Facial-Limb Defects as Major Feature

Miller Syndrome (Genee-Wiedemann syndrome, Postaxial Acrofacial Dysostosis Syndrome)

Treacher Collins–Like Facies; Limb Deficiency, Especially Postaxial

In 1979, Miller and colleagues brought together six cases, four of which were from the literature, and recognized this disorder as a concise entity. The facial appearance is similar to that of Treacher Collins syndrome and, in combination with limb defects, resembles Nager syndrome. The severity of the postaxial deficiencies distinguishes it from the latter syndrome. Both upper and lower limbs are usually affected. Roughly 40 cases have been reported.


  • Craniofacial. Malar hypoplasia, sometimes with radiologic evidence of a vertical bony cleft, with downslanting palpebral fissures; colobomata of eyelids and ectropion; sparse eyebrows; micrognathia; cleft lip and/or cleft palate; long philtrum.

  • Ears. Hypoplastic, cup-shaped ears.

  • Nose. Short, upturned; high columella.

  • Limbs. Absence of fifth digits of all four limbs, with or without shortening, and incurving of forearms with ulnar and radial hypoplasia; syndactyly; broad thumbs; short, broad halluces; single transverse palmar creases.

  • Other. Accessory nipple(s).

  • Imaging. Triangular-shaped terminal epiphyses; cone-shaped epiphyses of middle phalanges of feet; supernumerary vertebrae; rib defects.

Occasional Abnormalities

Postnatal growth deficiency, absent lower eyelashes, choanal atresia, conductive or sensorineural hearing loss, strabismus, short neck, thumb hypoplasia, low-arch dermal pattern, pectus excavatum, scoliosis, radioulnar synostosis, congenital hip dislocation, camptodactyly, heart defects, absence of hemidiaphragm, pyloric stenosis, renal anomalies, cryptorchidism, midgut malrotation, anal prolapse.

Natural History

These individuals usually have normal intelligence. Hearing evaluation is indicated in all cases. The craniofacial appearance sometimes changes with increasing age with a progressively greater degree of ectropion and facial asymmetry as well as a more triangular facial appearance with thin lips. Neonatal cholestasis may develop into persistent liver disease.


This disorder has an autosomal recessive inheritance pattern. Mutations of DHODH, which encodes the enzyme dihydroorotate dehydrogenase, are responsible. This enzyme is required for de novo biosynthesis of pyrimidines. Dihidroorotate accumulates in plasma and urine of affected individuals and can be used for biochemical screening. Identification of this gene represents the first successful use of exome sequencing to discover the cause of a Mendelian disorder.


  • Genée E: Une forme extensive de dysostose mandibulofaciale, J Hum Genet 17:45, 1969.

  • Smith DW, et al: Case report 28, Synd Ident 3(1):7, 1975.

  • Miller M, et al: Postaxial acrofacial dysostosis syndrome, J Pediatr 95:970, 1979.

  • Chrzanowska K, et al: Miller postaxial acrofacial dysostosis: The phenotypic changes with age, Genet Couns 4:131, 1993.

  • Ng SB, et al: Exome sequencing identifies the cause of a Mendelian disorder, Nat Genet 42:30, 2010.

  • Rainger J, et al: Miller (Genee-Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH, Hum Mol Genet 21:3969, 2012.

  • Duley JA, et al: Elevated plasma dihydroorotate in Miller syndrome: Biochemical, diagnostic and clinical implications, and treatment with uridine, Mol Genet Metab 119:83, 2016.

    FIGURE 1

    Miller syndrome.

    A–D, Affected individual showing striking malar and maxillary hypoplasia and lower lid defects. Note the hearing aid, required for middle ear deafness. The deficiency in the hands and feet is complete for the fifth ray and incomplete for the other digits.

    From Miller M et al: J Pediatr 95:970, 1979, with permission.

Nager Syndrome (Nager Acrofacial Dysostosis Syndrome)

Radial Limb Hypoplasia, Malar Hypoplasia, Ear Defects

Nager and de Reynier described a case of Treacher Collins syndrome–like in a patient with radial limb defects in 1948. Subsequently, more than 100 cases have been reported.


  • Performance. Intelligence normal; conductive deafness, usually bilateral (88%); problems with articulation.

  • Craniofacial. Malar hypoplasia (97%) with downslanting palpebral fissures (92%); high nasal bridge; micrognathia (89%); partial to total absence of lower eyelashes (81%); cleft palate (65%).

  • Ears. Low-set, posteriorly rotated ears; preauricular tags; atresia of external ear canal; malformed. Some anomaly (93%).

  • Limbs. Hypoplasia to aplasia of thumb, with or without radius; proximal radioulnar synostosis and limitation of elbow extension; short forearms. Upper limb defects (100%).

Occasional Abnormalities

Intellectual disability; microcephaly; hydrocephalus secondary to aqueductal stenosis; polymicrogyria; postnatal growth deficiency; ptosis; lower lid coloboma; projection of scalp hair onto lateral cheek; cleft lip; macrostomia; Robin sequence; velopharyngeal insufficiency; oligodontia; hypoplasia of larynx or epiglottis; absent epiglottis; temporomandibular joint fibrosis and ankylosis; syndactyly, clinodactyly, or camptodactyly of hands; duplicated and triphalangeal thumbs; missing or hypoplastic toes; overlapping toes; syndactyly of toes; posteriorly placed hypoplastic halluces, hallux valgus, broad hallux; absent distal flexion creases on toes; limb reduction defects; hip dislocation; clubfeet; hypoplastic first rib; scoliosis; cervical vertebral and spine anomalies; hypoplasia of deltoid and rotator cuff muscles; cardiac defects; diaphragmatic eventration; diaphragmatic hernia; genitourinary anomalies, including renal agenesis, duplicated ureter, vesicoureteral reflux, cryptorchidism, and epispadias; Hirschsprung disease; urticaria pigmentosa.

