Classic Types.

Classic type lissencephaly is characterized by abnormally thick, four-layer cerebral cortex without other major brain anomalies. It is caused by mutations in 4 genes: PAFA, H1B1 (LIS1), DCX, and TUBA1A .

Cobblestone Cortical Malformation.

Cobblestone cortical malformation was previously known as type 2 lissencephaly and is distinct from classic lissencephaly. The cortex appears irregular or pebbled and is thinner. There may also be irregularity in the gray-white matter boundary, dilated ventricles, white matter abnormalities, brainstem hypoplasia, and cerebellar abnormalities. Although this group is genetically heterogeneous, it is most commonly due to defects in α-dystroglycan O -glycosylation. Known causative genes include POMT1, POMT2, POMGNT1, FKRP, FKTN, ISPD, and LARGE . The three associated phenotypes are Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy (ranging from most to least severe).

X-Linked Lissencephaly With Ambiguous Genitalia.

Males affected with X-linked lissencephaly have severe developmental delay, small or ambiguous genitalia, and seizures. Microcephaly, feeding difficulties, and growth failure are also present. Death in the first year is common. It is caused by muations in the gene ARX .

Baraitser-Winter Syndrome.

Baraitser-Winter syndrome is a rare syndrome with anterior-predominant pachygyria and characteristic facial features (hypertelorism, broad nose, ptosis, ridged metopic suture, arched eyebrows). Other common features include iris or retinal coloboma, sensorineural deafness, microcephaly, polyhydramnios, increased nuchal translucency, congenital heart defects, and renal tract anomalies. Intellectual disability and epilepsy are common. Caused by gain-of-function mutations in the genes ACTB and ACTG1 .

Lissencephaly With Cerebellar Hypoplasia.

Lissencephaly with anterior-predominant pachygyria and severe abnormalities of the cerebellum, brainstem, and hippocampus is caused by mutations in TUBA1A and RELN (Norman-Roberts syndrome).

Microlissencephaly.

Microlissencephaly is lissencephaly with head circumference at birth of less than three standard deviations. It is caused by mutations in the NDE1 gene.

Neu-Laxova Syndrome.

NLS is a lethal lissencephaly disorder inherited in an autosomal-recessive manner, characterized by growth restriction, microcephaly, agenesis of the corpus callosum, cerebellar hypoplasia, facial dysmorphism, hydrops, ichthyosis, extremity contractures, and syndactyly. It is due to an inborn error of serine metabolism, with causative mutations in the gene PHGDH .

Definition.

Antley-Bixler syndrome is a sterol biosynthesis disorder characterized by craniosynostosis of the coronal and lambdoidal sutures, brachycephaly with frontal bossing, and facial dysmorphism (proptosis, downslanting palpebral fissues, severe depression of the nasal bridge, choanal stenosis or atresia, small mouth, high-arched narrow palate, low-set protruding ears). Hydrocephalus can be present. Limb anomalies include radiohumeral synostosis, bowing of the ulnas and femurs, slender hands and feet, contractions of the proximal interphalangeal joints, advanced bone age, and fractures.

Synonym.

Antley-Bixler syndrome is also known as trapezoidocephaly-multiple synostosis syndrome.

Etiology.

Caused by cytochrome P450 oxidoreductase (POR) deficiency, Antley-Bixler syndrome is the most severe end of the phenotypic spectrum of POR deficiency.

Incidence.

The incidence is unknown. Since POR mutations were first reported in 2004, approximately 50 affected individuals have been reported. More mildly affected individuals are likely underreported.

Pathogenesis.

The mechanism by which POR deficiency leads to multiple malformations remains under investigation. Ambiguous genitalia result from disordered steroidogenesis. Recently, cytochrome P450 activity in bone has been implicated in normal bone development, and, thus, POR deficiency may disrupt proper bone formation.

Diagnosis.

Malformations that may be detected on prenatal ultrasound examination include abnormal skull shape, facial dysmorphism, skeletal abnormalities (bowed femora, bilateral radioulnar synostosis), and ambiguous genitalia. During pregnancy, low maternal estriol may be found on serum screening. Maternal urine may also have increased fetal steroids, including the pregnenolone metabolite epiallopregnanediol and the androgen metabolite androsterone. POR deficiency can be diagnosed in affected infants by the detection of urinary sterol or steroid abnormalities, including increased pregnenolone and progesterone metabolites and an elevated ratio of metabolites associated with deficiency of 17-hydroxylase and 21-hydroxylase. Serum concentrations of pregnenolone, progesterone, 17-OH pregnenolone, and 17-OH progesterone may be elevated at baseline or following ACTH stimulation. Some cases are found on newborn screening (NBS), but NBS is not sensitive enough to detect all cases.

Genetics.

Antley-Bixler syndrome is caused by mutations in the gene encoding cytochrome P450 reductase ( POR ). Inheritance is autosomal recessive.

Recurrence Risk.

Recurrence risk is 25%.

Associated Anomalies.

Congenital heart disease, renal anomalies, abnormalities of the female genitalia, and signs of congenital adrenal hyperplasia are also present. Some degree of intellectual disability is often seen, but intelligence can also be normal.

Differential Diagnosis.

Other forms of congenital adrenal hyperplasia as well as other craniosynostosis syndromes should be considered.

Prognosis.

Prognosis improves with age. In infancy, respiratory complications can lead to early death.

Management.

Multidisciplinary evaluation is needed. Airway management is a primary concern owing to choanal atresisa/stenosis. Functional adrenal studies should be performed and hydrocortisone replacement therapy initiated if low cortisol levels are found. Genital abnormalities are often treatable and should be addressed.

Definition.

Apert syndrome is characterized by craniosynostosis, midface and orbital hypoplasia, and bilateral syndactyly of the hands and feet. These findings are accompanied by variable degrees of mental retardation in 50% of cases.

Incidence.

The incidence of Apert syndrome is 1 per 100,000 live births. It is seen in 4% to 5% of craniosynostosis cases.

Synonyms.

Apert syndrome is also known as acrocephalosyndactyly type 1 and Apert-Crouzon disease.

Etiology.

Apert syndrome has autosomal dominant inheritance. Most of the cases are sporadic, resulting from de novo mutations. The disorder is associated with advanced paternal age.

Sonographic Findings.

Brachycephaly and acrocephaly, high forehead, flat occiput, craniosynostosis involving the coronal sutures, flat face, and hypertelorism are seen. Other ultrasound findings include agenesis of the corpus callosum, mild ventriculomegaly, and fusion of the cervical vertebrae at the level of C5-C6. In the extremities, syndactyly of both bone and soft tissue is seen, involving the second, third, and fourth fingers. Polyhydramnios (caused by the decreased fetal swallowing) and increased nuchal translucency in the first trimester have also been reported.

Diagnosis.

Typical findings include bicoronal synostosis of the coronal sutures, flattened occiput, a wide, steep forehead, hypoplastic orbits with exophthalmos and hypertelorism, short nose with depressed nasal bridge, large ears, high palate (occassional cleft palate), and dental crowding. Hydrocephalus is rare. Hearing loss is common. Symmetric syndactyly of the limbs (“mitten-like” hands and feet) is present at least from the second to fourth digits in both the bony and soft tissue. Cardiovascular and genitourinary anomalies are present in 10% of patients.

Genetics.

Caused by mutations in the FGFR2 genes, most commonly substitutions S252W and P253R. Genetic molecular studies are recommended for the fetus (by chorionic villus sampling or amniocentesis) and for parents when Apert syndrome is suspected. Inheritance is autosomal dominant with complete penetrance.

