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.     

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.     

Herrmann multiple synostosis syndrome with neurological complications caused by spinal canal stenosis

A young man was found to have multiple synostosis syndrome type I after presenting with a neck injury causing a cervical spinal cord contusion. Neurological symptoms and signs suggested spinal cord compression. Magnetic resonance (MR) and computerized tomography (CT) imaging of the spine showed spinal canal stenosis with cord compression at C3-C6, a deformed spinal canal flattened in the anteroposterior dimension, vertebral fusions and deformed lateral processes of the vertebrae. He had a long broad nose with hypoplasia of the alae nasi, conductive hearing loss requiring hearing aids, muscular build, stiff spine, prominent acromia, pectus excavatum, ischial prominences, short fifth fingers, fusion at the proximal interphalangeal joints of the fifth fingers with indistinct overlying creases, and toe syndactyly. Spinal cord stenosis is a serious complication of multiple synostosis syndrome, that should be kept in mind in considering the risk of neck or back injury associated with certain sports or other activities. In both the multiple synostosis syndrome and the less severe proximal symphalangism deafness syndrome, mutations have been detected in the human homologue of the noggin gene on chromosome 17q21-q22.     

Detection of a de novo interstitial 2q microdeletion by CGH microarray analysis in a patient with limb malformations, microcephaly and mental retardation

We describe the cytogenetic diagnosis using BAC- and oligonucleotide microarrays of a 16-year-old Laotian-American female, who first presented at 2 1/2 years of age with microcephaly, developmental retardation, and skeletal abnormalities of the upper limb including mild syndactyly of the second and third and the third and fourth fingers, short middle phalanges and clinodactyly of the fifth digit at the distal interphalangel joint on both hands, and symphalangism of the metacarpal-phalangeal joints of the second and fifth digits bilaterally. Her lower limbs displayed symphalangism of the metatarsal-phalangeal joint of the second, third, and fourth digits on both feet, with fusion of the middle and distal phalanges of the second and fifth digits and hallux valgus bilaterally. G-banded chromosomal study at age 4 was normal. However, comparative genomic hybridization at age 15 with the Spectral Genomics 1 Mb Hu BAC array platform indicated a microdeletion involving two BAC clones, RP11-451F14 --> RP11-12N7 at 2q31.1. The maximal deletion on initial analysis comprised the HOXD cluster, which is implicated in limb development. Fluorescence in situ hybridization (FISH) using the RP11-451F14 probe confirmed the deletion. Both parents were negative for the deletion. Additional FISH using BAC RP11-387A1, covering the HOXD cluster, limited the maximal deletion to approximately 2.518 Mb, and excluded involvement of the HOXD cluster. The Agilent 44K and 244K platforms demonstrated a deletion of approximately 2,011,000 bp, which did not include the HOXD cluster. The malformations in our patient may be caused by deletion of a regulatory element far upstream of the HOXD cluster.     

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.     

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.     

Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A father with TPTPS and his daughter with THPTTS in a Thai family

We report on a Thai man who had triphalangeal thumb-polysyndactyly syndrome (TPTPS, MIM *190605) and his daughter who had tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS, MIM *188770). The father had polysyndactyly of triphalangeal thumbs, syndactyly of fingers, duplicated distal phalanx of the left great toe, brachymesophalangy of toes, and the absence of middle phalanges of some toes. He was diagnosed as having TPTPS. His daughter was more severely affected, having complete syndactyly of five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic tibiae, absent patellae, thick and displaced fibulae, preaxial polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some toes, the manifestations being consistent with THPTTS. Having two different syndromes in the same family suggests that they are actually the same disorder. A literature survey showed that there have been several families where THPTTS occurred with TPTPS or Haas-type syndactyly (and/or preaxial polydactyly type 2, PPD2). In addition, all loci for TPTPS, THPTTS, and PPD2 (and/or PPD3) have been assigned to chromosome band 7q36. These findings support our conclusion that TPTPS, PPD2 (and/or PPD3), and Haas-type syndactyly are a single genetic en-tity (THPTTS). We propose to call the condition "tibial hemimelia-polysyndactyly-triphalangeal thumbs syndrome." Copyright 2000 Wiley-Liss, Inc.     