Natural History

Almost half of mutation positive cases have had critical airway issues in the newborn period requiring tracheostomy (44%). The recommendations for early detection of hearing loss and for surgical reconstruction are similar to those for Treacher Collins syndrome. Delays in speech and language development are related to hearing loss, cleft palate, and jaw structure. Gastrostomy is often necessary. The incidence of prematurity is high. Perinatal mortality is approximately 20% and is related to airway concerns.


This disorder has an autosomal dominant pattern of inheritance. About two-thirds of cases are caused by mutations of SF3B4, which encodes SAP49, a component of the pre-mRNA spliceosomal complex. SAP49 plays a critical role in RNA splicing and inhibits BMP-mediated osteochondral cell differentiation. Most cases of Nager syndrome have been sporadic although inheritance from a mildly affected parent has been documented, which suggests marked intrafamilial variability.


In 1990 Rodriguez and colleagues published a report of a family in which three siblings had a particularly severe, lethal, and presumed autosomal recessive form of acrofacial dysostosis characterized by microtia, severe mandibular hypoplasia with respiratory insufficiency, cleft palate, upper limb phocomelia, absent scapulae, and absent fibula in the lower limbs. Subsequent cases were documented to have heterozygous mutations in SF3B4 including one of the original siblings. Rodriguez acrofacial dysostosis is now felt to represent the severe end of the spectrum of Nager syndrome. Recurrence in the original family has been attributed to gonadal mosaicism. Polyhydramnios in the presence of severe micrognathia and limb defects has allowed prenatal diagnosis in some cases.


  • Nager FR, et al: Das Gehörorgan bei den angeborenen Kopfmissbildungen, Pract Otorhinolaryngol (Basal) 10(Suppl 2):1, 1948.

  • Bowen P, et al: Mandibulofacial dysostosis with limb malformations (Nager’s acrofacial dysostosis), Birth Defects 10(5):109, 1974.

  • Rodriguez JI, et al: New acrofacial dysostosis syndrome in 3 sibs, Am J Med Genet 35:484, 1990.

  • Bernier FP, et al: Haploinsufficiency of SF3B4 , a component of the pre-mRNA spliceosomal complex, causes Nager syndrome, Am J Hum Genet 90:925, 2012.

  • Czeschik JC, et al: Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome, Hum Genet 132:885, 2013.

  • Petit F, et al: Nager syndrome: Confirmation of SF3B4 haploinsufficiency as the major cause, Clin Genet 86:246, 2014.

  • Irving MD, et al: Rodriguez acrofacial dysostosis is caused by apparently de novo heterozygous mutations in the SF3B4 gene, Am J Med Genet 170A:3133, 2016.

  • Drivas TG, et al: The final demise of Rodriguez lethal acrofacial dysostosis: A case report and review of the literature, Am J Med Genet 179A:1063, 2019.

    FIGURE 1

    Nager syndrome.

    A and B, Note the malar hypoplasia, downslanting palpebral fissures, high nasal bridge, micrognathia, and thumb aplasia.

    Courtesy of Dr. Stephen Braddock, University of Missouri, Columbia.

Townes-Brocks Syndrome

Thumb Anomalies, Auricular Anomalies, Anal Anomalies

Townes and Brocks first described this disorder in 1972, and at least 65 affected individuals have been reported. The estimated prevalence is 1 in 250,00 live births.


  • Performance. Sensorineural loss, ranging from mild to profound; a small conductive component is often present.

  • Craniofacial. Variable features of hemifacial microsomia.

  • Ears. Auricular anomalies, including overfolding of the superior helix and small, sometimes cupped ears; preauricular tags.

  • Limbs. Hand anomalies, including broad, bifid, hypoplastic, or triphalangeal thumb; hypoplastic thenar eminence; preaxial polydactyly; distal ulnar deviation of thumb; absent or hypoplastic third toe; clinodactyly of fifth toe.

  • Gastrointestinal. Imperforate anus, anterior placement, and stenosis; rectovaginal or rectoperineal fistula.

  • Genitourinary. Unilateral or bilateral hypoplastic or dysplastic kidneys, renal agenesis, multicystic kidney, posterior urethral valves, vesicoureteral reflux, meatal stenosis.

  • Imaging. Pseudoepiphysis of second metacarpals; fusion of triquetrum and hamate; absence of triquetrum and navicular bones; fusion or short metatarsals; prominence of distal ends of lateral metatarsals.

Occasional Abnormalities

Intellectual disability; microcephaly; microtia; preauricular pit; structural middle ear anomalies; cataracts; microphthalmia; optic nerve atrophy; horizontal nystagmus from absent optic chiasm; coloboma; epibulbar dermoids; mandibular hypoplasia; cardiac defect; duodenal atresia; cystic ovary; prominent perineal raphe; bifid scrotum; hypospadias; second and third, and third and fourth, syndactyly of fingers; abnormalities of toes, including fifth toe clinodactyly, absence or hypoplasia of third toe, third and fourth syndactyly of toes, overlapping second, third, and fourth toes; scoliosis.

Natural History

Hearing loss can be progressive and is worse in the high frequencies. Renal failure or impaired renal function occurs in some cases. Lifelong monitoring of renal function is indicated.


This disorder has an autosomal dominant inheritance pattern with marked variability in the severity of expression for each feature. Truncating mutations in SALL1, which is expressed in all organs affected in this disorder and is located at 16q12.1, are responsible for between 64% and 83% of cases. Deletions of 16q12.1, which include the SALL1 gene, have accounted for a few cases. Truncated SALL1 interacts with negative regulators of ciliogenesis, suggesting that aberrations in primary cilia contribute to the phenotype.


