Keywords
Arthrogryposis, fetal akinesia sequence, multiple congenital contractures, myasthenia syndromes
Introduction
Arthrogryposis is a term used to describe the presence of multiple contractures of joints in more than one area that are present at birth. The extended term, arthrogryposis multiplex congenita (AMC), has also been used historically to describe multiple congenital contractures (arthro=joint; gryp=curved; multiplex=multiple; congenita=present at birth). Such contractures are usually nonprogressive and may respond to physical therapy and orthopedic procedures. Arthrogryposis has been recognized for centuries in folklore, art, and medical reports. In the past, the term arthrogryposis was used as a diagnosis for any child born with multiple congenital contractures; however, over the years it has become apparent that there are many different types of conditions with multiple congenital contractures. Thus, the term has come to be used as a clinical sign or as a general category of disorders. For the purposes of this chapter, the term arthrogryposis is used as a generic term that encompasses many different conditions with varied causes. The common pathway to congenital contractures appears to be decreased fetal movement, which may occur for many different reasons. The challenge is to determine the specific cause of decreased fetal movement and then to be able to predict natural history, recurrence risk, and best therapies for a specific case. This chapter attempts to present a functional approach.
Historical Background
The first medical report of arthrogryposis was by Adolph Wilhelm Otto in 1841. In the 1930s, 1940s, and 1950s, orthopedists gathered together cases to report the effects of surgery. In the 1950s and 1960s, specific recognizable disorders began to emerge. In 1983, Moessinger proposed the unifying theory, based on animal studies, that lack of fetal movement leads to a whole set of secondary deformations including congenital contractures. Also in the 1980s, Hall and coworkers developed a clinical approach to congenital contractures. Many specific types of arthrogryposis began to be enumerated. In the 1990s, specific genes responsible for inherited forms of arthrogryposis began to be mapped and defined; in addition, multiple mechanisms leading to decreased fetal movement began to be elucidated.
Epidemiology
Approximately 1 in 100 children is born with some type of congenital contracture (clubfoot: 1/300; dislocated hip: 1/200; camptodactyly: 1/200; and so forth), but arthrogryposis implies more generalized involvement. The incidence of newborns with multiple congenital contractures from epidemiological studies is about 1 in 3000 live births. The most common specific condition is Amyoplasia, or “classical arthrogryposis,” which occurs in about 1 in 10,000 births and, as noted later, has a relatively good prognosis.
Some data suggest multiple congenital contractures are common among miscarriages and stillbirths; thus, the in utero frequency may be higher than at birth. Evaluation of fetal movement is not routinely a part of fetal ultrasound. However, affected babies often come to attention when clubfoot or an unusual positioning of a limb is noted during routine prenatal ultrasonography and further real-time investigations indicate a more generalized limitation of a joint movement in utero .
Difficult births occur in many cases of arthrogryposis. Abnormal positioning, such as breech and transverse lies, often requires cesarean section. Fracture of long bones during vaginal deliveries of infants with arthrogryposis is common both because of the abnormal, inflexible positioning of the limbs and the decreased ossification often seen related to decreased in utero fetal movement. Environmental events, including trauma to mother, maternal viral illnesses, bleeding, and medications taken by mother, have now been implicated as causative agents for some cases of arthrogryposis. Uterine abnormalities and oligohydramnios are rare findings, and even more rarely causative.
Arthrogryposis can be divided into three groups as defined by Hall in a large study of affected individuals: (1) primarily involving limbs; (2) involving limbs plus other body areas; and (3) involving central nervous system (CNS) abnormalities or leading to early death, or both. Clinically, this approach helps lead to the differential diagnosis and recognition of specific conditions.
Pathogenesis
It has become increasingly apparent, both from animal and human studies, that anything that leads to decreased fetal movement in utero may also lead to congenital contractures or fixation of the fetal joints. With decreased fetal movement, a series of abnormalities are seen to a greater or lesser extent: (1) contractures of joints; (2) polyhydramnios, apparently secondary to lack of fetal swallowing, which leads also to immature intestinal tract development with secondary feeding problems after birth; (3) pulmonary hypoplasia secondary to lack of fetal breathing with failure of maturation of alveolae and surfactin; (4) short umbilical cord; (5) intrauterine growth restriction; (6) osteoporosis of bones; and (7) craniofacial abnormalities including micrognathia, cleft palate (both hard and soft palate), underdeveloped maxilla, prominent bridge of the nose, and depressed tip of the nose. In its most severe form, this combination is called the fetal akinesia deformation sequence. Because it was first described phenotypically by Pena and Shokeir, when defining a specific familial syndrome, it is also sometimes called the Pena-Shokeir phenotype. However, the combination of morphological and pathological features can be seen with generalized decreased movement from many causes and is present in many other specific conditions.