Differential Diagnosis.

Other syndromes with craniosynostosis such as Crouzon, Pfeiffer, Carpenter, and Saethre-Chotzen syndromes should be considered. Molecular genetic studies can exclude these disorders. The pattern of syndactyly is the most helpful for the diagnosis of Apert syndrome.

Recurrence Risk.

Most mutations are de novo and the recurrence risk is low. If one of the parents carries the disorder, the recurrence risk is 50%.

Apert syndrome. Ultrasound images demonstrating frontal bossing and midface hypoplasia on two-dimensional (2D) ( A ) and 3D ( B ) images, as well as by magnetic resonance imaging ( C ). Ultrasound image also demonstrated syndactyly of the foot ( D ), which is characteristic of Apert syndrome.

Apert syndrome. Syndactyly of the hand demonstrated with two-dimensional (2D) ( A ) and 3D ( B ) ultrasound images. Syndactyly of the foot is also present ( C ).

Newborn with Apert syndrome. Note appearance of the head, with frontal bossing ( A and B ), and syndactyly of the hand ( C ) and foot ( D ).

Definition.

Carpenter syndrome is characterized by craniosynos­tosis with preaxial polydactyly of the feet. Hand anomalies include brachydactyly, syndactyly, and aplasia or hypoplasia of the middle phalanges.

Synonym.

Acrocephalopolysyndactyly type II is another name for Carpenter syndrome.

Incidence.

Carpenter syndrome is rare. Approximately 70 cases have been described.

Etiology/Pathogenesis.

RAB23 is a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog signaling. Abnormal hedgehog signaling may lead to much of the clinically recognized phenotype.

Diagnosis.

Unlikely other syndromic craniosynostoses, in which coronal sutures are most frequently affected, in Carpenter syndrome, fusion of the midline sutures (metopic and sagittal) is common. In severe cases, this leads to cloverleaf skull. On prenatal ultrasound examination, reported features include cystic hygroma, abnormal skull shape, bowed femora, polydactyly, and complex heart defects.

Genetics.

Carpenter syndrome is caused by mutations in RAB23 . The inheritance is autosomal recessive. A subtype of Carpenter syndrome with lateralization defects is thought to be caused by mutations in MEGF8 .

Recurrence Risk.

Recurrence risk is 25%.

Associated Anomalies.

Obesity, umbilical hernia, hearing loss, cryptorchidism, and cardiac defects are often present. Craniosynostosis leads to distinctive facial features. The degree of intellectual disability varies.

Differential Diagnosis.

Features overlap with Greig cephalopolysyndactyly syndrome. Molecular genetic testing can clarify the diagnosis.

Prognosis.

Phenotype is extremely variable, even within the same family. Life expectancy is shortened.

Definition.

Crouzon syndrome is an FGFR -related craniosynostosis characterized by premature fusion of the coronal and frontosphenoidal sutures leading to brachycephaly and a prominent forehead. Facial dysmorphism (proptosis from orbital and midface hypoplasia, external strabismus, mandicular prognathism) is present and extremities are normal.

Incidence.

The incidence of Crouzon syndrome is 1.6 per 100,000 live births. It is seen in 4.5% of craniosynostosis cases.

Diagnosis.

Sonographic findings include brachycephaly, midface hypoplasia, and a wide anterior cranial base. Hands and feet are normal. Exophthalmos is always present. About 20% of patients develop optic atrophy. Dental crowding and an open bite are common.

Genetics.

Caused by mutations in FGFR2 (except for Crouzon syndrome with acanthosis nigricans, which is caused by mutations in FGFR3 , seen in ~5% of individuals with Crouzon syndrome). Inheritance is autosomal dominant with complete penetrance and variable expressivity.

Recurrence Risk.

Recurrence risk is 50% if one parent carries the causative mutation. Occassionally it appears de novo.

Associated Anomalies.

Progressive hydrocephalus is seen in 30% of cases and can lead to tonsillar herniation. Sacrococcygeal tail can also be seen. Cardiovascular anomalies and cleft lip and palate have been reported but are rare.

Differential Diagnosis.

Other FGFR -related craniosynostoses should be considered, including Crouzon syndrome with acanthosis nigricans (should consider if choanal atresia is present).

Prognosis.

Intellect is generally normal, hearing loss is common, and complications related to hydrocephalus can be life threatening if not treated appropriately.

Definition.

Pfeiffer syndrome is characterized by bilateral coronal craniosynostosis, midface hypoplasia, syndactyly of hands and feet, and congenitally enlarged thumbs. Conductive hearing loss is present in more than 80% of patients. The syndrome is divided in three clinical subtypes, with diagnostic and prognostic implications:

• •
  

  Type I: classic appearance with craniosynostosis (leading to turribrachycephaly), broad thumbs, and syndactyly. This form is compatible with life, and patients often have normal intelligence.

  
  
• •
  

  Type II: cloverleaf skull, ocular proptosis, broad thumbs, variable visceral anomalies, elbow ankylosis, choanal atresia, and CNS involvement (hydrocephalus). Intellectual disability is common, and this form usually results in early death.

  
  
• •
  

  Type III: craniosynostosis, severe ocular proptosis without cloverleaf skull, elbow ankylosis, and variable visceral anomalies. Affected fetuses have severe neurologic compromise (including hydrocephalus and tonsillar herniation), with poor prognosis and early death.

Synonym.

Pfeiffer syndrome is also known as acrocephalosyndactyly type 5.

Incidence.

The incidence is 1 per 100,000 for all types combined.

Genetics.

Pfeiffer syndrome is genetically heterogeneous and is caused by mutations in either FGFR2 or FGRF1 (type I). Frequently, no mutation can be identified. Type I has autosomal dominant inheritance with complete penetrance and variable expressivity. Most mutations in type II and III are de novo and associated with advanced paternal age.

Recurrence Risk.

Recurrence risk is 50% if a parental mutation is present. If the mutation is de novo, recurrence risk is very low.

Diagnosis.

Sonographic signs of Pfeiffer syndrome include craniofacial anomalies (brachycephaly, acrocephaly, craniosynostosis of the coronal suture, hypertelorism, small nose, and low nasal bridge) and hands and feet anomalies (partial syndactyly of second and third fingers and second, third, and fourth toes, broad thumb, and big toe).

Associated Anomalies.

Choanal atresia, tracheomalacia and bronchomalacia, cloverleaf skull, fused vertebra, Arnold-Chiari malformation, hydrocephalus, and imperforate anus are associated with this syndrome. After birth, seizures and intellectual disability may be seen.

Differential Diagnosis.

Saethre-Chotzen and Jackson-Weiss syndromes should be considered in the differential diagnosis.

Prognosis.

The prognosis depends on the severity of associated anomalies, in particular the severity of the CNS compromise. Type I generally has a good prognosis. Types II and III are not compatible with life, and death occurs early.

Definition.

Saethre-Chotzen syndrome is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry, ptosis, and characteristic ear appearance (small pinna with a prominent crus). Often present is 2-3 syndactyly of the hand.

Synonyms.

Synonyms include acrocephalosyndactyly type III and Robinow-Sorauf syndrome (a mild variant).

Incidence.

Incidence is 1 in 25,000 to 50,000 individuals.

Diagnosis.