This single-gene disorder encompasses many of the features of both the VACTERL association and the facio-auriculo-vertebral malformation spectrum.


  • Townes PL, Brocks ER: Hereditary syndrome of imperforate anus with hand, foot and ear anomalies, J Pediatr 81:321, 1972.

  • Reid IS, et al: Familial anal abnormality, J Pediatr 88:992, 1976.

  • Kurnit DM, et al: Autosomal dominant transmission of a syndrome of anal, ear, renal and radial congenital malformations, J Pediatr 93:270, 1978.

  • Walpole IR, Hockey A: Syndrome of imperforate anus, abnormalities of hands and feet, satyr ears, and sensorineural deafness, J Pediatr 100:250, 1982.

  • Kohlhase J, et al: Molecular analysis of SALL1 mutations in Townes-Brocks syndrome, Am J Hum Genet 64:435, 1999.

  • Powell CM, et al: Townes-Brocks syndrome, J Med Genet 36:89, 1999.

  • Kosaki R, et al: Wide phenotypic variations within a family with SALL1 mutations: Isolated external ear abnormalities to Goldenhar syndrome, Am J Med Genet 143:1087, 2007.

  • Miller EM, et al: Implications for genotype-phenotype predictions in Townes-Brocks syndrome: Case report of a novel SALL1 deletion and review of the literature, Am J Med Genet 158:533, 2012.

  • Bozal-Basterra L, et al: Truncated SALL1 impedes primary cilia function in Townes-Brock syndrome, Am J Hum Genet 102:249, 2018.

    FIGURE 1

    Townes-Brocks syndrome.

    A–E, Variation of facial morphogenesis with large protruding ears, preauricular tags, and features resembling facio-auriculo-vertebral sequence (hemifacial microsomia, Goldenhar syndrome). Note the imperforate anus, hypoplastic thenar eminence and thumb, and hypoplastic third toe.

Laurin-Sandrow Syndrome

Cup-Shaped Hands, Mirror Image Feet, Flat Nose with Grooved Columella

Laurin and colleagues described, in 1964, a newborn boy with complete polysyndactyly of hands, mirror polysyndactyly of feet, bilateral ulnar and fibular dimelia, and absent tibia and radii. Sandrow and colleagues described a similarly affected father and daughter who had, in addition, anomalies of the ala nasi and columella. Martínez-Frías and colleagues referred to this disorder as Laurin-Sandrow syndrome.


  • Growth. Normal pre- and postnatal growth with short stature owing to limb anomalies.

  • Performance. Normal cognitive function; motor challenges secondary to limb anomalies.

  • Nose. Deep groove running the length of a short columella, flat nasal bridge, bulbous nasal tip, unfused nares, hypoplastic alar and columellar cartilage.

  • Limbs. Upper limbs: complete polysyndactyly; cup-appearing, rosebud, or mitten hands; phalanges of differing sizes and shapes; disorganized interphalangeal joints; abnormal carpal bones. Lower limbs: Polydactyly with variable syndactyly, mirror image feet, talipes equinovarus, abnormal tarsal bones, absent/hypoplastic tibia.

  • Imaging. Large mandibular condyles; duplication of ulna; malformed scaphoid and lunate bones; absence of the trapezia, triquetrum, and pisiform bones; synostosis/malformation of tarsals; synostosis of talus, calcaneus, cuboid, and navicular bones; supernumerary metacarpals and metatarsals; asymmetric shortening of metacarpals; bony syndactyly of phalanges; radioulnar synostosis; absent/hypoplastic patella.

Occasional Abnormalities

Frontal prominence, hydrocephalus, agenesis of corpus callosum, neuronal migration defects, developmental delay, hypotonia, absent radius, decreased pronation/supination at elbows, restricted extension at wrist, short fibula, fibular duplication, cryptorchidism.

Natural History

Although one affected 33-week premature infant with agenesis of the corpus callosum and dilatation of the lateral ventricles died of unknown etiology in the newborn period, life expectancy appears to be normal. An affected 54-year-old man with mild intellectual disability who appeared older than his age was described as cheerful and apparently healthy. The 55-year-old affected father of the most recently reported infant was healthy.


Based on two instances of male-to-male transmission, autosomal dominant is the most likely mode of inheritance. The causative gene has not been identified


  • Laurin CA, et al: Bilateral absence of the radius and tibia with bilateral reduplication of the ulna and fibula, J Bone Joint Surg Am 46:137, 1964.

  • Sandrow RE, et al: Hereditary ulnar and fibular dimelia with peculiar facies, J Bone Joint Surg Am 52:367, 1970.

  • Martínez-Frías ML, et al: Laurin-Sandrow syndrome (mirror hands and feet and nasal defects): Description of a new case, J Med Genet 31:410, 1994.

  • Mariño-Enríquez A, et al: Laurin-Sandrow syndrome: Review and redefinition, Am J Med Genet A 146A:2557, 2008.

  • Salinas-Torres VM: Male-to-male transmission of Laurin-Sandrow syndrome in a Mexican family, Clin Dysmorphol 23:39, 2014.

    FIGURE 1

    Laurin-Sandrow syndrome.

    Note frontal bossing, hypertelorism, broad nasal bridge, flat midface and nose with a deep longitudinal groove on the tip of the nose and the columella, downturned corners of mouth.

    From Mariño-Enríquez A, et al: Am J Med Genet A 146A:2557, 2008, with permission.

    FIGURE 2

    Note bilateral polysyndactyly with bilateral postaxial appendices and a thumb-appearing preaxial finger. Seven metacarpals and finger anomalies are noted on radiographs of the upper limbs. The thumbs have two phalanges, and postaxial appendices lack ossified bones.