Complex toe syndactyly with characteristic facial phenotype: a new syndrome?

Nonsyndromic syndactyly is a common, heterogeneous hereditary condition of webbed fingers and toes that can be cutaneous or bony, unilateral or bilateral. We describe a patient with complex toe syndactyly and oligodactyly, some interesting skeletal hand findings and atypical facial features without other case like this described before. Cenani-Lenz syndrome (CLS) is a rare disorder with total syndactyly and irregular synostosis of carpal, metacarpal and phalanges, it may involve ulna and radius and digital rays may be absent, some of these were described with atypical facial features and one patient had renal hypoplasia and vertebral anomalies but our patient does not have the oligodactyly or syndactyly of the hands that is consistently present in all patients with CLS. The atypical facial features of our patient resemble Kabuki syndrome but oligodactyly and complex syndactyly have not been described in Kabuki syndrome and this patient has normal intelligence, and extreme eyelid defect (resembling ablepharon). Therefore, for our patient, we suggested to treat in a new condition of limb anomalies and atypical face.     

A novel type of autosomal recessive syndactyly: clinical and molecular studies in a family of Pakistani origin

Non-syndromic syndactylies have been classified into five major types (I-V), all showing autosomal dominant mode of inheritance. Later, the classification was extended and three additional variants (VI-VIII) were defined. Type VII, the Cenani-Lenz syndactyly, is the only non-syndromic, autosomal recessive type. It is characterized by fusion of all phalanges with metacarpal synostosis, dislocated and dysplastic carpals and infrequently, radio-ulnar fusion. Here, we present a Pakistani family with a novel non-syndromic autosomal recessive syndactyly manifesting a unique combination of clinical features. In both hands, reduction of certain phalanges is evident. Radiological examination shows synostosis of third and fourth metacarpals bearing single phalanges. The first three toes are webbed, with hypoplastic terminal phalanx in all the toes. Besides Cenani-Lenz syndactyly, the phenotype segregating in our family is the second well-documented autosomal recessive, non-syndromic syndactyly. A phenotype similar to our family was described in a Turkish kindred but was considered to be a homozygous expression of type I syndactyly. Since the clinical features in our family had minimal overlap with syndactyly types I, II, and III, we have performed microsatellite marker screening to look for the cosegregation of this phenotype with any of the known loci for these respective types. We show that the phenotype in our family is not linked to chromosomal regions 2q34-q36, 2q31, and 6q22-q23 encompassing loci for syndactyly types I, II, and III.     

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.     

Are triphalangeal thumb‐polysyndactyly syndrome (TPTPS) and tibial hemimelia‐polysyndactyly‐triphalangeal thumb syndrome (THPTTS) identical? A father with TPTPS and his daughter with THPTTS in a Thai family

We report on a Thai man who had triphalangeal thumb‐polysyndactyly syndrome (TPTPS, MIM *190605) and his daughter who had tibial hemimelia‐polysyndactyly‐triphalangeal thumb syndrome (THPTTS, MIM *188770). The father had polysyndactyly of triphalangeal thumbs, syndactyly of fingers, duplicated distal phalanx of the left great toe, brachymesophalangy of toes, and the absence of middle phalanges of some toes. He was diagnosed as having TPTPS. His daughter was more severely affected, having complete syndactyly of five‐fingered hands in rosebud fashion (Haas‐type syndactyly), hypoplastic tibiae, absent patellae, thick and displaced fibulae, preaxial polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some toes, the manifestations being consistent with THPTTS. Having two different syndromes in the same family suggests that they are actually the same disorder. A literature survey showed that there have been several families where THPTTS occurred with TPTPS or Haas‐type syndactyly (and/or preaxial polydactyly type 2, PPD2). In addition, all loci for TPTPS, THPTTS, and PPD2 (and/or PPD3) have been assigned to chromosome band 7q36. These findings support our conclusion that TPTPS, PPD2 (and/or PPD3), and Haas‐type syndactyly are a single genetic en‐tity (THPTTS). We propose to call the condition “tibial hemimelia‐polysyndactyly‐triphalangeal thumbs syndrome.” Am. J. Med. Genet. 93:126–131, 2000. © 2000 Wiley‐Liss, Inc.     