It appears that any in utero process that leads to decreased movement can secondarily lead to fetal contractures. Swinyard and Bleck described a connective tissue response to the lack of joint movement with thickening of the joint capsule and fiber deposition. The earlier such a process starts in fetal development, the more severe and immobilizing the contractures. Thus, the timing during fetal development probably plays a critical role with regard to the position of the joint (i.e. flexion versus extension) and the severity of contractures at birth. Also, when the muscles of the limbs are not used in utero they atrophy and fail to mature or may be replaced by fat and fibrous tissue. Secondary changes can occur to other organ systems as described earlier in the fetal akinesia sequence. It would appear that lack of normal joint movement, or even an unusual degree of hypotonia, that is present for more than a month during the third trimester, can produce contractures. It may take an even shorter period of time during the first and second trimesters.
The potential causes of limitation of movement in utero are numerous. At least seven categories exist: (1) muscle abnormalities, including myopathies and abnormal muscle structure or function; (2) neuropathic processes, including abnormalities in nerve structure and function, either central or peripheral, including the failure of the CNS to myelinate and/or mature; (3) abnormalities of connective tissue including skin, bone, cartilage, and joint and tendon attachments; (4) limitation of space leading to restriction of fetal movement such as a structural abnormality of the uterus, amniotic bands, chronic leakage of amniotic fluid, multiple fetuses, or uterine masses such as fibroids; (5) those related to maternal illness such as myasthenia gravis, maternal infection, compromise of uterine blood supply, prolonged maternal fever, and other maternal illnesses; (6) those related to medications, drugs, exposures, and other environmental agents or deficiencies to which mother is exposed; and (7) compromise of maternal or fetal vascular supply, which leads to hypoxia or hypotension in fetal tissues. Multiple congenital contractures can occur as a manifestation of a large number of syndromes including chromosomal abnormalities, structural abnormalities of the CNS, and metabolic disorders; the exact cause is often hard to determine.
Whether a particular type of arthrogryposis has a recurrence risk depends, of course, upon whether it has a genetic basis or an environmental basis, or has been described as sporadic. The most common form of arthrogryposis, Amyoplasia, appears to be sporadic, although it is seen with increased frequency in one of monozygotic twins. In Amyoplasia, contractures are thought to occur on the basis of placental vascular compromise leading to hypotension and oxygen deprivation at critical periods in development of nerve and muscle. This sequence could theoretically recur in a second pregnancy, although this has not been observed as yet. Autosomal dominant, autosomal recessive, X-linked recessive single gene, and even mitochondrial inheritance have all been observed, including new mutations in the affected individual. Evidence of a genetic contribution in some cases is the higher frequency than expected of clubfoot or dislocated hip in the first- and second-degree relatives of affected individuals. Environmental factors such as an abnormal uterine structure, maternal use of misoprostol, or maternal illnesses such as the development of maternal antibodies to fetal neurotransmitters (see later) can all lead to recurrence in further children even though a genetic basis is not present.
Arthrogryposis is usually not due to an abnormality in formation of structures during the embryonic stage because bones and joints almost always have formed in a normal way (the exception is some types of synostosis and chondrodysplasias). Thus, arthrogryposis is not usually a problem with embryogenesis per se , but rather a failure to develop normal movement owing to abnormal mechanical forces or dysplasias (failure of a specific tissue to mature or function), which then lead to secondary changes in the bone and joints, as well as possibly secondary changes in other organ systems.
Clinical Features
The workup of a child with multiple congenital contractures is complex because there can be so many possible causes. Box 7.1 outlines some of the important differential features. The history (including family, prenatal, pregnancy, and delivery histories) may give clues to the particular type of arthrogryposis. The newborn examination is extremely helpful in defining whether there are other problems in addition to the contractures, whether the contractures involve all four limbs, whether they are distal or proximal, and whether the positioning is characteristic (as in the case of Amyoplasia and the distal arthrogryposes).
