Congenital stapes ankylosis, broad thumbs, and hyperopia: report of a family and refinement of a syndrome

We report on a family with conductive hearing loss due to congenital stapes ankylosis, and with hyperopia, broad thumbs, and broad first toes. Neither of the studied relatives had symphalangism, possibly distinguishing this syndrome as an entity separate from the facio-audio-symphalangism and proximal symphalangism syndromes. An alternative possibility is that this family falls within the spectrum of the facioaudio-symphalangism and proximal symphalangism syndromes. Visualization of the ossicular chain, and ophthalmologic and radiologic studies are important in the evaluation of families with congenital conductive hearing loss. A characteristic physiognomy in our patients is present; this autosomal dominant syndrome was first described by Teunissen and Cremers [1990: Laryngoscope 100:380-384].     

P35S mutation in the NOG gene associated with Teunissen-Cremers syndrome and features of multiple NOG joint-fusion syndromes

We report on a new family with Teunissen-Cremers syndrome. The proband presented with congenital conductive hearing loss due to stapes ankylosis and incus short process fixation with skeletal anomalies including symphalangism, broad thumbs and broad first toes, syndactyly, brachydactyly, contractures of the elbows and knees, hyperopia and lens opacities. This constellation of symptoms is compatible with the diagnosis of one of the joint-fusion syndromes namely the Teunissen-Cremers syndrome (TCS), which was first reported in 1990. Mutations in the NOG gene which encodes the noggin protein, a bone morphogenetic protein antagonist, have been identified in TCS as well as in four other autosomal dominant disorders including proximal symphalangism (SYM1), multiple synostosis (SYNS1), Tarsal-Carpal coalition syndrome and brachydactyly type B (BDB). Interestingly, we found that the mutation P35S described in this family has already been reported in patients affected with SYM1 as well as with BDB syndromes.     

Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome

Proximal symphalangism is an autosomal-dominant disorder with ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive deafness. These symptoms are shared by another disorder of joint morphogenesis, multiple synostoses syndrome. Recently, it was reported that both disorders were caused by heterozygous mutations of the human noggin gene (NOG). To date, seven mutations of NOG have been identified from unrelated families affected with joint morphogenesis. To characterize the molecular lesions of proximal symphalangism, we performed analyses of NOG in three Japanese individuals with proximal symphalangism. We found three novel mutations: g.551G>A (C184Y) in a sporadic case of symphalangism, g.386T>A (L129X) in a familial case of symphalangism, and a g.58delC (frameshift) in a family with multiple synostosis syndrome. Characteristic genotype-phenotype correlations have not been recognized from the mutations in the NOG gene.     

Family study of inherited syndrome with multiple congenital deformities: symphalangism, carpal and tarsal fusion, brachydactyly, craniosynostosis, strabismus, hip osteochondritis.

A syndrome of brachydactyly (absence of some middle or distal phalanges), aplastic or hypoplastic nails, symphalangism (ankylois of proximal interphalangeal joints), synostosis of some carpal and tarsal bones, craniosynostosis, and dysplastic hip joints is reported in five members of an Italian family. It may represent a previously undescribed autosomal dominant trait.     

Familial progressive sinoatrial and atrioventricular conduction disease of adult onset with sudden death,dilated cardiomyopathy,and brachydactyly. A new type of heart-hand syndrome?

We identified a family with 10 affected members in four generations suffering from adult-onset progressive sinoatrial and atrioventricular conduction disease, sudden death due to ventricular tachyarrhythmia, dilated cardiomyopathy, and a unique type of brachydactyly with mild hand involvement (short distal, middle, proximal phalanges and clinodactyly) and more severe foot involvement (short distal, proximal phalanges and metatarsal bones, short or absent middle phalanges, terminal symphalangism, duplication of the bases of the second metatarsals, extra ossicles, and syndactyly). The phenotype differences from other reported genetic abnormalities and linkage exclusion of Holt-Oram syndrome, ulnar-mammary syndrome, brachydactyly type B or Robinow syndrome, and cardiac conduction disease or Brugada syndrome loci suggest that we report on a new hereditary heart-hand syndrome.     

Craniotubular dysplasia with severe postnatal growth retardation,mental retardation,ectodermal dysplasia,and loose skin: Lenz-Majewski-Like syndrome

The heterogeneous group of craniotubular dysplasias is characterized by modeling errors of the craniofacial and tubular bones. Some conditions in this category cause not only skeletal abnormalities but also a variety of mesoectodermal dysplasias, as exemplified in Lenz-Majewski syndrome (MIM 151050), which comprises craniodiaphyseal dysplasia, failure to thrive, mental retardation, proximal symphalangism, enamel hypoplasia, and loose skin. We report on a boy with a hitherto unknown multisystem disorder, including skeletal changes that were regarded as a form of craniotubular dysplasia. The patient had a large head, exophthalmos, a broad nasal root, anteverted nostrils, large auricles, thick lips, micrognathia, severe postnatal growth retardation with emaciation, severe mental retardation, sparse hair growth, enamel hypoplasia, and thin, loose skin with hyperlaxity. Skeletal changes consisted of thickened calvaria, sclerosis of the skull base and facial bones, thick ribs, and metaphyseal undermodeling of the tubular bones. In addition, generalized osteopenia was evident. The present disorder overlaps phenotypically with Lenz-Majewski syndrome; nevertheless, the absence of diaphyseal hyperostosis and proximal symphalangism in the present patient was not consistent with Lenz-Majewski syndrome. Am. J. Med. Genet. 71:87–92, 1997. © 1997 Wiley-Liss, Inc.     