A clinical diagnosis can be made based on craniosynostosis (usually of the coronal sutures), brachycephaly, low frontal hairline, ptosis, facial asymmetry, small ears, and limb anomalies (2-3 syndactyly of the hand, brachydactyly, hallux abnormalities).

Genetics.

Saethre-Chotzen syndrome is caused by mutations in TWIST1 ; sequencing and deletion/duplication analysis should be performed. Mutations have also been reported in FGFR2 . Inheritance is autosomal dominant with incomplete penetrance and variable expressivity.

Recurrence Risk.

If one parent also carries the causative mutation, recurrence risk is 50%. It is significantly less if the mutation is de novo.

Associated Anomalies.

Associated anomalies include short stature, parietal foramina, radioulnar synostosis, cleft palate, maxillary hypoplasia, hypertelorism, congenital heart disease, and segmentation defects of the vertebrae.

Differential Diagnosis.

Many features are shared with Muenke syndrome, and, thus, genetic evaluation should also include analysis of the FGFR2 and FGFR3 genes. Pfeiffer syndrome and Jackson-Weiss syndrome should also be considered.

Prognosis.

Intelligence is often normal, although mild to moderate intellectual and developmental delay has been reported. Conductive and sensorineural hearing loss may be present.

Definition.

Branchiooculofacial syndrome (BOFS) is characterized by branchial skin defects (thin skin, erythematous lesions, erosions), ocular anomlies (microphthalmia, anophthalmia, coloboma, nasolacrimal duct stenosis/atresia), and facial anomalies (hypertelorism, broad nasal tip, upslanted palpebral fissues, cleft lip ± cleft palate, upper lip pits, lower facial weakness). Ear anomalies are common.

Incidence.

BOFS is rare. Fewer than 100 well-described cases have been reported.

Diagnosis.

Diagnosis is made on the clinical constellation of branchial skin defect, ocular anomaly, and characteristic facial appearance.

Genetics.

BOFS is caused by mutations in the gene TFAP2A . Inheritance is autosomal dominant. De novo mutations are present in 50% to 60% of affected individuals. Penetrance is complete.

Recurrence Risk.

Recurrence risk is 50% if a parental mutation is found.

Associated Anomalies.

Other anomalies include thymic anomalies, renal anomalies, hypoplastic teeth, dysplastic nails, premature hair graying, and defects in hearing and vision.

Prognosis.

Intellect is generally normal. Feeding difficulties, as well as cosmetic, visual, hearing, and speech issues are often present.

Definition.

Frontonasal dysplasia is characterized by a broad forehead, widow’s peak hairline, ocular hypertelorism, and abnormal nostrils (notched or completely divided) with absence of the nasal tip. A midline defect in the frontal bone (cranium bifidum) is also commonly seen.

Synonyms.

Synonyms include median cleft face syndrome, frontonasal malformation, and frontorhiny.

Incidence.

Incidence is unknown. Frontonasal dysplasia is rare; at least 100 cases have been reported in the literature.

Pathogenesis.

Frontonasal dysplasia is due to malformation of the frontonasal elevation. The implicated genes ( ALX1, ALX 3, and ALX 4 ) encode transcription factors that regulate development of the eyes, nose, and mouth.

Diagnosis.

The diagnosis is based on the constellation of eye, forehead, and nose findings described earlier.

Genetics.

The disorder is genetically heterogeneous, with autosomal recessive, autosomal dominant, and X-linked forms of inheritance all reported. The autosomal recessive form is associated with mutations in ALX1 and ALX3 . The autosomal dominant form is associated with ALX4 gene mutations.

Recurrence Risk.

The recurrence risk is dependent on mode of inheritance.

Prognosis.

Most individuals have normal intellectual development. Overall prognosis depends on the severity of the malformations and whether or not surgical intervention can improve breathing and feeding issues.

Management.

Multistage craniofacial surgery is generally needed; for less severe malformations, surgery is often performed at age 6 to 8 and can have excellent cosmetic results.

Definition.

Goldenhar syndrome is characterized by hemifacial microsomia, epibulbar dermoids, preauricular appendages, ear hypoplasia, transverse facial clefts, asymmetry of the skull, and spinal anomalies (vertebral segmentation errors).

Incidence.

Incidence is 1 in 3500 to 1 in 26,000 live births. Male-to-female ratio is 3 : 2.

Synonyms.

Synonyms include oculo-auriculo-vertebral dysplasia, hemifacial microsomia, craniofacial microsomia, Goldenhar-Gorlin’s syndrome, and facio-auriculo-vertebral dysplasia.

Etiology.

Goldenhar syndrome is caused by developmental abnormalities of the first and second branchial arches.

Diagnosis.

Findings are similar to Treacher Collins syndrome (see later) except that they are unilateral leading to significant facial asymmetry. Other features include dystopia, microtia, choanal atresia, cleft palate ± lip, jaw malocclusion, vertebral anomalies, cardiac anomalies, genitourinary anomalies, and CNS involvement.

Pathogenesis.

Possible fetal hemorrhage in the region of the first and second branchial arches when the blood supply of these arches switches from the stapedial artery to the external carotid artery.

Genetics.

Genetics for Goldenhar syndrome are unknown. Most cases are thought to be sporadic, although both autosomal recessive and autosomal dominant inheritance have been reported. Transmission is linked in some cases to a region on chromosome 14q32.

Differential Diagnosis.

Treacher Collins syndrome, Kaufman syndrome (oculocerebrofacial syndrome), acrofacial dysostosis, CHARGE syndrome ( c oloboma of the eye, h eart defects, a tresia of the choanae, r etarded mental and growth development, g enital anomalies, and e ar anomalies), VACTERL, and Nager syndrome should be considered.

Prognosis.

Treatment is generally cosmetic with multiple reconstructions required in some cases. Airway and vertebral complications have been reported.

Recurrence Risk.

Recurrence risk is minimal unless an autosomal dominant or autosomal recessive inheritance pattern is suggested.

Management.

Malar and orbital reconstructions are generally needed and are often performed after age 6. Structural anomalies of the eyes and ears can be corrected with plastic surgery.

Definition.

Gorlin syndrome is characterized by the development of jaw keratocysts and multiple basal cell carcinomas, as well as a characteristic facial appearance with macrocephaly, prominent forehead, coarse facial features, and facial milia.

Synonym.

Gorlin syndrome has also been referred to as nevoid basal cell carcinoma syndrome (NBCCS).

Incidence.

Incidence is estimated to be as high as 1 in 18,976.

Pathogenesis.

Mutations in PTCH1 lead to alterations in the hedgehog signaling pathway leading to neoplastic cell growth.

Diagnosis.

Prenatally, cranial and cerebral malformations can be seen, including macrocephaly and ventriculomegaly. Diagnosis is based on major clinical criteria including calcification of the falx, jaw keratocyst, palmar/plantar pits, and multiple basal cell carcinomas, as well as minor criteria.

Genetics.

Gorlin syndrome results from mutations in the gene PTCH1 . Inheritance is autosomal dominant. From 20% to 30% of mutations are de novo. Penetrance is complete; expressivity can be variable.

Recurrence Risk.

If a parental mutation is present, recurrence risk is 50%.

Associated Anomalies.

Most individuals have skeletal anomalies (bifid ribs, wedge-shaped vertebrae) and ectopic calcification (in the falx). Cardiac and ovarian fibromas can be seen. Children can develop medulloblastoma (5%). Other anomalies include lymphomesenteric or pleural cysts, cleft lip/palate, polydactyly, and ocular anomalies.

Differential Diagnosis.