History
Pregnancy (anything decreasing in utero movement leads to congenital contractures)
- •
Illness in mother, chronic or acute (diabetes, myasthenia gravis, myotonic dystrophy, etc.)
- •
Infections (rubella, rubeola, coxsackie, enterovirus, Akabane, etc.)
- •
Fever (>39°C, determine timing in gestation)
- •
Nausea (viral encephalitis, position of baby, etc.)
- •
Drugs (curare, robaxin, alcohol, dilantin, addictive drugs, misoprostol, etc.)
- •
Fetal movement (polyhydramnios, fetal kicking in one place, “rolling,” decreased)
- •
Oligohydramnios, chronic leakage of amniotic fluid
- •
Polyhydramnios, hydrops
- •
Trauma during pregnancy (blow to the abdomen, attempted termination, car accident, etc.)
- •
Other complications during pregnancy such as bleeding, abnormal lie, threatened abortion, etc.
- •
Prenatal diagnosis (early amniocentesis, ultrasound studies, etc.)
Delivery History
- •
Presentation (breech, transverse, etc.)
- •
Length of gestation
- •
Traumatic delivery (limb position, CNS, fracture, etc.)
- •
Intrauterine mass (twin, fibroid, etc.)
- •
Abnormal uterine structure or shape
- •
Abnormal placenta, membranes, or cord length or position
- •
Time of year, geographic location
Family History
- •
Marked variability within family
- •
Change with time – degenerate vs. improve
- •
Increased incidence of congenital contractures in second- and third-degree relatives
- •
Hyperextensibility or hypotonia present in family member
- •
R/O myotonic dystrophy, myasthenia gravis in parents (particularly mother)
- •
Consanguinity
- •
Advanced parental (mother or father) age
- •
Increased stillbirths or miscarriages
- •
If more than one consecutively affected child, consider maternal antibodies to fetal neurotransmitter
Newborn Evaluation
Description of Contractures
- •
Which limbs and joints
- •
Proximal vs. distal
- •
Flexion vs. extension
- •
Amount of limitation (fixed vs. passive vs. active movement)
- •
Characteristic position at rest
- •
Severity (firm vs. some give)
- •
Complete fusion or ankylosis vs. soft tissue contracture
Other Anomalies (contractures are most obvious, look carefully for other anomalies)
- •
Deformities
- •
Genitalia (cryptorchid, lack of labia, microphallus, etc.)
- •
Limbs (pterygium, shortening, webs, cord wrapping, absent patella, dislocated radial heads, dimples, etc.)
- •
Jaw (micrognathia, trismus, etc.)
- •
Facies (asymmetry, flat bridge of nose, hemangioma, movement, etc.)
- •
Scoliosis and kyphosis (fixed or flexible)
- •
Dimples (over specific joints or bones)
- •
Skin (hemangioma, defects, hirsutism)
- •
Dermatoglyphics (absent, distorted, crease abnormalities, etc.)
- •
Hernias, inguinal and umbilical, abdominal wall defect
- •
- •
Other features of fetal akinesia sequence:
- •
Intrauterine growth restriction
- •
Pulmonary hypoplasia
- •
Craniofacial anomalies (hypertelorism, cleft palate, depressed tip of nose, high bridge of nose)
- •
Functional short gut with feeding problem
- •
Short umbilical cord
- •
- •
Malformations
- •
Eyes (small, corneal opacities, malformed, ptosis, strabismus, etc.)
- •
CNS (structural malformation, seizures, MR, etc.)
- •
Palate (high, cleft, submucous, etc.)
- •
Limb (deletion anomalies, radioulnar synostosis, etc.)
- •
GU (structural anomalies of kidneys, ureters, and bladder)
- •
Skull (craniosynostosis, asymmetry, microcephaly, etc.)
- •
Heart (congenital structural anomalies vs. cardiomyopathy)
- •
Lungs (hypoplasia vs. weak muscles or hypoplastic diaphragm)
- •
Tracheal and laryngeal clefts and stenosis
- •
Changes in vasculature (hemangiomas, cutis marmorata, blue cold distal limbs, etc.)
