Unusual Brain and/or Neuromuscular Findings with Associated Defects

Amyoplasia Congenita Disruptive Sequence

Arms Extended with Flexion of Hands and Wrists, Shoulders Internally Rotated with Decreased Muscle Mass, Bilateral Equinovarus, Variable Contractures of Other Major Joints

Initially described by Paré in 1840, this disorder is the most frequent form of arthrogryposis occurring in 20% to 30% of cases. A complete review of the literature, including diagnosis, etiology, and management was published by Hall and colleagues in 2014.


  • Facies. Round face with micrognathia, small upturned nose, midline vascular malformation.

  • Shoulders. Rounded and sloping with decreased muscle mass, internally rotated.

  • Upper Limbs. Elbows usually in extension with wrists and hands flexed (“policeman tip” position). Severe flexion contractures at metacarpophalangeal joints with mild contractures at interphalangeal joints.

  • Lower Limbs. Hips, usually flexed, dislocated, adducted, or abducted; knees, flexed or extended; feet, usually equinovarus positioning bilaterally; many combinations of hip and knee positions observed.

  • Other. Stiff, straight spine.

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.


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.


  • Paré A. Chapitre XI. Exemple des monsters qui se font, la mere s’estant tenue trop longuement assise, avant eu les cuisses croisees, ou pour s’estre bande et serre trop le ventre durant qu’elle estroite grosse. In A. Paré Des Monsters et Prodigies . Geneva, Switzerland: Librairie Droz S.A. pp 25–26, 1840.

  • Howard R: A case of congenital defect of the muscular system and its association with congenital talipes equinovarus, Proc Soc Med 1:157, 1907.

  • Hall JG, Reed SD, Driscoll EP: Part I. Amyoplasia: A common sporadic condition with congenital contractures, Am J Med Genet 15:571, 1983.

  • Hall JG, et al: Part II: Amyoplasia: Twinning in amyoplasia—a specific type of arthrogryposis with an apparent excess of discordantly affected identical twins, Am J Med Genet 15:591, 1983.

  • Reid COMV, et al: Association of amyoplasia with gastroschisis, bowel atresia and defects of the muscular layer of the trunk, Am J Med Genet 24:701, 1986.

  • Robertson WL, et al: Further evidence that arthrogryposis multiple congenita in the human sometimes is caused by an intrauterine vascular accident, Teratology 45:345, 1992.

  • Sells JM, et al: Amyoplasia, the most common type of arthrogryposis: The potential for good outcome, Pediatrics 97:225, 1996.

  • Hall JG: Amyoplasia: A problem with angiogenesis? In David W. Smith Workshop on Malformations and Morphogenesis, Lake Arrowhead, CA, 2011.

  • Hall JG et al: Amyoplasia revisited, Am J Med Genet 164: 700, 2014 .

    FIGURE 1

    Amyoplasia congenita disruption sequence.

    A–G, Note the round face and micrognathia, “policeman tip” position of the arm and hand, the decreased muscle mass and internal rotation of the shoulders, and camptodactyly.

    G, Courtesy Dr. Lynne M. Bird, Children’s Hospital, San Diego, California.

Distal Arthrogryposis Syndrome, Type 1

Distal Congenital Contractures, Clenched Hands with Medial Overlapping of the Fingers at Birth, Opening of Clenched Hands with Ulnar Deviation

In 1932, Lundblom described a mother and her son with congenital ulnar deviation and flexion of the fingers. In addition, the son had a calcaneovalgus positioning of the feet. Hall recognized this condition as an entity in 1982 in her report of 37 patients with congenital contractures of the distal joints. Two groups of patients were recognized: type 1 (typical) and type 2 (atypical), based on the association of other specific anomalies. Bamshad and colleagues have revised and extended the classification to include type 1 through type 10.


  • Hands. Neonate’s hands are clenched tightly in a fist, with thumb adduction and medially overlapping fingers; hypoplastic/absent flexion creases; ulnar deviation and camptodactyly.

  • Feet. Position deformities (88%): bilateral calcaneovalgus (33%), bilateral equinovarus (25%), combinations (30%).

  • Hips. Hip involvement (38%): congenital dislocations, decreased abduction, mild flexion, contracture deformities.

  • Knees. Mild flexion contractures (30%).

  • Shoulders. Stiff at birth (17%).

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.


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.


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).


  • Lundblom A: On congenital ulnar deviation of the fingers of familial occurrence, Acta Orthop Scand 8:393, 1932.

  • Stewart JM, Bergstrom L: Familial hand abnormality and sensorineural deafness: A new syndrome, J Pediatr 78:102, 1971.

  • Hall JG, Reed SD, Greene D: The distal arthrogryposes: Delineation of new entities—review and nosologic discussion, Am J Med Genet 11:185, 1982.

  • McKeown CME, Harris R: An autosomal dominant multiple pterygium syndrome, J Med Genet 25:96, 1982.

  • Bamshad M, et al: A revised and extended classification of the distal arthrogryposis, Am J Med Genet 65:277, 1996.

  • Krakowiak PA: Clinical analysis of a variant of Freeman-Sheldon syndrome (DA2B), Am J Med Genet 76:93, 1998.

  • Sung SS, et al: Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes, Am J Hum Genet 72:681, 2003.

  • Stevenson DA, et al: A new distal arthrogryposis syndrome characterized by plantar flexion contractures, Am J Med Genet A 140A:2797, 2006.

  • Gurnett CA, et al: Myosin binding protein C1: A novel gene for autosomal dominant distal arthrogryposis type 1, Hum Mol Genet 19:1165, 2010.

  • McMillin MJ, et al: Mutations in ECEL1 cause distal arthrogryposis type 5D, Am J Hum Genet 92:150, 2013.