When macrocephaly is detected prenatally, the differential diagnosis includes several overgrowth syndromes, such as Sotos syndrome and Beckwith-Wiedemann syndrome (BWS).

Prognosis.

Life expectancy is not changed. Cosmetic issues with multiple skin tumors and their removal can lead to social difficulties and can affect quality of life.

Management/Prevention.

Radiotherapy can lead to the development of thousands of basal cell carcinomas and should be avoided if possible. X-ray exposure should be limited. Direct sun exposure should be avoided.

Definition.

Hallerman-Streiff syndrome is characterized by brachycephaly with frontal bossing, micrognathia, beaked nose, eye anomalies (microphthalmia, cataracts), dental anomalies, hypotrichosis, skin atrophy (especially of the face), and short stature.

Incidence.

The syndrome is rare, with approximately 150 cases reported.

Diagnosis.

Diagnosis is based on the clinical criteria described earlier.

Genetics.

Generally thought to be sporadic, in some cases, the syndrome has been associated with mutations in GJA1 with autosomal recessive inheritance.

Recurrence Risk.

Recurrence risk is unknown, but thought to be low.

Differential Diagnosis.

Many features overlap with oculodentodigital dysplasia (ODDD) and other progeroid syndromes.

Prognosis.

Intellectual disability is present in approximately 15%. Upper airway obstruction can be significant and can lead to cardiac failure and early death.

Management.

Initial management is focused on airway issues; later management includes cosmetic surgical procedures.

Definition.

Nager syndrome is characterized by preaxial limb anomalies (radial hypoplasia/absence, thumb hypoplasia/absence, triphalangeal thumbs, radioulnar synostosis) and facial anomalies (malar hypoplasia, downward slanting palpebral fissures, lower eyelid coloboma, severe micrognathia).

Synonym.

Nager syndrome is also known as preaxial acrofacial dysostosis.

Incidence.

Incidence is unknown, but the syndrome is rare.

Diagnosis.

Diagnosis is based on the clinical criteria described earlier, including craniofacial and limb malformations. Prenatally, severe micrognathia and upper limb anomalies may be seen.

Genetics.

The genetic basis is heterogeneous. Recent reports suggest that haploinsufficiency of the gene SF3B4 leads to the phenotype in families with suggested autosomal dominant inheritance, as well as many individuals with de novo mutations. Autosomal recessive inheritance has also been suggested in some cases.

Recurrence Risk.

Recurrence risk depends on mode of inheritance.

Differential Diagnosis.

Facial anomalies are similar to those seen with Treacher Collins syndrome. Differential diagnosis should include Miller syndrome.

Prognosis.

Upper airway issues can be significant, requiring tracheostomy. Hearing loss, vision loss, and hand anomalies can affect development and quality of life

Definition.

Oral-facial-digital syndrome, type I (OFD1), is characterized by anomalies in multiple areas. including the mouth (lobed tongue, tongue lesions, cleft palate, dental anomalies), face (hypertelorism, alae nasi hypoplasia, median cleft, micrognathia), digits (brachydactyly, syndactyly, polydacyly of the hands, duplicated great toe), brain (intracerebral cysts, cerebellar agenesis, agenesis of the corpus callosum), and kidneys (polycystic kidneys).

Synonym.

OFD1 is also known as Papillon-Léage-Psaume syndrome.

Incidence.

Almost all affected individuals are female, although males with OFD1 have also been described.

Pathogenesis.

OFD1 is due to dysfunction of primary cilia.

Diagnosis.

Many individuals are diagnosed at birth based on the characteristic anomalies. Some cases are diagnosed after polycystic kidney disease is found.

Genetics.

The syndrome is due to mutations in the OFD1 gene. Inheritance is X-linked dominant. Approximately 75% of individuals have no family history of OFD1. Penetrance is high, with highly variable expressivity.

Recurrence Risk.

Recurrence risk is 50% in pregnancies of a female with OFD1. The risk is low if no maternal mutation is present.

Differential Diagnosis.

Differential diagnosis includes the other oral-facial-digital syndromes, types 2 to 9, as well as other disorders with cystic renal disease, and Meckel-Gruber syndrome.

Prognosis.

Up to 50% of individuals have intellectual disability, but generally mild. Seizure disorder can be present.

Management.

Surgery for oral and facial anomalies is often needed. Renal disease should be monitored.

Definition.

The Pierre Robin sequence consists of the occurrence of three anomalies together: cleft palate, micrognathia, and glossoptosis. These anomalies are found together in multiple syndromes.

Synonyms.

Pierre Robin sequence is also called cleft palate-micrognathia-glossoptosis, Pierre Robin syndrome, and Robin anomalad.

Incidence.

Incidence is 1 in 8500 to 1 in 14,000 births. One half of patients with Pierre Robin sequence have an underlying syndrome.

Etiology.

Inheritance is autosomal-recessive, with a few X-linked cases. Some authors suggest a prenatal and neonatal brainstem dysfunction as a neuroembryologic hypothesis to explain the onset of some cases of Pierre Robin sequence.

Diagnosis.

Micrognathia is most visible on prenatal ultrasound imaging. Isolated cleft palate is more difficult to detect prenatally. Polyhydramnios may be seen as a result of swallowing difficulty.

Genetics.

This disorder is heterogeneous; it can be monogenic, chromosomal, or related to teratogens. The cause is unknown in some cases. Multiple forms of inheritance are involved, including autosomal dominant, autosomal recessive, and X-linked.

Differential Diagnosis.

Differential diagnosis includes syndromes that involve Pierre Robin sequence, such as Stickler syndrome, as well as fetal alcohol syndrome.

Associated Anomalies.

Other anomalies depend on the exact diagnosis. Cardiac abnormalities are common with an incidence approaching 20%.

Prognosis.

Upper airway obstruction, neonatal respiratory distress, and feeding problems are common issues.

Associated Syndromes.

See Table 16-3 for a complete list of associated syndromes.

Cerebrocostomandibular Syndrome.

Cerebrocostomandibular syndrome (CCMS) is characterized by costovertebral anomalies (dorsal rib defects) in addition to Pierre Robin sequence. Rib defects often lead to a bell-shaped thorax and can result in flail chest. Other anomalies include growth retardation, scoliosis, dental anomalies, feeding issues, and conductive hearing loss. Severity is highly variable, although prognosis is often poor. This disorder is very rare, with slightly over 80 cases reported. Genetics are unknown, although possible defects in sonic hedgehog signaling have been implicated.

Micrognathia. Profile of a fetus shows mild micrognathia.

Severe micrognathia in a fetus with Nager syndrome. This can result in severe airway compromise at birth.

Micrognathia in a fetus with Pierre Robin sequence.

Definition.

Treacher Collins syndrome is characterized by deficient generation of the lower two thirds of the face, including hypoplasia of the zygoma, maxilla, and mandible.

Synonyms.

Treacher Collins syndrome is also known as mandibulofacial dysostosis and Treacher Collins-Franceschetti syndrome.

Etiology.

The syndrome is due to abnormal development of the first and second branchial arches.

Incidence.

Incidence is 1 in 50,000 live births.

Diagnosis.

Affected individuals have maxillary and mandibular hypoplasia, choanal atresia/stenosis, downward slanting palpebral fissures, notching of the lower eyelid, sparse or absent eyelashes, microtia/absent external ear, middle ear hypoplasia, cleft palate ± lip, and dental anomalies.

Genetics.

