Skeletal System

Skeletal System

Louis P. Dehner, M.D.

Michael Kyriakos, M.D.

The complexity of the developing skeletal system was appreciated long before the advent of molecular biology. The molecular genetic understanding of skeletogenesis has continued to provide insights into the tightly regulated signaling pathways and transcription factors as highly conserved events throughout the vertebrate phyla (1,2,3,4). The morphologic events begin with the segregation of progenitor mesenchymal cells in the cranial portion of the neural crest (neuroectoderm) and mesoderm (craniofacial bone development, paraxial somite [axial skeleton], and lateral plate mesoderm [limb skeleton]). For instance, the neural crest cells have a central role in the development of bone and skeletal muscle in the head and neck (5). The blue print or patterning and migration are controlled by highly conserved transcriptional factors such as the HOX and PAX genes and their signaling pathways, which are integral to cell-to-cell communication and intracellular signaling. HOX genes are represented by 39 genes, which are critical for coordinated development of bone, tendons, and skeletal muscle in the axial and appendicular skeleton (6,7). Another set of developmental and patterning genes, PAX family, regulates the various pools of progenitor cells for various types of tissues, and the function of PAX1 is critical in the maintenance of a population of precursor mesenchymal cells for chondrogenesis (8). Mesenchymal cells after migration to their specific sites undergo the process of condensation whose end result is the formation of the 206 or so bones of the human skeleton. Once condensation has taken place, the next event is osteoblastic and chondrogenic differentiation, which is accompanied by a number of molecular events involved with lineage determination; SOX9 (SRY-box 9), a transcriptional factor gene, is critical in the differentiation of an osteochondral progenitor to a chondrocyte (9,10). Into this process of chondrogenesis and osteoblastogenesis, fibroblast growth factors and their high affinity receptors have critical roles in the activation of several transduction pathways (11). Goldring and associates (12) have pointed out that chondrogenesis is the earliest phase of skeletogenesis. Not only is SOX9 one of the earliest expressed genes in the condensation phase, but it is also necessary for the expression of COL2A1, which encodes the alpha-1 chain of type 2 collagen and other matrix proteins (13,14). The differentiation phase of chondrocytes occurs when two other members of the SOX family, SOX5 (SRY-box 5) and SOX6 (SRY-box 6), are expressed somewhat later than SOX9 (15,16). Extracellular matrix is synthesized with further chondrocytic differentiation to hypertrophic chondrocytes; these extracellular macromolecules include proteoglycans—aggrecan, decorin, biglycan, fibromodulin, and perlecan—in addition to collagens types II, IX, and XI (17). The next stage is the process of cartilage undergoing metamorphosis to bone (18). Just as SOX9 is critical in the development of chondroblasts, so the transcriptional factor, Runt-related 2 (Runx 2 or Cbfa-1) has a similar role in the differentiation of the osteoblast from the primordial osteochondral cell. The Runx 2 (Cbfa-1) is also involved in the development of the hypertrophic chondrocyte. In turn, there are several regulators of Runx 2 function.

The bones as the basic gross components of the skeleton develop by one of two processes, enchondral ossification in the formation of the appendicular and axial skeleton and membranous ossification in the formation of the craniofacial bones and portions of the clavicle (19,20,21). Membranous ossification is characterized by the direct differentiation of the common progenitor mesenchymal cell to an osteoblast even before the condensation stage; there is osteoid deposition with the formation of ossification centers that fuse into the platelike bone of the calvarium. The bone matrix proteins, osteocalcin/bone gla protein, collagen type 1, bone sialoprotein, and alkaline phosphatase, are induced by Runx 2 (Cbfa-1), which has been characterized as the “master regulator of osteoblast differentiation” despite the feat that Runx 2 does not induce osteoblastic differentiation alone, but interacts with TGF-β superfamily, bone morphogenic protein, and specific SMADs (22,23). Other important signaling molecules include Wnt/β-catenin and Hedgehog pathways (24,25).

Enchondral ossification requires the coordination of chondrocytes, osteoblasts, and osteoclasts. The osteoclast is
a bone marrow-derived cell of the monocyte lineage, which is required for the process of bone remodeling. Following the stage of condensation (6 to 7 weeks of gestation), the formation of the cartilaginous anlage template (18 to 19 weeks of gestation) occurs in a proximal to distal fashion and in anterior before posterior structures. The primary center of ossification is found in the midshaft of the bone anlage in the vicinity of the hypertrophied or terminally differentiated chondrocytes (20,26,27). There is also vascular invasion as the hypertrophied chondrocytes express vascular endothelial growth factor. A periosteal bone collar is formed by mesenchymal cells that undergo osteoblastic differentiation to initiate the process of cortical bone formation. With the vascular invasion, hematopoietic precursors including preosteoclasts have gained access to the bone. Secondary centers of ossification are formed at the proximal and distal ends of the bone and are separated from the primary center by the growth plate where the epiphyseal cartilage proliferates, hypertrophies, and undergoes apoptosis (26,28). This latter process is in part under the control of the gene, Indian hedgehog. The invading front of ossification from the primary and secondary centers of ossification and the proliferating cartilage together account for bone growth.

We have not mentioned the roles of parathyroid hormone (PTH)-related peptide and its receptor, which is controlled by COL2A1 promoter and fibroblast growth factor receptor 3 (FGFR3) (28,29,30). The receptors are present on the cell membrane of the osteoblasts; the role of this receptor tyrosine kinase at the growth plate is an important one since activating mutations are involved in several types of skeletal dysplasia. The third basic cell type, the osteoclast, is a multinucleated cell of mononuclear phagocytic derivation whose function is bone matrix resorption through its resorptive organelle, the ruffled membrane (31). Defective function or differentiation of osteoclasts is the underlying pathogenesis of osteopetrosis (OP). Osteoblasts and osteoclasts interact through cytokines and growth factors, which serve to choreograph the initial modeling and remodeling of bone through autocrine, paracrine, and endocrine (parathormone) mechanisms (32). It has come to be appreciated that the osteoclast is more than a “bone-eater” but has a role in the regulation of hematopoiesis as well as immune response (33,34).






Valproic acid and other antiepileptics

Limb reduction defects



“Lower limb defects”




“Short limbs,” stippled calcification of epiphyses of long bones, brachydactyly


Craniosynostosis, oligodactyly, syndactyly, mesomelic shortening of forearms, talipes, equinovarus


Skeletal anomalies consist of a broad range of anatomic defects, which may be an intrinsic abnormality in the development and growth of a single bone or is a generalized process affecting the entire skeleton as the manifestation of a mutated constitutional genetic determinant or an extrinsic teratogen (35,36,37,38). Examples of the former include the various chromosomal syndromes, heritable metabolic disorders, a multitude of congenital anomaly syndromes, and the numerous genetic skeletal disorders (GSDs) also known as skeletal dysplasias or osteochondrodysplasias. Several agents are well-documented or highly suspected teratogens affecting normal skeletal development (39,40,41) (Table 28-1). Some of the interpretive problems in the assessment of skeletal abnormalities as putatively teratogenic versus natural variations in skeletal development in humans are discussed thoughtfully elsewhere (42,43).

The estimated frequency of the various types of skeletal anomalies in children is derived from diverse sources including the experience of individual institutions, vital statistics, and registries (44,45). In one pediatric autopsy series that included children through 14 years of age, congenital anomalies and malformations were identified in 18% of cases; almost 20% of these were found in the skeletal system (46). Multiple organ anomalies were found in most of these children, and major musculoskeletal anomalies were documented at autopsy in 1.3% of previable fetuses and liveborn infants who died in the perinatal period with the exclusion of chromosomal syndromes (46). Major malformations of the limbs are found in approximately 2% of liveborn infants and minor limb abnormalities in another 5% to 7%. Overall, approximately 1:1000 neonates have some defective development of the limbs, most commonly limb reduction defects (LRDs) (44,46).

Among the three most common trisomy syndromes, trisomy 18 (Edwards syndrome) is characterized by overlapping fingers, radial aplasia, and other preaxial limb defects and less commonly rocker-bottom feet and equinovarus deformity, whereas trisomy 13 (Patau syndrome) has
postaxial polydactyly (47,48). Clinodactyly of the fifth finger with a hypoplastic middle phalanx is found in 50% to 60% of infants with trisomy 21 (49,50,51). Several other musculoskeletal abnormalities are found in the setting of trisomy 21 (52). Additional malformations of the axial skeleton in these three trisomic syndromes have been discussed elsewhere (52,53). Syndactyly and talipes equinovarus are the two most common limb anomalies in triploid fetuses (53).

Limb Reduction Defects

LRDs comprise one of the most common categories of congenital skeletal anomalies and is defined by the following anatomic categories: absence or hypoplasia of a phalanx, metacarpal, or metatarsal bone as a portion of any long bone with accompanying deformity; these anomalies are represented by the specific defects of amelia, aplasia to hypoplasia of individual long bones, oligodactyly, polydactyly, and syndactyly (Figure 28-1) (53,54). These developmental anomalies are seen as an isolated finding or as a component of a syndrome as one of several anomalies in other organ systems including the cardiovascular system, kidney, and intestinal tract. Approximately 70% to 75% of LRDs occur in the upper extremity, whereas 15% to 20% are detected in the lower extremity alone and both upper and lower in 10% of cases (55,56,57,58). The incidence of these defects is approximately 1:1000 to 2000 live births (59,60,61). LRDs are estimated to be present in 2% of perinatal autopsies and in less than 1% of stillborns (62). The genetic and developmental aspects of LRDs are discussed at length elsewhere (61,63,64).

The morphology of LRDs includes the following anatomic categories: terminal longitudinal defects (e.g., aplasia-hypoplasia of the radius with absence of the thumb), terminal transverse defects (loss of distal limb structure with preservation of proximal structure), intercalary defects (aplasia or hypoplasia of proximal limb structure), split hand-foot defects (loss of radial ray or central ray of hand or foot), and complex defects with multiple types of LRDs. The following distribution of 271 LRDs was reported in liveborn infants from the Congenital Malformation Registry: terminal longitudinal (25%), terminal transverse (35%), intercalary (10%), split hand-foot (26%), and multiple (4%) defects (65,66).

FIGURE 28-1 • Limb reduction defects. A: Symes amputation of the foot demonstrates absence of the fourth and fifth toes as an example of postaxial ray deficiency together with proximal syndactyly in a 9-month-old male. B: This amputation specimen of the foot from a 10-month-old female shows only four toes with absence of the fifth digit. The fibula was absent as well.