  • McMillin MJ et al: Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5, Am J Hum Genet 94:734, 2014.

  • Chong JX, et al. Autosomal dominant multiple pterygium is caused by mutaions in MYH3, Am J Hum Genet 96: 841, 2015 .

    FIGURE 1

    Distal arthrogryposis syndrome, type 1.

    A–C, Note the joint contractures involving hands and feet in a child at birth and at 7 months of age. D, Camptodactyly in an affected neonate.

    FIGURE 2

    Distal arthrogryposis syndrome, type 2B.

    Monozygotic twins at 9 months of age.

    From Krakowiak PA, et al: Am J Med Genet 76:93, 1998, with permission.

Pena-Shokeir Phenotype (Fetal Akinesia/Hypokinesia Sequence)

Arthrogryposis, Pulmonary Hypoplasia, Craniofacial Anomalies

In 1974, Pena and Shokeir identified an early lethal disorder involving multiple joint contractures, facial anomalies, and pulmonary hypoplasia with an autosomal recessive mode of inheritance. Subsequently a number of similar patients have been described. Hall has suggested that this clinical phenotype is secondary to decreased in utero movement, no matter what the cause. As such it is etiologically heterogeneous and is similar to the fetal akinesia deformation sequence, a pattern of structural defects described by Moessinger in rats that had been curarized in utero . Through an extensive review of published cases, Hall in 2009 delineated 20 distinct familial types.


  • Growth. Prenatal onset of growth deficiency; head circumference is frequently spared.

  • Craniofacial. Rigid, expressionless face; prominent eyes; hypertelorism; telecanthus; epicanthal folds; poorly folded, small, and posteriorly angulated ears; depressed nasal tip; small mouth; high-arched palate; micrognathia.

  • Limbs. Multiple ankylosis (e.g., elbows, knees, hips, and ankles), ulnar deviation of the hands, rocker-bottom feet, talipes equinovarus, camptodactyly, absent or sparse dermal ridges, with frequent absence of the flexion creases on the fingers and palms.

  • Lungs. Pulmonary hypoplasia.

  • Genitalia. Cryptorchidism.

  • Other. Apparent short neck; polyhydramnios, short-gut syndrome with malabsorption, small or abnormal placenta, relatively short umbilical cord.

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.


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.


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 .


  • Pena SDJ, Shokeir MHK: Syndrome of camptodactyly, multiple ankyloses, facial anomalies and pulmonary hypoplasia: A lethal condition, J Pediatr 85:373, 1974.

  • Pena SDJ, Shokeir MHK: Syndrome of camptodactyly, multiple ankyloses, facial anomalies and pulmonary hypoplasia: Further delineation and evidence of autosomal recessive inheritance. In Bergsma D, Schimke RM, editors: Cytogenetics, Environment and Malformation Syndromes , New York, 1976, Alan R. Liss, pp 201.

  • Dimmick JE, et al: Syndrome of ankylosis, facial anomalies and pulmonary hypoplasia: A pathologic analysis of one infant. In Bergsma D, Lowry RB, editors: Embryology and Pathogenesis and Prenatal Diagnosis , New York, 1977, Alan R. Liss, pp 133.

  • Chen H, et al: The Pena-Shokeir syndrome: Report of five cases and further delineation of the syndrome, Am J Med Genet 16:213, 1983.

  • Moessinger AL: Fetal akinesia deformation sequence: An animal model, Pediatrics 72:857, 1983.

  • Lindhout D, Hageman G, Beemer FA: The Pena-Shokeir syndrome: Report of nine Dutch cases, Am J Med Genet 21:655, 1985.

  • Hall JG: Invited editorial comment: Analysis of Pena-Shokeir phenotype, Am J Med Genet 25:99, 1986.

  • Lav E, et al: Fetal akinesia deformation sequence (Pena-Shokeir phenotype) associated with acquired intrauterine brain damage, Neurology 47:1467, 1991.

  • Brueton LA, et al: Asymptomatic maternal myasthenia as a cause of the Pena-Shokeir phenotype, Am J Med Genet 92:1, 2000.

  • Hall JG: Pena-Shokeir phenotype (fetal akinesia deformation sequence) revisited, Birth Defects Res (Part A) 85:677, 2009.

  • Laquerriere A, et al: De novo TUBB2B mutation casues fetal akinesia deformation sequence with microlissencephaly: An unusual presentation of tubulinopthy. Eur J Med Genet 59:249, 2016.

  • Barnerias ME, et al: A novel musculoskeletal form of glycogen storage disease IV with arthrogryposis, spinal stiffness and rare polyglucosan bodies in muscle. Neuromuscul Disord 26:681 2016.

  • Feingold-Zadok M, et al. Mutations in the NEB gene cause fetal akinesia/arthrogryposis multiplex congenital, Prenat Diagn 37:144, 2017 .

    FIGURE 1

    Pena-Shokeir phenotype.

    A–D, Two affected newborns. Note the multiple joint contractures. E, Predominant features of the disorder.

Cerebro-Oculo-Facio-Skeletal (COFS) Syndrome

Neurogenic Arthrogryposis, Microcephaly, Microphthalmia and/or Cataract

Described initially by Pena and Shokeir in 1974, the disorder has been recognized as an autosomal recessive, apparently degenerative problem of the brain and spinal cord that is usually manifest before birth. It is now recognized to be a disorder on the spectrum of defects in the nucleotide excision repair (NER) pathway


  • Brain and Neurologic. Reduced white matter of brain with gray mottling, subependymal focal gliosis of the third ventricle, focal microgyria, hypoplasia of temporal and hippocampal gyri, hypoplasia of optic tracts and chiasm, agenesis of corpus callosum, intracranial calcification in regions of lenticular nuclei and hemispheric white matter. Severe intellectual disability, occasional infantile spasms, axial hypotonia and peripheral hypertonia, hyporeflexia or areflexia, sensorineural hearing loss.