Three causative genes have been found: TCOF1 and POLR1D (autosomal dominant inheritance; most common) as well as POLR1C (autosomal recessive; only 1% of cases). Sixty percent of cases result from de novo mutations. Significant phenotypic variability is seen, even within families. Penetrance is high, but cases of nonpenetrance have been reported.

Pathogenesis.

Mutations in the preceding genes lead to abnormal production of ribosomal RNA important in the development of the first and second branchial arches, leading structural facial anomalies.

Recurrence Risk.

Recurrence risk is 50% for the autosomal dominant genes if a parental mutation is present, low if mutation is de novo, and 25% for the autosomal recessive form.

Differential Diagnosis.

Differential diagnosis includes the other mandibulofacial dysostoses, such as Toriello syndrome, Bauru syndrome, Hedera-Toriello-Petty syndrome, and Guion-Almeida syndrome. Treacher Collins syndrome also shares some features of Nager syndrome, Miller syndrome, Goldenhar syndrome, and craniofacial microsomia.

Prognosis.

Intelligence is normal. Middle ear hypoplasia causes conductive deafness (40-50% of individuals). Vision loss can also occur (37%). Speech issues are common.

Management.

Intervention may be needed for the airway and feeding issues.

Definition.

Van der Woude syndrome (VWS) is included in a spectrum of IRF6 -related disorders ranging from isolated cleft lip/palate and popliteal pterygium syndrome. VWS is characterized by lower lip pits, cleft lip and palate, cleft uvula, and hypodontia.

Synonym.

VWS has been classified as types 1 and 2.

Incidence.

Incidence is 1 in 40,000 to 1 in 100,000 births. VWS is the most common form of syndromic clefting, accounting for 2% of all cases of cleft lip and palate.

Pathogenesis.

IRF6 (interferon regulatory factor 6) is a transcription factor involved in orofacial development.

Diagnosis.

Prenatal ultrasound examination can detect a cleft lip ± cleft palate, but is likely to miss an isolated cleft palate and lip pits.

Genetics.

VWS type 1 is caused by mutations in the IRF6 gene; type 2 is caused by mutations in the GRHL3 gene (5% of all VWS cases). Inheritance is autosomal dominant. Penetrance is high but can be incomplete. De novo mutations have been reported.

Recurrence Risk.

If a parental mutation is present, recurrence risk is 50%.

Differential Diagnosis.

Bartsocas-Pappas syndrome (popliteal pterygium syndrome, lethal type), Kabuki syndrome, BOFS, and isolated cleft lip and palate are considered in the differential diagnosis.

Prognosis.

Multiple surgeries are often needed to treat lip pitting and can lead to scarring and decreased ability to open the mouth. Psychomotor development is generally normal.

Coronal ultrasound image showing unilateral cleft lip ( arrow ) in a fetus with van der Woude syndrome.

Definition.

X-linked Opitz G syndrome (XLOS) is characterized by facial anomalies (hypertelorism, prominent forehead, widow’s peak, broad nasal bridge, anteverted nares), laryngeotracheoesophageal defects, and genitourinary anomalies (hypospadias, cryptorchidism, bifid scrotum).

Incidence.

Incidence is 1 in 50,000 to 1 in 100,000 males.

Pathogenesis.

Mutations in MID1 lead to altered mTORC1 signaling, which is thought to affect the development of ventral midline anatomic structures.

Diagnosis.

Diagnosis is most often based on clinical findings with abnormalities in ventral midline structures, as described previously. Prenatally, those cases associated with congenital heart defects and cleft lip are more likely to be detected.

Genetics.

XLOS is due to mutations in MID1 . Inheritance is X-linked. Many individuals are the only ones known to be affected within their families. Penetrance is high; wide phenotypic variability is seen even within families.

Recurrence Risk.

If the mother is a carrier, there is a 50% chance of transmitting the disease-causing mutation in each pregnancy. Sons who inherit the mutation will be affected. Daughters will be carriers with isolated hypertelorism.

Associated Anomalies.

Other anomalies include cleft lip/palate (50%), congenital heart defects, imperforate or ectopic anus, and midline brain defects.

Differential Diagnosis.

FG syndrome, craniofrontonasal dysplasia, and Mowat-Wilson syndrome should be considered.

Prognosis.

Intellectual disability and developmental delay are seen in 50% of affected males. Prognosis depends on the severity of the associated anomalies.

Management.

A multidisciplinary team is needed to manage the multiple anomalies.

Definition.

TD is the most common lethal skeletal dysplasia and is characterized by severe rhizomelia, small thorax, normal trunk length, normal bone mineralization, no fractures, thickened redundant skin, and platyspondyly (flattened vertebral bodies). TD is divided into two subtypes:

• •
  

  Type 1: TD1 is the more common form. The femurs have a “telephone receiver” shape, and frontal bossing and midface hypoplasia are present. Cloverleaf skull is not seen. The hands and feet are normal, but the fingers are short.

  
  
• •
  

  Type II: TD2 is the less common form. Femurs are straight with flared metaphyses, and a cloverleaf skull is present (due to craniosynostosis of the lambdoid and coronal sutures).

Incidence.

Incidence is 1 in 20,000 births.

Etiology.

Mutations in FGFR3 are gain-of-function mutations that lead to a constitutively active protein. This leads to chondrocyte proliferation and premature maturation of bone.

Genetics.

TD1 is caused most frequently by mutations in the fibroblast growth factor receptor 3 gene ( FGFR3 ); the most common mutations are R248C and Y373C. TD2 is also caused by mutations in FGFR3 , specifically the mutation K650E . Inheritance is autosomal dominant. Because the disorder is lethal, new diagnoses are generally the result of de novo mutations. Advanced paternal age has been associated with an increased risk.

Recurrence Risk.

Recurrence risk is low because most mutations are de novo; germline mosaicism remains a possibility but has not been reported in individuals without signs of skeletal dysplasia.

Diagnosis.

Prenatal findings include severe rhizomelia (seen as early as 12-14 weeks) and a hypoplastic thorax. Craniofacial dysmorphisms include macrocephaly, frontal bossing, midface hypoplasia, and cloverleaf skull. Other features include brachydactyly, platyspondyly, hypotonia, and redundant skinfolds. Other brain anomalies may be seen including polymicrogyria, deep and transverse temporal sulci, and temporal lobe enlargement. Polyhydramnios is seen in approximately 50% of cases. Increased nuchal translucency may be present.

Differential Diagnosis.

The differential diagnosis includes other types of short-limbed dwarfism and disorders with a cloverleaf skull (such as Apert, Crouzon, Pfeiffer, and Carpenter syndromes). The features can closely resemble homozygous achondroplasia with autosomal recessive inheritance; it can be distinguished from TD by the presence of positive carrier status for heterozygous FGFR3 mutations in each parent in the case of achondroplasia.

Prognosis.

In general, affected infants die shortly after birth of respiratory insufficiency due to a small thorax and lung hypoplasia.

Management.

The option of pregnancy termination should be offered before viability. Sonographic evaluation of hydrocephalus is recommended because it can lead to malpresentation and difficult delivery. If massive hydrocephalus has developed, cephalocentesis or elective cesarean delivery should be considered to avoid maternal trauma.

Typical cloverleaf skull such as that seen in thanatophoric dysplasia in sagittal ( A ), coronal ( B ), and axial ( C ) planes.

Thanatophoric dysplasia. A, Markedly short femur with telephone receiver morphologic appearance; B, axial images demonstrating small thorax with short ribs; C, frontal bossing.