The etiopathogeneses of LRDs are divisible into the following categories: dominant—recessive inheritance (15% to 20% of cases), chromosomal abnormalities (5% to 10%), known syndromes, some with a multiorgan pattern of anomalies (5% to 10%), and teratogens (3% to 5%). The latter four categories are collectively thought to account for 30% to 35% of all LRDs, and another 30% to 35% of cases are ascribed to vascular disruption. A determination as to etiopathogenesis is inconclusive for almost one-third of cases. Among those LRDs associated with congenital anomalies (12% to 33% of cases), there are patterns or associations that repeat themselves (67). Seven specific anatomic categories of LRDs are defined in Table 28-2. The various LRDs have several associated major congenital anomalies, some of which are better known than others (61). Preaxial limb defects have the highest frequency (68); they are recognized in the VATER/VACTERL association, which acronymically refers to vertebra, anorectal atresia, congenital heart, tracheoesophageal fistula, renal and distal urinary tract, and limb anomalies (69,70,71,72). These may be a consequence of perturbations in the sonic hedgehog homologue gene (7q36) and its signaling pathway since a murine knockout produces a similar pattern of anomalies as seen clinically (73). Vertebral anomalies including vertebral fusion and butterfly vertebra as examples are present in approximately 25% of VACTERL cases, whereas limb defects are found in 10% of cases with the
preaxial absence of the radius and/or thumb and first metacarpal. A phenotype similar to VACTERL has been observed in the setting of Fanconi anemia (FA); the preaxial limb anomalies are more common in FA than in the VACTERL association (74). Tibial aplasia-hypoplasia, another preaxial defect, is very uncommon when it is compared to the radial aplasia in the VACTERL association (75).





Complete or partial absence of thumbs, first metacarpal and radius and/or absence of hallux, first metatarsal, and tibia


Absence of distal metacarpal in phalanges with normal or deficient proximal structures


Complete or partial absence of fifth finger


Absence or hypoplasia of humerus or femur and remaining long bones as a single bone or multiple bones involvement, hands, and feet minimally involved

Split hand-foot

Defects in central ray including metacarpal-metatarsal with nearly normal lateral digits


Complete or near complete limb absence


Presence of multiple limb defects


Defects not included in previous definitions

Transverse limb defects with the loss of fingers and toes are associated with anorectal atresia, craniofacial anomalies, syndactyly, and genital defects. Absence of fingers and toes, cleft palate, and constriction band acrosyndactyly are anomalies associated with the amniotic rupture sequence (ARS) or amniotic band syndrome whose prevalence varies from 1: 1200 to 15,000 live births (76,77) but are commonly seen in stillbirths. Most cases of ARS are sporadic, but there is an apparent increased prevalence in type 4 Ehlers-Danlos syndrome and severe osteogenesis imperfecta (OI) (78). Similar distal limb defects are found in association with ventral body wall defects, which are commonly accompanied by a short umbilical cord (79). A vascular disruption has been proposed as a possible pathogenetic factor in both ARS and ventral body wall defect (80). Whether the tethered threads of amnion after the rupture of the amniotic sac are the entire explanation remains an unresolved issue.


Tubulocytopenia—absent radius syndrome (HOXA11-IGKV3D-20 mutation on 7p15-p14)

Holt-Oram syndrome (TBX5 mutations on 12q24.1)

Fanconi anemia (FANCD1/BIRCA2 on 13q12.3, FANCN/PALB2 on 16p12.3 and FANCJ/BRIP1, TORCA2 mutations on 17q 22-24)

Renal hypoplasia—bilateral/radial ray aplasia

Hypothalamic hamartoblastoma syndrome

Multiple epiphyseal dysplasia (COL9A1 ON 6q12-q14, COL9A3 ON 20q13.3, COMP/TSP-5 on 5q31.2, MATS3 ON 1p33-p32)

Chromosome 22q11 deletion syndrome

Preaxial acrofacial dysostosis (Nager and de Reynier)

Trisomy 18

RAPADILINO syndrome (RECQ64 mutations on 8q24.3)

Baller-Gerold syndrome (craniosynostosis) (RECQ64 mutations on 8q24.3)

Another preaxial limb defect, radial hypoplasia-aplasia, occurs in a number of syndromic settings, and it is estimated that as many as 50% to 80% of infants with absent radii have other anomalies as a component of a defined syndrome (81,82,83,84,85) (Table 28-3).

Lower limb deficiencies are less common than those in the upper extremities accounting for 20% to 40% of cases with or without defects in the upper extremity. Isolated deficiencies or defects of the lower extremity are uncommon, as illustrated by the fact that congenital deficiency of the tibia, or tibial hemimelia, is found in 1:1 million live births (86,87). Other anomalies are found in the same extremity, often other extremities and visceral organ systems in 70% to 80% of cases. Tibial hypoplasia/aplasia is found in almost 70% of cases of the VACTERL association (70). Congenial fibular deficiency in contrast to the rarity of congenital tibial deficiency is one of the most common lower extremity deficiencies (88). Congenital radial-tibial deficiency is defined by an absence or hypoplasia of the preaxial structures of the extremity including the thumb, first metacarpal, radius, hallux, first metatarsal, and tibia; this anomaly is associated with nonlimb abnormalities in 70% of cases (89). Among those are the Poland sequence and Holt-Oram syndrome (90). Isolated femoral or fibular deficiency is equally uncommon. Somewhat more frequent is ulnar-fibular deficiency, which
is typically manifested by postaxial ray deficiency in the hands and feet with defects of the ipsilateral ulna and fibula. In most cases, ulnar-fibular deficiency is an isolated defect without anomalies elsewhere (88).

Split hand-foot limb defect or malformation (SHFM) occurs as a sporadic (more common) or familial anomaly on the basis of a failure in the initiation and maintenance of the median apical ectodermal ridge (91,92). One case of SHFM is seen in 8500 to 25,000 newborns (93). Seven chromosomal foci have been identified in isolated cases (94). In the less common familial SHFM, both autosomal recessive and X-linked patterns of inheritance are documented (95). Duplication in 17p13.3 (BHLHA9) and mutations FGFR1 and WNT10B have been identified (96,97,98). In addition to the split hand malformation, polydactyly and syndactyly may be present. Congenital heart disease is found in almost 50% of those with an SHFM 5 mutation. Ectrodactyly, ectodermal dysplasia, and facial cleft syndrome are associated with a p63 (homologue of tumor suppressor gene, p53) mutation; p63 function is critical in the development of the limb bud and hair follicle (99).

Patellar aplasia (absence) and hypoplasia as a lower limb deficiency are found in a number of syndromes, which are discussed at length elsewhere (100,101). Some of these syndromes include neurofibromatosis type 1 (NF1), campomelic dysplasia (CD) with SOX9 (17q24.3) mutations, KAT6B-related disorders, and nail-patella syndrome (NPS) with LMX1B (9q 34.1) mutation, which has a downstream effect on collagen type 4 expression in the glomerular basement development (102). The so-called iliac horns are triangular-shaped outgrowths of the posterior ilium, which are diagnostic of NPS (see Chapter 17).

Amelia denotes incomplete or absent limb. This rare anomaly is seen in 0.15:10,000 live births and occurs with equal frequency in the upper and lower extremities (103,104). Amelia is associated with encephalocele, gastroschisis, omphalocele, anorectal atresia, trisomy 8, VACTERL association, and splenogonadal fusion. Severe lower limb defects are found in association with an omphalocele and diaphragmatic defect (105). A seemingly related or similar phenotypic association is the omphalocele-exstrophy-imperforate anus-spinal defects complex with severe lower limb defects.

Caudal Dysgenesis

CD or caudal regression syndrome and sirenomelia are pathogenetically related disorders of the caudal developmental field or axial mesodermal patterning (Figure 28-2) (106,107,108). Debate continues about the relationship between CD and sirenomelia (so-called mermaid syndrome) (109,110). Axial mesodermal dysplasia (oculo[facio]auriculovertebral spectrum and CD), CD, and sirenomelia are seen more commonly in infants of diabetic mothers to support the hypothesis of a diabetic embryopathy (111,112,113,114). However, there is no consensus whether the hyperglycemia itself is the teratogen. Limb deficiencies are another proposed manifestation of diabetic embryopathy. Dysgenesis or agenesis of the sacrum, renal agenesis, fused ectopic kidneys, ectopic ureters, müllerian duct agenesis or hypoplasia, agenesis of the bladder, cloacal exstrophy, cryptorchidism, anorectal atresia, penile-scrotal transposition, limb deficiencies, and fusion of a single dysmorphic lower limb are the range of anomalies in the genitourinary tract and lower extremities in sirenomelia (115). The estimated frequency of CD-sirenomelia is 1:7500 births. CD has been reported in i(18q), 18p-, and trisomy 18 syndromes, VACTERL association, and heterotaxy. Retinoic acid and synthetic retinoids have been shown to cause CD experimentally. Currarino syndrome is considered a variant of caudal regression by some; hemisacrum; anorectal malformation, usually stenosis or atresia; and presacral developmental cyst are the basic phenotypic features (116). The cyst has been interpreted as a cystic teratoma, but in some cases, it is not always clear as to the exact nature of the cyst. Hirschsprung disease and spinal dysraphia are other findings. Mutations in the homeobox gene H9 (HLXB9, MNX1 on 7q 36) have been detected in Currarino syndrome with a pattern of autosomal dominant (AD) transmission, but not in CD (116).

FIGURE 28-2 • Caudal dysgenesis (caudal regression syndrome). A constellation of findings is present including absence of the lumbosacral spine, hypoplastic and flattened pelvis, and absence of the pubis. Bilateral radial agenesis, one of the more common terminal longitudinal defects, is also present and the ribs are hypoplastic and deficient. Bilateral equinovarus deformities are also noted.

Anomalies of the axial skeleton include various abnormalities in the ribs, vertebra, and sacrum. Some of these are important in their own right, whereas others are associated with more severe anomalies, such as CD including the Currarino syndrome, anorectal malformations, and
VATER/VACTERL association (117). It has been reported that approximately 60% of those with congenital vertebral anomalies also have major or minor abnormalities in other organ systems.

Polydactyly and Syndactyly

Polydactyly is defined by the presence of six or more digits on the hand(s) or foot (feet) or both and is the obvious antithesis to the previously discussed LRDs. A defect in anterior-posterior patterning is considered the pathogenetic basis of polydactyly (118,119). Anatomically, similar designations to LRDs are applied to polydactyly: preaxial (lateral ray), postaxial (medial ray), and the rare central polydactyly. Polydactyly or duplication of the thumb (preaxial) is the most common example with an incidence of almost 1:100 live births. The overall prevalence is estimated to be 0.3 to 3.6:1000 live births (119). The duplicate digit is either partially formed or a severely hypoplastic structure with minimal features to suggest a digit but rather a small polyp (120). Histologically, the various fibrous, vascular, neural, and adipose tissues are not well organized; the peripheral nerve fibers may have traumatic neuroma-like appearance. Isolated preaxial polydactyly is more common in those of European descent, and isolated postaxial polydactyly occurs more frequently in those of African rather than European descent with incidences of 1:140-1300 live births, respectively (119). Postaxial polydactyly in a Caucasian infant has several syndromic associations (Table 28-4). Polydactyly can usually be observed by fetal ultrasonography at 14 to 16 weeks of gestation; one such study reported that 26 fetuses (0.15%) had polydactyly from a total of 17,760 examinations (121).