- •
Other visceral anomalies
- •
Other Features
Neurologic examination (detailed)
- •
Vigorous vs. lethargic
- •
Deep tendon reflexes (present vs. absent, slow vs. fast)
- •
Sensory intact or not
Muscle
- •
Mass (normal vs. decreased)
- •
Texture (soft vs. firm)
- •
Fibrous bands
- •
Normal tendon attachments or not
- •
Changes with time
Connective tissue
- •
Skin (soft, doughy, thick, extensible)
- •
Subcutaneous (decreased fat, increased fat)
- •
Hernias (inguinal, umbilical, diaphragmatic or eccentric)
- •
Joints (thickness, symphalangism, etc.)
- •
Tendon attachment and length
Course
Changes with Time
- •
Developmental landmarks (motor vs. social and language)
- •
Growth of affected limbs
- •
Progression of contractures
- •
Lethal vs. CNS damage vs. stable vs. improvement
- •
Asymmetry (decreases or progresses)
- •
Trunk vs. limb changes
- •
Intellectual abilities
- •
Socialization
- •
Feeding problems
Response to Therapy
- •
Spontaneous improvement
- •
Response to physical therapy
- •
Response to casting
- •
Which surgery at which time
- •
Development of motor strength proportionate to limb size
- •
Abnormal reaction to drugs
Laboratory Evaluation
Tests
Documentation of range of motion and position with photographs
Radiographs if:
- •
Bony anomalies (gracile, fusions, extra or missing carpals and tarsals, etc.)
- •
Disproportionate
- •
Scoliosis
- •
Ankylosis
- •
Dislocation (hips, radial head, patella, etc.)
CT scan, MRI, or functional MRI to evaluate CNS or muscle mass obscured by contractures
Ultrasonic evaluation of CNS, other anomalies, or to establish potential muscle tissue
Chromosome studies or CGH if:
- •
Multiple system involvement
- •
CNS abnormality (eye, microcephaly, MR, lethargic, degenerative)
- •
Streaky or segmental involvement
- •
Consider fibroblasts if lymphocytes were normal and patient has MR with no diagnosis
- •
Gene testing if fits known disorder in which gene testing available
Video of movement including facial, range of movement, strength; repeat at regular intervals
Viral culture±specific antibodies or IgM levels in newborn
Muscle biopsy in normal and affected areas at time of surgery to distinguish myopathic from neuropathic (do special histopathology and electron micrographic studies; if CPK or unusual muscle response, do muscle biopsy earlier, examine mitochondria)
EEG if seizures or episodes
EMG in normal and affected area
Nerve conduction in normal and affected area
CPK if:
- •
Generalized weakness
- •
Doughy or decreased muscle mass
- •
Progressively worse
Eye examination (opacities, retinal degeneration, etc.)
Maternal antibodies to neurotransmitters, if myasthenia gravis or recurrent affected pregnancies without diagnosis
Spinal muscular atrophy (SMN) DNA testing if accompanying hypotonia
Mitochondrial DNA if other suggestions of mitochondropathy
Metabolic screening
Autopsy
Visceral anomalies
CNS–brain neuropathology
Spinal cord (number and size of anterior horn cells, presence or absence of tracts at various levels)
Ganglion, peripheral nerve
Eye (neuropathology)
Muscle tissue from different muscle groups (EM & special stains, R/O ragged red fibers)
Diaphragm for thickness or hernia
Fibrous bands replacing muscle
Cartilagenous or bony fusion
Tendon attachments
Other malformations, deformations, or disruptions
CGH array if multiple congenital anomalies
Save DNA for molecular testing
It is very useful to separate patients into three groups once the initial evaluation has been done in order to develop a differential diagnosis: (1) those with primarily limb involvement; (2) those with limb plus other body areas; and (3) those with severe CNS structural abnormalities or dysfunction. Box 7.2 gives a differential diagnosis of specific entities within each of these categories.
