Osteochondrodysplasias

Natural History and Comment

The defect in the development of cartilage and bone is severe. In type IA, normal-appearing but a hypervascular cartilage matrix is present with increased cellular density. Large lacunae surround the chondrocytes, which contain round cytoplasmic inclusion bodies. In type IB, sparse interterritorial cartilaginous matrix is present, with a marked deficiency of collagen fibers. The chondrocytes are large, have a central round nucleus, and are surrounded by a dense collagenous ring. Developmental pathology beyond the skeletal system is implied by the frequent findings of polyhydramnios, hydrops, and early lethality. Most infants are stillborn or die shortly after birth. Occipital encephalocele has been reported in one child with type IA disease.

Etiology

This disorder has an autosomal recessive inheritance pattern. Achondrogenesis type IA is caused by mutations in the thyroid hormone receptor interactor gene ( TRIP11 ), which leads to a deficiency of Golgi microtubule-associated protein 210 (GMAP-210) in chondrocytes. Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulfatase transporter (DTDST) gene ( SLC26A2 ). Inactivation of the gene product, a sulfate-chloride exchanger of the cell membrane, leads to intracellular sulfate depletion and to synthesis of undersulfated proteoglycans in susceptible cells. Mutations in this gene are responsible for four recessively inherited chondrodysplasias, including achondrogenesis type IB, diastrophic dysplasia, multiple epiphyseal dysplasia, and atelosteogenesis type II.

Natural History

The vast majority of affected individuals have been stillborn or have died in the neonatal period.

Etiology

There are both autosomal dominant and autosomal recessive forms of this disorder. Mutations in the gene encoding the proa1(XI) chain of type XI collagen, COL11A1, are responsible for the recessively inherited mutations; mutations in the gene encoding the proa2 (XI) chain of type XI collagen, COL11A2, are responsible for the dominantly inherited mutations.

Comment

Microscopic examination of long bones demonstrates gross disorganization of growth plate cartilage, fibrous appearance of the matrix, and normal metaphyseal and diaphyseal bone formation.

Occasional Abnormalities

Cleft palate, laryngeal stenosis, retinal dysplasia involving the optic disc, macrocephaly, renal mcrocysts, abnormal branching of pancreatic dust, malrotation of caecum.

Natural History

All affected infants have been stillborn or have died immediately after birth.

Etiology

This disorder has an autosomal dominant inheritance pattern with all cases representing fresh gene mutations. Mutations in the gene encoding filamin B ( FLNB ) located at chromosome 3p14.3 are responsible. FLNB seems to have an important role in vertebral segmentation, joint formation, and endochondral ossification.

Comment

Mutations in FLNB include a spectrum of disorders ranging from mild (spondylocarpotarsal synostosis syndrome and Larsen syndrome) to severe (atelosteogenesis types I and III and boomerang dysplasia).

Occasional Abnormalities

Craniosynostosis, omphalocele, frontal encephalocele, cleft palate, cardiac defect.

Natural History

Prenatally polyhydramnios, narrow thorax, short limbs, and defective ossification of the vertebrae and limbs are evident on ultrasound examination. Most are stillborn or die shortly after birth of respiratory insufficiency secondary to pulmonary hypoplasia.

Etiology

This disorder has an autosomal dominant mode of inheritance, with all cases representing fresh gene mutations. Mutations in the gene encoding filamin B ( FLNB ) located at chromosome 3p14 are responsible.

Comment

FLNB is mutated in a spectrum of phenotypes ranging from spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome at the mild end, and atelosteogenesis types I and III and boomerang dysplasia at the severe end. Boomerang dysplasia is distinguished from atelosteogenesis on the basis of a more severe defect in mineralization, with complete absence of ossification in some limb bones and vertebrae. Heterozygous mutations associated with the most severe phenotypes almost invariably occur in exons 2 to 5. These are apparently de novo , but germline or somatic mosaicism has been reported for the milder phenotypes. Flnb -deficient mice closely resemble those of human skeletal disorders with mutations in FLNB . Histology shows disorganized cartilage of the developing long bone and multinucleated chondrocytes in areas of a hypocellular cartilage matrix.