Preaxial and postaxial polydactyly have differing genetic mechanisms by which these malformations develop. In the case of preaxial polydactyly, point mutations in sonic hedgehog are expressed along the so-called zone of polarizing activity. Postaxial polydactyly has at least three different mutated genes: 7p13, 19p 13.2, and 13q21-32; there are also frameshift mutations in GL13 (122). The latter gene is a mediator of hedgehog signaling (123). Two types of postaxial polydactyly have two genophenotypic expressions: type A with a well-formed digit and a normal fifth digit and type B with a hypoplastic structure resembling a small papilloma or acrochordon. When these lesions autoamputate, a traumatic neuroma is a known sequel but is less common in those hypoplastic digits, which are surgically excised. There are in excess of 300 entities in syndromic and nonsyndromic settings with polydactyly as one phenotypic feature (118).

Syndactyly is defined by soft tissue fusion of fingers and toes with or without fusion of the small bones. Like the other anomalies in this section, syndactyly occurs as an isolated finding or as a manifestation of one of approximately 300 syndromes including acrocephalosyndactyly with its several types (Apert, Waardenburg, Pfeiffer, Summitt, and Saethre-Chotzen syndromes), Poland, Fraser, and F-syndrome (124). Syndactyly is also a well-documented feature of the amniotic band syndrome without any specific pattern of digital or limb involvement. Polydactyly and syndactyly can also occur together with heterogeneous phenotypes.





Orofaciodigital II

Short rib—polydactyly II

Townes Brock


Diabetic embryopathya

Femoral-facial syndrome



Partial trisomy 4q

WAGR syndrome

14q(22) deletion

Ellis van Creveld

Orofaciodigital III

Short-rib polydactyly I








Orofaciodigital IVd

Deletion 22q11 (DiGeorge)c

Partial trisomy 1q

Distal trisomy 10q


Triphalangeal thumb polysyndactyly

Amniotic band, cleft lip plate

Trisomy 21


a Preaxial hallucal polydactyly.

b Pre- and postaxial polydactyly.

c Central polydactyly.

d Postaxial upper and preaxial lower extremities.


Arthrogryposis or congenital contracture is represented by two phenotypes: isolated or limited with single area involvement and multifocal with two or more joint contractures (125). Multiple congenital contractures are further classified into amyoplasia, distal arthrogryposis, and related syndromes (126,127). The latter category includes failure in forebrain development, chromosomal abnormalities, and motor neuron disorders like spinal muscular atrophy, congenital myopathies (myosinopathies), and heritable peripheral neuropathies (128). It has been estimated that more than 300 disorders are accompanied by multiple joint contractures and their arthrogryposis is not a specific diagnosis, but rather a phenotype (129). The contractures are often symmetrical in both upper and lower extremities in over 50% of cases (130) (Figure 28-3).

Fetal akinesia-hypokinesia deformation (FAD) sequence has an estimated prevalence of 1:12,000 to 19,000 live births, and it can be recognized after the first trimester (131,132). These infants have the so-called Pena-Shokeir phenotype
with limb contractures (arthrogryposis), intrauterine growth restriction, an attenuated umbilical cord because of diminished fetal activity, secondary pulmonary hypoplasia, and craniofacial anomalies (133,134). The FAD sequence is itself a clinical phenotype with several specific genetic mutations including the Escobar syndrome (multiple pterygium syndrome) with multiple mutations involving the gamma subunit gene (CHRNG) of acetylcholine receptor (135,136).

FIGURE 28-3 • Congenital arthrogryposis. A: Various deformities are present in these postmortem images. B: Severe contraction deformities are depicted in this postmortem image. Death occurred shortly after birth because of pulmonary hypoplasia.

Genetic Skeletal Disorders

GSD or skeletal dysplasias are the encompassing designation for the 40 groups of conditions that affect the normal development of bones and supporting tissues in terms of their shape and size and often with a reduction in normal stature (137). The number of recognized GSDs currently comprises some 456 conditions as of the 2010 revision of the Nosology and Classification of Genetic Skeletal Disorders (138). Among the 456 disorders, almost 70% are associated with mutations in 216 different genes. The 2010 revision was expanded to include 40 groups as defined by similar mutational and/or phenotypic characteristics (Table 28-5). These 40 groups are arranged in clusters: (a) groups 1 to 8 by common underlying gene or pathway defect; (b) groups 9 to 17 by specific bone structure or segment involvement by imaging studies; (c) groups 18 to 20 by macroscopic criteria and clinical features; (d) groups 21 to 25 and 28 by altered bone density, mineralization, stippling, or osteolysis; (e) group 27 by lysosomal disorders with skeletal manifestations; (f) group 29 by exostosis or enchondromas (ECs); (g) group 23 or OP group; (h) group 25 or OI group; (i) group 26 by hypophosphatemic rickets; (j) group 29 by disorganized skeletal development; (k) group 30 with overgrowth including skeleton; (l) group 31 by genetic inflammatory disorders involving bones and joints; and (m) groups 32 to 40 or dysostoses with abnormalities in individual bones or groups of bones (139).

The prevalence rate of the skeletal dysplasias is approximated at 2.4 to 34.5:10,000 stillbirths and live births, but among infants who died in the perinatal period, the frequency is higher at 9 to 10:1000 perinatal deaths (140,141,142,143,144). Several types of skeletal dysplasias are inconsistent with survival beyond the neonatal or early infancy period and are collectively referred to as lethal chondrodysplasias (145,146) (Table 28-6). The point prevalence at birth of the lethal chondrodysplasias was 15.4:100,000 births in one geographic region of Denmark (145,147). Whether the particular clinical observations had been obtained from prenatal diagnosis by ultrasonography or perinatal autopsies, thanatophoric dysplasia (TD) and OI type 2 are the most common lethal skeletal dysplasias, accounting for 50% to 65% of cases (148,149,150) (Table 28-7). Short-rib dysplasias (SRDs), achondrogenesis, and CD comprise the next most common lethal disorders (126,132). A somewhat different experience in the context of

International Skeletal Dysplasia Registry is based on referral cases with the following distribution: OI type 2 (20% of all cases), TD (11%), achondrogenesis type 2 (8%), CD (4%), and other specific disorders (36%) (157). Approximately 4.5% of cases were unclassified. In virtually all of the lethal GSDs, there is a severe narrowing or reduction in the volume of the thoracic cavity with restricted lung growth and resulting secondary pulmonary hypoplasia (158,159).



FGFR 3 chondrodysplasia group (e.g. thanatophoric dysplasia, types 1 and 2, TD type 2)


Type 2 collagen group (e.g., achondrogenesis type 2)


Type 11 collagen group (e.g., Stickler syndrome type 2)


Sulfation disorders group (e.g, achondrogenesis type1B)


Perlecan group (e.g., Schwartz-Jampel syndrome)


Aggrecan group (e.g., (spondylometaphyseal, Kimberly type))


Filamin group and related disorders (e.g., frontometaphyseal dysplasia)


TRPV4 group (e.g., metatropic dysplasia)


Short-ribs dysplasia (with or without polydactyly) group (e.g. chondroectodermal dysplasia)


Multiple epiphyseal dysplasia and pseudochondroplasia (e.g., pseudochondroplasia)


Metaphyseal dysplasia (e.g., metaphyseal dysplasia Schmid type)


Spondylometaphyseal dysplasia (e.g., spondyloenchondrodysplasia)


Spondyloepi (-meta) physeal dysplasias (e.g., immune-osseous dysplasia, Schimke)


Severe spondylodysplastic dysplasias (e.g., achondrogenesis type 1A)


Acromelic dysplasias (e.g., trichorhinophalangeal dysplasia types 1/3)


Acromesomelic dysplasias (e.g., acromesomelic dysplasia type Maroteaux)


Mesomelic and rhizo-mesomelic dysplasias (e.g., dyschondrosteosis, Leri-Weil)


Bent bone dysplasias (e.g., campomelic dysplasia)


Slender bone dysplasias (e.g., Kenny-Caffey dysplasia type 1)


Dysplasias with multiple joint dislocations (e.g., Desbuquois dysplasia)


Chondrodysplasia punctata group (e.g., Conradi-Hünermann type)


Neonatal osteosclerotic dysplasias (e.g., Caffey disease)


Increased bone density group (without modification of bone shape) (e.g., osteopetrosis, severe neonatal or infantile forms)


Increased bone density group with metaphyseal and/or diaphyseal involvement (e.g., craniometaphyseal dysplasia, autosomal dominant)


Osteogenesis imperfecta and decreased bone density group (e.g., OI type 1)


Defective mineralization group (e.g., hypophosphatasia, osteogenesis imperfecta, non-deforming, type 1, perinatal lethal and infantile forms)


Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group) (e.g., mucopolysaccharidosis type 1H/1S)


Osteolysis group (e.g., progeria, Hutchinson-Gilford type)


Disorganized development of skeletal components group (e.g., multiple cartilaginous exostoses, types 1-3)


Overgrowth syndromes with skeletal involvement (e.g., Proteus syndrome)


Genetic inflammatory/rheumatoid-like osteoarthropathics (e.g., chronic recurrent multifocal osteomyelitis)


Cleidocranial dysplasia and isolated cranial ossification defects group (e.g., cleidocranial dysplasia)


Craniosynostosis syndrome (e.g., Pfeiffer syndrome [FGFR1-related]]


Dysostoses with predominant craniofacial involvement (e.g., mandibulo-facial dysostosis of Treacher-Collins)


Dysostosis with predominant vertebral with and without costal involvement (e.g., Currarino triad)


Patellar dysostoses (e.g., nail-patella syndrome)


Brachydactylies (with or without extraskeletal manifestations) (e.g., Albright hereditary osteodystrophy)


Limb hypoplasia-reduction defects group (e.g., Fanconi anemia)


Polydactyly-syndactyly-triphalangism group (e.g., Pallister-Hall syndrome)


Defects in joint formation and synostoses (e.g., radio-ulnar synostosis with amegakaryocytic thrombocytopenia)

Source: Adapted from Warman ML, Cormier-Daire V, Hall C, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet Part A 2011;15:945-968.



