Skeletal Dysplasias and Heritable Connective Tissue Disorders

Presentation

OI type II (perinatal lethal type) is estimated to affect 1 in 20,000 to 1 in 60,000 infants. Affected infants may be born prematurely, with low birth weight and disproportionately short stature. The limbs are short and bowed with extra circular skin creases; the hips are abducted and flexed. The head is soft and boggy, and minimal calvarial bone can be felt. The sclerae are dark blue, and the chest is narrow. The infant cries with handling because there may be many fractures at different stages of healing. Sixty percent of affected babies are stillborn or die during the first day of life, and 80% die by 1 month. With the growing use of ultrasonography, affected fetuses may be detected in the second trimester because of short and bowed or angulated limbs and narrow thoraces ( Fig. 90.1 ).

OI type III (progressive deforming type) can manifest itself prenatally, perinatally, or during the first 2 two years after birth. Prenatal and perinatal clinical features resemble those in OI type II but are less severe ( Fig. 90.2 ), and perinatal death is not uncommon. The highest prevalence of fractures in OI, up to 200 in a lifetime, occurs in type III. Extremely short stature, with an adult height of 92 to 108 cm, can result from microfractures in growth plates. The head may be large because the calvarium is soft with a large anterior fontanel. The sclerae may be blue initially but are white by puberty. The head assumes a triangular shape, with a bossed, broad forehead and a tapered, pointed chin. Later in childhood, dentinogenesis imperfecta and hearing loss may develop. Severe kyphoscoliosis may occur, leading to cardiopulmonary compromise, which is the major cause of early death.

Radiographic Features

Radiographs show the femurs in OI type II to be short, broad, and “telescoped” or “crumpled.” The tibiae are short and bowed or angulated, and the fibulae may be thin (see Fig. 90.1B ). There is minimal to no calvarial mineralization. The acetabular and iliac wings may be somewhat flattened. The ribs are short, wavy, and thin or broad, with “beading” from callus formation at fetal fracture sites.

In OI type III, the femurs are short and deformed but not crumpled as in OI type II (see Fig. 90.2B–D ). The other long bones are thinner than usual, with healing fractures incurred in utero, bowing, and deformations. The calvarium is undermineralized with a large anterior fontanel, and there are many Wormian bones (small islands of bone in the suture spaces; see Fig. 90.2D ). The ribs are thin and gracile.

Etiology

OI is most commonly caused by mutations in one of the two genes encoding collagen type I ( COL1A1 and COL1A2 ), the predominant protein building block of bone. More clinically severe forms of OI are the result of qualitatively abnormal collagen synthesis rather than decreased production, as well as the result of numerous recessive types affecting noncollagen proteins.

Inheritance

A fetus or infant with OI type II or III is usually the result of a spontaneous dominant-acting gene mutation, but there is a small risk of recurrence (approximately 6%) in subsequent siblings because of possible parental somatic or gonadal mosaicism. The parent is usually asymptomatic but may have minimal manifestations, such as short stature. Prenatal diagnosis is available if the particular gene mutation has been identified in the affected individual. Most cases of OI are inherited as autosomal dominant traits, although rare recessive forms have been shown to be caused by mutations in genes encoding, for example, cartilage-associated protein ( CRTAP ), prolyl 3-hydroxylase ( P3H1 ), and cyclophilin B ( PPIB ).

Differential Diagnosis

Other lethal skeletal dysplasias may have abnormalities similar to those in OI type II and may be difficult to distinguish by prenatal ultrasonography; however, in experienced hands, they can be differentiated on the basis of several ultrasound findings. Krakow et al. published a retrospective analysis of 1500 prenatally diagnosed cases of skeletal dysplasias. The three most common prenatal-onset skeletal dysplasias were OI type II, thanatophoric dysplasia, and achondrogenesis type II, which together accounted for almost 40% of all cases. Postnatal radiographs clearly reveal distinctive differences among thanatophoric dysplasia, campomelic dysplasia, achondrogenesis, and perinatal hypophosphatasia, among other disorders.

Management

If the diagnosis of OI is made prenatally, cesarean delivery has not been shown to decrease the fracture rate or increase the survival rate of severely affected fetuses. Those severely affected with OI type II are not expected to survive the neonatal period. In OI type III, the neonate needs careful handling to minimize pain and prevent further fractures. Analgesia alleviates pain. Consideration can be given to treatment with bisphosphonates (with the use of intravenously administered pamidronate), which increase bone density, reduce the frequency of fractures and pain, possibly prevent short stature and deformations, and permit ambulation. It is prudent to treat only severely affected children in whom the clinical benefits outweigh potential long-term effects.

