Autosomal-dominant inheritance of distal arthrogryposis

We report on a 32-year-old Italian man, his 5-year-old daughter, and his 3 1/2-year-old son, all of whom had congenital joint contractures. Each has severe ulnar deviation of fingers and soft-tissue contractures of both hands; and each had bilateral clubfeet at birth. The father is short in stature, as are the children, who also have delayed carpal ossification. The findings in this family suggest autosomal-dominant inheritance of the condition. The clinical features are consistent with the condition currently referred to as “distal” arthrogryposis.     

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.     

Extending the spectrum of distal arthrogryposis

We describe a mother and son with multiple, non-progressive, congenital contractures, camptodactyly and absent flexion creases, expressionless face, blepharophimosis, microstomia, and short stature. Although these cases share similarities with the autosomal-recessive Schwartz-Jampel and Marden-Walker syndromes, they have a different mode of inheritance and lack myotonia, one of the most characteristic findings of the Schwartz-Jampel syndrome. Our cases most closely resemble those previously reported as distal arthrogryposis type IIb, although in our patients the proximal joints are severely affected and extraocular involvement is absent. Hearing loss is present in one and cleft palate in the other of our patients; these findings were previously described in arthrogryposis syndromes other than type IIb. We suggest extending the spectrum of distal arthrogryposis to include these manifestations, since there appears to be significant overlap between the different syndromes. © 1996 Wiley-Liss, Inc.     

The distal arthrogryposes: Delineation of new entities – review and nosologic discussion

We report on 44 patients (18 with additional affected family members), with con genital distal limb contractures identified from a large study of over 350 patients with congenital joint contractures. Fourteen propositi (seven familial cases, seven isolated cases) had a newly recognized form of arthrogryposis, which we have designated distal arthrogryposis type I, with the predominant manifestations of autosomal dominant inheritance; tightly clenched fists at birth, with medially overlapping fingers, ulnar deviation, and camptodactyly in adults; and positional foot deformities. Contractures at other major joints are variable. There are no associated visceral anomalies; intelligence is normal. There can be marked intrafamilial and interfamilial variability. Twenty-two propositi with similar distal contractures had additional findings and were classified into five subcategories of distal arthrogryposis (type IIA-E). Among type II patients cleft palate, cleft lip, small tongue, trismus, ptosis, epicanthal folds, keratoconus, short stature, scoliosis, a unique hand position, and dull normal intelligence were seen. These characteristics were seen in various combinations and patterns and allowed sorting into groups that were the basis for the categorization. The remaining eight propositi were recognized to have previously described conditions with distal contractures and autosomal dominant inheritance, ie, the Freeman-Sheldon syndrome, trismus-pseudocamptodactyly syndrome, congenital contractual arachnodactyly, and familial camptodactyly. Pathogenetically we postulate similar underlying defects of abnormal tendon attachments, attenuation, and absence; careful nosologic comparisons are important for prognostic counseling and habilitative management.     

Distal arthrogryposis type 5 and PIEZO2 novel variant in a Canadian family

The group of distal arthrogryposis (DA) disorders is characterized by congenital contractures of the distal joints. In most instances, these are genetic disorders are inherited in an autosomal dominant fashion; however, there is wide genetic and phenotypic spectrum. Distal arthrogryposis type 5 (DA5) is clinically characterized by short stature, deep‐set eyes, ptosis, ophthalmoplegia, triangular facies, restrictive pulmonary function, and “firm” muscles. DA5 is produced by a gain‐of‐function mutations in PIEZO2 gene, encoding for an ion‐channel required to convert mechanical stimulus to biological signals in mammals essential to proprioception. Heterozygous mutations in PIEZO2 may lead to other phenotypes like Gordon Syndrome and Marden Walker syndrome. In this report, we present a 3‐generation family affected with DA5, who all carry a variant of unknown clinical significance c.8068A>C (p.Ser2690Arg) in the PIEZO2 gene. DA5 is a very rare condition with less than 20 cases previously reported. Our report expands the phenotype and contributes to evidence of this variant's pathogenicity.     