At the most severe end of the FLNB -related skeletal disorders is the Piepkorn type of osteochondrodysplasia. The principal features of that early lethal disorder include underossification of the skeleton associated with extremely short flipper-like limbs, short ribs, polysyndactyly, craniosynostosis, a prominent forehead, ocular hypertelorism, prominent eyes, an upturned nose, microstomia, Pierre-Robin sequence, and posteriorly rotated, low-set ears. Omphalocele, CNS defects, cardiac defects, and urogenital abnormalities have also been seen.

Occasional Abnormalities

Patent ductus arteriosus, atrial septal defect, horseshoe kidney, hydronephrosis, imperforate anus, chylous ascites, radioulnar synostosis, soft tissue syndactyly of fingers and toes, acanthosis nigricans in long-term survivors.

Natural History

Feeble fetal activity and polyhydramnios are frequent in this disorder. These patients usually die shortly after birth, partially owing to the small thoracic cage and respiratory insufficiency. Although survival beyond the neonatal period is rare, a few affected individuals have been reported, one up to 28 years of age. All had profound developmental delay, severe growth deficiency, and were ventilatory-dependent.

Etiology

This disorder has an autosomal dominant inheritance pattern. All cases represent fresh gene mutations, and most, if not all, are caused by mutations in the fibroblast growth factor receptor 3 ( FGFR3 ) gene. All cases with a Lys650Glu substitution had straight femora with craniosynostosis and frequently a cloverleaf skull (TDII). All other mutations were associated with curved femora; cloverleaf skull was present only infrequently (TDI).

Occasional Abnormalities

Polydactyly, usually of hands and feet, notching of distal end of metacarpal and metatarsal bones; lacunar skull; direct hyperbilirubinemia with prolonged jaundice; pancreatic defects, including fibrosis and cysts; Hirschsprung disease; retinal dysplasia/foveal hypoplasia (15%); lobation of the tongue and gingiva; cardiac defects (1.6%); abdominal muscle dysplasia; foregut dysmotility and malrotation; situs inversus; intellectual disability; Dandy-Walker complex.

Natural History

Early death, usually the consequence of asphyxia with or without pneumonia, occurs frequently, almost always prior to 2 years of age. Procedures to expand the chest have been successful and should be considered in select cases. For those who survive, progressive improvement in the relative growth of the thoracic cage occurs and there may be only slight to moderate shortness of stature. However, respiratory difficulties occur in all survivors. Chronic nephritis leading to renal failure is a serious potential feature of this disorder occurring in approximately one-third of the 30% who have renal abnormalities. Renal insufficiency may be evident by 2 years of age and accounts for most deaths between 3 and 10 years of age. Although infrequent, progressive hepatic dysfunction also occurs and may contribute to the relatively poor long-term prognosis for individuals with this disorder. Survival to the fourth decade has occurred. However, little information is available for affected individuals older than 20 years.

Etiology

This disorder has an autosomal recessive inheritance pattern. Mutations in IFT80, DYNC2H, TTC21B , WDR19 , and WDR34 are responsible. IFT80 encodes a protein that is important in intraflagellar transport and is essential for the development and maintenance of motile and sensory cilia. DYNC2H1 encodes a cytoplasmic dynein protein involved in retrograde transport in the cilia and functions in intraflagellar transport. TTC21B encodes the retrograde intraflagellar transport protein IFT139. Mutations of both IFT80 and DYNC2H have also been identified in short rib–polydactyly type III, suggesting that these two disorders are variants of the same condition.

Comment

A follow-up protocol has been proposed. In the first 2 years of life, focus should be on treatment of severe respiratory problems. Laboratory evaluation of urine and blood should be done twice a year, and abdominal ultrasound should be performed at 2, 5, 10, and 15 years. Spirometry should be done yearly, and an ophthalmology examination should be performed at 5 and 10 years of age.

Occasional Abnormalities

Cardiac defects, renal anomalies, polyhydramnios, hypoplastic cochlea and semicircular canals, anomalies of incus and stapes, hearing loss.

Natural History

The great majority of patients die in the neonatal period from respiratory insufficiency. Although there have been some survivors with normal intelligence, most have mild to moderate intellectual disability. At birth the limbs are short with a trunk of normal length, but with development of the kyphoscoliosis, which is progressive, the trunk becomes short relative to the arms. Conductive hearing loss, myopia, dental caries, and recurrent apnea and respiratory problems are complications with advancing age. Absence of cervical and thoracic pedicles present a challenge during spine surgery.