    From Mariño-Enríquez A, et al: Am J Med Genet A 146A:2557, 2008, with permission.

    FIGURE 3

    Feet of affected child.

    A, Bilateral polysyndactyly with prominent preaxial accessory digit. B, Radiographic appearance showing four lateral toes with three identically shaped phalanges, and other phalanges showing variable shapes and sizes. Preaxial accessory digit has three bones on the left side and two on the right. There are seven metatarsals and a single anomalous tarsal bone. C, On the radiograph of the lower limbs, note the hypoplastic tibiae, which are shorter than the fibula.

    From Mariño-Enríquez A, et al: Am J Med Genet A 146A:2557, 2008, with permission.

Oral-Facial-Digital Syndrome (OFD Syndrome, Type I)

Oral Frenula and Clefts, Hypoplasia of Alae Nasi, Digital Asymmetry

Papillon-Léage and Psaume set forth this condition as a clinical entity in 1954. More than 200 cases have been reported. More than 14 different oral-facial-digital (OFD) syndromes have been delineated clinically. All share in common oral hamartoma, multiple frenula, and digital anomalies. Clinical subtypes have been distinguished based on inheritance pattern and/or unique associated malformations. As the molecular basis for each subtype is elucidated, it has become clear that these disorders represent families of ciliopathies with overlapping phenotypes and molecular pathogenesis. The clinical classification has lost much of its relevance. Only types I, IV, and VI retain recognizable patterns of malformation. Types I and II have been set forth in detail in this chapter (type II in part for historic purposes as it was the first of the OFD syndromes to be delineated). OFD type I, by far the most common, affects primarily females. Prevalence estimates range from 1 in 50,000 to 1 in 250,000.


  • Performance. Variable degrees of intellectual disability or neurologic impairment in approximately 60% including motor delay (25%), epilepsy (15%), hypotonia (7%), cranial nerve dysfunction (7%), sensorineural hearing loss (6%), spasticity (4%), reduced ability to process verbal information; difficulty with attention; long-term memory deficits.

  • Craniofacial. Ocular hypertelorism or telecanthus (50%); hypoplasia of alar cartilages, medial cleft or pseudocleft of upper lip (32% to 58%); cleft hard or soft palate; multiple and/or hyperplastic frenuli between the buccal mucous membrane and alveolar ridge (64% to 79%); lobated/bifid tongue with nodules (∼80%); cleft of alveolar ridge at area of lateral incisor; ankyloglossia; micrognathia.

  • Teeth. Dental caries; hypodontia; missing lateral incisors; malformed teeth; malocclusion.

  • Limbs. Asymmetric shortening of digits (52% to 63%); clinodactyly (50%); syndactyly; brachydactyly of hands; preaxial polydactyly of feet; radial or ulnar deviation of the third digit; duplicated hallux.

  • Skin. Dry, rough, sparse hair (21% to 41%); dry scalp; milia of ears and upper face in infancy (30%).

  • Gastrointestinal. Hepatic and pancreatic cysts (over time).

  • Genitourinary. Polycystic kidney disease (over age 18 close to 100%); histologically, there is a predominance of glomerular cysts; ovarian cysts

  • Imaging. Agenesis/hypoplasia of corpus callosum (81%); intracerebral cyst (47%); porencephaly; hydrocephalus (27%); neuronal migration defects (54%); cortical infolding of gyri; cerebellar agenesis; vermis hypoplasia; focal polymicrogyria; cortical, periventricular, subarachnoid heterotopia; Dandy-Walker malformation; molar tooth sign; brainstem anomalies; increased naso-sella-basion angle at base of cranium; renal cysts; fine reticular radiolucencies with irregular mineralization of hand bones with or without spicule formation of the phalanges.

  • Prenatal. Agenesis of corpus callosum; porencephaly; hydrocephalus; intracerebral cysts; polydactyly.

Occasional Abnormalities

Nystagmus, hemiparesis, ataxia, hypothalamic hamartoma, enamel hypoplasia, supernumerary teeth, hamartoma of tongue, fistula in lower lip, choanal atresia, frontal bossing, hypoplastic mandibular ramus and zygoma, nonprogressive metaphyseal rarefaction, alopecia, granular seborrheic skin, pre- and postaxial polydactyly of hands (1% to 2%), tibial pseudarthrosis.

Natural History

As many as one-third of cases die in the neonatal period. Management is directed toward reconstruction of oral clefts and dental care, including dentures, when indicated. Close monitoring of development is warranted because over half of the reported patients have intellectual disability or some neurologic dysfunction. Polycystic renal disease is progressive, with onset of hypertension and renal insufficiency after 18 years of age. Fibrocystic disease of liver and pancreas may become a problem in adulthood.


This disorder has an X-linked dominant inheritance pattern with lethality in the majority of affected males. Most of the published male cases represent malformed fetuses of women with OFD type I. Over 70% of affected individuals are simplex cases (no family history) and most are female. Mutations in OFD1, which encodes a centrosomal/basal body protein located at the base of the primary cilia, are responsible for type I. Most variants that produce this phenotype are truncating mutations. Long-term surviving males with mutations in OFD1 tend to have in-frame or missense mutations and present with a milder phenotype that does not suggest OFD type I.


Gurrieri and colleagues set forth the major features that clinically appeared to distinguish types III through XIII as listed below. With the exception of type V, all have similar oral, facial, and digital abnormalities. As the molecular basis of these conditions has been elucidated, the distinction between most of these subtypes has become less relevant.

  • Type III (Sugarman syndrome), an autosomal recessive disorder, is distinguished clinically by intellectual disability, early onset renal failure, postaxial polydactyly, a bulbous nose, extra and small teeth, and macular red spots associated with see-saw winking of eyelids, myoclonic jerks, or both. Mutations in TMEM231 have been documented.