Fetal arthrogryposis: Challenges and perspectives for prenatal detection and management

Antenatal identification of fetuses with multiple congenital contractures or arthrogryposis multiplex congenita (AMC) may be challenging. The first clinical sign is often reduced fetal movement and/or contractures, as seen on prenatal ultrasounds. This can be apparent at any point, from early to late pregnancy, may range from mild to severe involvement, with or without associated other structural anomalies. Possible etiologies and their prognosis need to be interpreted with respect to developmental timing. The etiology of AMC is highly heterogeneous and making the specific diagnosis will guide prognosis, counseling and prenatal and perinatal management. Current ultrasound practice identifies only approximately 25% of individuals with arthrogryposis prenatally before 24 weeks of pregnancy in a general obstetrics care population. There are currently no studies and guidelines that address the question of when and how to assess for fetal contractures and movements during pregnancy. The failure to identify fetuses with arthrogryposis before 24 weeks of pregnancy means that physicians and families are denied reproductive options and interventions that may improve outcome. We review current practice and recommend adjusting the current prenatal imaging and genetic diagnostic strategies to achieve early prenatal detection and etiologic diagnosis. We suggest exploring options for in utero therapy to increase fetal movement for ongoing pregnancies.     

Gene ontology analysis of arthrogryposis (multiple congenital contractures)

In 2016, we published an article applying Gene Ontology Analysis to the genes that had been reported to be associated with arthrogryposis (multiple congenital contractures) (Hall & Kiefer, 2016). At that time, 320 genes had been reported to have mutations associated with arthrogryposis. All were associated with decreased fetal movement. These 320 genes were analyzed by biological process and cellular component categories, and yielded 22 distinct groupings. Since that time, another 82 additional genes have been reported, now totaling 402 genes, which when mutated, are associated with arthrogryposis (arthrogryposis multiplex congenita). So, we decided to update the analysis in order to stimulate further research and possible treatment. Now, 29 groupings can be identified, but only 19 groups have more than one gene.     

Distal arthrogryposis type II: a family with varying congenital abnormalities

Five family members with distal arthrogryposis in two generations are reported. Cleft lip and palate, micrognathia, ptosis, webbed neck, kyphoscoliosis, and short stature are seen in one or more affected family members. All individuals with distal arthrogryposis also have trismus. This family does not fit any of the recently proposed five subcategories of type II distal arthrogryposis, nor does it fit any other recognized autosomal dominant condition with distal contractures.     

Arthrogryposis multiplex congenita,craniofacial, and ophthalmological abnormalities and normal intelligence: A new syndrome?

We report on an 8-year-old boy with clinical manifestations suggestive of a new arthrogryposis syndrome. These included characteristic craniofacial abnormalities, cleft palate, arthrogryposis multiplex congenita, pulmonary hypoplasia, cryptorchidism, and unusual ophthalmological findings. There was no intrauterine growth retardation or decreased fetal movements. Despite the poor prognosis expected in early life, the patient presented with normal mental capability on follow-up. Family data showed that a maternal first cousin of the mother (mother's brother's son) had similar findings and died in infancy. Differential diagnosis included Pena-Shokeir syndrome or phenotype, Gordon syndrome, Marden-Walker syndrome, and the syndrome of arthrogryposis with ophthalmoplegia and retinopathy. The possibility of autosomal dominant inheritance with reduced penetrance is suggested for this apparently new syndrome. Am. J. Med. Genet. 71:401–405, 1997. © 1997 Wiley-Liss, Inc.     

Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita

Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous nonprogressive multiple joint contractures appearing at birth. We present a consanguineous Israeli‐Druze family with several members presenting with AMC. A variable intra‐familial phenotype and pected autosomal recessive inheritance prompted molecular diagnosis by whole‐exome sequencing. Variant analysis focused on rare homozygous changes, revealed a missense variant in MYBPC1, NM_002465:c.556G>A (p.E286K), affecting the last nucleotide of Exon 8. This novel variant was not observed in the common variant databases and co‐segregated as expected within the extended family. MYBPC1 encodes a slow skeletal muscle isoform, essential for muscle contraction. Heterozygous mutations in this gene are associated with distal arthrogryposis types 1b and 2, whereas a homozygous nonsense mutation is implicated in one family with lethal congenital contractural syndrome 4. We present a novel milder MYBPC1 homozygous phenotype.     