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.     

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].     

De novo complete trisomy 5p: Clinical and neuroradiological findings

A Thai mother and son with distal symphalangism and other associated abnormalities are reported. Distal and middle phalanges of fingers and toes 2–5 were either aplastic/hypoplastic or fused between the corresponding digits. The second fingers and fourth fingernails were most severely affected in both patients. The mother's hands were less severely affected; the middle and distal phalanges of her hands were malformed and fused. Besides the absence of fusion lines, the shape of the fused middle and distal phalanges was quite different from that of other types of fusion, i.e., fused bones in both patients did not maintain the normal configuration of bone, referring to as “middle‐distal phalangeal complex”. Distal symphalangism was observed in toes 2–5 of the mother and in toe 3 of the son. Both patients had additional clinical manifestations such as narrowing of the zygomatic arch, dental pulp stone, microdontia of a mandibular permanent central incisor, cone‐shaped epiphyses of middle phalanges of fingers, and absence of scaphoid, trapezium, trapezoid, and pisiform bones. Mutation analysis of NOG and ROR2, the genes responsible for proximal symphalangism and brachydactyly type B, respectively, was negative. © 2002 Wiley‐Liss, Inc.     

Syndactyly: frequency of specific types

Syndactyly without other combined limb anomalies, Poland complex, or amniotic bands, was diagnosed in 174 of 599, 109 consecutive newborn infants (3/10,000). Syndactyly was the only diagnosed anomaly in 133 cases, and it was associated with other anomalies in 41. The most common type of syndactyly was isolated syndactyly of the second and third toes (70 cases), which affected more males than females, and had a higher than expected frequency of white non-Latin-European ancestry. The second most frequent type was isolated syndactyly of the middle and ring fingers (18 cases), and the third was isolated syndactyly of the fourth and fifth toes (13 cases). Considering both isolated and syndromal cases, 66% (114/172) could be assigned to one or another of the fourth genetic categories of syndactyly described by Temtamy and McKusick [1978]. This, plus the high frequency of affected first degree relatives observed (25/434:6%), suggests that the genetic forms of syndactyly may be more common than might be suspected from the small number of pedigrees in the literature.     

De novo complete trisomy 5p: clinical and neuroradiological findings

A Thai mother and son with distal symphalangism and other associated abnormalities are reported. Distal and middle phalanges of fingers and toes 2-5 were either aplastic/hypoplastic or fused between the corresponding digits. The second fingers and fourth fingernails were most severely affected in both patients. The mother's hands were less severely affected; the middle and distal phalanges of her hands were malformed and fused. Besides the absence of fusion lines, the shape of the fused middle and distal phalanges was quite different from that of other types of fusion, i.e., fused bones in both patients did not maintain the normal configuration of bone, referring to as "middle-distal phalangeal complex". Distal symphalangism was observed in toes 2-5 of the mother and in toe 3 of the son. Both patients had additional clinical manifestations such as narrowing of the zygomatic arch, dental pulp stone, microdontia of a mandibular permanent central incisor, cone-shaped epiphyses of middle phalanges of fingers, and absence of scaphoid, trapezium, trapezoid, and pisiform bones. Mutation analysis of NOG and ROR2, the genes responsible for proximal symphalangism and brachydactyly type B, respectively, was negative.     

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).     

Conductive deafness, symphalangism, and facial abnormalities: the WL syndrome in a Japanese family

We report on a family in which four relatives were affected with an autosomal dominant syndrome of unusual facial appearance, nasal abnormality, conductive deafness, pectus carinatum, and symphalangism. This appears to be only the second report of the WL symphalangism syndrome of Herrmann and the first studied in a Japanese family.