Symphalangism with multiple anomalies of the hands and feet: a new genetic trait

We report a new autosomal dominant condition involving hands and feet of an Arabic father and 5 of his 11 children. This trait is characterized by symphalangism, syndactyly, brachydactyly type D, clinodactyly, and hypoplasia of the thenar and hypothenar eminences. Affected persons had symphalangism and syndactyly plus some or all or part of the other anomalies. Symphalangism, the main defect in this syndrome, showed variable expressivity. A distinct dermatoglyphic pattern was observed in all affected relatives. Linkage studies were done; however, no linkage was demonstrated.     

Multiple synostoses syndrome: Clinical report and retrospective analysis

Multiple synostoses syndrome (SYNS1; OMIM# 186500) is a rare autosomal dominant disorder reported in a few cases worldwide. We report a Chinese pedigree characterized by proximal symphalangism, conductive hearing loss, and distinctive facies. We examined the genetic cause and reviewed the literature to discuss the pathogeny, treatment, and prevention of SYNS1. Audiological, ophthalmological, and radiological examinations were evaluated. Whole‐exome sequencing (WES) was performed to identify mutations in the proband and her parents. Sanger sequencing was used to verify the results for the proband, parents, and grandmother. The literature on the genotype–phenotype correlation was reviewed. The patient was diagnosed with multiple synostoses syndrome clinically. WES and bioinformatic analysis revealed a novel missense mutation in the NOG gene, c.554C>G (p.Ser185Cys), cosegregated in this family. The literature review showed that the phenotype varies widely, but the typical facies, conductive hearing loss, and proximal symphalangism occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there are regional hot spots for these mutations. However, no distinct genotype–phenotype correlations have been identified for mutations in NOG in different races. Regular systematic examinations and hearing aids are beneficial for this syndrome. However, the outcomes of otomicrosurgery are not encouraging owing to the regrowth of bone. This study expanded the mutation spectrum of NOG and is the first report of SYNS1 in a Chinese family. Genetic testing is recommended as part of the diagnosis of syndromic deafness. A clinical genetic evaluation is essential to guide prevention, such as preimplantation genetic diagnosis.     

Symphalangism, short stature, skeletal anomalies, and accessory testis: a new malformation syndrome.

A 17-year-old Jewish Sephardi male is described with symphalangism, short stature, multiple skeletal anomalies, and an accessory testis, which appears to be a new malformation syndrome of possible genetic aetiology.     

Multiple synostosis syndrome: study of a large Brazilian kindred

We report a large Brazilian kindred with 28 cases of the autosomal dominant multiple synostosis syndrome. The main anomalies were symphalangism and carpal and tarsal synostoses. Other common findings included synostosis involving other bones, absence of phalanges and nails, short metacarpals, pes planovalgus with prominent lateral border, hypoplastic alae of nose, short upper lip, and dermatoglyphic abnormalities. This may be a variant of the WL syndrome.     

Distal symphalangism with involvement of the thumbs and great toes

A family is presented in which five individuals in four generations have shown variable expression of distal symphalangism in hands and feet. The mode of inheritance is autosomal dominant. Two individuals show involvement of the thumbs and halluces; this has not been noted previously in true distal symphalangism.     

Cryptic 17q22 deletion in a boy with a t(10;17)(p15.3;q22) translocation, multiple synostosis syndrome 1, and hypogonadotropic hypogonadism

We report on a boy who had multiple synostosis syndrome 1, an autosomal dominant disorder characterized by progressive symphalangism, multiple joint fusions, conductive deafness, and mild facial dysmorphism. In addition the boy developed delay of puberty, bone age, and closure of the epiphyseal lines of long bones with tall stature. These findings and decreased plasma LH and FSH levels at age 19 years were compatible with hypogonadotropic hypogonadism. G-banded chromosomes showed a balanced translocation t(10;17)(p15.3;q22). Chromosomal FISH analysis, using a series of BAC clones surrounding the translocation breakpoints, detected a 2.2-3.9 Mb deletion at 17q22. The deletion encompassed NOG, a gene responsible for multiple synostosis syndrome 1. It was assumed that a gene for pituitary secretion of gonoadotropic hormones was deleted at the 17q22 segment.     

Brachydactyly, distal symphalangism, scoliosis, tall stature, and club feet: a new syndrome.

Five members of a kindred with brachydactyly and distal symphalangism, normal stature, pes cavus, and scoliosis were ascertained. The pedigree was consistent with autosomal dominant inheritance. The combination of clinical and radiological features is believed to be distinct from those previously reported in patients with brachydactyly/symphalangism.     