Definition.

Osteogenesis imperfecta (OI) is a heterogeneous group of genetic disorders (classically divided in four types: I, II [congenital], III, and IV) characterized by severe bone fragility, leading to abnormal ossification and multiple fractures. The clinical features range from perinatal lethality (type II) to severe skeletal deformities to those with minimal features. The four types are described as follows:

• •
  

  Type I: classic nondeforming OI with blue sclerae. Deformities are not seen prenatally.

  
  
• •
  

  Type II: perinatal lethal OI. This is the most severe form and can be seen prenatally.

  
  
• •
  

  Type III: progressively deforming OI. Some features can be seen prenatally.

  
  
• •
  

  Type IV: common variable OI with normal sclerae. Deformities are not generally seen prenatally.

Synonyms.

OI is also called brittle bone disease.

Incidence.

The incidence is 6 to 7 per 100,000 for all types of OI, with types I and IV representing more than one half of all cases. Types II and II each have an incidence of 1 to 2 per 100,000.

Etiology.

COL1A1 and COL1A2 encode for type I collagen (found in skin, ligaments, tendons, demineralized bone, and dentine). Defective production of type I collagen leads to decreased bone mineralization and bone fragility.

Genetics.

OI is due to mutations in COL1A1 or COL1A2 . Inheritance is autosomal dominant. Approximately 60% of cases of type I and IV OI are caused by de novo mutations, whereas almost 100% of cases of type II and III OI are caused by de novo mutations. Penetrance is complete, but expression can vary significantly.

Recurrence Risk.

Recurrence risk depends on whether the mutation was inherited or de novo. Gonadal mosaicism may be present in 3% to 5% of cases with apparent de novo mutations. Less commonly, OI can also be autosomal recessive.

Diagnosis.

Type II is the most severe form and affected individuals usually die in utero or shortly after birth from severe fractures and pulmonary hypoplasia. Key prenatal findings include severe micromelia (femur length more than 3 standard deviations [SD] below the mean), small thorax, normal head circumference, short trunk, decreased bone mineralization (including decreased ossification of the skull), and multiple bone fractures. Multiple fractures may lead the long bones to appear angulated. Both cortices of a bone are often seen. Some findings can be seen as early as 13 to 15 weeks’ gestation.

The other types of OI may not be detected prenatally. Type I is characterized by blue sclerae and normal stature. The first fractures generally occur in infancy. Progressive hearing loss is present in 50% of adults. Type III is apparent at birth; fractures may be caused just by handling the infant. Rib fractures can lead to pulmonary failure in the first few weeks or months of life. Those who survive generally need assistance for mobility and are extremely short. Hearing loss often begins in the teenage years. Type IV is characterized by mildly short stature, adult-onset hearing loss, and normal-to-gray sclerae; phenotype is the most variable. Dentinogenesis imperfecta is common.

Differential Diagnosis.

The differential diagnosis includes hypophosphatasia (infantile form), achondrogenesis, and other short-limbed dwarfisms.

Prognosis.

Type II OI is uniformly lethal. The other forms develop after birth and are characterized by progressive deformities of the long bones and short stature.

Management.

Owing to the uniformly fatal outcome, termination of pregnancy should be offered when type II is diagnosed early in pregnancy and palliative care provided if delivery is undertaken. If continuation of the pregnancy is chosen, cesarean delivery is often recommended for nonlethal OI for prevention of fetal and maternal trauma.

A, B, and C, Osteogenesis imperfecta type II. Markedly short bilateral extremities with fracture deformities of the femurs. LT, left; RT, right.

The skull demonstrates markedly decreased echogenicity and is readily compressible even with moderate transducer pressure ( left ).

Frontal x-ray scans of the fetus. Note the poor mineralization and the numerous fractures.

Definition.

Achondrogenesis is a heterogeneous group of lethal skeletal dysplasias characterized by severe micromelia, small thorax, short trunk, decreased bone mineralization (particularly of the vertebrae, sacrum, and pubic bones), and occasional fractures. The most common types are described here:

• •
  

  Type 1: includes type 1A and type 1B. Deficient bone mineralization also affects the calvarium.

  
  
• •
  

  Type 2: similar to type 1, with less severe mineralization deficits.

Synonyms.

Synonyms include type 1A, Houston-Harris type; type 1B, Fraccaro type; type 2, Langer-Saldino type.

Incidence.

Incidence is 0.9 to 0.23 per 10,000 births. Type 1 represents 20% of cases; type 2 represents 80% of cases.

Etiology.

In type 1A, TRIP11 mutations lead to defects in Golgi-mediated glycosylation and altered transport of multiple cellular proteins. In type 1B, mutations in SLC26A2 impair activity of the sulfate transporter in chondrocytes and fibroblasts leading to defective cartilage matrix assembly. In type 2, COL2A1 mutations lead to structural abnormalities in type 2 collagen.

Genetics.

Type 1 is inherited in autosomal recessive fashion; type 1A is caused by mutations in TRIP11 , and type 1B is caused by mutations in SLC26A2 ( DTDST ). Type 2 is an autosomal dominant condition caused by de novo mutations in COL2A1 .

Recurrence Risk.

Recurrence risk depends on the mode of inheritance. Type 1 has a 25% recurrence risk. The recurrence risk for type 2 is low.

Diagnosis.

Type 1 is characterized by severe micromelia, facial dysmorphism (flat face), decreased skull, vertebral, and pelvic bone ossification, short thin ribs, and short long bones with deformity. Other features include short fingers and toes (seen more in type 1B), protuberant abdomen, abundant soft tissue (which can lead the fetus to appear hydropic), and short neck with thickened tissue. Skull is normally sized. Polyhydramnios is present in 25% of affected fetuses. Breech presentation is common.

Type 2 presents with similar findings but the mineralization deficit is less severe and the long bones less short. Fingers and toes may appear normal.

Differential Diagnosis.

The differential diagnosis includes other lethal chondrodysplasias. Cartilage histologic examination can assist in distinguishing between the subtypes of achondrogenesis. OI (specifically types II and III) and hypophosphatasia also present with bone demineralization, but the limb shortening is not usually as severe. Abnormal mineralization and shortened trunk length distinguish it from TD in which these are normal.

Prognosis.

The disorder is perinatally lethal with death occurring prenatally or shortly after birth.

Achondrogenesis. A, Coronal image of the fetus with a markedly small thorax; B, diffuse lack of bony mineralizaton, with particular involvement of the spinal vertebrae.

The appearance of transparent bones in which both cortices can be seen.

Micromelia with the arms failing to join in front of the chest.

Achondrogenesis. The appearance of the fetus at 19 weeks.

Definition.

Campomelic dysplasia (derived from the Greek word for “bent limb”) is a skeletal dysplasia characterized by bowing and shortening of the long bones, club feet, and distinctive facial features including Pierre Robin sequence with cleft palate.

Synonyms.

Campomelic dysplasia is also known as campomelic syndrome and campomelic dwarfism.

Incidence.

Incidence is 1 in 40,000 to 1 in 80,000 births.

Etiology.

SOX9 regulates chondrocyte differentiation by regulating the expression of several genes, including the collagen genes COL2A1 and COL11A2 . It also functions as a testes-determining gene downstream of SRY .

Genetics.

Campomelic dysplasia is due to mutations in SOX9 . Inheritance is autosomal dominant; most individuals have de novo mutations, although cases of parental diagnosis following identification of an affected child have been reported.