Mutated Gene






Achondrogenesis type 2


Kniest-like dysplasia


Platyspondylic dysplasia


(Torrance type)

Achondrogenesis type 1B


(Fracco type)

Diastrophic dysplasia


Dyssegmental dysplasia, Silverman-Handmaker type

HSPG2 (1p36.1-p34)



Boomerang dysplasia


Short rib polydactyly

Type 1 (Saldino-Noonan)

DYNC2H1 (11q21-q22.1)

Type 2 (Majewski)


Type 4 (Mohr-Majewski)


DYNC2H1 (11q21-q22.1)

Metaphyseal dysplasia, Jansen type


Metatrophic dysplasia, types 1 and 2


Achondrogenesis type 1A

TRIP11 (14q31-q32)

Spondylometaphyseal dysplasia, Sedaghatian type



Schneckenbecken dysplasia




Rhizomelic CDP

Type 1

PEX7 (6q23.3)

Type 2

6NPAT (1q42)

Type 3

AGPS (2q31.2)

Astley-Kendall dysplasia

Blomstrand dysplasia

PTHR1 (3p22-p21.1)

Osteosclerotic bone dysplasia (Raine syndrome)

FAM20C (7p22.3)

OI, type 2

CRTAP (3p22.3)

LEPRE1 (1p34.1)

Spondylothoracic dysplasia (Jarcho-Levin syndrome)

DLL3(?), MESP2(?)

HP, perinatal lethal

ALP (1p36.12)

Desbuquois dysplasia

CANT1 19q25.3

Postmortem examination in GSDs. Although it may seem obvious, radiographs with anterior-posterior and lateral views should be obtained as a prerequisite to the postmortem examination on any dysmorphic infant, including one with a suspected skeletal dysplasia (160). No conventional autopsy can hope to demonstrate the entire range of abnormalities in the skeletal system without a total body image (161,162). In fact, the GSDs were largely classified on the basis of their radiographic features, but molecular genetic and biochemical studies have served as the basis for classification in the majority of cases (138).

Acquisition of tissues, mainly soft tissues rich in fibroblasts, is recommended for standard metaphase cytogenetics. Although a few hours may have lapsed since death, it is still possible to obtain cellular growth, provided that the body has been placed in a temperature-controlled environment. Samples of cartilage at the costochondral junction or joint space can be snap frozen in liquid nitrogen. The utility of standardized sections from various specific sites for optimal pathologic examination has been discussed by Yang and associates (163).

Before the internal examination is performed, a careful documentation of the various standard measurements in the perinatal autopsy and photographs from the anterior, posterior, and lateral profiles should be obtained (164). Various sites, with particular emphasis on the regions of the growth plate, have been recommended for the sampling of membranous bone, including the ribs, vertebral bodies, proximal and distal humerus and/or femur, and cranium (163,165). The costochondral junctions of the fourth through sixth ribs are regarded by some as the optimal sites for identifying disturbances in the growth plate (166,167). Decalcified and undecalcified sections have complementary value. It is helpful to have microscopic sections available from the osteochondral junction of an age-matched infant without any known skeletal abnormalities for purposes of reference and orientation. A particularly useful review of the morphologic aspects of the growth plate has been provided by Brighton (26). Many of the histologic abnormalities in a GSD are semiquantitative, in addition to individual cellular alterations. The cellularity of the various zones of cartilage (resting, proliferating, and hypertrophic) and their organization into columns in the hypertrophic zone and the actual chondroosseous junction or zone of provisional ossification are the specific foci of histologic interest in this group of disorders. In some but not all disorders, the morphologic abnormalities are consistent from one case to another within a specific diagnostic entity. The discussion of chondrodysplasias by Gilbert-Barness with its high-quality images, which correlate the radiographic, gross, and microscopic features, is recommended (168).

The following discussion of GSDs is based on the various “groups” as defined in the 2010 revised classification (138). Selected groups are considered based upon their frequency and models of morphologic and molecular pathology.


Schramm (148)

Bankova (143)

Stevenson (144)

Wood and Dimmick (160)

Lahmar-Bodfaroua (146)

Konstantinidou (148)

Total (%)

TD and other group 1







147 (31)

OI and other group 25







127 (27)

Achondrogenesis and other group 2







35 (7)

SRD and other group 9







51 (11)

CD and other group 18






20 (4)

CDP and other group 21





20 (4)

DD and other group 4





19 (4)

HP and other group 26




9 (2)

Metatrophic dysplasia and other group 8


1 (<1)

Severe spondy-lodysplastic dysplasias and other group 14



5 (1)






81 (17)









FGFR3 Chondrodysplasias (Group 1)

FGFR3 chondrodysplasia group is characterized by short limbs relative to a somewhat longer trunk. The individual entities in this group are achondroplasia (ACH), severe ACH with developmental delay and acanthosis nigricans (SADDAN), hypochondroplasia (HCP), hypochondrodysplasia-like dysplasia, and thanatophoric (TD) types 1 and 2 (169,170,171). Several mutations have been identified in the FGFR3 gene (4p16.3); the germ-line mutations in FGFR3 gene inhibit chondrocyte proliferation (172).

Achondroplasia, the most common type of chondrodysplasia, is a nonlethal disorder in the heterozygote (AD inheritance), with a birth prevalence of 1:10,000 to 30,000 live births (173). Most cases are sporadic, with greater than 80% of cases representing a new mutation. Approximately 50% of FGFR3 chondrodysplasias are examples of ACH (144). There is a gain of FGFR3 function, which at the growth plate has an arresting effect upon the chondrocytes with the development of rhizomelic shortening of the extremities. It has been reported that the mutation impairs endochondral bone growth by preventing SOX9 downregulation (174). Morphologically, the growth plate is regular with periosteal overgrowth.

Hypochondroplasia is also a nonlethal disorder with AD inheritance and a prevalence of 1.5:100,000 live births. The point mutations on the FGFR3 gene (p. ASN540 Lys) in 70% to 75% of cases differ from ACH (p.Glu 380 Arg); other mutations in the FGFR3 gene have been identified in HCP (175). The clinical and radiographic heterogeneity of HCP is substantial to serve as a challenge in the diagnosis. Compound carriers of the heterozygous mutations on the FGFR3 gene (G380R and N540K) appear to have a more morbid phenotype than those with either one or other point mutations (176). Like ACH, the growth plate is more or less normal appearing. The latter is not surprising in that there is considerable phenotypic overlap between ACH and HCP (176,177).

Thanatophoric dysplasia occurs in 1:20,000 to 60,000 births and is the most common type of lethal chondrodysplasia in most series based upon prenatal ultrasonography and/or autopsy (178,179,180,181,182,183). Like the other FGFR3 opathies, TD has AD inheritance. Two phenotypes of TD are recognized: type I with curved femora and missense point mutations, p.Arg 248 Lys and p.Tyr 373 Lys (90% of cases), and type II with straight femora and cloverleaf skull with the exclusive mutation, p. Lys 650 Glu (100% of cases) (176,178). Approximately 80% to 85% of TD cases are type I and the remainder are type II. In the ISDR with mutational analysis of the FGFR3 opathies, 65% of the cases were examples of TD types I and II, ACH (25%), and HCP (9%) (176).

Another phenotype of the FGFR3 opathies is severe achondrodysplasia with developmental delay and acanthosis nigricans (SADDAN) (184,185). In SADDAN, the point mutation is at codon 650 (p.Lys 650 Net) (184). Acanthosis nigricans and epidermal nevus are other expressions of FGFR3 mutations (186).

In population-based studies, both types of TD are almost as common as ACH (144). Type 1 TD is characterized by
angulated or curved humeri and femora and craniosynostosis in 28% and mild cloverleaf skull in 3%, whereas type 2 is relatively straight femora, cloverleaf skull in 50%, and craniosynostosis in 90% (Figure 28-4) (178,179). Angulated femora are also present in CD and OI type II (178). Most infants die in the neonatal period of respiratory failure on the basis of severe secondary pulmonary hypoplasia as a consequence of the reduced volume of the thoracic cavity, which impedes normal lung growth (180,182). The lung/body weight ratio is low in contrast to the brain/body weight ratio (180). The chondroosseous junction of the growth plate is substantially reduced in width with disorderly columnation of the chondrocytes as a reflection of the impaired FGFR3 signaling; there is fibrosis in place of regular chondroid ossification (Figure 28-5) (181,182,183). Other findings include the flattening of ossification centers (platyspondyly). Another aspect of the pathologic findings in TD is the range of neuropathologic abnormalities, which include overgrowth of the temporal lobe, hyperconvolution, and neuronal heterotopia (187,188).

FIGURE 28-4 • Thanatophoric dysplasia type I. A: Radiograph shows flattened, U-shaped vertebrae; short, squared iliac bones with small sacrosciatic notches; shortened long bones with metaphyseal flaring; “French telephone receiver”-like left femur (right femur removed for special studies); and short ribs. B: The large head with frontal bossing, rhizomelic extremities, and narrow thorax are the characteristic external findings.

Osteogenesis Imperfecta and Decreased Bone Density Group

Group 25 (ISDS classification) or OI is represented by two general categories: the so-called collagenous types or COL1A1-/2-related disorders with AD inheritance (OI types I, II, III, and IV) and the noncollagenous types with autosomal recessive inheritance (Table 28-8) (189,190). It is estimated that 90% of all cases of OI have a defect in one of the type I collagen genes and the remainder are mutations in genes responsible for the synthesis of proteins that interact with collagen (190,191). With the failure of normal collagen type I synthesis by osteoblasts, the bones are less dense with the consequence
of structural fragility, which varies considerably in severity within the various types of OI (192,193). A severity index in a sense has been formulated and is based upon the type of OI (194). The incidence of OI including all types is estimated at 1:10,000 to 20,000 live births; one case of OI type II is encountered for every two to five cases of TD in the perinatal-neonatal period (195,196).

FIGURE 28-5 • Thanatophoric dysplasia type I. The chondroosseous function is reduced in width but retains some degree of organization though the chondrocyte columnation is modestly irregular.




Phenotype (Sillence classification)

Specific characteristics

Type 1 Collagen Defects



Type I, II, III, and IV

Blue/gray/white sclerae, hypermobility, hearing loss, dentinogenesis imperfecta



Type I, II, III, and IV

Type 1 Collagen Processing and Maturation



Increased bone mineral density, blue sclerae

Collagen Chaperone



Type II, III, and IV



Type II and III



Type II, III and IV



Type II and III

Blue sclerae, dentinogenesis imperfecta (Dachshund model)



Type III and IV

Congenital contractures of the limbs possible (Bruck syndrome type 1 and Kuskokwim syndrome)



Type III

Pterigium, congenital contractures (Bruck syndrome type 2)

Bone Formation, Homeostasis and Regulation of Bone Density



Type (III, IV) VI

Normal at birth, progressive course, poor response to bisphosphonate treatment



Type III

Delayed dentition

LRPS (WNT1 coreceptor)


Type III and IV

Blind (osteoporosis-pseudoglioma syndrome)



Type III and IV

Progressive course, poor response to bisphosphonate treatment



Type III



Type V

Hypertrophic callus, metaphysical bands, interosseous membrane calcification



Type III

Fractures in utero, IUGR, fractures, bone deformities, cardiac insufficiency



Cole-Carpenter syndrome OI-like

Craniofacial malformations, scoliosis, large epiphyses, deformity of upper and lower extremities, “popcorn epiphyses”



Cole-Carpenter syndrome OI-like

Multiple pre- and postnatal fractures, craniofacial malformations

TAPT1 (transmembrane anterior-posterior transformation 1)





Osteoporosis with fractures

AD, autosomal dominant; AR, autosomal recessive; contributed through the kind efforts of Dr. Cecilia Giunta, April, 2015.

