Frameshift Mutation in a Chinese Patient with Brachydactyly Type C Involving the Third Metacarpal: A Case Report.

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.

Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly.

Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth-plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone-related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)-like skeletal malformations without a clear clinical diagnosis were analyzed by whole-exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho-rhino-phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)-binding zinc-containing domain) and Ikaros-like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO-like features, and the need for a close interdisciplinary workout in these rare patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

What to consider when pseudohypoparathyroidism is ruled out: iPPSD and differential diagnosis.

BACKGROUND: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright's hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. METHODS: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. RESULTS: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. CONCLUSIONS: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes.

Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel-Manzke syndrome in a fetus.

Pierre-Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel-Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel-Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G>T; p.(Ala100Ser) and the so far undescribed variant c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel-Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel-Manzke syndrome.

Blepharophimosis Ptosis Epicanthus Inversus Syndrome With Congenital Hypothyroidism and Brachydactyly in a 7-Year-Old Girl.

A 7-year-old female presented with blepharophimosis ptosis epicanthus inversus syndrome with congenital hypothyroidism and brachydactyly. She displayed typical manifestations of type II blepharophimosis ptosis epicanthus inversus syndrome (normal uterus position, ovarian volume, and normal serum hormone levels). She takes levothyroxine sodium daily due to her congenital hypothyroidism. Karyotype analysis and genetic analysis of FOXL2 coding sequence was found to be normal. mtDNA A3243G, A8344G, 8993, and 13513 genes were also normal. The absence of mutations excluded mitochondrial encephalomyopathies. To the best of our knowledge, this is the first reported case of blepharophimosis ptosis epicanthus inversus syndrome with congenital hypothyroidism and brachydactyly.

Variable expressivity of the phenotype in two families with brachydactyly type E, craniofacial dysmorphism, short stature and delayed bone age caused by novel heterozygous mutations in the PTHLH gene.

Brachydactyly refers to shortening of digits due to hypoplasia or aplasia of bones forming the hands and/or feet. Isolated brachydactyly type E (BDE), which is characterized by shortened metacarpals and/or metatarsals, results in a small proportion of patients from HOXD13 or PTHLH mutations, although in the majority of cases molecular lesion remains unknown. BDE, like other brachydactylies, shows clinical heterogeneity with highly variable intrafamilial and interindividual expressivity. In this study, we investigated two Polish cases (one familial and one sporadic) presenting with BDE and additional symptoms due to novel PTHLH mutations. Apart from BDE, the affected family showed short stature, mild craniofacial dysmorphism and delayed bone age. Sanger sequencing of PTHLH revealed a novel heterozygous frameshift mutation c.258delC(p.N87Tfs*18) in two affected individuals and one relative manifesting mild brachydactyly. The sporadic patient, in addition to BDE, presented with craniofacial dysmorphism, normal stature and bone age, and was demonstrated to carry a de novo heterozygous c.166C>T(p.R56*) mutation. Our paper reports on the two novel truncating PTHLH variants, resulting in variable combination of BDE and other symptoms. Data shown here expand the knowledge on the phenotypic presentation of PTHLH mutations, highlighting significant clinical variability and incomplete penetrance of the PTHLH-related symptoms.

Duplication of PTHLH causes osteochondroplasia with a combined brachydactyly type E/A1 phenotype with disturbed bone maturation and rhizomelia.

Parathyroid hormone-like hormone (PTHLH, MIM 168470) plays an important role in endochondral bone development and prevents chondrocytes from differentiating. Disease-causing variants and haploinsufficiency of PTHLH are known to cause brachydactyly type E and short stature. So far, three large duplications encompassing several genes including PTHLH associating with enchondromatas and acro-osteolysis have been described in the literature. Here, we report on a three-generation pedigree with short humerus, curved radius, and a specific type of severe brachydactyly with features of types E and A1 but without the enchondromatas and the acro-osteolysis. Microarray-based comparative genomic hybridization (array-CGH) revealed a 70-kb duplication on chromosome 12p11.22 encompassing only PTHLH. Our data extend the phenotypic spectrum associated with copy number variations of PTHLH, and this family is to our knowledge the first description harboring a microduplication encompassing only PTHLH.

Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review.

Autosomal-dominant brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Alterations that predict haploinsufficiency of PTHLH, the gene coding for parathyroid hormone related protein (PTHrP), have been identified as a cause of this disorder in seven families. Here, we report three patients affected with brachydactyly type E, caused by PTHLH mutations expected to result in haploinsufficiency, and discuss our data compared to published reports.

Cleidocranial dysplasia syndrome (CCD) with an unusual finding in a young patient.

Cleidocranial dysplasia (CCD), an autosomal dominant disorder with a prevalence of 1 in 1,000,000 individuals, presents with a wide range of variability. Dentists are often the first to encounter patients with CCD, some of whom do not show typical manifestations. Since it has similar features to other pathologies, CCD is misdiagnosed as other conditions. A 10-year-old boy suffering from CCD was misdiagnosed as having rickets and was referred for non-eruption of a few permanent teeth along with an unaesthetic facial appearance. Clinically and radiologically, a diagnosis of CCD was made. Currently, management of this patient's orofacial manifestations is underway.

A Novel Missense Mutation of NOG Interferes With the Dimerization of NOG and Causes Proximal Symphalangism Syndrome in a Chinese Family.

