Facial-Limb Defects as Major Feature

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.

Etiology

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.

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.

Etiology

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.

Comment

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.

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.

Etiology

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.

Comment

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

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.

Etiology

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

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.

Etiology

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.

Comment

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

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.

Etiology

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.