一个中国近端指(趾)骨间关节黏连家系NOG基因新突变鉴定

目的 检测一个中国近端指(趾)骨间关节黏连家系的致病基因突变.方法 收集该家系患者和家系成员的临床资料,采集外周血提取基因组DNA.运用聚合酶链式反应和Sanger测序法筛查先证者的NOG和GDF5基因.确定突变位点后,在家系成员中进行共分离分析并在200名正常对照中筛查该突变.结果 该家系患者中存在NOG基因c.502 T＞C错义突变,该突变导致其编码蛋白Noggin第168位氨基酸由苯丙氨酸变为亮氨酸(p.F168L).在家系正常成员和200名正常对照中未检测到相同突变.该突变在dbSNP、ExAC等数据库中未见报道.在GDF5基因上未发现可疑突变.结论 NOG基因c.502 T＞C错义突变是该家系发病的原因.     

Distal symphalangism associated with camptodactyly.

A Japanese family in which four patients in three generations had distal symphalangism associated with camptodactyly is reported. All of these patients had extension limitation of the proximal interphalangeal joints of the toes of both feet. Radiographs of the hands and feet, undertaken in three cases, showed no bone fusion of the distal and proximal interphalangeal joints. This malformation is caused by an autosomal dominant gene. To our knowledge, no previous case of distal symphalangism with extension limitation of the proximal interphalangeal joints has been reported.     

A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)

The NOG gene encodes noggin, a secreted polypeptide that is important for regulating multiple signaling pathways during human development, particularly in cartilage and bone. The hallmark of NOG-related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet. Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia. The variable clinical presentations led to the designation of five different autosomal dominant syndromes, all subsequently found to have resulted from NOG mutations. These include (1) proximal symphalangism; (2) multiple synostoses syndrome 1; (3) stapes ankylosis with broad thumbs and toes; (4) tarsal-carpal coalition syndrome; and (5) brachydactyly type B2. Herein, we review the phenotypic features associated with mutations in the NOG gene, demonstrating the overlapping characteristics of these syndromes. Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD), to aid in the clinical recognition and evaluation of all affected individuals with these phenotypes. These NOG gene variants are available in a new locus-specific database (https://NOG.lovd.nl).     

Arthrogryposis, ophthalmoplegia, and retinopathy: confirmation of a new type of arthrogryposis.

Arthrogryposis multiplex congenita is a heterogeneous condition and many different types are clinically recognisable. Recently, a new type of autosomal dominant arthrogryposis was described in a father and son. We report on a male patient with similar clinical features, confirming this distinct type of arthrogryposis. The condition is characterised by congenital contractures of the hands and feet with diminished or absent phalangeal creases, ophthalmoplegia, a rigid trunk, deep set eyes, and (in the oldest patient) an abnormal electroretinogram. Differential diagnosis from amyoplasia, the different types of distal arthrogryposis, and symphalangism is discussed.     

Esophageal atresia/tracheoesophageal fistula and proximal symphalangism in a patient with a NOG nonsense mutation

Esophageal atresia and tracheoesophageal fistula (EA/TEF) are relatively common malformations of the human foregut. The etiology remains incompletely understood with genetic causes identified in a small minority of affected patients. We present the case of a newborn with type C EA/TEF along with proximal symphalangism found to have a de novo NOG nonsense mutation. Patients with chromosome 17q deletions including the NOG gene have previously been reported to have EA/TEF but mutations in the gene have not been identified in patients with this malformation. This case provides evidence that haploinsufficiency for NOG may be the cause for EA/TEF in the 17q deletion syndrome and suggests that the clinical spectrum of NOG-related symphalangism spectrum disorders may include EA/TEF.     

Apparently new osteodysplastic and primordial short stature with severe microdontia,opalescent teeth,and rootless molars in two siblings

A Thai man and his sister affected with a newly recognized syndrome of proportionate primordial short stature are reported. The patients had severe intrauterine and postnatal growth retardation, prominent nose and nasal bridge, small pinnae, large sella turcica, areas of hypo- and hyperpigmentation of skin, dry and thin scalp hair, and long and straight clavicles. Ivory epiphyses and cone-shaped epiphyses of the hands were found when they were young, but most of them disappeared as they grew up. Scaphoid and trapezium had angular appearance. The second toes were unusually long. Distal symphalangism of toes and barchymesophalangy of fingers were noted. The findings that appear to distinguish this syndrome from the previously reported syndromes are long second toes, opalescent and rootless teeth, severe microdontia, severely hypoplastic alveolar process, and unerupted tooth. The mode of inheritance is suspected to be autosomal recessive.     

Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism

Symphalangism (SYM or SYM1) is an autosomal dominant disorder characterized by multiple joint fusions. The disease is caused by mutations of the NOG gene, that maps to chromosome 17q22. So far, only six independent NOG mutations have been identified. We have analysed an Italian family in which father and son had bilateral symphalangism and detected a novel NOG mutation (P35S), originated in the father from a c.914C>T transition. A different mutation in the same codon (P35R) has been previously described. Comparison between different noggin gene hortologs shows that codon 35 is conserved. Therefore, this codon should play an important role in NOG gene function. This is the first mutation described for NOG after the initial report of NOG mutations being causative of SYM.