OI type II, known as the perinatal lethal type, is the manifestation of a new mutation in most cases and is characterized by severe osteopenia, blue sclera, short and bowed or angulated extremities, a diminutive thorax, and crumpled or collapsed long bones, especially the femora (Figure 28-6A, B) (195,197). The cranium is soft and intracranial hemorrhage is not uncommon. Shortened, deformed extremities are also features of
achondrogenesis types 1A and 2, TD, and hypophosphatasia (HP). A small thoracic cavity with its deformities results in severe pulmonary hypoplasia with smaller than normal weight of lungs for gestational age and structural abnormalities of the thoracic cage. The bones are shortened, with multiple fractures with minimal normal callus formation, and multinodular chondroid masses are present that resemble an endosteal cartilaginous neoplasm or EC (198). The cortex is quite attenuated, and the trabecular bone consists of delicate strands and is often disorganized, with an overall osteopenic appearance. The bone may appear hypercellular and the mosaic lines of osteoid seams are increased in number. The apparent hypercellularity is explained by a reduction in osteoid matrix secondary to defective type 1 collagen. The physis may be normal in many respects or may be disorganized (Figure 28-7A-D) (199,200). Chondrocyte columnation often appears normal, but osteoid forms directly on the cartilage without orderly endochondral ossification (201,202). These infants also exhibit neuropathologic changes, including perivenous microcalcifications and impaired neuroblastic-neuronal migration (203).

FIGURE 28-6 • Osteogenesis imperfecta, type II. A: This postmortem roentgenogram demonstrates poor ossification of the cranium and multiple fractures of the ribs, long bones, and pelvis and normal vertebra. B: Shortening of the femora secondary to fractures and marked curvature of the lower extremities are some of the more obvious external abnormalities. Note also the abnormal positioning of the upper extremities.

OI type III, unlike type II, is usually not lethal in the perinatal period, but its severe phenotype is characterized by fractures and deformities of the lower extremities; these complications are present at birth and continue throughout life with the development of severe kyphoscoliosis (194,204). In one series, 25% of infants and children with OI have type III (205). Lung infections with acute respiratory failure occur throughout the first decade of life because of the thoracic cage abnormalities (206,207). Marrow fibrosis and disorganized trabecular bone in OI type III can simulate fibrous dysplasia (FD). There are no specific histologic features to permit the differentiation of one type of OI from another (208). Immature woven bone is prominent, and lamellar bone is poorly formed.

OI type V, unlike OI types I to IV, is not defined by mutations in collagen type I, but rather by a mutation in IFITM5-like protein, which interferes with the collagen triple helix and bone mineralization (209,210,211). A moderate to severe phenotype and hyperplastic callus formation, especially in femoral fractures, can be mistaken for osteosarcoma (OS) (212). Pseudoarthrosis, aortic and mitral valvular insufficiency, and aortic dissection are other manifestations (213,214). Multiple fractures in the absence of a prior diagnosis of OI can be mistaken for child abuse (215). Rare examples of bone neoplasms and cysts have been reported in OI, including OS, chondrosarcoma (CS), ossifying fibroma (OF), and aneurysmal bone cyst (ABC) (216,217,218).

OI and its definition have been challenging with the recognition of the autosomal recessive forms of the disease accounting for 10% of cases (191,193,219,220). There are presently eight genes that have been identified. Clinically, the recessive forms of OI present with bone fragility. One of these, Bruck syndrome, is associated with joint contractures (221). The various recessive genes encode proteins, which are required for collagen transcriptional modification (220,222).

Defective Mineralization Group

Defective mineralization group (group 26) includes HP, an inborn error of metabolism associated with a deficiency of tissue nonspecific alkaline phosphatase with ALPL missense mutations in most cases (1p36.12) (223,224). The inheritance of the perinatal lethal and infantile forms of this disorder is AR with a prevalence of 1:100,000 births (223). Approximately 2% to 4% of lethal GSDs are examples of perinatal HP. There are six clinical forms of HP, and these reflect the heterogeneity of the missense mutations on the ALPL gene (225). There are some overlapping radiographic features among HP, OI types II and III, and achondrogenesis type 1A; however, these conditions can be differentiated from each other by radiographic analysis of the entire skeleton (139). The histopathologic findings at the physis
include a hypercellular, disordered osteochondral junction with cartilaginous overgrowth and minimal bone formation. Uncalcified osteoid with cores of cartilage is demonstrated in undecalcified sections. Some pathologic features of HP resemble those of rickets-osteomalacia.

FIGURE 28-7 • Osteogenesis imperfecta, type I. A: A long bone at low magnification shows the overall architecture and the physeal growth plate. B: Though there are few abnormalities in the physeal plate itself in terms of growth, a fracture is present at the lateral aspect of the growth plate. C: A higher magnification shows fragmentation and necrosis of the growth plate. D: Osteoclasts and macrophages are present in a focus of necrotic bone with very early callus formation.

Type 2 Collagen Group

Type 2 collagen group (group 2) comprises a phenotypically diverse category including lethal achondrogenesis type 2 (Langer-Saldino form), hypochondrogenesis, nonlethal spondyloepiphyseal metaphyseal dysplasia (Strudwick type), platyspondylic dysplasia (Torrance type), and Kniest dysplasia. In aggregate, this group of GSDs accounted for approximately 7% of cases in the Utah study (144). Achondrogenesis type 2 (ACG 2) accounts for 5% to 7% of lethal GSDs whose inheritance is AD, and most cases are new mutations (226). Hypochondrogenesis is a closely related entity, also with AD inheritance, with amino acid substitutions for glycine at different sites in type II procollagen. In addition to absent or minimal vertebral body ossification, cystic hygroma and/or hydrops fetalis are other features (227). Severe pulmonary hypoplasia is the cause of death in the perinatal period in those cases that are carried to term. Complex congenital cardiovascular anomalies have been reported in hypochondrogenesis (228). A papillomatous epidermal proliferation of the scalp with central ulceration has been reported in an infant with ACG 2 whose features are those of an epidermal nevus with possible aplasia cutis congenita (229). Chondrocytes reside in enlarged lacunae, and the apparent hypercellularity is a consequence of diminished matrix in both ACG2 and hypochondrogenesis. Apparent “ballooning” of chondrocytes is described. Vascularity is increased in the reserve (resting) and proliferating zones of chondrocytes, and the columns of chondrocytes in the hypertrophic zone are irregular. Persistent central cores of cartilage are found within the bony trabeculae, as in HP and OP.

FIGURE 28-8 • Short-rib dysplasia with polydactyly. A: This stillborn fetus with SRD (Majewski, type 2) weighed 325 g. Various external anomalies are seen in this anterior view with a cleft lip, narrow thoracic cage, and severe shortening of the long bones of the upper and lower extremities. B: The posterior view demonstrates these same findings in addition to the bulging flanks. C: The upper extremity shows postaxial polydactyly and syndactyly. D: Exposure of the thoracic and abdominal organs reveals the extremely small thorax, which contributes to the severe secondary pulmonary hypoplasia, which is largely responsible for the lethal nature of this disorder.

Short-Rib Dysplasia

SRD with or without polydactyly (group 9) includes chondroectodermal dysplasia (Ellis-van Creveld syndrome, EVC), which is generally compatible with life through the perinatal-neonatal period (230,231,232). Several other entities in this group are Saldino-Noonan, Verma-Naumoff types 1 to 3, Majewski (type 2), Beemer (type 4) syndromes, and asphyxiating thoracic dysplasia (Jeune) (233,234,235) are the other entities in this morphologic group (Figure 28-8A to D) (233,234). Postaxial hexadactyly is a common feature of EVC. There is general recognition that group 9 dysplasias (ciliary chondrodysplasias) have mutations affecting the function of primary cilia in dynein motor, intraflagellar transport complexes, and basal body (236,237,238,239). Some minor histologic differences are noted in the physes in the various types of SRD, but in general, chondrocytic proliferation is diminished, as evidenced by a reduction in the thickness of the growth plate and disorganization of the columns of chondrocytes (Figure 28-9) (240,241,242,243). Overlapping pathologic features are seen in EVC, ATD, and
renal-hepatic-pancreatic dysplasia (RHPD) of Ivemark; these conditions and others with similar RHPD-like changes are examples of primary ciliopathies (244,245,246). Both EVC and Weyers acrodental dysostosis share mutations on the EVC2 gene (4p16); ectodermal dysplasia with enamel hypoplasia, hypodontia, and early eruption and exfoliation of teeth are seen on both disorders (247,248). Atrial septal or atrioventricular septal defects are present in 65% to 70% of EVC cases. Sensenbrenner syndrome (cranioectodermal dysplasia) with RHPD-like features is another related disorder (249).

FIGURE 28-9 • Short-rib dysplasia with polydactyly (Majewski, type 2). The growth plate shows irregular columnation of chondrocytes and disordered maturation of bone with retention of central cartilage.

Severe Spondylodysplasias

Severe spondylodysplasias (SSDs) (group 14) are a category of platyspondylic lethal GSDs with overlapping phenotypic features with the FGFR3 group (group 1), including TD. Achondrogenesis type 1A (ACG1A) and Schneckenbecken dysplasias are two representative GSDs in this category (250). Maternal polyhydramnios, fetal hydrops, and prematurity are accompanying complications. Absent or severely deficient ossification of the skull, vertebral bodies, and sacrum; shortened, beaded ribs; and small crescent-shaped ilia are some of skeletal anomalies in addition to shortened, bowed long bones. Microscopically, the growth plate in ACG1A is hypercellular, and the enlarged chondrocytes have a periodic acid-Schiff-positive, diastase-resistant inclusion within a cytoplasmic vacuole (251). Mutations in TRIP11 (14q31-q32) in ACG1A result in apparent loss of function of the golgins GMAP-210 and reduced expression of COL10A1 (252,253). Schneckenbecken (snail pelvis) dysplasia, a PLSD with AR inheritance and mutation in SLC35DI, is also characterized by a snaillike pelvis and short limbs; there is some resemblance to TD (Figure 28-10) (254,255,256). Because of hypercellularity of the resting and proliferating zones of chondrocytes, the lacunar spaces are inapparent and the intercellular matrix is relatively inconspicuous. Reduced columnation of chondrocytes and hypervascularization are seen in the proliferating zones, and the chondrocytes have uniformly centralized nuclei. The classification points out that PLSDs are found in group 1 (TD), group 2 (ACG 2 and Torrance dysplasia), group 3 (fibrochondrogenesis), group 4 (ACG1B), and TRPV4 group (metatropic dysplasia) (138).