  • Craniofacial. Microcephaly, prominent root of the nose, large ear pinnae, upper lip overlapping lower lip, micrognathia (mild).

  • Eyes. Blepharophimosis with deep-set eyes, microphthalmia, cataracts, nystagmus, microcornea with optic atrophy.

  • Limbs. Camptodactyly, mild flexion contractures of the elbows and knees, rocker-bottom feet with vertical talus, posteriorly placed second metatarsal, longitudinal groove in the soles along the second metatarsal.

  • Other. Unusual skin pigmentation on sun-exposed areas, photosensitivity, hirsutism, kyphoscoliosis, widely set nipples, shallow acetabular angles, coxa valga, longitudinal groove on soles, osteoporosis, renal defects, genital hypoplasia.

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.


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.


  • Pena SDJ, Shokeir MHK: Autosomal recessive cerebro-oculo-facio-skeletal (COFS) syndrome, Clin Genet 5:285, 1974.

  • Preus M, Fraser FC: The cerebro-oculo-facio-skeletal syndrome, Clin Genet 5:294, 1974.

  • Surana RB, Fraga JR, Sinkford SM: The cerebro-oculo-facio-skeletal syndrome, Clin Genet 13:486, 1978.

  • Grizzard WS, O’Donnell JJ, Carey JC: The cerebro-oculo-facio-skeletal syndrome, Am J Ophthalmol 89:293, 1980.

  • Linna SL: Intracranial calcifications in cerebro-oculo-facio-skeletal (COFS) syndrome, Pediatr Radiol 12:28, 1982.

  • Harden CL, et al: Infantile spasms in COFS syndrome, Pediatr Neurol 7:302, 1991.

  • Meira LB, et al: Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B ( CSB ) gene, Am J Hum Genet 66:1221, 2000.

  • Graham JM, et al: Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy, Am J Hum Genet 69:291, 2001.

  • Jaspers NJF, et al: First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide repair and severe developmental failure, Am J Hum Genet 80:457, 2007.

  • Laugel V, et al: Cerebro-oculo-facio-skeletal syndrome: Three additional cases with CSB mutations, new diagnostic criteria, and an approach to investigation, J Med Genet 45:564, 2008.

  • Jaakkola E, et al: ERCC6 founder mutation identified in Finnish patients with COF syndrome, Clin Genet 781:541, 2010 .

    FIGURE 1

    COFS syndrome.

    A, Predominant features of the syndrome. B and C, Affected siblings. D and E, Note the prominent nasal bridge and large ear pinnae.

Bohring-Opitz Syndrome

(Oberklaid-Danks Syndrome)

Trigonocephaly, Hypotonic Facies with Full Cheeks, and Characteristic Posture with Flexed Elbows, Ulnar Deviation, and Flexion of Wrists

The first report of this condition was in a 1999 paper describing four sporadic cases plus two from the literature of infants with severe Opitz C trigonocephaly syndrome, suggesting this pattern of malformation was a new disorder. To date roughly 50 patients have been described slightly less than half of whom have had molecular confirmation of the diagnosis.


  • Growth. Pre- but more typically postnatal growth deficiency, failure to thrive, microcephaly.

  • Development. Truncal hypotonia with peripheral hypertonia, poor neonatal transition, moderate to profound global developmental delay, seizures.

  • Craniofacial. Trigonocephaly, metopic ridge, bitemporal narrowing, hypoplastic supraorbital ridge, proptotic or prominent eyes, upslanting palpebral fissures, ocular hypertelorism, synophrys, broad nasal bridge, anteverted nares, cleft lip, cleft palate, high arched palate, broad secondary alveolar ridge, microgrognathia, facial nevus flammeus (simplex).

  • Eyes. Strabismus, retinal dystrophy, persistent tunica vasculosa lentis, pale choroid, pigmentary retinopathy, myopia.

  • Ears. Posteriorly rotated, overfolded helices, thick lobes.

  • Neck. Short, loose skin, low posterior hair line.

  • Cardiac. Septal defects, patent ductus arteriosus (PDA).

  • Intestinal. Gastroeophageal reflux, gastrointestinal dysmotility, constipation.

  • Genitourinary. Cryptorchidism, hypoplastic scrotum, inguinal hernia.

  • Musculoskeletal. Scoliosis, talovalgus deformity, equinovarus, small feet.

  • Extremities. Characteristic posture of upper extremities with external rotation and/or adduction of shoulders, flexion of elbows and wrists, ulnar deviation of wrists and fingers, normal palmar creases, camptodactyly.

  • Skin. Hypertrichosis, rapidly growing hair and nails.

  • Imaging. Dandy-Walker malformation, ventriculomegaly, hypoplastic/absent corpus callosum, delayed myelination, tortuous and cavernous carotid and vertebral arteries, enlarged hyperechogenic pancreas.

  • Prenatal findings. Polyhydramnios, intrauterine growth retardation, oligohydramnios, short femurs.

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.


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.


  • Bohring A, et al: Severe end of Opitz trigonocephaly (C) syndrome or new syndrome? Am J Med Genet 85:438, 1999.

  • Hoischen A, et al: De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome, Nat Genet 43:729, 2011.

  • Dangiolo SB, et al: Bohring-Opitz syndrome (BOS) with a new ASXL1 pathogenic variant: Review of the most prevalent molecular and phenotypic features of the syndrome, Am J Med Genet Part A 167A:3161, 2015.