Primarily Limb Involvement
Absence of finger prints [4q22.3 ( SMARCADI )]
Bruck syndrome [17p12 (TLH) (PLOD2), 17q21.2 (FKBP10) and 3q23-24 linkage]
Clasped thumbs [1q25-q31(PRG4)]
Continuous contractures [12p13.3 ( KCNA1 )]
Distal arthrogryposis types 1 and 2B [9p11.3 (TPM2), 11p15.5 (TNNI2),11p15.5 (TNNT3), 17p13MYH3 12q23.2 (MYBPC1)]
Lower limb DA—Fleury type [12q23-24 ( TRPV4 )]
Mesomelic dysplasia [Xq24-32]
Patella aplasia-hypoplasia [17q21-22 ( PTLAH )]
Symphalangism/synostosis, coalitions [17q21-22 (NOG), 20q (GDF5)]
X-linked arthrogryposis, lower limbs only [Xq23-27]
Musculoskeletal Involvement Plus Other System Anomalies
Camptodactyly-arthropathy–coxa vara–pericarditis syndrome [( ARC ) 1q24-q25 ( PRG4 )]
Congenital fiber disproportion [1q42-13 ( ACTA1 )]
Conradi-Hunermann [(Xp11.23) (EBP)]
Contracture arachnodactyly [5q23-31 ( FBN2 ) 12q13]
Craniosynostosis syndrome [4p16.3 (FGFR3), 8p11.23 (FGFR1)]
Deafness, camptodactyly (DA 6) [11q25 ( CATSAL, CATSHL )]
Diastrophic dysplasia [5q32 (SLC26A2)]
Digital arthrogryposis I [9q21.2 ( TNNT3 ), 11p15.5 ( TNN12, TNNT3 ), and 17p13 ( MYH3 )]
Distal arthrogryposis type 2B (Sheldon-Hall) [9q21.2 (TNNT3), 11p15.5 (TNN12, TNNT3), and 17p13 (MYH3)]
Dundar-Sonoda syndrome TARP [15q15.1 ( CHST14 )]
Ehlers-Danlos VI [2q32.2 (COL3A1)]
Ehlers-Danlos VIII [12p13]
Ehlers-Danlos VIB-2 [15q15 ( CHST14 )]
Epidermolysis bullosa dystrophica [3p21.31 (COL7A1)]
Freeman-Sheldon syndrome (DA 2A) [17p13 ( MYH3 )]
Genitopatallar syndrome [10q22.1 (KAT6B)]
Gordon syndrome (DA IIA, DA3) [17p13.1 ( MYH3 )]
Hand-foot-uterus syndrome [7p15-p14.2 (HOXA13)]
Holt-Oram syndrome [12q24.1 ( TBX5 )]
Inclusion-body myopathy [17p13.1 (MYH2, MYH3)]
Kniest dysplasia [12q13.1 ( COLA21 )]
King-Denborough syndrome/multiple pterygium and malignant hyperthermia [Genes for malignant hyperthermia in 19q13.1 (RYR1) and 17q (MHS3)]
Larsen syndrome [3p14.3 ( FLNB ), 3p21.31 ( COL7A1 ), AR 8q12.1 ( IMPAD ), 17q25.3 ( CANT ), 5q32 ( DTDST )]
Marfan syndrome (severe neonatal) [15q21.1 (FBN1), 3p24.2-p25?]
