Unusual Brain and/or Neuromuscular Findings with Associated Defects

Occasional Abnormalities

Cord wrapping of limb, amniotic bands, smashed digits, loss/amputation of digits, cryptorchidism, hypoplastic labia, dimples at contracture sites, torticollis, scoliosis, hernias, gastroschisis, nonduodenal intestinal atresia, defects of muscular layer of trunk and abdominal musculature, Poland sequence, Moebius anomaly, hypoplasia of deltoids and biceps, hemangiomas.

Natural History

Decreased movement in utero. Of pregnancies, 70% have first-trimester complications such as bleeding, flu, or fever. Delivery is often difficult and breech presentation is common. Fractures of the limbs secondary to traumatic delivery occur. Intelligence is usually normal unless birth trauma owing to stiff joints has occurred. There is decreased bone growth of involved limbs and possibly increased flexion and pterygium at large joints with time. By 5 years of age, most patients (85%) become ambulatory with good physical therapy. It is important to begin physical therapy and occupational therapy early to mobilize any muscle tissue present (particularly intrinsic muscles). Splinting and casting are used to maintain and improve range of joint mobility. More than two-thirds will require orthopedic surgery, an average of 5.7 procedures per child. All four limbs are involved in most patients; in those with only legs involvemeny, there is an excess of males with bowel atresia and in those with arms alone involved there is an excess of females with gastroschisis. Four percent have three limbs involved: both arms and the right leg or both legs and the left arm. Most will attend regular classrooms at appropriate grade levels and most will be independent in their activities of daily living.

Etiology

This disorder is sporadic. A higher incidence than expected is seen in identical twins, with only one affected. Based on the fact that many of the associated abnormalities have been shown to be caused by an intrauterine vascular accident, most likely hypotension with multiple origins is involved, including placental, maternal, and embryo/fetal factors as well as bleeding, drugs, trauma, and infections. Prenatal diagnosis with the use of serial real-time ultrasonography, looking for abnormal movement, could be used to allay parental anxiety.

Occasional Abnormalities

Trismus, mild scoliosis, limited range of motion of proximal joints, small calves, dimples, cryptorchidism, hernias.

Natural History

“Trisomy 18 position” of hand at birth in the vast majority of cases. Variable talipes involvement. The hands eventually unclench and may have residual camptodactyly and ulnar deviation. Of adults, 20% have straight and fully functional fingers. Both neurologic examinations and intelligence findings are normal. There is remarkably good response to treatment in all joints.

Etiology

This disorder has an autosomal dominant inheritance pattern with extensive intrafamilial and interfamilial variability. The parent of an affected child might possibly express the gene through mild hand contractures only. Documentation of the genetic basis of DA1 has been elusive. Mutations in three contractile genes have been identified in either a single patient or family with DA1. These include TPM2 , TNN12 , and TNNT3 . In addition, mutations in skeletal muscle slow-twitch myosin binding protein C1 ( MYBPC1 ) have been identified in two familial cases as well as a mutation in MYH3 , a gene coding for the heavy chain of myosin, in another family.

Comment

Nine additional disorders, all autosomal dominant, have been designated as DA syndromes; they are listed below.

• DA2A. Freeman-Sheldon syndrome (see page 300).

• DA2B. Sheldon-Hall syndrome. Less severe than DA2A, but more severe than DA1. Affected individuals have vertical talus; ulnar deviation; severe camptodactyly; and a distinctive facies, including a triangular shape, prominent nasolabial folds, downslanting palpebral fissures, small mouth, and a prominent chin. However, no patients have had a pinched mouth or “H-shaped” dimpling of the chin. Inheritance is autosomal dominant. Mutations in one of three skeletal muscle contractile genes— MYH3, TPM2, TNNI2, and TNNT3 —are responsible. In addition, in one other patient who lacked any of the known DA2B mutations a de novo microdeletion in 8q21 was found.

• DA3. Gordon syndrome. Distal arthrogryposis in association with short stature, cleft palate, submucous cleft palate or bifid uvula, ptosis, epicanthal folds, mild facial asymmetry, and short neck (see Hall et al., 1982). Mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) are responsible in mos of the cases.

• DA4. Distal arthrogryposis in association with scoliosis (see Hall et al., 1982).

• DA5. Distal arthrogryposis in association with short stature; ocular abnormalities including ptosis, ophthalmoplegia, strabismus; unusual stance with short heel cords and pes cavus; short neck; immobility of face; smooth, shiny, tapering fingers with mild camptodactyly; restrictive chest disease (see Hall et al., 1982). Mutations in PIEZO2 are responsible for most cases of DA5 as well as of DA3 and Marden-Walker syndrome (McMillin et al. 2013).