OBJECTIVES: NOG is an antagonist to bone morphogenetic proteins and plays an important role in proper bone and joint development. Dominant mutations in NOG may lead to a series of symphalangism spectrum disorders. In this study, we aimed to identify the genetic cause and the pathogenic mechanism of an autosomal dominant disorder with cosegregating proximal symphalangism and conductive hearing impairment in a Chinese family. METHODS: Mutation screening of NOG was performed in the affected family members by polymerase chain reaction (PCR) amplification and direct sequencing. Western blotting analysis of NOG was performed in the leukocyte samples of the family members. RESULTS: A novel p.W150C heterozygous mutation in NOG was identified cosegregating with the proximal symphalangism disorder in the family. Western blotting analysis showed that the p.W150C mutation interferes with the dimerization of the mutant NOG. CONCLUSIONS: Our results agreed with previously published results of in vitro studies and suggested that impaired dimerization of mutant NOG is an important pathogenic mechanism for the NOG-related symphalangism spectrum disorder.

Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature.

Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone (PTHLH) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated.

Absence of nasal bone and brachydactyly: a probable new familial syndrome.

Brachydactyly is a relatively common congenital abnormality and can be associated with many other malformations. However, brachydactyly in association with absence of nasal bone is rare. Two Chinese siblings with a combination of nasal bone absence and brachydactyly are presented, apparently without other abnormalities. This combination of features do not fit into any previously described syndrome and we suggest that this case represents a new familial syndrome. Molecular genetics screening didn't revealed any specific pathogenic variants in the two siblings.

Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.

Deletions of the chromosomal region 2q37 cause brachydactyly-mental retardation syndrome (BDMR), also known as Albright hereditary osteodystrophy-like syndrome. Recently, histone deacetylase 4 (HDAC4) haploinsufficiency has been postulated to be the critical genetic mechanism responsible for the main clinical characteristics of the BDMR syndrome like developmental delay and behavioural abnormalities in combination with brachydactyly type E (BDE). We report here on the first three generation familial case of BDMR syndrome with inheritance of an interstitial microdeletion of chromosome 2q37.3. The deletion was detected by array comparative genomic hybridization and comprises the HDAC4 gene and two other genes. The patients of this pedigree show a variable severity of psychomotor and behavioural abnormalities in combination with a specific facial dysmorphism but without BDE. Given that only about half of the patients with 2q37 deletions have BDE; we compared our patients with other patients carrying 2q37.3 deletions or HDAC4 mutations known from the literature to discuss the diagnostic relevance of the facial dysmorphism pattern in 2q37.3 deletion cases involving the HDAC4 gene. We conclude that HDAC4 haploinsufficiency is responsible for psychomotor and behavioural abnormalities in combination with the BDMR syndrome-specific facial dysmorphism pattern and that these clinical features have a central diagnostic relevance.

A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.

Brachydactyly type C (BDC), a well-recognized autosomal dominant hand malformation, displays brachymesophalangy of the second, third, and fifth fingers, a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger. An "angel-shaped phalanx" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias, such as angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. BDC and ASPED result from mutations in the CDMP1 gene. We report here a Mexican patient with BDC and clinical features of ASPED who carries a novel mutation in CDMP1, confirming that BDC and ASPED are part of the CDMP1 mutational spectrum. Based on the large number of clinical features in common, we suggest that both anomalies are part of the same clinical spectrum. Supported by an extensive review of the literature, a possible genotype-phenotype correlation in the mutational spectrum of this gene is proposed.

Brachydactylia as a phenotypic feature of mitochondrial disorder.

Mitochondrial disorders (MIDs) may occasionaly go along with dysmorphism but hand deformities, as in the following case, have been only rarely reported. A 72 year old female with ptosis, hypoacusis, tremor, myopathy, diabetes mellitus, arterial hypertension, severe cardiac disease, pulmonary hypertension, gastric carcinoid, hepatopathy, generalised atherosclerosis, anemia, polyarthrosis, and hyperlipidemia, additionally presented with brachydactylia. Upon neurological work-up a MID was suspected. The family history was positive for diabetes but negative for brachydactylia or other features of a MID. MIDs may be associated with brachydactylia. Skeletal deformities may be a phenotypic manifestation of MIDs.

Unilateral congenital terminal finger absences: a condition that differs from symbrachydactyly.

PURPOSE: To describe a type of nonhereditary unilateral transverse deficiency, which we have named hypodactyly, that is distinct from symbrachydactyly or amniotic disruption sequence. METHODS: We identified 19 patients with unilateral congenital anomalies consisting of absent or short bulbous fingers that lack terminal ectodermal elements. Medical records and radiographs were retrospectively reviewed and contrasted with the typical findings of symbrachydactyly and amniotic disruption sequence. RESULTS: No associated syndromes or potentially causative diagnoses were identified in the hypodactyly patients. The digital absences were of a truncated pattern with thickened, tubular soft tissue coverage. Radiographs revealed a pattern of severity progression that is different from that of symbrachydactyly. Distal phalanges were the bony elements absent most frequently, followed sequentially by the middle phalanx and proximal phalanx. In all cases, metacarpals were present. Unlike symbrachydactyly, the ulnar 2 digits were more involved than the index and long fingers, and the thumb was the least involved digit. CONCLUSIONS: Hypodactyly appears to be a congenital hand anomaly that is clinically and radiographically different from symbrachydactyly or amniotic disruption sequence and is presumed to be caused by a distinct pathomechanism. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.