Amyoplasia congenita of the lower extremity: report in a premature baby

Amyoplasia congenita is a diagnostic subgroup of children with arthrogryposis multiplex congenita (AMC). AMC is a relatively rare syndrome characterized by multiple joint contractures at birth. Amyoplasia congenita is the most common type of this syndrome with an occurrence rate of 1 in 10,000 live births, and mainly refers to the disorders with limb involvement. In this report, the author presents a premature baby with amyoplasia congenita, whose hips showed flexion, abduction, and external rotation contractures. The knees showed fixed extension contractures, so that his lower extremities were cylindrical with absent skin creases at birth.     

Three distinct types of X-linked arthrogryposis seen in 6 families

Six families with arthrogryposis (congenital contractures) inherited in an X-linked recessive manner are reported. Family histories from a study of over 350 patients with congenital contractures of the joints (arthrogryposis) were reviewed and of these, three probands had family histories consistent with X-linked recessive inheritance. Three other families were recognized through correspondence. Three forms of X-linked recessively inherited arthrogryposis are described: (1) Severe lethal X-linked arthrogryposis with severe contractures, scoliosis, chest deformities, hypotonia, and death due to respiratory insufficiency within 3 months of birth (1 family); (2) Moderately severe X-linked arthrogryposis with severe contractures, ptosis, microphallus, cryptorchidism, inguinal hernias, and normal intelligence (2 families); and (3) Resolving X-linked arthrogryposis with mild to moderate contractures at birth which improve dramatically with time (2 families and 1 sporadic case).     

Uterine structural anomalies and arthrogryposis—death of an urban legend

In a review of 2,300 cases of arthrogryposis collected over the last 35 years, 33 cases of maternal uterine structural anomalies were identified (1.3%). These cases of arthrogryposis represent a very heterogeneous group of types of arthrogryposis. Over half of individuals affected with arthrogryposis demonstrated asymmetry and some responded to removal of constraint, 29 of the 33 cases of arthrogryposis whose mother had a uterine structural anomaly could be identified as having a specific recognizable type of arthrogryposis. Only two cases (0.08%) had primarily proximal contractures that returned to almost normal function within 1 year. Craniofacial asymmetry was the most striking finding in these two cases. A quarter of cases had ruptured membranes between 32 and 36 weeks and either oligohydramnios or prematurity. The pregnancy histories of the mothers with uterine structural anomalies were typical in having infertility, multiple miscarriages, and stillbirths. The finding of only two cases which are likely to have multiple congenital contractures on the basis of uterine constraint suggests that it is a very rare primary cause of arthrogryposis. © 2012 Wiley Periodicals, Inc.     

Arthrogryposis associated with unsuccessful attempts at termination of pregnancy

We report three cases of failed termination of pregnancy in which the children were subsequently born with arthrogryposis (AMC) (multiple congenital contractures). Arthrogryposis is a sign with many causes. We suggest that the multiple congenital contractures seen in these children are due to vascular compromise during the attempted termination with secondary loss of functional neurons leading to fetal akinesia and subsequent contractures. Two of the children have additional evidence of intrauterine vascular compromise. Limitation of movement secondary to the rupture of the fetal membranes and continuous leakage of amniotic fluid after the attempted termination may have compounded the contractures in two of the children. © 1996 Wiley-Liss, Inc.     

CHRNG‐related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical,histopathological, and molecular genetic findings

Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS). Herein we present a long‐term follow‐up of seven patients with CHRNG‐related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics, but also the type and degree of muscle involvement on whole‐body magnetic resonance imaging (WBMRI). CHRNG mutations lead to a distinctive phenotype characterized by multiple congenital contractures, pterygium, and facial dysmorphism, with a stable clinical course over the years. Postnatal abnormalities at the neuromuscular junction were observed in the muscle biopsy of these patients. WBMRI showed distinctive features different from other arthrogryposis multiple congenita. A marked muscle bulk reduction is the predominant finding, mostly affecting the spinal erector muscles and gluteus maximus. Fatty infiltration was only observed in deep paravertebral muscles and distal lower limbs. Mutations in CHRNG are mainly located at the extracellular domain of the protein. Our study contributes to further define the phenotypic spectrum of CHRNG‐related nonlethal MPS, including muscle imaging features, which may be useful in distinguishing it from other diffuse arthrogryposis entities.     