Handling an Infant With Osteogenesis Imperfecta

When the diapers of an infant with OI are being changed, a hand should be placed behind the infant's buttocks with the forearm supporting the legs. Similarly, when the infant is lifted, the buttocks, head, and neck must be supported. The infant can be laid on a pillow to be carried. To transport the infant, an infant seat that reclines as much as possible and allows easy placement or removal should be used. The seat can be padded with egg crating or 1-inch foam. A layer of foam can be placed between the seat's harnesses and the child for extra protection. The car seat must always be placed in the back seat. Sling carriers and “umbrella” strollers should not be used for infants with OI because they do not give sufficient leg, head, and neck support.

Presentation

Perinatal hypophosphatasia is a lethal condition characterized by short, deformed limbs, a soft skull, blue sclerae, and undermineralization of the entire skeleton, such that many bones cannot be visualized and may seem absent in radiographs. In the skull, only the base can be visualized radiologically. There may be rachitic changes and fractures. Seizures that are responsive to pyridoxine may occur. There is polyhydramnios during pregnancy, and death can occur in utero. The disorder affects approximately 1 in 100,000 live births, and neonatal death is common.

Radiographic Features

The radiographic features of perinatal hypophosphatasia include polyhydramnios (prenatal); underossification, especially of the calvarium and long bones (with marked variability); small thoracic cavity; short, bowed limbs; spurs in the middle portion of the forearms and lower legs; and dense vertebral bodies.

Etiology

Mutations in the ALPL gene are responsible for deficiency of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), thus causing perinatal hypophosphatasia. The serum alkaline phosphatase value is low. Serum values of inorganic pyrophosphate and pyridoxal 5′-phosphate (putative natural substrates for TNSALP) may be elevated, and urinary phosphoethanolamine level is elevated.

TNSALP acts on multiple substrates: the essential function of TNSALP is in osteoblastic bone matrix mineralization. TNSALP hydrolyzes inorganic pyrophosphate to phosphate, which is thought to be critical in promoting osteoblastic mineralization. If TNSALP is deficient, there is an extracellular accumulation of inorganic pyrophosphate, which inhibits hydroxyapatite crystal formation and mineralization of the skeleton. TNSALP is also needed for the delivery of pyridoxal 5′-phosphate into cells, where it is a cofactor (vitamin B6).

Inheritance

Perinatal hypophosphatasia is inherited as an autosomal recessive trait, with a 25% recurrence risk in future pregnancies. Prenatal diagnosis is optimized with the use of ultrasonography, an assay of TNSALP activity in amniocytes, DNA mutation analysis if the previously affected infant's mutations were identified, or a combination of these methods.

Differential Diagnosis

Differential diagnoses include OI type II and achondrogenesis.

Management

Until very recently, treatment was primarily supportive and directed toward minimizing pain and discomfort. Clinical trials with a bone-targeted human recombinant enzyme replacement therapy have been shown to be effective in nonlethal cases.

Presentation

Achondroplasia is the most common of the nonlethal chondrodysplasias; it affects 1 in 25,000 live births. It is characterized by short stature with short limbs, particularly rhizomelic (proximal) and acromelic (hands) shortening with trident hand configuration, large head with frontal prominence (“bossing”), flat nasal bridge and midface, long narrow trunk, joint laxity, and development of thoracolumbar kyphosis (“gibbus”) in infancy ( Fig. 90.3 ).

The foramen magnum and cervical spinal canal may be narrow and can cause compression of the spinal cord. Standards have been published for foramen magnum size in achondroplasia. Compression of the lower brainstem and cervical spinal cord can lead to hypotonia, central apnea, retardation, quadriparesis, and (rarely) sudden death.

Radiographic Features

The calvarium is large with a relatively small foramen magnum and a short base. The lateral cerebral ventricles may be large, but hydrocephalus is not a common complication. The proximal long bones (humeri and femurs) are short, including the femoral neck. Fibulae are longer than tibiae. There is metaphyseal flaring. The hand is short with a trident configuration of the fingers, with short proximal and middle phalanges. Vertebrae are small and cuboid with short pedicles, and there may be anterior beaking of the first or second lumbar vertebrae; there is a lack of widening of the interpedicular distance in the lumbar vertebrae. The pelvis has squared iliac wings (“elephant ear” appearance), a narrow greater sciatic notch, and flat acetabular roofs (see Fig. 90.3C ). Compression of the cervical cord, if present, can be ascertained with magnetic resonance imaging with cerebrospinal fluid flow studies in flexion and extension.

Etiology

The cause of achondroplasia is a mutation of the FGFR3 gene, which encodes fibroblast growth factor receptor 3, a membrane-spanning tyrosine kinase receptor. More than 99% of individuals with achondroplasia have a common recurrent mutation in the transmembrane domain of the FGFR3 gene, in which arginine is substituted for glycine (Gly380Arg). The same gene is mutated at different sites in hypochondroplasia, thanatophoric dysplasia, SADDAN, Muenke craniosynostosis, and Crouzon craniosynostosis syndrome with acanthosis nigricans. Histopathologic examination demonstrates a defect in the organization and maturation of the cartilage growth plates of long bones because of differing degrees of constitutive activation of the receptor.