MASP1 (3M, Carnevale) [3q27.3 ( MASP1 ), 2p25.3 ( COLEC11 )]
Metaphyseal dysplasia (Jansen) [3p21.31 (PTH1R)]
Metatrophic dysplasia [12q24.1 ( TRPV4 )]
Mobius syndrome [13q12.2-q13]
Moore-Weaver [11p15 ( TNN12 )]
Multiple pterygium (Escobar type) [2q31.1 (CHRNA1), 2q37.1 (CHRNG, CHRND)]
Multiple synostosis, symphalangism [17q21-22 ( NOG ), 20q11.22 ( GDF5 ), 13q11 ( FGF9 ), 4p16.3 ( DOK7 )]
Myelinopathies [1q23.3 (MPZ), 10q21.1 (ERG2), 17p12 (PMP22), 19q13.2 (PRX)]
Myopathies [22q12.3 ( LARGE ), 6q25 (SYNE1), many others]
Nail-patella syndrome [9q34.1 (LMX1B)]
Nemaline myopathy [2q22 ( NEB ), 1q42.13 ( ACTA1 )]
Neurofibromatosis [17q11-q12 (NF1)]
Neuropathic Israeli-Arab (autosomal recessive) [5qter]
Nevo syndrome [1p36.22 ( PLOD1 )]
Oculo-dental-digital syndrome [6q22.31 (GJA1)]
Otospondylomegaepiphyseal dysplasia [6p21.32 ( COL11A2 )]
Parastremmatic dwarfism [12q24.1 (TRPV40)]
Pfeiffer cardiocranial syndrome [10q26 ( FGFR2 ), 8p11.23 ( FGFR1 )]
Popliteal pterygium syndrome [1q32-q41 (IRF6)]
Proteus syndrome [14q32.32 ( AKT1 )]
Puretic-Murray syndrome (infantile hyalinosis) [4q21 (ANTXR2)]
Rigid spine muscular dystrophy [1q36.11 ( SEPN1 )]
Robino syndrome [3p14.3 (WNT5A)]
Sacral agenesis [7q36 ( MNX1 , Currarino syndrome)]
Schwartz-Jampel syndrome [1p36.1 (HSPG2)]
Spondyloepiphyseal dysplasia congénita [12q13.1 ( COLA21 )]
Stiff man syndrome [5q33.1 (GLRA1), 4q32.1 (GLRAB)]
Trismus-pseudocamptodactyly [17p12-p13.1 ( MYH8 )]
Tuberous sclerosis [9q (TSC1) and 16q (TSC2)]
Ullrich congenital muscular dystrophy [2q37 ( COL6A3 ), 21q22.3 ( COL6A1 ), 21q22.3 ( COL6A2 )]
VATER Association [2q31.1 (HOXD13)]
Van den Ende-Gupta syndrome [22q11.21 ( SCARF2 )]
Waardenburg-Klein [2q25-q37.12 (PAX3)]
Weill-Marchesani syndrome [19p13.3-13.2 ( ADAMS10 )]
Winchester syndrome [16q13 (MMP2)]
X-linked moderately severe [Xp11.3-q11.2]
Muscoloskeletal Involvement Plus Central Nervous System Dysfunction and/or Mental Retardation
Acrocallosal syndrome [7p13 ( GLI3 ), 15q26.1 ( K1F7 )]
Adenyl succinate lyase deficiency [22q13.1-13.2 (ADSL)]
Aicardi-Goutierres syndrome [3p21 ( TREX1 ), 11q13.2 ( RNASEH2C ), 13q14.3 ( RNASEH2A ), 19p13.13 ( RNASEH2A ), 20Q11.23 ( SAMHD1 )]
Al-Awadi syndrome [3p25 (WNT7A)]
Antley-Bixler syndrome [7q11.2 ( POR ), 10q26 ( FGFR2 )]
ARC (Nezelof syndrome) [15q26.1 (VPS33B), 14q24.3 (VIPAR)]
Bartsocas-Papas syndrome [20Q11.21 ( ASXL1 )]
Bohring-Opitz syndrome [21q22.3 (RIPK4)]
Bowen-Conradi syndrome [12p13.3 ( EMG1 )]
Camptomelic dysplasia [17q24.3-q25.1 (SOX9)]
Carbohydrate deficient glycoprotein syndrome [16p13 ( PMM2 ), 15q22-qter ( PM11 )]
Central core disease [19q13.1 (RYR1)]
Cerebro-oculo-facial-skeletal (COFS) syndrome [19q13.2 ( ERCC1 ), 13q33.1 ( ERCC5 ), 10q11.23 ( ERCC6 ), 19q13.32 ( ERCC2 )]
Chondrodysplasia punctata (rhizomelic) [6q22-q24 (PEX7)]
Clasped thumb & mental retardation [Associated with X-linked hydrocephaly]
Cocoon syndrome [10q24.31 ( CHUK )]