FIGURE 28-10 • Schneckenbecken dysplasia. This GSD is seen in these stillborn, monozygotic twins. There is a range of skeletal abnormalities including short ribs, hypoplastic iliac bones with a snaillike configuration, hypoplastic flattened vertebral bodies, and shortened long bones.

Spondyloepi(meta)physeal Dysplasias

Group 13 dysplasias account for 5% or fewer of skeletal dysplasias (144). This category of GSDs has undergone substantial revision, especially in regard to metatropic dysplasia, which has been assigned to the TRPV4 group (group 8). Schimke immunoosseous dysplasia is an AR disorder with biallelic missense mutations in the SMARCA1 gene (2q34-q35) (257,258,259). There is one case per 1 to 3 million live births (260). A range in clinical severity with death is seen within the first 5 years of life or clinical onset in later childhood with the development of the nephrotic syndrome whose pathologic findings are the collapsing variants of focal segmental glomerulosclerosis (261). There is in utero growth restriction. T-cell immunodeficiency is complicated by autoimmune thyroiditis, infections, and neoplasms like lymphoma, poorly differentiated carcinoma, and OS (262,263,264). Accelerated atherosclerosis with complications of cerebral ischemia is thought to be a consequence of reduced elastogenesis (265). The histologic findings in the physis are a hypocellular, attenuated growth plate. There is little evidence of chondrocyte enlargement and poorly defined chondrocyte columnation.

TRPV4-Associated Disorders

Group 8 includes those skeletal dysplasias with AD mutations in the TRPV4 gene (12q24.1) (266). This clinical category includes GSDs and neuromuscular disorders. Brachydactyly is a consistent feature of TRPV4—GSDs and short stature with progressive spinal deformity in the severe forms. There are individuals with a hybrid phenotype of peripheral neuropathy and skeletal dysplasia, including fetal akinesia (267). The TRPV4 gene encodes a protein that is thought to form a cation-conductive pore or calcium channel (268). Metatropic dysplasia (MD) has a spectrum of clinical severity from the perinatal and early childhood lethal forms to the mild to severe nonlethal forms (269,270). The phenotype of MD is as heterogenous as its clinical manifestations (271). Short extremities, bowing of long bones, craniosacral anomalies, decreased bone density, and flattened vertebral bodies (platyspondyly) are the manifestations of irregular enchondral ossification. Short ribs and a diminutive thorax correlate with pulmonary hypoplasia in the lethal form. A caudal appendage has been reported in lethal MD (272) (Figure 28-11A, B). A disorganized primary spongiosa with irregular trabeculae, diminished ossification of epiphyseal cartilage in tubular bones, and poor chondroosseous columnation and hypercellular cartilage are some of the microscopic findings.

Sulfation Disorders

Sulfation disorders (SDs) (group 4) were present in 2% of infants with GSDs in the Utah population study (144). These AR disorders include four with mutations in the DTDST gene (5q 32-33): achondrogenesis type 1B (ACG1B) (Figure 28-12A, B), atelosteogenesis type 2 (AO2), diastrophic

dysplasia (DD), and multiple epiphyseal dysplasia, recessiva (273). There is considerable phenotypic overlap between AO2 and DD (274). The pathologic features of DD and AO are similar: an attenuated growth plate, irregular clumping of chondrocytes in the resting zone, and foci of myxoid degeneration, not necessarily confined to the resting zone. One of the hallmark features is a dense rim of collagenous matrix around each lacuna (275,276). Giant chondrocytes may be found as well. ACG1B, in addition to severe micromelia with marked shortening of the femora and humeri, is characterized by minimal or absent ossification of the vertebral bodies and malformed tibiae and fibulae (Figure 28-13) (277).

FIGURE 28-11 • Metatropic dysplasia type I (lethal variant). (A) Anterior-posterior and (B) lateral radiographic views demonstrate shortened long bones with trumpetlike flaring of the metaphyses, accessory vertebrae with flattened vertebral bodies, a caudal appendage, and a small conical thorax with hyperossified ribs.

FIGURE 28-12 • Achondrogenesis type 1B. A: Severe micromelia and hydrops fetalis are noted in this anterior view. B: A profile view shows not only the severe micromelia but the presence of a cystic hygroma. (Contributed by Bahig M. Shehata, MD, Atlanta, GA.)

Filamin Group and Related Disorders

Group 7 is defined by the presence of mutations in the FLNA gene (Xq28) that encodes filamin A and includes the following X-linked dominant dysplasias: frontometaphyseal dysplasia, Melnick-Needles osteodysplasia, and otopalatodigital syndromes types 1 and 2 (278). Mutations in FLNB gene (3p14.3) are both AD and AR and include the following: AO1, AO3, Larsen syndrome, spondylocarpotarsal syndrome, Piepkorn, and boomerang dysplasias (the latter two have been included with AO1) (138,279,280,281). The filamins are actin binding that stabilize the structure of actin and link them to the cell membrane (282). The filamin A-associated disorders are diverse from the skeletal dysplasia to periventricular nodular heterotopia to severe congenital lung disease with cysts and pulmonary vascular hypertensive changes (283,284,285). Otopalatodigital syndrome type 2 is a potentially lethal disorder with thoracic and pulmonary hypoplasia. Other defects include hypomineralized calvarium, poorly formed small bones of the hands and feet, septal and right ventricular outflow tract defects, omphalocele, and genitourinary tract anomalies. Boomerang dysplasia and AO1 are lethal disorders due to the small thorax and hypoplastic lungs (286,287). Multinucleated and giant chondrocytes may be seen in a focally hypocellular reserve or resting zone. Similar giant chondrocytes have been seen in Piepkorn dysplasia, which may be allelic to boomerang dysplasia (288). Near-complete
absence of ossification and mineralization are seen in boomerang dysplasia. Marked disorganization in the columns of chondrocytes is the histologic features in boomerang dysplasia.

FIGURE 28-13 • Achondrogenesis type 1B. A: This field shows the epiphyseal cartilage and growth plate with obvious absence of any resemblance to a normal growth plate. B: The growth plate in another micromelic long bone shows a complete absence of any physeal organization. C: The zone of proliferating chondrocytes demonstrates an eosinophilic stroma in the background, which is collagen surrounding each cell. D: The multifocal cystic degeneration present in panel A is seen in this higher magnification field with hemorrhage and degenerating chondrocytes in the background. (Contributed by Bahig M. Shehata, MD, Atlanta, Georgia.)

FIGURE 28-14 • Chondrodysplasia X-linked dominant (Conradi-Hünermann-Happle syndrome). A: The external examination reveals severe shortening of the upper and lower extremities with rhizomesoacromelic features. Note also the bilateral talipes equinovarus deformities. B: Multifocal stippled epiphyseal calcifications are the characteristic findings in CDP. This image of the foot shows the numerous calcifications in the epiphyses. (Panel A from Rakheja D, Read CP, Hull D et al. A severely affected female infant with X-linked dominant chondrodysplasia punctata: a case report and a brief review of the literature. Pediatr Dev Pathol 2007;10:142-148.)

Chondrodysplasia Group

Chondrodysplasia (CDP) group (group 21) comprised 4% of GSDs in the Utah study (144). There are also acquired causes of CDP-like changes in children unrelated to the GSDs with similar punctate-stippled calcifications in the epiphyses and around the spine; examples are prenatal exposure to warfarin and neonatal lupus erythematosus (289). In terms of pathogenesis, CDP can be classified into inborn errors of cholesterol biosynthesis, peroxisomal biogenesis disorders, disruption of vitamin K metabolism, and chromosomal abnormalities (290,291). Rhizomelic CDP type I and Zellweger syndrome, both AR peroxisomal disorders, are lethal in most cases (292). Conradi-Hünermann-Happle (CHH) syndrome, with X-linked dominant inheritance (Xp11.23-p11.22), may be lethal in the affected neonate (Figure 28-14A, B) (293,294). One of the characteristic and accessible pathologic findings in CHH syndrome is lamellar orthokeratosis and dystrophic calcifications in keratotic plugs in a skin biopsy as the features of the linear ichthyosiform lesions (295). Rhizomelic CDP is represented by three AR disorders: peroxisomal CDP1 (PEX7 on 6q22-q24), CDP2 (DHAPAT on 1q42), and CDP3 (AGPS on 2q31) (296). The incidence is 1:100,000 live births. Severe shortening of proximal long bones (rhizomelia), cataracts, dysmorphic facies, and severe growth abnormalities are the various clinical features. Approximately 50% or more of children do not survive beyond the age of 6 years. The cause of death is usually respiratory in nature after multiple respiratory tract infections. Dystrophic calcifications in the region of an otherwise unremarkable growth plate and cystic myxoid degeneration in the subarticular cartilage are the principal histologic features in rhizomelic CDP (297). In other conditions, association with stippled calcifications, dystrophic calcifications, and degenerative changes in the chondroid matrix are the microscopic findings (Figure 28-15). OI-like features are present in the lethal Astley-Kendall syndrome as one of the overlap syndromes, which in this case is classified with the group 21 disorders (298).

Bent Bone Dysplasia

Bent bone dysplasias (BBDs) (group 18) are characterized by short limb dysplasia and bowing of the long bones of the lower extremity (299,300). However, the presence of “bent bones”
may be seen at birth in several other GSDs (138). The Utah study had six (4%) cases of BBD and five were examples of CD (144). CD has a reported incidence of 1:200,000 births and accounts for approximately 4% to 6% of all lethal skeletal dysplasias (301,302). Mutations in the SOX9 gene (17q24-q25) are the molecular genetic defect in this AD disorder (303). The role of SOX9 is multifold in development and in the context of this discussion—chondrogenesis with the activation of multiple cartilage-specific genes (304). Anterior bowing of the long bones of the lower extremities, hypoplastic thorax with secondary pulmonary hypoplasia, and craniofacial anomalies are the phenotypic abnormalities in addition to the characteristic sexual anomalies with so-called sex reversal; it is estimated that gonadal dysgenesis with male to female sex reversal is present in 75% of CD cases (305). Abnormalities of both müllerian and wolffian duct structures and incomplete ovarian or testicular development are other findings; gonadoblastoma may be seen in the dysgenetic testis (306,307). The physes of the long bones exhibit minimal histologic abnormalities; however, some alterations in the proliferative and hypertrophic zones of chondrocytes may be seen. In place of normal cortical bone, immature woven bone, osteoclastic activity, and vascularized intraosseous spaces are the microscopic features. Stuve-Wiedemann syndrome (SWS), another group 18 GSD, is a severe AR disorder with mutations in the LIFR gene (5p13.1) (308,309). Cortical thickening is present in bowed long bones with flared metaphyses and progressive decalcification. Dysautonomic hyperthermia, respiratory complications on the basis of aspiration pneumonitis, pulmonary artery hypertension, and cutaneous infections all contribute to death by 2 years of age (310,311). These children like those with CD have obstructive airway problems (312). BBD is also seen in FGFR2 mutation (313,314).