• A subtype of DA5, referred to as DA5D, has been delineated and includes severe camptodactyly of hands, including adducted thumbs and wrists, mild camptodactyly of toes, clubfoot and/or calcaneovalgus deformities; extension contractures of knees, ptosisa round-shaped face, arched eyebrows, a bulbous up-turned nose and micrognathia. Ophthalmoplegia is not present. Autosomal recessive inheritance is most likely the cause. Mutations in ECEL1 are responsible in most cases (see McMillin et al., 2014).

• DA6. Distal arthrogryposis in association with sensorineural hearing loss (see Stewart and Bergstrom, 1971).

• DA7. Hecht syndrome (see page 312).

• DA8. Autosomal dominant multiple pterygium syndrome characterized by pterygia, camptodactyly of hands, vertebral fusions, and scoliosis. Mutations in MYH3 are responsible. (see Chong JX et al. 2015 and page 841)

• DA9. Beals congenital contractural arachnodactyly (see page 666).

• DA10. Plantar flexion contractures associated with mild contractures of hips, elbows, wrists, and fingers (see Stevenson et al., 2006).

Occasional Abnormalities

Cleft palate, cardiac defect.

Natural History

Some of these babies are born prematurely. Those born at term are invariably small for the estimated dates. Approximately 30% are stillborn. Although the majority of those born live die of the complications of pulmonary hypoplasia within the first month of life, it is important to recognize that the ultimate prognosis for children with this disorder depends on the cause of the decreased fetal movement. The central nervous system and most skeletal muscles are normal, with the exception of disuse atrophy.

Etiology

An autosomal recessive inheritance has been implied in more than one-half of the published cases. However, recognition that this phenotype does not have a single etiology makes accurate recurrence risk counseling difficult. A 0% or 25% risk for recurrence seems most appropriate in a sporadic case.

Comment

Nineteen additional familial disorders have been recognized, based on differences in natural history and autopsy finding (see Hall 2009). The predominant features of all types are secondary to decreased intrauterine movement. In three of these—referred to as lethal congenital contracture syndrome (LCCS) types 1, 2, and 3—the altered gene has been identified. LCCS-1 is caused by mutations in GLE , LCCS-2 is caused by mutations in ERBB3 , and LCCS-3 is caused by mutations of PIP5K1 . All three disorders have an autosomal recessive mode of inheritance. More recently mutations in a number of other genes have been identified which result in this phenotype, including GBB1 resulting in the neuromuscular form of glycogen storage disease IV, NEB leading to nemaline myopathy, KLHL40 , DEB , MUSK FOXP3 , RAPSN , TUBB2B , and PDHA1 .

Occasional Abnormalities

Low nasal bridge, maxillary retrusion, microdontia.

Natural History

Babies with this disorder are usually born at term. Prenatal growth deficiency varies. In the majority of cases the phenotype is evident at birth. However, in a few cases, the phenotype undergoes a dramatic evolution toward the full-blown picture in a matter of weeks to months. The course of the disorder in all cases is progressive, with downhill deterioration. It is characterized by severe feeding difficulties in the neonatal period, virtually no growth, and increasing cachexia despite apparently adequate caloric intake, ending in death, which is usually from pulmonary infections that complicate emaciation. Survival is usually fewer than 5 years.

Etiology

This disorder has an autosomal recessive inheritance pattern. It is caused by mutations in genes that are critical for nucleotide excision repair of ultraviolet-induced damage, including mutations in ERCC6 associated with the classic COFS phenotype , ERCC2 associated with the the COFS phenotype plus severe cutaneous photosensitivity , ERCC5, and ERCC1.

Occasional Abnormalities

Prenatal growth deficiency, buccal-alveolar frenula, supernumerary nipples, pectus excavatum, high fetal pads, annular pancreas, malrotation, obstructive sleep apnea, sacral subarachnoid cyst, Genitourinary reflux, kidney stones, pulmonary hypertension.

Natural History

Intellectual disability varies, but is usually severe to profound. A high infant mortality rate (26% of initial 43 patients) has been reported; however, aggressive medical management has led to increased longevity. Surviving infants have feeding difficulties, including cyclic vomiting; failure to thrive; recurrent infection; and sleep disorders. Over half of individuals have needed gastrostomy tubes; however, feeding issues improve over time. Medical and surgical management has been needed for obstructive sleep apnea. Melatonin has helped sleep disturbance. Myopia tends to be progressive. Wilms tumor has been reported in two patients who were ASLX1 mutation positive. Tumor surveillance has been recommended, but the magnitude of the risk is unknown. Early puberty has been noted in two patients. Fatal persistent pulmonary hypertension has been reported in one individual. Expressive language is severely impaired, but affected individuals have been described as having a happy and social demeanor.