Congenital muscular dystrophy (merosin deficient) [6q22-23 (LAMA2)]
Contractural arachnodactyly [5q23-31 ( FBN2 )]
Crisponi syndrome [19p13.11 (CRLF1)]
Dandy-Walker, MR, basal ganglion seizures [Xq25-27]
Dyggve-Melchior-Clausen syndrome [18q12-q21.1 ( DYM )]
Episodic ataxia/myokymia syndrome [12p13.32 (KCNA1)]
FG syndrome [Xq13 ( MED12 ), Xq28 ( FLNA )]
Fowler type hydranencephaly [14q24.3 (FLVCR2)]
Fukuyama congenital muscular dystrophy [9q31.2 ( FKTN ); 14q24.3 ( POMPT2 ), 9q31-33 ( FCMD ), 19q13.2 ( FKRP )]
Gaucher disease—perinatal lethal [1q22 (GBA)]
Geleophysic dysplasia [9q342 ( ADAMTSG2 ), 15q21.1 ( FBN1 )]
Glycogen storage IV [9q34 (GLE1)]
Leprechaunism [19p13.2 ( INSR )]
Lethal arthrogryposis with AHC disease [9q34.11 (GLE1)]
Lethal congenital contractures syndrome (Finnish) I [9q34.11 ( GLE1 )]
Lethal congenital contractures syndrome (Finnish) II [12q13 (ERBB3)]
Lethal congenital contractures syndrome (Finnish) III [19p13.3 ( PIP5K1C )]
Lissencephaly with FADS [7q22.1 (RELN), 17p13.3 (PAFAH1B1)]
Martsoff syndrome [1q41 ( RAB3GAP2 ), 2q21.3 ( RAB3GAP1 ), 10p12.2 ( RAB18 )]
MASA syndrome [Xq28 (L1CAM)]
Miller-Dieker syndrome [17q13.2 ( L1S1 )]
Multiple pterygium syndrome—lethal [2q31.1 (CHRNA1), 2q37.1 (CHRND; CHRNG), 22q12.3 (LARGE)]
Muscular dystrophy, congenital, rigid spine [1p35-36 ( SEPN1 )]
Myasthenia, congenital [11p11.2-p11.1 (RAPSN), 17p12-p11 (CHRNB1), 17p13-p12 (CHRNE)]
Myelinopathies [1q23.3 ( MP2 ), 10q21.1 ( ERG2 ), 17p12 ( PMP22 ), 19q13.2 ( PRX )]
Myopathy centronuclear [2q14.2 (BIN1)]
Myotonic dystrophy [19q13.3 ( DMPK )]
Neuromuscular disease of larynx [5q31]
Nevo syndrome
Oculodentodigital syndrome [6q21-23.2 ( GJA1 )]
Osteogenesis imperfecta [7q21.3-q22.1 (COL1A2), 17q21.23 (COL1A1)]
Otopalatodigital syndrome type II [Xq28 ( FLNA )]
Pfeiffer syndrome [10q26 (FGFR2), 8p11.23 (FGFR1)]
Phosphofructokinase deficiency infantile (glycogen storage VII) [12p13.3 ( PFKM )]
Potter syndrome [11q11.2 (RET), 22q13.31 (UPK3A)]
Raine syndrome [7q22.3 ( FAM20C )]
Renal adysplasia [10q11.21 (RET), 22q13.31 (UPK3A)]
Restrictive dermopathy [4p16.3 ( DOK7 ), 11p11.2 ( RAPSN ), 1p34.2 ( 2MPSTE24 ), 1q22 ( LMNA )]
Robert syndrome [8p21.1 (ESCO2)]
Schinzel-Gideon syndrome [18q21.1 ( SETBP1 )]
Schwartz-Jampel syndrome [1p36.12 (HSPG2)]
Smith-Lemli-Opitz syndrome [11q12-q13 ( DHCR7 )]
Spinal muscular atrophy [5q13.2 (SMN)]
Spastic paraplegia (Goldblatt syndrome) [Xq21-q22]
Spinal muscular atrophy [5q13.2 ( SMN )]
Spastic paraplegia (Goldblatt syndrome) [Xq21-q22]
Spinal muscular atrophy [5q13.2 (SMN)]
Trigonocephaly (C syndrome) [3q13.3-q13.2 ( CD96 )]
Waardenburg Shah syndrome [22q13.1 (SOX10)]
Walker-Warburg syndrome [3p22.1 ( GTDC2 )]
Weaver syndrome [5q35 (NSD1)]
X-linked lethal arthrogryposis 1 [Xp11.3-q11.2 ( UBE1 )]
Zellweger syndrome [Multiple PEX genes]
5q deletions (spinal muscular atrophy) [5q13.3 (SMN) microdeletions]
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