Marden—Walker syndrome versus isolated distal arthrogryposis: Evidence that both conditions may be variable manifestations of the same mutated gene

In this report we present evidence that Marden-Walker syndrome and isolated distal arthrogryposis may be variable manifestations of the same entity.
We describe the clinical and pathological findings in two affected siblings, the first two children of normal, non-consanguineous parents. The first child, a female, presented a typical Marden–Walker syndrome with Dandy–Walker type CNS malformation, corpus callosum hypoplasia and enlarged ventricles. In the second pregnancy, echographic examination revealed joint contractures of the hands and feet. Feto-pathological examination revealed a normocephalic male fetus with severe distal arthrogryposis. There was no facial dysmorphism and pathological examination of the brain, the spinal cord and muscle was normal.     

Identification of three novel ECEL1 mutations in three families with distal arthrogryposis type 5D

Arthrogryposis refers to congenital contracture in at least two different body parts. When distal joints are primarily involved, the term distal arthrogryposis (DA) is used. The recognition of clinically distinct subtypes of DA has proven very useful in mapping the disease genes for this genetically heterogeneous condition. DA5D is characterized by ocular involvement usually in the form of ptosis and incomitant strabismus, but extraocular manifestations have also been reported. In a multiplex consanguineous family with DA5D, we combined autozygosity mapping and exome sequencing to identify a novel mutation in ECEL1. This was followed by targeted sequencing of this gene in another two extended consanguineous family with the same phenotype, which revealed two additional novel homozygous mutations. Our results support the recent identification of mutations in ECEL1 as a disease gene in DA5D and expand the clinical and allelic spectrum of this condition.     

Severe mental retardation - distal arthrogryposis in the upper limbs and complex chromosomal rearrangements resulting from a lOq25→qter deletion

Lukusa T, Devriendt K, Holvoet M, Fryns JP. Severe mental retardation - distal arthrogryposis in the upper limbs and complex chromosomal rearrangements resulting from a 10q25→qter deletion. CIin Genet 1998: 54: 224–230. 8 Munksgaard, 1998
We present the first report of chromosomal rearrangement involving chromosomes 4, 10 and 12. The proband was a 42–year-old woman with severe mental retardation and multiple congenital anomalies. The most striking physical anomalies were upper limb contractures resulting in distal arthrogryposis. As upper limb flexion contrdctures have been previously reported in individuals with partial distal 1Oq deletion, this sign should be considered as part of the clinical manifestations of 10q25→qter monosomy.     

Nosology of fetal hypokinesia sequence based on CNS abnormalities: is there an Aase-Smith syndrome?

Aase-Smith syndrome (ASS) is usually defined as a dominantly inherited combination of arthrogryposis, Dandy-Walker malformation and cleft palate. We describe a sporadic case of foetal akinesia with abnormal fossa posterior, fitting the diagnosis of ASS, and discuss the nosology of this entity among syndromes with distal arthrogryposis. ASS shows a "hybrid" phenotype: adults with mild ASS could be classified as distal arthrogryposis, whereas severely affected newborns overlap with the Marden-Walker phenotype, which is recessively inherited. The specificity of the disorder comes from the coexistence of both forms in the same pedigree, so that ASS appears impossible to diagnose with certitude in sporadic cases. We suggest that the severe expression of ASS is only the extreme but aspecific expression of a dominantly inherited form of distal arthrogryposis. Implications for genetic counselling in distal arthrogryposis are outlined.     

Part II. Amyoplasia: Twinning in amyoplasia—a specific type of arthrogryposis with an apparent excess of discordantly affected identical twins

We report on 11 cases of amyoplasia in one of identical twins. In total, 135 patients with amyoplasia were ascertained from a study of 350 patients with multiple congenital joint contractures (arthrogryposis). These 11 cases of identical twins with amyoplasia represent 8% of our patients with amyoplasia. At least 18 sets of twins with congenital contractures have been reported previously. However, only four of these appear to involve identical twins discordant for amyoplasia. Thus, 15 cases in which only one of identical twins are affected with amyoplasia have been identified.