  • Russell B, et al: Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance, Am J Med Genet Part A 167A: 2122, 2015 .

    FIGURE 1

    Same boy at 10 days (left) and 3 years of life with Bohring Opitz syndrome with mutation in ASXL1. A, In the newborn picture, note the slightly upslanting palpebral fissures, mild retrognathia, and typical Bohring-Opitz syndrome posture consisting of slouching shoulders, bent elbows and wrists, ulnar deviation of the hands, and camptodactyly. B, At 3 years of age, note a low temporal hairline, mild prominence of the metopic suture, synophrys, mild proptosis, hypertelorism, epicanthal folds, low-set ears, anteverted nares, full cheeks, and mild micrognathia.

    FIGURE 2

    A 2-year-old male with Bohring Opitz syndrome with nevus flammeus , hypoplastic supraorbital ridges, prominent eyes, and tented upper lip. The hand shows the characteristic ulnar deviation.

    Courtesy of Drs. Roser Urreizti, Susanna Balcells and Daniel Grinberg, University of Barcelona

Lethal Multiple Pterygium Syndrome

Gillin and Pryse-Davis described three female siblings with this early lethal disorder in 1976. It was separated from other conditions associated with pterygia by Hall and colleagues in 1982.


  • Growth. Deficiency of prenatal onset.

  • Facies. Epicanthal folds; ocular hypertelorism; flat nose; cleft palate; small mouth; micrognathia; downslanting palpebral fissures; low-set, malformed ears.

  • Limbs. Flexion contractures involving elbows, shoulders, hips, knees, ankles, hands, and feet.

  • Pterygia. Present in the following areas: chin to sternum, cervical, axillary, antecubital, crural, popliteal, and ankles.

  • Other. Small chest; cryptorchidism; hypoplastic dermal ridges and creases; neck edema and loose skin; radiologic evidence of undermodeling of long bones and hypoplasia of vertebrae, sacrum, ileum, ischium, ribs, clavicles, and scapulae; thin, gracile long bones.

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.


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.


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.


  • Gillin MD, Pryse-Davis J: Pterygium syndrome, J Med Genet 13:249, 1976.

  • Hall JG, et al: Limb pterygium syndromes: A review and report of eleven patients, Am J Med Genet 12:377, 1982.

  • De Die-Smulders CEM, et al: The lethal multiple pterygium syndrome, Genet Couns 1:13, 1990.

  • Spearritt DJ, et al: Lethal multiple pterygium syndrome: Report of a case with neurological anomalies, Am J Med Genet 47:45, 1993.

  • Hertzberg BS, et al: Lethal multiple pterygium syndrome: Antenatal ultrasound diagnosis, J Ultrasound Med 19:657, 2000.

  • Cox PM, et al: Diversity of neuromuscular pathology in lethal multiple pterygium syndrome, Pediatr Dev Pathol 6:59, 2002.

  • Vogt J, et al: CHRNG genotype-phenotype correlations in the multiple pterygium syndromes, J Med Genet 49:21, 2012.

  • McKie AB et al: Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome, Acta Neuropathologica 2:148, 2014 .

    FIGURE 1

    Lethal multiple pterygium syndrome.

    A–C, Stillborn infant with ocular hypertelorism, epicanthal folds, multiple joint contractures, and pterygia bridging virtually all joints.

Neu-Laxova Syndrome

Microcephaly/Lissencephaly, Canine Facies with Exophthalmos, Syndactyly with Subcutaneous Edema

Neu and colleagues reported three siblings with microcephaly and multiple congenital abnormalities in 1971. An additional family with three affected siblings from a first-cousin mating was reported by Laxova and colleagues in 1972. In 2014, Shaheen and colleagues identified the genetic defect as well as serene deficiency in affected individuals, documenting that Neu-Lexova syndrome is an inborn error of serene metabolism. More than 70 cases have been reported subsequently.


  • Growth . Prenatal onset of marked growth deficiency (100%).

  • Central Nervous System. Microcephaly (84%); lissencephaly (40%); absence of corpus callosum (53%); hypoplasia of cerebellum (53%) and hypoplasia of pons; absence of olfactory bulbs.

  • Facies. Sloping forehead (100%); ocular hypertelorism (94%); protruding eyes with absent lids (40%); flattened nose; round, gaping mouth and thick everted lips; micrognathia (97%); large ears; short neck.

  • Skin. Yellow subcutaneous tissue covered by thin, transparent, scaling skin and edema (85%); ichthyosis (50%).

  • Limbs. Short limbs, syndactyly of fingers and toes (60%), extreme puffiness of hands and feet, overlapping of digits, calcaneovalgus, vertical talus, flexion contractures of major joints with pterygia (79%), poorly mineralized bones.

  • Other. Cataracts (25%), microphthalmia, persistence of some embryonic structures of eye, absent eyelashes and head hair, muscular atrophy with hypertrophy of fatty tissue, hypoplastic or atelectatic lungs, hypoplastic genitalia (50%), polyhydramnios, short umbilical cord, small placenta.

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.


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 .


  • Neu RL, et al: A lethal syndrome of microcephaly with multiple congenital anomalies in three siblings, Pediatrics 47:610, 1971.

  • Laxova R, Ohdra PT, Timothy JAD: A further example of a lethal autosomal recessive condition in siblings, J Ment Def Res 16:139, 1972.

  • Curry CJR: Letter to the editor: Further comments on the Neu-Laxova syndrome, Am J Med Genet 13:441, 1982.

  • Shved IA, Lazjuk GI, Cherstovoy ED: Elaboration of the phenotypic changes of the upper limbs in the Neu-Laxova syndrome, Am J Med Genet 20:1, 1985.