Etiology

Campomelic dysplasia (CD) has an autosomal dominant inheritance pattern, with most cases representing fresh gene mutations. The small number of recurrences are owing to gonadal mosaicism. Mutations in SOX9, a member of the SRY-related gene family, are responsible for the majority of cases. Acampomelic campomelic dysplasia (ACD) is associated with similar, but milder, skeletal abnormalities and lacks long bone curvature. However, in one case of ACD, bowing of the long bones was evident on prenatal ultrasound until the 18 ^th week of gestation. Although both CD and ACD can be caused by heterozygous mutations in SOX9 or chromosomal aberration affecting SOX9 or the putative enhancer region, the type of mutations and chromosomal aberrations differ. CD is primarily caused by nonsense or frameshift mutations or by chromosomal aberrations disrupting SOX9. ACD, on the other hand, is more often caused by missense mutations or by chromosomal aberrations affecting the enhancer region. SOX9 is involved in both bone formation and control of testes development. It regulates the expression of COL2A1 and is a transcription factor essential for chondrocyte differentiation and formation of cartilage.

Occasional Abnormalities

Hydrocephalus, spinal cord or root compression; pulmonary hypertension, synostosis of multiple sutures.

Natural History

Macrocephaly may represent mild hydrocephaly relating to a small foramen magnum. Therefore, ultrasound studies of the brain should be performed if the fontanel size is particularly large, the occipitofrontal circumference increases too rapidly, head circumference above the 95th percentile, or any symptoms of hydrocephalus develop. Respiratory problems secondary to a small chest, upper airway obstruction, and sleep-disordered breathing are common. Cervical cord compression occurs frequently, leading to an increased risk for death in the first year of life. Indications for decompression include lower limb hyperreflexia, central apnea, and foramen magnum measurements below the mean for achondroplasia. Computed tomography dimensions for the foramen magnum of children with achondroplasia have been established by Hecht and colleagues. It is important to recognize that evaluation of affected children with symptoms relating to cervical cord compression should be performed by individuals experienced with, and aware of, the natural history of achondroplasia. Osteotomies for severe bowlegs are usually deferred until full growth has occurred. By discouraging the sitting position or other positions that cause the trunk to curve anteriorly until an age when good trunk strength has developed, a permanent gibbus or kyphosis, which is caused by anterior wedging of the first two lumbar vertebrae, can be prevented as well as obviating many of the problems with spinal stenosis and spinal cord compression that are so debilitating to adults with this condition. Exercises may also be used in an attempt to flatten the lumbosacral curve. Relative overgrowth of the fibula may accentuate bowing and require early stapling. Short eustachian tubes may lead to middle ear infection and conductive hearing loss. Tympanic membrane tubes may be indicated. Verbal comprehension is frequently impaired. Obstructive sleep apnea requiring oxygen supplementation is associated with airway malacia. The mandibular teeth may become crowded, possibly requiring removal of one or more. Todorov and colleagues developed a screening test that establishes normal milestones for children with achondroplasia up to 2 years of age. Some degree of developmental delay, primarily motor, is common, as is a decrease in IQ score compared with siblings. There is a tendency toward late childhood obesity, and females are more likely to have menorrhagia, fibroids, and large breasts. Complications from spinal stenosis increase in adults. By 10 years of age, a significant number of affected children have developed neurologic symptoms with claudication and increased reflexes in their legs. Long-term growth hormone treatment contributes to 2.6% and 2.1% of final adult height in males and females, respectively. Surgical leg lengthening is controversial because of the need for repeated surgeries, the long period of time that orthopedic appliances must be used, superficial infections, and the stretching of nonskeletal tissues. The average life expectancy is decreased by 15 years.

Etiology

This disorder has an autosomal dominant inheritance pattern; approximately 90% of the cases represent a fresh gene mutation. Older paternal age has been a contributing factor in these cases. Because of gonadal mosaicism, there is a 0.2% recurrence risk for siblings of achondroplastic children with unaffected parents. Mutations in the gene encoding fibroblast growth factor receptor 3 ( FGFR3 ), located at 4p16.3, have been documented in all cases reported to date. Interestingly, virtually all cases demonstrate the same single base pair substitution, possibly accounting for the consistency of the phenotype seen in this disorder.

Comment

Health Supervision Guidelines for Children with Achondroplasia have been established by the American Academy of Pediatrics. An excellent review has been published by Richard Pauli in 2019.