Recurrence Risk.

Recurrence risk is low if the parents are unaffected, although germline mosaicism has been reported.

Diagnosis.

The most striking feature is anterior bowing of the long bones, particularly the femur and tibia. Other features seen on ultrasound imaging include 11 pairs of ribs, a bell-shaped narrow chest, relatively large head, Pierre Robin sequence with cleft palate, flat face with high forehead, laryngotracheomalacia, cervical spine anomalies, scoliosis, scapular hypoplasia, ambiguous genitalia (or normal female genitalia in a 46,XY individual), dislocated hips, clubfeet, and hydrocephalus. Cardiac and renal anomalies have also been reported. Polyhydramnios may be present.

Differential Diagnosis.

The differential diagnosis includes OI types II and III, hypophosphatasia, other disorders leading to congenital bowing of the long bones, TD, and spondyloepiphyseal dysplasia.

Prognosis.

Most cases (>75%) are lethal owing to respiratory insufficiency caused by airway instability or cervical spine instability. Survivors may have respiratory issues, hearing loss, and progressive scoliosis. Intellectual abilities are generally normal.

Campomelic dysplasia. Bowing of the femur ( arrows ). Note the gentle curve that differentiates this entity from the more acute angles seen in fetuses with osteogenesis imperfecta.

Definition.

Hypophosphatasia congenita is characterized by severe micromelia, small thorax, normal head circumference, normal trunk length, decreased bone mineralization, and occasional fractures. The cranium is compressible from deficient mineralization.

Synonyms.

Hypophosphatasia congenita is also called perinatal lethal hypophosphatasia.

Prevalence.

Hypophosphatasia congenita is seen in 1 in 100,000.

Etiology.

Hypophosphatasia congenita is associated with reduced activity of serum alkaline phosphatase.

Genetics.

Hypophosphatasia congenita is due to mutations in ALPL , the gene encoding alkaline phosphatase, tissue-nonspecific isozyme (TNSALP). Inheritance is autosomal recessive. Significant phenotypic variability can occur.

Recurrence Risk.

Recurrence risk is 25% if both parents are found to be mutation carriers. Carriers can be asymptomatic (with only biochemical abnormalities) or may have mild clinical features.

Diagnosis.

The perinatal lethal form of hypophosphatasia is generally diagnosed on prenatal ultrasound imaging. Features include a small thorax, short bowed limbs, flail chest, and poorly mineralized skull. Fetal radiographs demonstrate a generalized deficiency in ossification, with tubular bones that appear short, thin, and bowed.

Differential Diagnosis.

In the prenatal period, the differential includes OI type II, campomelic dysplasia, and chondrodysplasias with defective bone mineralization.

Prognosis.

Pregnancies may end in stillbirth. Liveborn infants most frequently die of pulmonary insufficiency. Hypercalcemia is common and can lead to apnea and seizures.

Definition.

Short rib–polydactyly syndromes (SRPSs) are heterogeneous group of lethal skeletal dysplasias typically divided into four subgroups. General findings include severe micromelia, small thorax with short ribs, a trident aspect of the acetabular roof, normal head circumference, normal bone mineralization, and polydactyly. Cardiac and genitourinary abnormalities may be seen. The SRPSs are divided into five subtypes, types I through V. Two related syndromes with a milder phenotype include Ellis–van Creveld syndrome (EVC) and Jeune syndrome. Features of the subtypes can overlap, making diagnosis challenging.

Synonyms.

Synonyms include type I, Saldino-Noonan syndrome; type II, Majewski syndrome; type III, Verma-Naumoff syndrome; type IV, Beemer-Langer syndrome; and type V.

Prevalence.

Prevalence is unknown; the syndrome is rare.

Etiology.

All SRPSs are classified as ciliopathies because of dysfunction of the primary cilium.

Genetics.

SRPSs are due to mutations in genes affecting primary cilium function, including mutations affecting the dynein motor ( DYNC2H1 ), intraflagellar transport complexes ( IFT80, IFT122, IFT43, WDR35, WDR19, TTC21B ), and basal body ( NEK1, EVC, EVC2 ). Other genes identified include WDR34 and WDR60 that also are important for primary cilium function. Inheritance is autosomal recessive.

Diagnosis.

The most striking ultrasound finding is a very narrow chest with short limbs. The limbs, however, are not as short as those of other lethal conditions such as TD, achondrogenesis, and OI type II.

Differential Diagnosis.

The differential diagnosis should include the range of SRPSs.

Prognosis.

There is a phenotypic spectrum, and although many affected infants die, some do survive.

Definition.

Achondroplasia is a relatively common nonlethal skeletal dysplasia characterized by rhizomelia, macrocephaly, and characteristic facial features (frontal bossing and flat midface). Other features include redundant skinfolds on limbs, short fingers, bowed legs, and exaggerated lumbar lordosis.

Incidence.

Incidence is 1 in 26,000 to 28,000 live births.

Etiology.

The FGFR3 mutation, p.Gly380Arg, seen in achondroplasia leads to constitutive activation of FGFR3 . This results in inhibition of chondrocyte proliferation and differentiation and negatively regulates bone growth.

Genetics.

Achondroplasia is due to a mutation in FGFR3 , specifically p.Gly380Arg. Inheritance is autosomal dominant; 80% of mutations are de novo and are exclusively inherited from the father. Advanced paternal age increases the risk of de novo mutations.

Recurrence Risk.

Recurrence risk is low if both parents have average stature. If one parent is affected, recurrence risk is 50%. If both parents are affected, the risk to offspring is as follows: 25% will have average stature, 50% will have achondroplasia, and 25% will have homozygous achondroplasia (which is lethal).

Diagnosis.

Prenatally, a shortened femur in comparison to the head circumference can been seen in the second trimester; femur length is often at the 3rd percentile or less by 25 weeks’ gestation (see Fig. 16-46 ). Fetuses with normal interval growth in femoral length during the second trimester are expected to be unaffected. The craniofacial features, including macrocephaly, frontal bossing, and flat midface, can also be seen. Occasionally more subtle anomalies, such as the trident hand (an increased space between the third and fourth digit) or the lack of widening of the lumbar canal, can also be identified.

Differential Diagnosis.

The differential diagnosis includes TD, hypochondroplasia, achondrogenesis, OI type II, and diastrophic dysplasia.

Prognosis.

Developmental milestones are often delayed, but intelligence is normal. Craniocervical junction compression increases the risk of death in infancy as a result of central apnea (risk ~ 7.5%). Obesity is a common problem that often begins in childhood. Spinal stenosis at L1-L4 is the most common medical complaint in adulthood.

Management.

Medical issues require ongoing surveillance, and guidelines have been established (see ). Strong support groups exist, including the Little People of America, Inc.

Achondroplasia. Frontal bossing.

Achondroplasia. Lack of widening of the spinal canal.

Fetal size charts for femur length ( A ), head circumference ( B ), and abdominal circumference ( C ) against gestational age in fetuses with achondroplasia. Note the curvature in the femur length chart as growth declines in the third trimester. Comparison with normal fetuses is demonstrated by overlaying measurements from affected fetuses on charts of fetuses of normal size ( D – F , respectively) and by plots of Z-scores showing the deviation from the normal range ( G – I , respectively).

(From Chitty LS, Griffin DR, Meaney C, et al: New aids for the non-invasive prenatal diagnosis of achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-free fetal DNA in maternal plasma. Ultrasound Obstet Gynecol 37(3):283-289, 2011, Fig. 1.)