  • Ostrovskaya TI, Lazjuk GI: Cerebral abnormalities in the Neu-Laxova syndrome, Am J Med Genet 30:747, 1988.

  • Shapiro I, et al: Neu-Laxova syndrome: Prenatal ultrasonographic diagnosis, clinical and pathological studies, and new manifestations, Am J Med Genet 43:602, 1992.

  • King JAC, et al: Neu-Laxova syndrome: Pathological evaluation of a fetus and review of the literature, Pediatr Pathol Lab Med 15:57, 1995.

  • Manning MA, et al: Neu-Laxova syndrome: Detailed prenatal diagnostic and post-mortem findings and literature review, Am J Med Genet A 125A:240, 2004.

  • Shaheen R, et al: Neu-Laxova syndrome, an inborn error of serene metabolism, is caused by mutations in PHGDH, Am J Hum Genet 94:898, 2014.

  • Acuna-Hidalgo R, et al: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serene biosynthesis pathway. Am J Hum Genet 95:285, 2014 .

    FIGURE 1

    Neu-Laxova syndrome.

    A–C, Newborn with microcephaly, sloping forehead, protruding eyes with absent lids, flat nose, gaping mouth and thick lips, scaling skin with edema, extreme puffiness of hands and feet, syndactyly, and joint contractures.

    From Manning M, et al: Am J Med Genet A 125A:240, 2004, with permission.

Restrictive Dermopathy

Initially described in two infants by Toriello and colleagues in 1983, this disorder has now been reported in approximately 60 patients. Most of the features are constraint-related, the result of restricted in utero movement secondary to the defective skin.


  • Growth. Intrauterine growth deficiency.

  • Craniofacial. Enlarged fontanels, hypertelorism, entropion, small pinched nose, small mouth with ankylosis of the temporomandibular joints, mouth fixed in the “O” position, micrognathia, dysplastic ears.

  • Skin. Tightly adherent, thin, translucent skin with prominent vessels; erosion may be present; fissures often occur in groin, axilla, and neck; nails may be short or very long; eyelashes, eyebrows, and lanugo are sparse or absent; head hair may be normal; histologically there is hyperkeratosis, delayed maturation of the pilosebaceous and eccrine sweat apparatus, and absence of elastin; the epidermis and subcutaneous fat layer are thickened; the dermis is thin with dense, thin collagen fibers in parallel with the epidermis; there is absence of the rete ridges.

  • Skeletal. Multiple joint contractures; rocker-bottom feet; bipartite clavicles, ribbon-like ribs, overtubulated long bones of the arms, and a poorly mineralized skull are present on radiographs.

  • Other. Polyhydramnios, enlarged placenta with short umbilical cord, premature rupture of membranes, absent or small nails, increased anteroposterior diameter of chest, pulmonary hypoplasia.

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.


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.


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).


  • Toriello HV, et al: Autosomal recessive aplasia cutis congenita—report of two affected sibs, Am J Med Genet 15:153, 1983.

  • Witt DR, et al: Recessive dermopathy: A newly recognized autosomal recessive skin dysplasia, Am J Med Genet 24:631, 1986.

  • Reed MH, et al: Restrictive dermopathy, Pediatr Radiol 23:617, 1992.

  • Verloes A, et al: Restrictive dermopathy, a lethal form of arthrogryposis multiplex with skin and bone dysplasias: Three new cases and review of the literature, Am J Med Genet 43:539, 1992.

  • Mau U, et al: Restrictive dermopathy: Report and review, Am J Med Genet 71:179, 1997.

  • Wesche WA, et al: Restrictive dermopathy: Report of a case and review of the literature, J Cutan Pathol 28:211, 2001.

  • Smigiel R, et al: Novel frameshift mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature, Am J Med Genet A 152A:447, 2010.

  • Barowman J, et al: Human ZMPSTE24 disease mutations: Residual proteoltic activity correlates with disease severity, Hum Mol Genet 21:4084, 2012.

  • Navarro CL, et al: New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update, Eur J Hum Genet 22:1002, 2014 .

    FIGURE 1

    Restrictive dermopathy

    A–C, A newborn infant. Note the small nose, translucent dermis, and flat helix with auricle attached to skin of scalp.

    From Toriello HV, et al: Am J Med Genet 15:153, 1983. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Meckel-Gruber Syndrome (Dysencephalia Splanchnocystica)

Originally described by Meckel in 1822, later by Gruber, and more recently brought to recognition by Opitz and Howe, more than 200 cases of this severe disorder have been reported. It is now known that Meckel-Gruber syndrome is caused by primary cilia dysfunction and is thus characterized as a ciliopathy.


  • Growth. Variable prenatal growth deficiency.

  • Central Nervous System. Occipital encephalomeningocele; microcephaly with sloping forehead, cerebral and cerebellar hypoplasia; anencephaly; hydrocephaly with or without an Arnold-Chiari malformation; absence of olfactory lobes, olfactory tract, corpus callosum, and septum pellucidum.

  • Facial. Microphthalmia; cleft palate; micrognathia; ear anomalies, especially slanting type.

  • Neck. Short.

  • Limbs. Polydactyly (usually postaxial), talipes.

  • Kidney. Dysplasia with varying degrees of cyst formation.

  • Liver. Bile duct proliferation, fibrosis, cysts.

  • Genitalia. Cryptorchidism, incomplete development of external and/or internal genitalia.

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.


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.


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.


  • Meckel JR: Beschreibung zweier durch sehr ähnliche Bildungsabweichung ensteller Geschwister, Deutsch Arch Physiol 7:99, 1822.

  • Gruber GB: Beiträge zur Frage “gekoppelter” missbildungen (Akrocephalosyndactylie und Dysencephalia splanchnocystica), Beitr Pathol Anat 93:459, 1934.