FIGURE 28-15 • Chondrodysplasia punctuate, X-linked dominant (Conradi-Hünermann-Happle syndrome). Dystrophic calcifications and cystic degeneration of the epiphysis are present. (Contributed by Charles Timmons, MD, Dallas, Texas.)

Neonatal Osteosclerotic Dysplasias

Neonatal osteosclerotic dysplasias (NOD) and increased bone density (IBD) group are designated as group 22 and group 23, respectively. Group 22 GSDs comprise five disorders including Caffey disease (infantile cortical hyperostosis), which is primarily an inflammatory and reactive condition arising in the diaphyseal region of long bones, but also in the mandible and clavicle in infants. There is fever and soft tissue swelling overlying the affected bone (315). The mandible is most commonly involved in 70% to 90% of cases (316). A mutation in the COL1A1 gene is present in the prenatal or infantile forms of Caffey disease but is uncommon in the later presenting form (317,318,319). Blomstrand dysplasia is an AR lethal neonatal disorder, which is characterized by generalized osteosclerosis and advanced skeletal maturation (320). Group 22 also includes desmosclerosis and Raine dysplasia. Inactivating recessive mutations in the PTH-related peptide type I receptor gene PTH PTH1 (3p22-21.1) are present in Blomstrand dysplasia (321,322). This same gene is mutated in Jansen chondrodysplasia. In addition to very short stature, the limbs are micromelic with accelerated ossification of virtually the entire skeleton. Like the other lethal skeletal dysplasias, the thorax is short and narrow. Early ossification of the epiphyseal center, a reduction in the epiphyseal cartilage, irregularity of the transformation zone, subperiosteal ossification, and cortical hyperostosis are some of the histologic findings.

Increased Bone Density: Osteopetrosis

IBD or OSP (group 23) is characterized by osseous hyperdensity without alteration in the shape of the bones. The basic defect occurs in the osteoclast in either development or function (323,324,325). Based upon the particular mutation, OSP is divided into the “osteoclast rich” whose mutations affect function and “osteoclast poor.” The severe, neonatal forms with AR inheritance are seen in 1:250,000 births and are associated with several mutations (326,327,328). Loss-of-function mutations have been identified in five genes: TCIRG1 (11q13), CLCN7 (16p13), OSTM1(6q21), RANKL (TNFSF11, 13q14), and RANK (TNFRSF11A, 18q22.1) (325,329,330). Among these mutations in the AR OSP, the TCIRG1 mutation is detected in 50% to 60% and CLCN7 mutations account for 20% of cases and CLCN7 mutation in 20% to 25% of cases (324,325). Leukopenia and hepatosplenomegaly are the consequences of bony overgrowth of the marrow space with bone marrow failure, phthisic anemia, and organomegaly on the basis of extramedullary hematopoiesis. Early death may result from pathologic fractures, hydrocephalus, or anemia; the pathologic fractures are typically transverse breaks in the long bones. Without bone marrow or stem cell transplantation, survival beyond infancy is rare. Another expression of AR OSP is renal tubular acidosis (RTA) with cerebral calcifications; there are mutations in the carbonic anhydrase II gene (8q21.2). OSP-RTA is usually detected in the first 2 years of life with growth failure, mental retardation, visual and auditory deficiencies, pathologic fractures, and metabolic acidosis (325). Cerebral calcifications are detectable after 18 months of age. Cortical bone thickening is present in all forms of OSP, but in the most severe cases, the marrow cavity is obliterated and the corticomedullary demarcation is lost (Figure 28-16A to D). Osteosclerosis may be uniform or alternating, as seen in the vertebrae, where transverse striations of alternating lucent and dense bone formation with the so-called ruggerjersey spine. Lucency of the central portions of bones may convey the appearance of “bone within bone.” Coxa vara and lateral bowing of the long bones are common findings, and rachitic features may be observed in infants. The microscopic hallmark is the persistence of calcified cartilage, surrounded by dense woven or lamellar bone of endochondral origin (Figure 28-17A, B) (331). The zone of proliferating cartilage is often extremely wide at sites of active endochondral ossification in infants, which reflects the failure in remodeling of mineralized cartilage and bone. Woven bone persists in the absence of lamellar bone formation. The number of osteoclasts in a bone biopsy may depend on the sampling or the osteoclast-rich or osteoclast-poor status of the particular type. Howship lacunae are often difficult to identify. Osteoblasts are generally present in normal numbers, but they often appear flattened and inactive. The marrow space is more or less obliterated by woven rather than lamellar bone, which is thought to account for the extreme fragility of the bone
despite its increased density. Ultrastructurally, the osteoclasts adjacent to the bone surface may lack the ruffled membrane that is necessary for bony resorption, which is impaired in all forms of OSP. AD OSP has mutations in CLCN7 and does not present until late childhood or adolescence with fractures, scoliosis, osteoarthropathy, and osteomyelitis of the mandible (325). The previous type of AD OSP with an LRP5 mutation is no longer regarded as a classic form of OSP (332).

FIGURE 28-16 • Osteopetrosis, autosomal recessive lethal type. A: The images of the chest, abdomen, and pelvis demonstrate the generalized IBD. B: Sclerosis of the long bones of the lower extremities shows metaphyseal fragmentation, mild metaphyseal expansion, periosteal new bone formation, and an absence of the medullary canal. C: Sclerosis of the bones in the hand shows the most marked changes at the proximal ends of the phalanges and distal ends of the metacarpals. D: Lateral view of the skull demonstrates diffuse sclerosis, especially marked at the base. (Contributed by William H. McAlister, M.D., St. Louis, MO.)

FIGURE 28-17 • Osteopetrosis, autosomal recessive type. A: The bone biopsy shows thickened trabeculae with retained central cores of cartilage. Note also the absence of bone marrow and hematopoiesis. B: A follow-up biopsy 2.5 years after a bone marrow transplant shows a reduction in the thickness of the trabeculae and the presence of hematopoiesis. A follow-up image at that time showed decreased bone density and an identifiable marrow. (From Tolar J, Teitelbaum SL, Orchard PJ. Mechanisms of Disease: Osteopetrosis. N Engl J Med 2004;351:2839-2849.)

Lysosomal Storage Disease

Lysosomal storage diseases (LSDs) with skeletal involvement or dysostosis multiplex group (group 27) comprise a family of heritable metabolic diseases with a defect in a specific acid hydrolase or enzyme activator whose functional and morphologic consequences are an accumulation or storage of the catabolic product at the blocked biochemical step. There are approximately 50 LSDs recognized, and the storage products include mucopolysaccharides, glycoproteins, amino acids, and lipids (333,334). Currently, 22 disorders with similar radiographic abnormalities are included in the ISDS classification (138). The incidence of LSDs is approximately 1:1500 to 8000 live births (335,336). Hypoplastic iliac bones with pseudoenlargement of the acetabula, pointed proximal metacarpals, defective development of the anterosuperior portions of the vertebral bodies at the thoracolumbar junctions, and widened ribs that taper near the vertebral margins are among the more consistent skeletal abnormalities among the LSDs with some differences among the specific types (Figure 28-18A to C) (337,338). The changes in the tubular bones, which are more pronounced in the upper extremities, include diaphyseal and metaphyseal expansion, delayed epiphyseal ossification, and osteopenia. Other changes include macrocrania, coxa valga, small carpal bones with V-shaped deformities of the distal radius and ulna, cardiomegaly, and hepatosplenomegaly. A consistent histologic finding in various parenchymal and mesenchymal cells, from hepatocytes to chondrocytes, is cellular enlargement, which
reflects the presence of numerous membrane-bound vacuoles representing distended lysosomes that are clear or contain finely granular material (339,340,341) (see Chapter 5).

FIGURE 28-18 • Dysostosis multiplex congenita group. A: A 7-year-old boy with Hunter syndrome demonstrates proximal pointing of the metacarpals, widening of the proximal phalanges, tapering of the distal phalanges, and poor carpal bone development. B: A 9-month-old boy with Hurler syndrome shows the gibbous deformity of the spine and anterior beaking of the L2 vertebra. C: This 2-year-old boy with mucolipidosis has underdevelopment of the supra-acetabular portions of the iliac bones, coxa valga, and widening and tapering of the lower ribs near the spine. (Contributed by William H. McAlister, M.D., St. Louis, MO.)

Mucopolysaccharidoses (MPSs) are the most familiar and common LSDs. There are seven distinct eponymic types of MPS with a total of 11 enzymatic defects (342,343). The overall incidence of the MPSs ranges from 1:100,000 to 600,000 live births with AR inheritance in all but MPS/H with X-linked recessive inheritance. A specific chromosomal defect has been identified in all of the MPSs. The natural history of the MPSs depends upon the severity of the CNS involvement and the development of cardiorespiratory complications (344,345,346,347). Shortened stature and progressive skeletal deformities are indicative of growth plate and bony abnormalities with subluxation of joints and progressive kyphoscoliosis, as in MPS type 7 (Sly syndrome). The growth plate is reduced in thickness and is disorganized in appearance. The prominence of enlarged, vacuolated chondrocytes varies somewhat among the types of MPS (Figure 28-19). Abrupt calcification of the cartilage without the formation of primary trabeculae is another feature of the growth plate in several of these disorders, including MPS type 1H (Hurler syndrome), MPS type IH/1S (Hurler-Scheie syndrome), and MPS type 4A (Morquio syndrome) (348). In addition to abnormalities in the axial and appendicular skeleton, histologic changes in the temporal bone have been correlated with deafness in MPS type 1H, type 1 IS (Scheie syndrome), MPS type 1H/1S, and MPS type 2 (Hunter syndrome).

Gaucher disease (GD), the most common LSD, occurs in 1:100,000 individuals in the general population, but 1:800 to 1000 Ashkenazi Jews (349). Type 1 GD accounts for 99% of cases, which becomes symptomatic in adolescence and early
adulthood. Bone changes in the distal femur and/or proximal tibia are present in 70% to 100% with type 1 GD (so-called adult) or type 3 (juvenile) GD (350,351,352). In addition to the Erlenmeyer flask-like deformities, osteopenia with pathologic fracture, bone infarcts, and osteomyelitis are the other skeletal complications. Macrophages with glucocerebrosides have a granular eosinophilic and fibrillary appearance.

FIGURE 28-19 • Mucopolysaccharidosis, type 7 (Sly syndrome). The chondrocytes are distended with finely vacuolated cytoplasm.

Several other LSDs distinct from MPS also have dysostosis multiplex features, including mucolipidosis 2 (I-cell disease) and mucolipidosis 3 (pseudo-Hurler polydystrophy). Yet another category of metabolic disorders includes those in which glycoprotein degradation and structure are defective: fucosidosis, α-mannosidosis, β-mannosidosis, sialidosis, aspartylglycosaminuria, sialic acid storage disease, multiple sulfatase deficiency, and galactosialidosis (353,354,355). Carpal tunnel syndrome is a complication in both the MPSs and mucolipidoses secondary to the accumulation of material in swollen fibroblasts and the presence of foamy histiocytes (356).