Etiology

This syndrome is caused by loss of function mutation in the additional sex combs-like 1 ( AXSL1 ) gene. The vast majority of cases represent de novo events. One published report describes inheritance from a germline mosaic mother.

Occasional Abnormalities

Short neck, long philtrum, midforehead hemangioma, attenuated ascending and transverse colon, intestinal malrotation, no appendix, cardiac hypoplasia, diaphragmatic hernia, megaureter and hydronephrosis, kyphoscoliosis, posterior vertebral fusion, fusion of long bones, neuropathologic abnormalities including cerebellar and pontine hypoplasia with absence of pyramidal tracts, polymicrogyria, and ventricular dilatation, decreased size of white matter tracts in spinal cord, microcephaly.

Natural History

All patients were stillborn or died in the immediate neonatal period, probably secondary to pulmonary hypoplasia. Polyhydramnios is present in approximately one-third of cases and hydrops in more than one-half. Decreased fetal activity and an increased incidence of breech presentation have been documented.

Etiology

This disorder has an autosomal recessive mode of inheritance in most cases. However, a clinically indistinguishable X-linked recessive form has been reported. De Die-Smulders and colleagues distinguished an “early” and a “late” form of the lethal multiple pterygium syndrome. The “early” form is characterized by intrauterine death in the second trimester and the presence of hydrops and/or cystic hygroma, whereas fetuses with the “late” form survive into the third trimester and are not hydropic. The early group is genetically heterogeneous with both autosomal and X-linked recessive cases represented. Within the late group, all familial cases have pedigrees consistent with autosomal recessive inheritance. Within the autosomal recessive cases, mutations in CHRNG, which encodes the γ subunit of the embryonal acetylcholine receptor, have been identified in about 8% of cases. In addition, mutations in CHRNA1 and CHRND have each been seen in 3% of cases. Neither developmental defects of the central nervous system (CNS) nor cleft palate were seen in the CHRNG -positive group, but were seen in the CHRNG -negative group. It has been suggested that mutations in RYR1 , which encodes the skeletal muscle ryanodine receptor, should be considered in cases in which mutations in CHRNG , CHRNA1 , or CHRNAD are not identified.

Comment

Mutations in CHRNG have also been seen in the nonlethal multiple pterygium (Escobar) syndrome (see Escobar syndrome, page 434). Although the lethal multiple pterygium syndrome and the Escobar syndrome phenotypes are seen in different families with the same CHRNG mutation, estimate is of a 95% chance that subsequent siblings in the same family will have the same phenotype as the proband.

Occasional Abnormalities

Hydranencephaly, spina bifida, Dandy-Walker malformation, hypoplastic cerebrum, choroid plexus cysts, hypodontia, patent foramen ovale and ductus arteriosus, atrial septal defect, ventricular septal defect, transposition of great vessels, cleft lip, cleft palate, hepatomegaly, renal agenesis, bifid uterus, cryptorchidism.

Natural History

Althought the majority of patients are stillborn or die in the immediate neonatal period, survival beyond 10 months has been reported. The usual cause of death is respiratory failure or sepsis secondary to skin breakdown.

Etiology

Neu-Laxova syndrome has an autosomal recessive inheritance pattern. It is now recognized that this disorder is genetically heterogeneous and can be caused by mutations in all three genes involved in L-serene biosynthesis including PHGDH , PSAT1 , and PSPH .

Occasional Abnormalities

Natal teeth, microcephaly, short palpebral fissures, eyelid ectropion, choanal atresia, submucous cleft palate, cleft palate, hypospadias, ureteral duplication, dorsal kyphoscoliosis, camptodactyly, adrenal hypoplasia, patent ductus arteriosus, atrial septal defect, dextrocardia.

Natural History

Pregnancy is frequently abnormal, with polyhydramnios and decreased fetal activity usually beginning at about 6 months’ gestation. Prematurity is common. The majority of affected individuals are stillborn as a result of pulmonary hypoplasia. Intubation is extremely difficult because of the temporomandibular joint ankylosis. Most survivors die within the first week. The longest survival time has been 120 days.

Etiology

The majority of cases are caused by autosomal recessive ZMPSTE24 mutations and, less frequently, to de novo dominant mutations in the lamin A gene ( LMNA ). Mutations in both of these genes lead to defective functioning of lamin A, resulting in the characterization of restrictive dermopathy as a laminopathy.

Comment

Twenty ZMPSTE24 alleles have been identified which are associated with diseases of varying severity. Complete loss-of-function alleles are associated with restrictive dermopathy (most severe), whereas maintenance of partial activity result in Hutchinson-Gilford progeria syndrome ((less severe) and Mandibloacral dysplasia (least severe).