  • Opitz JM, Howe JJ: The Meckel syndrome (dysencephalia splanchnocystica, the Gruber syndrome), Birth Defects 5:167, 1969.

  • Hsia YE, Bratu M, Herbordt A: Genesis of the Meckel syndrome (dysencephalia splanchnocystica), Pediatrics 48:237, 1971.

  • Meckel S, Passarge E: Encephalocele, polycystic kidneys, and polydactyly as an autosomal recessive trait simulating certain other disorders: The Meckel syndrome, Ann Genet (Paris) 14:97, 1971.

  • Fraser FC, Lytwyn A: Spectrum of anomalies in the Meckel syndrome, or “Maybe there is a malformation syndrome with at least one constant anomaly,” Am J Med Genet 9:67, 1981.

  • Seppänen U, Herva R: Roentgenologic features of the Meckel syndrome, Pediatr Radiol 13:329, 1983.

  • Salonen R: The Meckel syndrome: Clinicopathological findings in 67 patients, Am J Med Genet 18:671, 1984.

  • Nyberg DA, et al: Meckel-Gruber syndrome. Importance of prenatal diagnosis, J Ultrasound Med 9:691, 1990.

  • Tallila J, et al: Mutation spectrum of Meckel syndrome genes: One group of syndromes or several distinct groups? Hum Mutat 30:E813, 2009.

  • Valente EM, et al: Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes, Nat Genet 42:619, 2010.

  • Hopp K, et al: B9D1 is revealed as a novel Meckel syndrome ( MKS ) gene by targeted exon-enriched next-generation sequencing and deletion analysis, Hum Mol Genet 20:2524, 2011.

  • Hartill V et al: Meckel-Gruber syndrome: An update on diagnosis, clinical management and research advances, Frontiers in Pediatrics 5:1, 2017 .

    FIGURE 1

    Meckel-Gruber syndrome.

    A, A 2-day-old male infant with palpable enlarged kidney who was having frequent seizures and other evidence of central nervous system abnormality. B, Intravenous pyelogram showed no visualization on one side and an aberrant calyceal system on the other side. The baby died at 4½ months of age, the oldest known survivor with this syndrome. (Patient of E. Hutton, Anchorage, Alaska.) C, Stillborn infant with posterior encephalocele, postaxial polydactyly, and flank masses caused by massively enlarged cystic kidneys.

Pallister-Hall Syndrome

Hypothalamic Hamartoblastoma, Hypopituitarism, Imperforate Anus, Postaxial Polydactyly

In 1980, Hall and colleagues described six unrelated newborn infants with this pattern of malformation. All died in the neonatal period. However, in subsequent reports, prolonged survival has been documented frequently.


  • Growth. Mild intrauterine growth retardation.

  • Central Nervous System. Hypothalamic hamartoblastoma located on the inferior surface of the cerebrum, extending from the optic chiasma to the interpeduncular fossa, replacing the hypothalamus and other nuclei originating in the embryonic hypothalamic plate; pituitary aplasia/dysplasia; panhypopituitarism.

  • Craniofacial. Flat nasal bridge and midface with midline capillary hemangioma; short nose; anteverted nares; bathrocephaly; external ear anomalies, including posteriorly rotated, absent external auditory canals, microtia, malformed pinnae, and simple auricles; micrognathia.

  • Mouth. Multiple frenuli between alveolar ridge and buccal mucosa.

  • Respiratory. Bifid, hypoplasia, or absence of epiglottis; dysplastic tracheal cartilage; cleft trachea; absent lung; abnormal lung lobation.

  • Limbs. Nail dysplasia, variable degrees of syndactyly and postaxial polydactyly involving both hands and feet; oligodactyly; small, distally placed fourth metacarpal with one or two small fingers associated with it; third metacarpal less frequently affected; fourth metatarsal dysplastic; distal shortening of limbs, particularly the arms.

  • Anus. Anal defects, including imperforate anus, colonic aganglionosis and variable degrees of rectal atresia.

  • Other. Renal ectopia/dysplasia; congenital heart defects, including endocardial cushion defect, patent ductus arteriosus, ventricular septal defect, mitral and aortic valve defects, and proximal aortic coarctation; pituitary dysplasia/hypopituitarism.

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.


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.


  • Hall JG, et al: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly. A new syndrome? Part I: Clinical, causal, and pathogenetic considerations, Am J Med Genet 7:47, 1980.

  • Clarren SK, Alvord EC, Hall JG: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly: A new syndrome? Part II: Neuropathological considerations, Am J Med Genet 7:75, 1980.

  • Culler FL, Jones KL: Hypopituitarism in association with postaxial polydactyly, J Pediatr 104:881, 1984.

  • Iafolla K, et al: Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome), Am J Med Genet 33:489, 1989.

  • Finnigan DP, et al: Extending the Pallister-Hall syndrome to include other central nervous system malformations, Am J Med Genet 40:395, 1991.

  • Biesecker LG, Graham JM: Pallister-Hall syndrome, J Med Genet 33:585, 1996.

  • Kang S, et al: GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome, Nat Genet 15:266, 1997.

  • Roscioli T, et al: Pallister-Hall syndrome: Unreported skeletal features of a GLI3 mutation, Am J Med Genet A 136A:390, 2005.

  • Narumi Y, et al: Genital abnormalities in Pallister-Hall syndrome: Report of two patients and review of the literature, Am J Med Genet A 152A:3143, 2010.

  • Hall JG. Pallistr-Hall syndrome has gone the way of modern medical genetics, Am J Med Genet 166C:414, 2014.

