnosed with BOCD between 2000 and 2019 in the Prenatal Diagnosis Unit and Medical Genetics were reviewed, along with postmortem examination results and confirmatory molecular results.Results: All fetuses presented with severe sonographic findings of LSDs comprising tetramicromelia, thoracic hypoplasia, and retro-micrognathia. Marked cervical hyperextension was present in three fetuses. Flared metaphyses were prenatally identified in only one fetus. X-rays of four fetuses evaluated postmortem showed advanced bone maturation, generalized osteosclerosis, and dumbbell-like appearance of long bones due to metaphyseal enlargement. Conclusion:The presence of retro-micrognathia along with a protruding tongue and severe metaphyseal flaring can suggest a diagnosis of BOCD, when prenatal ultrasound findings are indicative for LSD. The diagnosis can be ascertained through postmortem clinical and radiological evaluation and/or molecular testing. Key pointsWhat's already known about this topic? � Postmortem radiologic diagnosis of Blomstrand osteochondrodysplasia (BOCD) has been well characterized. However, no specific antenatal ultrasound finding has been implemented in the diagnosis of this ultrarare skeletal dysplasia, except for severe tetramicromelia.

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Section: Resultsmentioning

confidence: 99%

Section: Molecular Test Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prenatal ultrasonographic features in Blomstrand osteochondrodysplasia: Antenatal case series confirmed by postmortem radiology and molecular diagnosis

et al. 2022

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Identification of a novel heterozygous PTH1R variant in a Chinese family with incomplete penetrance

Wang,

Zhao,

Zhang

et al. 2023

Molec Gen & Gen Med

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BackgroundMutations in PTH1R are associated with Jansen‐type metaphyseal chondrodysplasia (JMC), Blomstrand osteochondrodysplasia (BOCD), Eiken syndrome, enchondroma, and primary failure of tooth eruption (PFE). Inheritance of the PTH1R gene can be either autosomal dominant or autosomal recessive, indicating the complexity of the gene. Our objective was to identify the phenotypic differences in members of a family with a novel PTH1R mutation.MethodsThe proband was a 13‐year, 6‐month‐old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High‐throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three‐dimensional structures were analyzed and displayed using the I‐TASSER website and PyMOL software.ResultsHigh‐throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic.ConclusionsWe identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.

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Usefulness of fetal autopsy in the diagnosis of blomstrand chondrodysplasia: a report of three cases

Cited by 2 publications

References 6 publications

Prenatal ultrasonographic features in Blomstrand osteochondrodysplasia: Antenatal case series confirmed by postmortem radiology and molecular diagnosis

Prenatal ultrasonographic features in Blomstrand osteochondrodysplasia: Antenatal case series confirmed by postmortem radiology and molecular diagnosis

Identification of a novel heterozygous PTH1R variant in a Chinese family with incomplete penetrance

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