Occasional Abnormalities

• Craniofacial. Craniosynostosis (possibly secondary), coloboma of iris, hypoplastic optic nerve, hypotelorism or hypertelorism, hypoplastic to absent philtrum and/or nasal septum, cleft lip—sometimes midline.

• Mouth. Lobulated tongue, cleft epiglottis, neonatal teeth.

• Neck. Webbed.

• Limbs. Relatively short bowed limbs, syndactyly, simian crease, clinodactyly.

• Cardiac. Septal defect, patent ductus arteriosus, coarctation of aorta, pulmonary stenosis.

• Lungs. Hypoplasia.

• Other. Dandy-Walker malformation, single umbilical artery, patent urachus, omphalocele, intestinal malrotation, enlarged missing and/or accessory spleens, defects in laterality, adrenal hypoplasia, imperforate anus, missing or duplicated ureters, absence or hypoplasia of urinary bladder, enlarged placenta.

Natural History and Management

These patients seldom survive longer than a few days to a few weeks. Death may be related to the severe central nervous system defects and/or renal defects.

Etiology

Meckel-Gruber syndrome has an autosomal recessive inheritance pattern, with no recognized expression in the presumed carriers of the gene. Mutations in seventeen genes— MKS1, TMEM67, TMEM107, TMEM216, TMEM231, CEP290, CC2D2A, RPGRIP1L, B9D1, B9D2, NPHP3, TCTN2 , C5of42, CSPP1, KIF14, TXNDC15, and CEP55 —have been reported as responsible. Mutations in these genes are believed to explain 50% to 60% of cases of this disorder. Many of the involved proteins have been localized to the centrosome, the pericentriolar region, or the cilium itself. This disorder is thus referred to as a ciliopathy. A number of other disorders, including Bardet-Biedl syndrome, oral-facial-digital syndrome type 1, Alstrom syndrome, hydrolethalus syndrome, and Joubert syndrome, are also caused by genes that affect ciliary function and are also referred to as ciliopathies.

Comment

Surprising variability of the clinical features exists. In a study of affected siblings of probands, 100% had cystic dysplasia of the kidneys. However, 63% had occipital encephaloceles and only 55% had polydactyly; 18% had no brain anomaly.

Occasional Abnormalities

Holoprosencephaly with associated midline cleft lip and palate; arrhinencephaly; Dandy-Walker malformation, polymicrogyria, occipital encephalocele; cleft lip, palate, or uvula; laryngeal cleft; microphthalmia; coloboma; microglossia; natal teeth; narrow cervical vertebrae; hemivertebrae, fused ribs, and multiple manubrial ossification centers; subluxation of the radius; congenital hip dislocation; knee subluxation; fibular hypoplasia; forearm bowing; blunted metaphyses; acromesomelic limb shortening; simian crease; camptodactyly; hypoplasia of pancreas; underdevelopment of thyroid gland; testicular hypoplasia with micropenis; bifid scrotum, hypospadias; hydrometrocolpos and/or vaginal atresia.

Natural History

Although Pallister-Hall syndrome is not invariably lethal, death before 3 years of age is not uncommon. The major cause of death in the newborn period is hypoadrenalism. Many of the long-term survivors have required l -thyroxine, growth hormone, and corticosteroids from an early age as well as glucose infusions in the neonatal period. The complete spectrum of this disorder varies. It is now clear that hypothalamic hamartomas and neonatal death are not obligatory features; a number of affected individuals have reproduced, and normal mental capacity has been observed.

Etiology

This disorder has an autosomal dominant inheritance pattern with variability of expression. A thorough evaluation of the parents of affected children, including brain MRI in some cases, should be performed in order to provide appropriate recurrence risk counseling. Truncated functional repressor mutations of GLI3 are responsible for this disorder, whereas functioning haplo-insufficiency mutations in the same gene cause the Greig cephalopolysyndactyly syndrome.

Occasional Abnormalities

Ptosis, nystagmus, trigeminal anesthesia (in one case CT scan revealed absence of bilateral foramina rotunda and trigeminal nerve fibers), retinal detachment, craniosynostosis (particularly lambdoid sutures), bifid uvula, brisk reflexes, spasticity, ataxia, dysmetria, dysarthria, growth hormone deficiency, gastroesophageal reflux, single azygous anterior cerebral artery, lipoma of quadrigeminal plate.

Natural History

Most affected individuals have significant intellectual disability, although normal cognitive function has also been reported. Trigeminal anesthesia may lead to recurrent facial injuries.

Etiology

Unknown. All cases to date have been sporadic.

Comment

Only rhombencephalosynapsis and alopecia are consistently present in Gomez-Lopez- Hernandez syndrome. Along with Gomez-Lopez-Hernandez syndrome, a group of patients with rhombencephalosynapsis with VACTERL features and at least two with holoprosencephaly have been identified.