  • Li MH, et al: Total colonic aganglionosis and inperforate anus in a severely affected infant with Pallister-Hall syndrome, Am J Med Genet 167A:617, 2015 .

    FIGURE 1

    Pallister-Hall syndrome.

    A–C, Male infant who died at 7 days of age. He has camptodactyly, nail dysplasia, postaxial polydactyly, syndactyly, lack of ossification of distal phalanges, and a hypoplastic fourth metacarpal giving rise to two phalanges. D and E, Note the hamartoblastoma apparent on the inferior cerebral surface and in the sagittal section.

    A–E, From Hall JG, et al: Am J Med Genet 7:47, 1980, with permission. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Gómez–López-Hernández Syndrome (Cerebello-Trigeminal Dysplasia, Cerebello-Trigeminal-Dermal Dysplasia)

Parieto-Temporal Alopecia, Trigeminal Anesthesia, Rhombencephalosynapsis

Gómez and subsequently López-Hernández described three unrelated children with a similar pattern of malformation, including postnatal growth deficiency, microcephaly, parieto-temporal alopecia, turribrachycephaly with lambdoid synostosis, trigeminal anesthesia. To date, more than 30 cases have been reported in the literature.


  • Growth. Mild prenatal and significant postnatal growth deficiency, microcephaly.

  • Performance. Mild to moderate cognitive disability, jerky movements, head bobbing, central hypotonia with peripheral hypertonia, seizures.

  • Behavior. Self-abusive behavior, attention deficit disorder, bipolar disorder, aggressive behavior, impulsiveness.

  • Craniofacial. Turribrachycephaly, wide anterior fontanel, parieto-temporal alopecia with underdeveloped pili-sebaceous structures and no scarring, corneal opacities, strabismus, ocular hypertelorism, downslanting palpebral fissures, low-set posteriorly rotated or protruding ears, midface hypoplasia, small nose, smooth philtrum, thin upper lip.

  • Limbs. Hypoplastic/absent thumb. Altered thenar crease. Decreased movement interphalangeal thumb joint, fifth finger clinodactyly, hypoplastic radius and ulna, cubitus valgus, metatarsus adductus.

  • Genitalia. Hypoplastic labia.

  • Imaging. Rhombencephalosynapsis (single horse-shoe-shaped cerebellar hemisphere, fused cerebellar peduncles, deficient vermis, fused dentate nucleus), ventriculomegaly, arachnoid cyst, absent septum pellucidum, dysgenesis of corpus callosum, brainstem hypoplasia.

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.


Unknown. All cases to date have been sporadic.


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.


  • Fernández-Jaén A, et al: Gomez-Lopez-Hernandez syndrome: Two new cases and review of the literature, Pediatr Neurol 40:58–62, 2009.

  • Gómez MR: Cerebellotrigeminal and focal dermal dysplasia: A newly recognized neurocutaneous syndrome, Brain Dev 1:253–256, 1979 (original report).

  • Gomy I, et al: Two new Brazilian patients with Gómez-López-Hernández syndrome: Reviewing the expanded phenotype with molecular insights, Am J Med Genet A 146A:649–657, 2008.

  • López-Hernández A: Craniosynostosis, ataxia, trigeminal anaesthesia and parietal alopecia with pons-vermis fusion anomaly (atresia of the fourth ventricle). Report of two cases, Neuropediatrics 13:99–102, 1982.

  • Sukhudyan B, et al: Gomez-Lopez-Hernandez syndrome: Reappraisal of the diagnostic criteria, Eur J Pediatr 169:1523, 2010.

  • Tully HM, et al: Beyond Gomez-Lopez-Hernandez syndrome: Recurring phenotypic themes in rhombencephalosynapsis, Am J Med Genet 158A:2393, 2012.

  • Choudhri AF, et al: Trigeminal nerve agenesis with absence of foramina rotunda in Gomez-Lopez-Hernandez syndrome, Am J Med Genet 167A:238, 2015 .

    FIGURE 1

    Gómez–López-Hernández syndrome.

    A and B, Note the parieto-occipital alopecia, strabismus, ocular hypertelorism, smooth philtrum, and thin upper lip.

    Courtesy R. Clark, Loma Linda University. C, Rhombencephalosynapsis is noted on the MRI. From Tully H, et al: Am J Med Genet 158:2393, 2012.

X-Linked Hydrocephalus Spectrum (X-Linked Hydrocephalus Syndrome, MASA Syndrome, L1 syndrome)

Hydrocephalus, Short Flexed Thumbs, Mental Deficiency

In 1949, Bickers and Adams first described X-linked recessive hydrocephalus associated with aqueductal stenosis. In 1974, Bianchine and Lewis delineated an X-linked recessive disorder referred to as MASA syndrome, an acronym for m ental retardation, a dducted thumbs, s huffling gait, and a phasia. Based on the similarities of their clinical phenotype as well as molecular studies that have placed the locus for both disorders, as well as X-linked corpus callosal agenesis and X-linked complicated hereditary spastic paraplegia type 1, at Xq28, it seems clear that the four conditions are phenotypic variations of mutations in the same gene.


  • Performance. Intellectual disability and spasticity, especially of lower extremities.

  • Brain. Hydrocephalus. Stenosis of aqueduct of Sylvius. Pyramidal tract agenesis/hypoplasia. Agenesis/hypoplasia of corpus callosum.

  • Hands. Thumb flexed over palm (cortical thumb) in 88%.