  • Type IV (Baraitser-Burn syndrome), an autosomal recessive disorder, is distinguished by severe tibial dysplasia, occipitoschisis, brain malformations, ocular colobomas, intrahepatic and renal cysts, anal atresia, and joint dislocations. Mutations in TCNT3 have been reported.

  • Type V (Thurston syndrome), an autosomal recessive condition, includes midline cleft lip, duplicated frenulum, and postaxial polydactyly of hands and feet. Caused by mutations in DDX59.

  • Type VI (Varadi-Papp syndrome), an autosomal recessive condition, is distinguished by preaxial polysyndactyly of toes and postaxial polydactyly of fingers, Y-shaped metacarpal with central polydactyly, and cerebellar anomalies (vermis hypoplasia/aplasia, molar tooth sign, or Dandy-Walker anomaly). Occasional features include growth hormone deficiency, hypogonadotrophic hypogonadism, and hypothalamic hamartoma. Caused by mutations in OFD1, TMEM216, C5orf42, TMEM138, TMEM107, KIAAO753.

  • Type VII (Whelan syndrome) has been reported in a mother-daughter pair. Features that distinguish this condition include congenital hydronephrosis, coarse hair, facial asymmetry, facial weakness, and preauricular tags. OFD type VII is caused by mutation in OFD1 making it allelic to OFD type I.

  • Type VIII (Edwards syndrome) is an X-linked recessive disorder distinguished from type I by pre- and postaxial polydactyly of hands and bilateral duplication of halluces, shortness of long bones, abnormal tibiae, short stature, laryngeal anomalies, absent or abnormal central incisors, broad or bifid nasal tip, and metacarpal forking. It overlaps with type II and IV.

  • Type IX (Gurrieri syndrome) is an autosomal recessive disorder. Features that distinguish this condition are retinal coloboma and hallucal duplication. Caused by mutations in SCLT1, TBC1D32/C6orf170.

  • Type X (Figuera syndrome) has the distinguishing features of mesomelic limb shortening owing to radial hypoplasia and fibular agenesis. The digital defects include oligodactyly and preaxial polydactyly.

  • Type XI (Gabrielli syndrome) is distinguished by craniovertebral anomalies, including fusion of vertebral arches of C1, C2, and C3 and clefts in vertebral bodies, midline cleft of the palate, vomer, ethmoid and crista galli, and apophysis.

  • Type XII (Moran-Barroso syndrome) has distinguishing features, including myelomeningocele, stenosis of aqueduct of Sylvius, and cardiac anomalies.

  • Type XIII (Degner syndrome) has distinguishing features that include major depression, epilepsy, and MRI findings of the brain such as patched loss of white matter of unknown origin.

Bruel and colleagues proposed a simplified classification in which only clinical types I, IV, and VI would be retained based on clinical features, whereas the remainder would be defined by the mutation. It remains to be seen if this classification will prove practical.

  • Type 1: Polycystic kidney disease and corpus callosal agenesis—mutation in OFD1.

  • Type IV: Tibial dysplasia—mutation in TCTN3.

  • Type VI: Mesoaxial polydactyly, vermis hypoplasia, molar tooth sign—mutations in TMEM216, TMEM231, TMEM138, TMEM107, C5orf42, KIAA0753

  • INTU, WDPCP associated with cardiac defects

  • SCLT1, TBC1, D32/C7orf170 associated with retinopathy

  • C2CD3 associated with severe microcephaly

  • IFT57 associated chondrodysplasia


  • Papillon-Léage E, Psaume J: Une malformation héréditaire de la muqueuse buccale: Brides et freins anormaux, Rev Stomatol (Paris) 55:209, 1954.

  • Gorlin RJ, Psaume J: Orodigitofacial dysostosis—a new syndrome, J Pediatr 61:520, 1962.

  • Toriello HV: Oral-facial-digital syndromes, 1992, Clin Dysmorphol 2:95, 1993.

  • Toriello HV, et al: Six patients with oral-facial-digital syndrome IV: The case for heterogeneity, Am J Med Genet 69:250, 1997.

  • Doss BJ, et al: Neuropathologic findings in a case of OFDS type VI (Varadi syndrome), Am J Med Genet 77:38, 1998.

  • Ferrante MI, et al: Identification of the gene for oral-facial-digital type I syndrome, Am J Hum Genet 68:569, 2001.

  • Gurrieri F, et al: Oral-facial-digital syndromes: Review and diagnostic guidelines, Am J Med Genet 143:3314, 2007.

  • Bisschoff IJ, et al: Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: A study of extensive clinical variability, Hum Mutat 34:237, 2013.

  • Del Giudice E, et al: CNS involvement in OFD1 syndrome: A clinical, molecular, and neuroimaging study, Orphanet Journal of Rare Diseases 9:74, 2014.

  • Bruel AL, et al: 15 years of research on oral-facial-digital syndromes: From 1 to 16 causal genes, J Med Genet 54:371, 2017.

    FIGURE 1

    Oral-facial-digital syndrome, type I.

    A–C, Note the milia of the ears and upper face in infancy, the median cleft lip, and the hypoplastic ala nasi.

Mohr Syndrome (OFD Syndrome, Type II)

Cleft Tongue, Conductive Deafness, Partial Reduplication of Hallux

Mohr described this pattern in several male siblings in 1941 making this the first of the OFD syndromes to be delineated. More than 30 cases have been reported. As with other OFD syndromes, type II is a ciliopathy. As the molecular basis of the OFD syndromes is elucidated, it is unclear if Mohr syndrome will remain a distinct recognizable clinical entity.