Definition.

Klippel-Feil syndrome (KFS) is characterized by a classic triad of short neck, low posterior hairline, and fusion of cervical vertebrae. Different classification schemes for subtypes have been proposed. KFS1 and KFS3 are autosomal dominant disorders, whereas KFS2 is autosomal recessive.

Incidence.

Incidence is 1 in 40,000 to 42,000 live births. A slight female predominance has been reported.

Etiology.

The implicated genes encode for proteins in the bone morphogenetic protein family, which is involved in regulating the differentiation of bone and cartilage.

Genetics.

KFS1 is due to mutations in the GDF6 gene, and KFS3 is due to mutations in the GDF3 gene; both have autosomal dominant inheritance. KFS2 is due to mutations in MEOX1 and has autosomal recessive inheritance.

Recurrence Risk.

Recurrence risk depends on the mode of inheritance and presence of parental mutations.

Diagnosis.

The short neck may be associated with opisthotonos (retroflexion of the head), and disorganization of the cervical vertebrae is potentially recognizable. Other associated anomalies include ocular malformations, cleft lip and palate, oligodontia, craniofacial asymmetry, maxillary constriction and velopharyngeal insufficiency, persistent trigeminal artery, congenital heart defects, and urogenital anomalies. Some cases occurring with situs inversus totalis have been reported.

Differential Diagnosis.

The differential diagnosis includes other disorders with vertebral anomalies.

Prognosis.

Complications result from vertebral fusion and include cord compression syndrome, cervical instability, and motility impairment.

VACTERL Association

See separate entry at the end of this chapter.

Second trimester sonogram of a fetus with Klippel-Feil syndrome. Persistent retroflexion of the head on the neck should raise suspicion for this diagnosis.

Reformatted computer tomographic scan of a 2-year-old child with Klippel-Feil syndrome. Note the fused ribs.

(Courtesy of Ian Suchet, 2002. Available at thefetus.net .)

A child with Klippel-Feil syndrome. Note the opisthotonotic position, low-set ears, and micrognathia.

Definition.

Spondylocostal dysostosis (SCDO) is characterized by multiple segmentation defects of the vertebrae and rib abnormalities, leading to a short trunk, short neck, and scoliosis.

Prevalence.

SCDO is rare; SCDO associated with DLL3 mutations is the most common.

Etiology.

The causative genes identified to date all encode key proteins in the Notch-signaling pathway, which is essential for vertebral development.

Genetics.

SCDO is due to mutations in one of four genes: DLL3, MESP2, LFNG, HES7 . Inheritance is autosomal recessive.

Recurrence Risk.

Recurrence risk is 25% if both parents are mutation carriers.

Diagnosis.

Diagnosis is based on radiologic features including vertebral segmentation defects and rib abnormalities. These features can be seen prenatally as early as the late first trimester.

Differential Diagnosis.

The differential diagnosis includes other rarer conditions with similar vertebral anomalies as well as syndromes associated with multiple vertebral segmentation defects ( Table 16-4 ).

Prognosis.

The size of the thorax can compromise respiratory function in neonates and can lead to pulmonary hypertension. Males have increased risk for inguinal hernia. Neurologic complications are rare.

Definition.

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenital of the scalp vertex and terminal transverse limb defects (amputations, syndactyly, brachydactyly, oligodactyly).

Incidence.

Incidence is estimated at 1 in 225,000.

Etiology.

The implicated genes encode for proteins implicated in embryonic development. Some are thought to affect pericyte function leading to the observed anomalies.

Genetics.

The genetic cause is heterogeneous, and includes heterozygous mutations in ARHGAP31 and RBPJ (autosomal dominant inheritance) as well as biallelic mutations in DOCK6 and EOGT (autosomal recessive inheritance). Recently, heterozygous mutations in NOTCH1 were also implicated in AOS.

Recurrence Risk.

Recurrence risk depends on mode of inheritance and presence of parental mutations.

Diagnosis.

Prenatally, transverse limb defects may be detected sonographically. Other commonly observed features in affected individuals include vascular anomalies (pulmonary hypertension, portal hypertension, cutis marmorata, venous ectasia, thrombophilia) and congenital heart defects (both right- and left-sided).

Differential Diagnosis.

The differential diagnosis includes other causes of transverse limb defects.

Prognosis.

Prognosis depends on the associated anomalies, which can range from mild to severe. Pulmonary hypertension can be life threatening.

Definition.

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism (synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, micrognathia), growth restriction and microcephaly (prenatal onset), hirsutisum, and upper limb reduction defects (phalangeal abnormalities, oligodactyly).

Synonym.

It is also known as Brachmann-de Lange syndrome.

Incidence.

Estimates range from 1 in 10,000 to 1 in 100,000. The milder form is likely underdiagnosed.

Diagnosis.

Diagnosis is based on clinical findings. Other features may include cardiac septal defects, cleft palate, GI dysfunction, hearing loss, myopia, and cryptorchidism. Congenital diaphragmatic hernia (CDH) can occur (1%).

Genetics.

Implicated genes include NIPBL (60% of cases) as well as SMC1A and SMC3 (5% and <1% of cases, respectively). Inheritance of NIPBL – and SMC3 -related CdLS is autosomal dominant; SMC1A -related CdLS is X-linked. Most NIPBL mutations are de novo. In general, the phenotype associated with mutations in SMC1A and SMC3 is milder. Phenotypic expression in families is relatively consistent. Penetrance is complete.

Recurrence Risk.

Recurrence risk depends on the implicated gene. Germline mosaicism is increased with NIPBL -related CdLS and recurrence is estimated to be 1.5%.

Differential Diagnosis.

Other disorders to consider include partial duplication of 3q, deletions of 2q31, Fryns syndrome, and FAS.

Prognosis.

Intellectual disability is generally present. Autistic and self-destructive tendencies are common. Life expectancy is generally normal, although an increased mortality rate has been reported related to aspiration, apnea, congenital heart disease, volvulus, and postsurgical complications.

Management.

Management guidelines have been published and involve multidisciplinary care for both medical and developmental issues.

Definition.

Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is characterized by abnormalities in ectodermal structures (skin, hair, teeth, nails, sweat glands) as well as cleft lip ± palate and limb defects (ectrodactyly and syndactyly of the hands and feet).

Incidence.

Incidence is unknown; the disorder is rare.

Etiology.

The TP63 gene encodes for a transcription factor crucial in the development of limbs and ectodermal-derived tissues.

Genetics.

EEC syndrome is due to mutations in TP63 . Inheritance is autosomal dominant. Significant intra- and interfamilial phenotypic variability exists.

Recurrence Risk.

Recurrence risk is 50% if a parental mutation is identified.

Diagnosis.

Prenatally, ectodactyly and syndactyly of the hands and feet, as well as cleft lip/palate may be detected. The hands may have a “lobster claw” appearance. Renal anomalies may also be present.

Differential Diagnosis.

The differential includes other syndromes caused by TP63 mutations, in particular ankyloblepharon-ectodermal defects-cleft lip/palate syndrome.

Prognosis.

Correction of orofacial clefting and hand and foot anomalies may be complicated by the presence of ectodermal dysplasia. Corrective surgery should be performed in centers that perform a greater number of complex repairs.

Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome. Ectrodactyly of the lower ( A ) and upper ( B ) extremities. Sonographic findings of ectrodactyly, especially in association with cleft lip ± palate, should prompt evaluation for EEC syndrome.

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