Occasional Abnormalities

Asymmetry of somewhat coarse facies; brain defects such as fusion of thalamic fornices, small brainstem, porencephalic cyst. Hirschsprung disease

Natural History

Prenatal hydrocephalus may be sufficiently severe to impede delivery. Patients with severe hydrocephalus usually have severe intellectual disability (ID), IQ < 30. However, many of the affected males have no hydrocephalus. Such individuals often have a narrow scaphocephalic cranium with a more variable mild to moderate ID, with IQ in the range of 30–70, and tend to have spasticity, a shuffling gait, and aphasia.


This disorder has an X-linked recessive inheritance pattern. A number of different mutations in the gene encoding for the neural cell adhesion molecule, L1CAM located at Xq28, have been reported in X-linked hydrocephalus families, in families with MASA syndrome, in families with X-linked agenesis of the corpus callosum, and in families with X-linked complicated hereditary spastic paraplegia type 1. The carrier female is usually normal, but may have dull intelligence and/or adducted thumbs.


Prenatal diagnosis is not always reliable in that ventriculomegaly usually starts after 20 weeks’ gestation. Ultrasonographic studies should be performed every 2 to 4 weeks from 16 through 28 weeks’ gestation. However, it should be recognized that hydrocephalus might develop postnatally or might never occur.


  • Bickers DS, Adams RD: Hereditary stenosis of the aqueduct of Sylvius as a cause of congenital hydrocephalus, Brain 72:246, 1949.

  • Edwards JH: The syndrome of sex-linked hydrocephalus, Arch Dis Child 36:486, 1961.

  • Holmes LB, et al: X-linked aqueductal stenosis, Pediatrics 51:697, 1973.

  • Bianchine JW, Lewis RC Jr: The MASA syndrome: A new heritable mental retardation syndrome, Clin Genet 5:298, 1974.

  • Fryns JP, et al: X-linked complicated spastic paraplegia, MASA syndrome, and X-linked hydrocephalus owing to congenital stenosis of the aqueduct of Sylvius: Variable expression of the same mutation at Xq28, J Med Genet 28:429, 1991.

  • Van Camp G, et al: A duplication in the L1CAM gene associated with X-linked hydrocephalus, Nat Genet 4:421, 1993.

  • Schrander-Stumpel C, et al: The spectrum of complicated spastic paraplegia, MASA syndrome and X-linked hydrocephalus: Contribution of DNA linkage analysis in genetic counseling of individual families, Genet Couns 5:1, 1994.

  • Schrander-Stumpel C, Fryns J-P: Congenital hydrocephalus: Nosology and guidelines for clinical approach and genetic counselling, Eur J Pediatr 157:355, 1998.

  • Weller S, Gartner J: Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene, Hum Mutat 18:1, 2001.

  • Takenouchi T, et al: Hydrocephalus with Hirschsprung disease: Severe end of X-linked hydrocephalus spectrum, Am J Med Genet 158A:812, 2012.

  • Adle-Biassette H, et al: Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: Evidence for closely related clinical entities of unknown molecular bases, Acta Neuropathol 126:427, 2013 .

    FIGURE 1

    X-linked hydrocephalus spectrum.

    A male infant, who later died, was shown to have aqueductal stenosis as the cause for hydrocephalus.

    FIGURE 2

    A and B, Boy with MASA syndrome. He has intellectual disability, adducted thumb, shuffling gait, and aphasia.

Hydrolethalus Syndrome

Hydrocephalus, Micrognathia, Polydactyly

This disorder was described initially by Salonen and colleagues in 1981. Hydrolethalus refers to hydramnios, hydrocephalus, and lethality, three of the most common features of this condition. The majority of cases have been from Finland.


  • Central Nervous System. Severe prenatal onset of hydrocephalus; absent corpus callosum, septum pellucidum, and olfactory structures; hypoplastic temporal and occipital lobes; hypothalamic hamartoma; hypoplastic brainstem and cerebellum; abnormal gyrations; colobomatous dysplasia and hypoplasia of the optic nerve; cleft in the base of the skull. The foramen magnum and the bony cleft extending posterior from it form a “keyhole-shaped” opening in the base of the skull, which is a constant finding in this disorder.

  • Craniofacial. Micrognathia, cleft palate, cleft lip that is lateral or midline, broad nose especially at the root, microphthalmia, broad neck relative to the shoulders, malformed low-set ears.

  • Limbs. Postaxial polydactyly of hands, preaxial polydactyly of feet, clubfeet.

  • Cardiac. Defects in 50%, most commonly a large ventricular septal defect combined with an atrial septal defect to form an atrioventricular canal.

  • Respiratory. Defective lung lobation, malformed or hypoplastic larynx, stenotic or, rarely, dilated trachea and/or bronchi.

  • Genitourinary. Duplicated uterus, hypospadias, malformations of vagina.

Occasional Abnormalities

Absent pituitary, arrhinencephaly, hydranencephaly, anencephaly, clefts in the lower lip, bifid nose, agenesis of tongue, hydronephrosis, urethral atresia, short arms, syndactyly, agenesis of the diaphragm, omphalocele.

Natural History

The gestation of most affected patients is complicated by polyhydramnios. Intrauterine growth deficiency is the rule. Of cases, 70% are stillborn. Live-born infants survive for only a few minutes to a few hours.


Autosomal recessive mutations of two genes involved in ciliogenesis are responsible. HYLS-1 is required for the apical targeting/anchoring of centrioles at the plasma membrane. Mutations impair HYLS-1 function in ciliogenesis. Mutations in KIF7 (the human orthologue of Drosophila Costal2, a key component of the hedgehog signaling pathway) also play an important role in human primary cilia, indicating that the hydrolethalus syndrome is a ciliopathy. Mutations in KIF7 are also responsible for the acrocallosal syndrome (see page 308).


Jun 28, 2021 | Posted by in PEDIATRICS | Comments Off on Unusual Brain and/or Neuromuscular Findings with Associated Defects

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