  • Growth and Performance. Mild shortness of stature, conductive deafness, apparently owing to an incus defect.

  • Craniofacial. Low nasal bridge with lateral displacement of inner canthi; broad nasal tip, sometimes slightly bifid; midline partial cleft of lip; hypertrophy of usual frenula; midline cleft of tongue; tongue hamartomas; flare to alveolar ridge; hypoplasia of zygomatic arch, maxilla, and mandible body.

  • Dental. Taurodontia, oligodontia, missing incisors, talon cusps on incisors and canines.

  • Limbs. Partial reduplication of hallux and first metatarsal, cuneiform, and cuboid bones; relatively short hands with clinodactyly of fifth finger; bilateral postaxial polydactyly of hands; bilateral preaxial polysyndactyly of feet (occasionally only unilateral); metaphyseal flaring and irregularity.

  • Imaging. Broad or bifid hallux, mesomelic long bone shortening; Wormian cranial bones; plump vestibulae and lateral semicircular canals.

Occasional Abnormalities

Cleft palate, submucous cleft palate, multiple frenula, pectus excavatum, scoliosis, tortuosity of retinal vessels.

Natural History

Most of these patients have normal intelligence. Prosthodontic and surgical reconstruction is indicated for the missing teeth, clefts, frenula, and partial reduplication of the hallux. Although renal function has been normal in all patients in whom it has been evaluated, the nature of the genetic etiology suggests that long-term monitoring of renal function may be prudent.


This disorder has an autosomal recessive inheritance pattern. Compound heterozygous mutations in NEK1 (never in mitosis gene A-related kinase 1) underlie some cases of this disorder. Homozygous variants in NEK1 cause short-rib polydactyly syndrome Majewski type, which clinically has been considered allelic to OFD type II. NEK1 is a known ciliary gene that plays a role in the formation of the primary cilium as well as roles in cell-cycle regulation and DNA damage repair. Homozygous mutations in DDX59, DEAD-box helicase 59, are responsible for an OFD syndrome that bears considerable resemblance to Mohr syndrome (cleft palate, midline cleft lip), although affected individuals have cognitive impairment, microcephaly, vermis hypoplasia, agenesis of the corpus callosum, and cardiac defects.


  • Mohr OL: A hereditary sublethal syndrome in man, Skr Norske Vidensk Akad I Mat Naturv Klasse 14:3, 1941.

  • Rimoin DL, Edgerton MT: Genetic and clinical heterogeneity in the oral-facial-digital syndromes, J Pediatr 71:94, 1967.

  • Baraitser M: The orofacial digital (OFD) syndromes, J Med Genet 23:116, 1986.

  • Sakai N, et al: Oral-facial-digital syndrome type II (Mohr syndrome): Clinical and genetic manifestations, J Craniofac Surg 13:321, 2002.

  • Shamseldin HE, et al: Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome, Am J Hum Genet 93:555, 2013.

  • Monroe GR, et al: Compound heterozygous NEK1 variants in two siblings with oral-facial digital syndrome type II (Mohr syndrome), Eur J Hum Genet 24:1752, 2016.

  • Faily S, et al: Confirmation that mutations in DDX59 cause an autosomal recessive form of oral-facial-digital syndrome: Further delineation of the DDX59 phenotype in two new families, Eur J Med Genet 60:527, 2017.

    FIGURE 1

    Mohr syndrome.

    A–C, Note the midline cleft of the upper lip, lateral displacement of the medial canthi, broad nasal tip, and tongue nodules. D–F, Note the postaxial polydactyly of hands and feet and preaxial polydactyly of feet.

22q11.2 Microdeletion Syndrome (Velo-Cardio-Facial Syndrome, DiGeorge Syndrome, Shprintzen Syndrome)

In 1965 DiGeorge described a patient with hypoparathyroidism and cellular immune deficiency secondary to thymic hypoplasia. The pattern of malformation expanded rapidly to include other defects of the third and fourth branchial arches as well as dysmorphic facial features. In 1978, Shprintzen and colleagues reported a group of children with cleft palate or velopharyngeal incompetence, cardiac defects, and a prominent nose (velo-cardio-facial syndrome). Subsequent studies determined that individuals with velo-cardio-facial syndrome and the majority of those with the condition described by DiGeorge have a deletion of chromosome 22q11.2. The two disorders represent different manifestations of the same genetic defect. The prevalence of this disorder is 1 in 4000 to 1 in 6000. It is likely under-diagnosed particularly in non-Caucasian populations.


  • Performance. In a large international cohort, mean full scale IQ, verbal IQ, and performance IQ were 75, 75, and 73 with standard deviation of 14 in each category. Individuals with A-B deletions performed better than those with the more common A-D deletions (see etiology). A plethora of neuropsychiatric phenotypes present, many of which are age dependent: attention deficit hyperactivity disorder (32%) and autism (21%) in younger ages; anxiety (35%) in all ages, mood disorders (depression) over time; schizophrenia spectrum disorders in 24% of emerging adults and 41% in those more than 25 years of age. Cognitive decline over time occurs in a subset of patients.

  • Decreased motor tone and axial instability; motor milestones delayed (walking at a mean age of 16 months); conductive hearing loss secondary to cleft palate; epilepsy (11%); febrile seizures (24%).

  • Growth. Postnatal onset of short stature (36%); microcephaly (24% to 30%) in infancy; mean adult head circumference (9%).

  • Craniofacial. Cleft of the secondary palate, either overt or submucous; velopharyngeal incompetence (67%); small or absent adenoids; prominent nose with squared nasal root and narrow alar base; narrow palpebral fissures; ptosis; eyelid hooding; abundant scalp hair; deficient malar area; vertical maxillary excess with long face; retruded mandible with chin deficiency.