Inheritance

The inheritance pattern in achondroplasia is autosomal dominant. Approximately 80% of cases are sporadic occurrences in a family, representing new mutations. Cases may be associated with advanced paternal age, and molecular studies have confirmed that new mutations are of paternal origin. Rare recurrences due to gonadal mosaicism in a parent have been reported. Affected individuals are fertile, and achondroplasia is transmitted as a fully penetrant autosomal dominant trait, meaning that each person who inherits the mutant gene will manifest the condition.

Differential Diagnosis

Differential diagnoses include SADDAN and hypochondroplasia.

Management

The infant with achondroplasia is often hypotonic; together with the large head, the hypotonia leads to delayed motor milestones. Development of thoracolumbar kyphosis may be exacerbated by unsupported sitting before truncal muscle strength is adequate; therefore, infants should not be carried in flexed positions (including soft sling carriers and umbrella strollers). Rear-facing car safety seats should always be used. Physical therapy in the first year of life may strengthen core musculature at a faster rate. Most infants lose their kyphosis and develop the typical exaggerated lumbar lordosis when they begin walking.

Hydrocephalus may occasionally develop during the first 2 years, so the head circumference and body length should be carefully measured and plotted on standard achondroplasia growth charts. Routine imaging of the skull and brain is not recommended; however, the development of hyperreflexia, hypotonia, or apnea may herald the development of clinically significant cord compression in infancy or early childhood and requires prompt evaluation. Surgical decompression at the foramen magnum or the upper cervical spine may prevent neurologic damage, although most patients usually gain motor milestones late but spontaneously because the foraminal diameter expands faster than the cord.

The upper airway in individuals with achondroplasia is small, often leading to obstructive apnea, snoring, and chronic serous otitis media beyond infancy. Treatment may consist of tonsillectomy, adenoidectomy, and placement of myringotomy tubes. Parents should be counseled about the clinical and hereditary aspects of the disorder and given a copy of the guidelines for health supervision of children and adults with achondroplasia issued by the American Academy of Pediatrics.

Drugs designed to impede the overexpression of the FGFR3/tyrosine kinase pathway are currently in clinical trials and thus far look promising. However, trials as yet have not included newborns and infants.

Presentation

Thanatophoric dysplasia is one of the most common lethal dysplasias, occurring once in 45,000 births. It is characterized by extremely short limbs, long narrow trunk, large head with a bulging forehead, prominent eyes, flat nasal bridge, wide fontanel, and occasionally cloverleaf skull deformity ( Fig. 90.4 ). It is differentiated into types I and II based on radiologic features and mutation specificity. Death typically occurs in the neonatal period from respiratory insufficiency, although rare survivors have been reported with multiple chronic problems. Polyhydramnios is common during pregnancy.

Radiographic Features

Femurs are short, flared at the metaphyses with a medial spike, and are bowed (type I) or straight (type II); other long bones are also short and bowed (see Fig. 90.4 ). The calvarium is large with a short base and small foramen magnum; the cloverleaf skull is sometimes present in type I thanatophoric dysplasia and is severe in type II. Vertebrae are strikingly flat (platyspondyly) with a U shape or an H shape in anteroposterior projection and uniform interpediculate narrowing. Ribs are short, cupped, and splayed anteriorly.

Etiology

Thanatophoric dysplasia represents the severe end of the FGFR3 spectrum. In thanatophoric dysplasia type I, the most common mutation is a substitution of cysteine for arginine at position 248 (Arg248Cys) in the receptor's extracellular domain, but other mutations have been described throughout the gene. In all studied cases of thanatophoric dysplasia type II, there is a substitution of glutamate for lysine at position 650 (Lys650Glu). These mutations have been shown to constitutively activate FGFR3 to a greater extent than the common mutation seen in achondroplasia, thus resulting in a more severe phenotype.

Inheritance

All cases of thanatophoric dysplasia, as with most cases of achondroplasia and hypochondroplasia, occur sporadically and result from new autosomal dominant-acting mutations. Nevertheless, there may be a small risk of recurrence in siblings of an infant with sporadic thanatophoric dysplasia, possibly due to gonadal mosaicism. Prenatal diagnosis is available if the particular gene mutation has been previously identified in an affected individual.

Differential Diagnosis

Differential diagnoses include OI types II and III, achondroplasia (severe), achondrogenesis, and hypochondrogenesis.

Management

If the condition is suspected prenatally and diagnosed by molecular means (mutation analysis following amniocentesis), the parents should receive genetic counseling and anticipate neonatal death. If the diagnosis is suggested after delivery and radiographically confirmed, management is solely supportive, with death from pulmonary insufficiency usually occurring within hours to days.