Melorheostosis With and Without Osteopoikilosis, Pyknodysostosis, and Osteopathia Striata

Melorheostosis with and without osteopoikilosis, pyknodysostosis, and osteopathia striata is an example of a group 23 disorder (138). The estimated prevalence of melorheostosis is 1:1,000,000 individuals (357,358). The overwhelming majority of cases are sporadic in occurrence, but isolated examples have been reported in association with osteopoikilosis with mutations in the LEM domain containing 3 gene (12q14) (156). Mutations in this same gene are found in Buschke-Ollendorff syndrome. The diagnosis is rarely made in infancy, but 40% to 50% of cases are discovered before the age of 20 years (359). Any bone or bones may be affected; however, involvement is frequently unilateral, with one or more hyperostotic long bones, usually in the lower extremity, with so-called flowing hyperostosis (360). The fibrosing component in the contiguous soft tissues has fibromatosis-like or atypical decubitus fibroplasialike histologic features, which result in contractures, a cause of substantial morbidity in this disorder (361). Fibrofatty and myositis ossificans-like lesions have also been observed. Unlike the marrow space in OP, the marrow space remains intact, but the cortex is thickened and dense, with a paucity of haversian canals. Mosaic lines may be prominent. Osteoclastic activity is inapparent, whereas osteoblasts are present, but not in appreciable numbers. Endochondral ossification extends well into the zone of articular cartilage. Osteopoikilosis is an AD disorder in which bone islands form at the ends of a bone and in the vicinity of the metaphysic. Histologically, the foci are identified as rounded expansions of hyperdense bone with some mosaic lines. Multiple dermal fibrous papules in association with osteopoikilosis are the features of Buschke-Ollendorff syndrome.

Metaphyseal Dysplasias

Metaphyseal dysplasias (MPD) (group 11) comprise a genetically heterogenous group of disorders, which are characterized by a failure in enchondral bone growth and remodeling of the end of the long bones with the development of Erlenmeyer flask-like deformity of the metaphysis with an increased diameter (362,363). The distal femur and proximal tibia are the most frequently affected sites. Similar deformities are seen in GD and other GSDs, which are not classified among the group 11 diseases. Shwachman-Diamond syndrome, one of the inherited bone marrow failure syndromes, in addition to FA, Diamond-Blackfan anemia, dyskeratosis congenita, and Kostmann severe congenital neutropenia, is an AR disorder with an incidence of 1:75,000 births; 90% of cases have mutations in the SBDS gene (7q11) (364,365). Metaphyseal dysplasia of the femoral head is present in 50% of cases, but abnormalities in ribs (shortened with flared ends) can result in a hypoplastic thorax with lethal consequences in the neonatal period (366). There is an apparent failure in the formation of the zone of hypertrophic cartilage; however, a case has been reported with features of spondylometaphyseal dysplasia in a neonate with a SBDS gene mutation in which the hypertrophic zone was hypercellular with minimal matrix extending into the metaphysis (367). Cartilage-hair hypoplasia (CHH, McKusick type) is one of four skeletal dysplasias with mutations in the RMRP gene (9p21-p13) (368,369). The incidence is 1:23,000 live births (370). In addition to short stature, these children have ectodermal dysplasia and T-cell immunodeficiency (371). Granulomatous inflammation of the skin may occur in infancy (372,373). Another type of MPD is the Schmid type with a mutation in COL10A1 gene (155,374).

Genetic Inflammatory Rheumatoid-Like Osteoarthropathies

Genetic inflammatory rheumatoid-like osteoarthropathies (GIRLOs) (group 31) include several autoinflammatory disorders with both AR inheritance and AD inheritance (138). The pathogenesis of these hereditary autoinflammatory disorders is an apparent disruption in the linkage of IL-1 function and the regulation of the innate immune response (375,376). Mutations in two IL-1-regulating genes, NLRP3 and IL1RN, are responsible for cryopyrin-associated periodic syndromes (CAPS) and deficiency of IL-1 receptor antagonist (DIRA). CAPS is a spectrum disorder whose earliest and severest manifestations are present in the neonatalonset multisystem inflammatory disease (377,378). There is overgrowth in the region of the growth plate with exostosislike features, defects in limb lengths, and contractures. A skin biopsy shows a neutrophilic infiltrate of an urticarial or neutrophilic dermatosis (pyoderma gangrenosum). In addition to growth retardation, there is diffuse osteopenia. Muckle-Wells syndrome is a less severe form of NOMID/CINCA spectrum (379). Chronic recurrent multifocal osteomyelitis (CRMO) and nonbacterial acute osteitis are associated with mutations in IL1RN or LPIN2 (Majeed syndrome) (380,381). Other mutations in CRMO include GALNTS and RAGS. The median age at diagnosis is 10 years ,and the presentation is the development of osteolytic bone lesions with the pathologic features of acute to subacute to chronic osteomyelitis; however, the lesions are sterile for microorganisms. Progressive pseudorheumatoid dysplasia develops in children between 3 and 6 years and has a mutation in the WISP3
gene (382). There are minimal signs of inflammation unlike the other disorders in this group. Growth abnormalities are present, and multiple large and small joints are involved with a particular early predilection for the hip joints where there is enlargement of the femoral heads.

Disorganized Development of Skeletal Component Group

Disorganized development of skeletal component group (group 29) constitutes several tumefactive lesions of bone, some of which are familiar to pathologists including polyostotic FD, multiple osteochondromas (OCs), or multiple hereditary exostoses, cherubism or multiple giant-cell reparative granulomas (GCRGs), and enchondromatosis with or without hemangiomas (138). These various tumor and tumorlike lesions are discussed in the subsequent section on neoplasms.


The major acquired disorders in children include infectious-inflammatory conditions involving bone or joint space, nutritional-metabolic conditions, and tumefactions of bone. Each of these three categories is related in the clinical differential diagnosis of a mass or swelling with or without pain and fever.

Metabolic and Nutritional Conditions

Vitamin deficiency disorders with notable clinical effects upon the skeletal system include vitamin C or ascorbic acid deficiency, which causes scurvy, and vitamin D deficiency, which causes rickets-osteomalacia. At one time in the past, both vitamin deficiencies were found with some frequency in infants.

Scurvy is characterized by a failure in the formation of the primary spongiosa of bone, where the earliest recognizable bone formation at the growth plate takes place. The inability to form extracellular collagenous matrix is secondary to the loss of hydroxylation of lysine and proline, which depends on vitamin C as a cofactor (383). Rather than bone formation, fibroblastic proliferation with extravasation of red cells occurs, reminiscent of nodular fasciitis. Subperiosteal hemorrhage and microfractures through the metaphyses are other findings. The medullary trabecular bone is markedly osteopenic; these radiographic changes are found predominantly in infancy and early childhood (384,385). The radiographic findings in the long tubular bones include diffuse demineralization; some sclerosis and irregularity in the provisional zone of calcification, in part secondary to microfractures; metaphyseal spurs; transverse metaphyseal bands of diminished bone density (“scurvy line”) with peripheral fractures (“corner sign”); epiphyses with marked central rarefaction and relatively sclerotic margins (Wimberger sign); and periosteal new bone. Swelling of the knees is a presenting sign, and metaphyseal microfractures and dislocation may be falsely interpreted as evidence of child abuse. However, the presence of severe demineralization together with lateral metaphyseal spurs, and a dense irregular provisional zone of calcification makes differentiation relatively easy in most cases. Cupping of the epiphysis-metaphysis is a rare residual manifestation of infantile scurvy.

Rickets-osteomalacia is the consequence of deficient growth plate mineralization secondary to inadequate intake of calcium or a state of calciferol deficiency. There are numerous inherited and acquired disorders with rachitic and osteomalacic features (386,387,388). In congenital rickets secondary to maternal vitamin D deficiency, elements of hyperparathyroidism are noted in the fetus in response to maternal hypocalcemia. A substantial proportion of the childhood cases of rickets-osteomalacia in the developed countries of the world are secondary to hereditary defects in vitamin D activation or phosphate reabsorption by the renal tubules. However, rickets has been seen in recent years in the United States and Canada in infants breast-fed for a prolonged period without vitamin D supplementation (389,390). In some parts of the underdeveloped world, calcium malnutrition and/or vitamin D deficiency in children is a cause of rickets (391,392). Malabsorption syndromes, chronic hepatic disease, and infantile OP in children are complicated by rickets-osteomalacia. Linear sebaceous nevus syndrome, hemangiomatosis of bone, phosphaturic mesenchymal tumor (FGF23 mediated), nonossifying fibroma (NOF), osteoblastoma (OB), and OS are some of the causes of oncogenic hypophosphatemic rickets-osteomalacia (393,394). The radiographic appearance frequently differs according to the underlying disease. Infantile rickets is characterized by disruption of enchondral ossification and persistence and overgrowth of nonmineralized cartilage into the metaphysis (395). In undecalcified sections, the osteoid seams surrounding the bony trabeculae are widened and uncalcified. Myelofibrosis as a result of secondary hyperparathyroidism has been reported in an infant with vitamin D-deficient rickets (396). There has been discussion about the metaphyseal lesions of child abuse and their possible relationship to rickets since cartilaginous overgrowth is seen in both (397,398,399).

Hyperparathyroidism in the pediatric age population is usually secondary to chronic renal failure (400,401,402). Primary hyperparathyroidism is seen throughout the first two decades, even in the neonatal period, and is commonly associated with skeletal abnormalities and four gland hyperplasia (403,404). A classic but quite uncommon manifestation of hyperparathyroidism is the brown tumor, which has microscopic features very similar to GCRG. Both osteoclastic and osteoblastic activities, often with medullary fibrosis, in a bone biopsy should suggest the diagnosis of hyperparathyroidism (see Chapter 21).

Pseudohypoparathyroidism (PHP) is an inherited disorder, which is functionally characterized by peripheral resistance to PTH due to a mutation in the imprinted gene, GNAS (20q13.3) (405,406,407). There are two subtypes of PHP: type 1a with maternal inheritance and the Albright hereditary osteodystrophy (AOH) phenotype (short stature, brachydactyly, and extraskeletal osteomas in the dermis, subcutis,
and skeletal muscles) and type 1b with paternal inheritance and AOH phenotype in the absence of the endocrinopathies (405). Progressive osseous heteroplasia (POH) is another of the GNAS-inactivating mutation disorders with heterotopic ossification in the skin with extension into the underlying soft tissues whose onset may be seen in infancy or in later childhood (407,408,409). There is an absence of the AOH phenotype; there is an overlap between PHP1b and POH in this respect. The formation of heterotopic bone resembles intramembrane bone with its direct development from mesenchymal-derived osteoblasts. A progressive osteodystrophy resembling that seen in PHP has been reported in mucolipidoses types I and II (410,411).

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