  • Ears. Minor auricular anomalies

  • Limbs. Slender and hypotonic with hyperextensible hands and fingers (63%).

  • Cardiac. Defects present in 85%, the most common being ventricular septal defect (62%); right aortic arch (52%); tetralogy of Fallot (21%); aberrant left subclavian artery; truncus arteriosus; type B interrupted aortic arch.

  • Imaging. Structural brain defects, including cerebral atrophy, cerebellar hypoplasia, cerebral vascular defect, septum pellucidum cyst, cavum septum pellucidum; white matter abnormalities; hydrocephalus, hypoplastic corpus callosum, polymicrogyria, periventricular nodular heterotopia, and enlarged ventricles; butterfly vertebrae; 13 ribs; renal anomalies; middle ear anomalies.

  • Prenatal. Cardiac defects, renal anomalies, brain anomalies, neural tube defects, diaphragmatic hernia, polyhydramnios.

Occasional Abnormalities

Robin malformation sequence; cleft lip; asymmetric crying facies; facial nerve palsy; tortuosity of retinal vessels (30%); small optic disks; ocular coloboma; cataracts; sclerocornea; posterior embryotoxin; holoprosencephaly; neural tube closure defect; choanal stenosis; nasal dimple; enlargement, medial displacement, tortuosity, or other abnormalities of internal carotid arteries (25%); laryngeal cleft/web; laryngomalacia; tracheomalacia; umbilical or inguinal hernias; diaphragmatic hernia; genitourinary anomalies (15%), including absent, dysplastic, or multicystic kidneys, hydronephrosis, duplicated collecting systems, horseshoe kidney, posterior urethral valves, vesicoureteral reflux, ureterocele, megaurethra, cryptorchidism, hypospadias, uterine didelphys, vaginal agenesis, and absent uterus; anal anomalies; intestinal malrotation; Hirschsprung disease; hypothyroidism; abnormal T-cell function and absent thymic tissue; pre- and postaxial polydactyly; syndactyly; camptodactyly; patellar dislocation; talipes equinovarus; scoliosis (50% with 5% to 6 % requiring surgery).

Natural History

An overall mortality of 4%, mostly as a consequence of congenital heart disease, is reported. Mean age of death is 5 months. For adults, the presence of a major heart defect has an impact on longevity. The likelihood of survival to ages 40 and 50 with a major heart defect is 82% and 63%, respectively, whereas without a heart defect survival is 98% and 85%. Twenty-three percent will outlive both parents.

Hypotonia in infancy is frequent (70% to 80%). Feeding problems are common (68%), including weak suck, nasopharyngeal reflux, gastroesophageal reflux (10%), and dysphagia with a risk for aspiration. Chronic constipation is common. Transient neonatal hypocalcemia occurs in 60% of cases. Seizures (21%) are usually the result of hypocalcemia. Rare individuals have lifelong hypocalcemia. Periodic hypocalcemia has occurred with stress (surgery), puberty, and pregnancy. Only 1% have no T cells requiring referral for thymic transplant. The majority have reduced T-cell numbers and function with frequent upper respiratory infection, otitis, and pneumonia. Patients have high rates of atopy (77%) and autoimmune disease, including Graves disease, Hashimoto thyroiditis, juvenile arthritis, autoimmune hemolytic anemia, thrombocytopenia, and vitilago. Speech and language development is often delayed (first words 19 months, phrases 34.5 months) Speech is almost always hypernasal, with the pharyngeal musculature being hypotonic. Surgery for velopharyngeal insufficiency improves intelligibility, but may increase the risk for obstructive sleep apnea. The abnormalities of the internal carotid arteries can be diagnosed by the demonstration of visible pulsations in the posterior pharyngeal wall musculature using fiberoptic nasopharyngoscopy or with magnetic resonance imaging.

Socialization skills may surpass intellectual skills. Personality may tend toward perseverative behavior, with concrete thinking secondary to intellectual impairment or learning disorders. Cognitive decline over time occurs in a subset of individuals. Sleep disorders occur in 60%. Movement disorders are reported. Some adults have early onset Parkinson disease.

Approximately 25% of affected individuals will develop a psychiatric condition in late teen or young adult years, primarily schizophrenia. Emerging evidence indicates that significant cognitive decline precedes the onset of psychosis.


This disorder has an autosomal dominant inheritance pattern. The deletion is mediated by a series of low-copy repeats (LCRs) that bring about a meiotic nonallelic homologous recombination that results in either deletion or duplication of various intervals in the region. The LCRs have been lettered from A to H. Affected individuals usually have a 1.5 (A-B, 8% to 10%) or 3 Mb (A-D, 85% to 90%) interstitial deletion of chromosome 22q11.2. Of deletions, 95% are detectable using fluorescent in situ hybridization (FISH). However, 5% require a different platform. Array comparative genomic hybridization (aCGH) detects the common deletions as well as the nested and distal deletions and duplications. At least 30 genes have been mapped to the critical region. Much of the neural crest phenotype appears related to haploinsufficiency of TBX1. TBX1 encodes a T-box transcription factor, which plays an important role in early vertebrate development. Strong evidence for its role in the deletion 22q11.2 syndrome is based on the fact that individuals with TBX1 mutations who lack del(22)(q11.2) have clinical features consistent with the deletion 22q11.2 syndrome and that Tbx1 -null mouse mutants express all the malformations associated with deletion 22q11.2 syndrome. Because of the marked variability of expression both parents of an affected child should be tested to determine if they carry the deletion. Between 85% and 90% of cases represent de novo deletions. The remainder are inherited from an affected parent (usually mother) who may or may not have been diagnosed previously. A-D deletions are typically de novo . A-B deletions are often inherited and associated with a milder phenotype. Gonadal mosaicism has occurred resulting in a 1% risk for recurrence for deletion-negative parents.


Because of T-cell lymphopenia newborn screening for severe combined immunodeficiency syndrome (SCIDS), which was not designed to detect this condition, has none-the-less allowed early identification of the 1% who have severe immunodeficiency as well as many who will eventually prove immunocompetent. Testing infants who have positive newborn screens for SCIDS (but do not have SCIDS) for this condition is suggested.

22Q11.2 Microduplication

Reciprocal duplications for all of the 22q11.2 microdeletions (A-H) have been reported in an aggregate of more than 200 patients with a highly variable but generally milder phenotype. Features include normal cognition to learning difficulties/intellectual disability, autism spectrum disorders (14% to 25%), growth retardation, hypotonia, and shared structural abnormalities with the 22q11.2 deletion syndrome, although with a much lower frequency, including heart defects (25%, most commonly outflow track abnormalities, but also hypoplastic left heart and atrial septal defects), urogenital abnormalities, and velopharyngeal insufficiency with or without cleft palate. The subtle and variable dysmorphic features do not constitute a recognizable pattern of malformation. Most individuals (70%) have inherited the duplication, typically from an unaffected parent. Duplications are felt to convey a risk for autism spectrum disorders, speech and language delays, and behavioral abnormalities. Occasional abnormalities include Robin sequence, glaucoma, and esophageal atresia. Dysregulation of TBX1 dosage in animal models confirm its role in both deletion and duplication syndromes.

Atypical Distal 22q11.2 Microdeletions

Deletions located distally to the approximate 1.5 (A-B) Mb proximal deletion region in DG/VCFS phenotypically differ from deletions in the common A-D interval (3 Mb) or the smaller proximal interval (1.5 Mb) containing TBX1 as a major causal gene.

B-D and C-D deletions (called central deletions) are associated with growth restriction (24%), developmental delay or intellectual disability (49%), and dysmorphic features, including upslanting palpebral fissures, abnormal ears, and cardiac defects (20%). Over 76 cases have been reported. Central deletions often present prenatally with cardiac, renal, or other structural anomalies and intrauterine growth restriction. Central deletions have a lower rate of immune deficiency, hypotonia, and palatal anomalies. Of these deletions, 40% are inherited. CRKL , CRK-like protooncogene, is a candidate gene for the phenotype associated with central deletions.

Distal deletions are divided into three types. Distal type 1 deletions (C-E, D-E, D-F) are mostly de novo (62%) and have a high rate of requiring pregnancy management for ultrasound anomalies and fetal growth restriction. Over half of cases are delivered prematurely. More than 45 cases have been reported. MAPK1/ERK2, mitogen-activated protein kinase 1, is implicated in the phenotype of distal type 1 deletions. Cardiac defects have been noted in 53%, including both conotruncal and left-sided flow-related defects. Dysmorphic features include arched eyebrows, hypoplastic ala nasi, upslanting palpebral fissures, and micrognathia. Distal type 2 deletions (E-F) are rare with only eight reports in the literature. Most cases have been de novo . Developmental delay was noted in 88%. Prenatal findings have included increased nuchal translucency and cardiac anomalies. Distal type 3 deletions (D-H, E-H, F-H) share in common deletion of SMARCB1 ( INI1 ), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, which confers a markedly increased risk for malignant rhabdoid tumors. Over 17 cases have been reported. Most are de novo . Features include developmental delay (35%), microcephaly (24%), cardiac defects (29%), and dysmorphic features, including upslanting palpebral fissures and ear tags/pits. Young age at identification of this deletion is associated with a worse outcome with respect to the development of tumor.


  • Di George AM: Discussions on a new concept of the cellular base of immunology. J Pediatr 67:907, 1965 (abstr).

  • DiGeorge AM: Congenital absence of the thymus and its immunological consequences: Concurrence with congenital hypoparathyroidism, Birth Defects OAS 4:116, 1968.

  • Shprintzen RJ, et al: A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: Velo-cardio-facial syndrome, Cleft Palate J 15:56, 1978.

  • Driscoll DA, et al: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome, Am J Med Genet 44:261, 1992.

  • Scrambler PJ, et al: The velo-cardio-facial syndrome is associated with chromosome 22 deletions which encompass the DiGeorge syndrome locus, Lancet 339:1138, 1992.

  • Yagi H, et al: Role of TBX1 in human del22q11.2 syndrome, Lancet 362:1366, 2003.

  • Liao J, et al: Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage, Hum Mol Genet 13:1577, 2004.

  • Habel A, et al: Towards a safety net for management of 22q11.2 deletion syndrome. Guidelines for our times, Eur J Pediatr 173:757, 2014.

  • Burnside RD: 22q.11.21 deletion syndromes: A review of proximal, central, and distal deletions and their associated features, Cytogenet Genone Res 146:89, 2015.

  • Wenger TL, et al: 22q11.2 duplication syndrome: Elevated rate of autism spectrum disorder and need for medical screening, Molecular Autism 7:27, 2016.

  • Kruszka P, et al: 22q11.2 deletion syndrome in diverse populations, Am J Med Genet 173A:879, 2017.

  • Fiksinski AM, et al: Understanding the pediatric psychiatric phenotype of 22q11.2 deletion syndrome, Am J Med Genet 176A:2182, 2018.

  • Campbell IM, et al: What’s new with 22q? An update from the 22q and You Center at the Children’s Hospital of Philadelphia, Am J Med Genet 176A:2058, 2018.

  • Van L, et al: All-cause mortality and survival in adults with 22q11.2 deletion syndrome, Genet Med 21:2328, 2019.

Jun 28, 2021 | Posted by in PEDIATRICS | Comments Off on Facial-Limb Defects as Major Feature

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