Chondrodysplasia punctata denotes a group of skeletal dysplasias characterized by locally disordered bone mineralization that results in bone stippling observed on radiographs obtained during the newborn period (Pryde et al., 1993). The areas of punctate calcification were first described by Conradi in 1914. In 1931, Hünermann designated the disorder “chon-drodystrophia calcificans congenita.” This term was defined as the X-ray finding of small calcified densities in the epiphyses (Hyndman et al., 1976). The disorder recognized by Hünermann also included micromelia, a saddle nose deformity, flexion contractures, cataracts, and a dermopathy. As used today, the term chondrodysplasia punctata comprises a group of genetically heterogeneous disorders (Spranger et al., 1971). Some of these are associated with rhizomelia (proximal limb shortness) and some are not. The rhizomelic form is generally more severe. It has been subdivided into three types, each of which is associated with a mutation in a different gene (see Figure 99-1). All three types are inherited as autosomal recessive conditions. The nonrhizomelic form of chondrodysplasia punctata, also known as Conradi–Hünermann syndrome, is milder and can be inherited as an autosomal dominant, X-linked recessive, or X-linked dominant condition. A rarer form of mild chondrodysplasia punctata, known as the tibia-metacarpal type, is inherited as an autosomal dominant condition.

Rhizomelic chondrodysplasia punctata is a disorder of the peroxisomes. Peroxisomes are intracellular organelles that catalyze a number of metabolic functions (Wanders and Waterham, 2004). These include β-oxidative chain shortening of fatty acids and their derivatives, synthesis of ether phospholipids, and detoxification of glyoxalate (Hoefler et al., 1988; Schutgens et al., 1989; Wanders et al., 1993). Human peroxisomal disorders are subdivided into two categories: those in which the organelle is not normally formed (per-oxisome biogenesis disorders) and those that involve a single peroxisomal enzyme (Moser, 1999).

In patients with rhizomelic chondrodysplasia punc-tata, the peroxisomes are present, but they have lost many of their normal functions. Four distinct abnormalities have been found in patients with rhizomelic chondrodysplasia. These involve deficiency of enzymes important in phospholipid synthesis and phytanic acid oxidation (Hoefler et al., 1988; Schutgens et al., 1989; Wanders et al., 1993). A severe deficiency in plasmalogen synthesis is associated with deficient activities of the peroxisomal enzymes acyl coenzyme A (acyl CoA, dihydroxyacetone phosphate [DHAP] acyltransferase) and alkyl-dihydroxyacteone phosphate synthase. In addition, there is deficient activity of phytanic acid oxidase, and the enzyme peroxisomal 3-oxo-acyl-CoA thiolase is present in an abnormal unprocessed form (Gendall et al., 1994; Suzuki et al., 1994). Because of these enzyme abnormalities, the characteristic biochemical abnormality in rhizomelic chondrodysplasia punctata is increased phytanic acid levels and decreased plasmalogens (Singh et al., 1988). In rhizomelic chondrodysplasia punctata, unlike in other peroxisomal conditions, the amount of very long-chain fatty acids is normal. In the absence of a known familial DNA mutation, one way to identify rhizomelic chondrodysplasia punctata prenatally is to analyze the plasmalogen levels in chorionic villi and ery-throcytes (Wanders et al., 1993).

To date, 32 peroxisomal (peroxins, or PEX) genes have been identified (Wanders and Waterham, 2004). Most of them are also found in yeast, indicating their essential importance for cellular metabolism. Thus far, 16 PEX genes have been identified in humans (Subramani, 1997; Wanders and Waterham, 2004). Of these, twelve have been implicated in human disorders. Patients with rhizomelic chondrodysplasia punc-tata are deficient in a subset of peroxisomal enzymes.

The incidence of rhizomelic chondrodysplasia punctata is approximately 1 in 100,000 livebirths (Connor et al., 1985; Stoll et al., 1989). Parental consanguinity has been noted in 8% to 10% of recessively inherited cases (Stoll et al., 1989). The incidence of dominantly inherited Conradi–Hünermann syndrome is presumably higher, as clinically the condition appears to be at least twice as common (Stoll et al., 1989). Precise incidence figures are unavailable because many mildly affected patients go unrecognized. The incidence of Zellweger syndrome, another peroxisomal disorder that can be associated with punctate calcifications around the extremities, is 1 in 50,000, with an estimated gene frequency of 1 in 110 individuals in the United States (Zellweger et al., 1988).

The major sonographic criterion for a diagnosis of rhizomelic chondrodysplasia punctata includes profound humeral shortening that is less marked than the femoral shortening, without shortening of other bones. In addition, expanded epiphyses are present, which contain multiple hyperechoic foci (the so-called puncta) (Figure 99-2). In normal fetuses, the distal femoral epiphyseal ossification center is never identified before 28 weeks and is more commonly appreciated after 34 weeks (Pradhan et al., 2002). In addition, nasal hypoplasia or midface depression with frontal bossing may be observed in the fetal profile. Approximately 10% of cases have associated congenital heart disease, predominantly pulmonic stenosis, and pulmonary artery and aortic calcifications (Fourie, 1995). In nonrhizomelic chondrodysplasia punctata (Conradi–Hünermann syndrome), the major finding is the long bone epiphyseal calcifications. Similar facial abnormalities to those seen in the rhizomelic form may also be present.

The first prenatal diagnosis of Conradi–Hünermann syndrome was made incidentally, when radiography was performed to assess fetal maturity in a woman who was post-term (Hyndman et al., 1976). The radiograph demonstrated stippling of the epiphyses at the fetal ankles, knees, pubic and ischial bones, and femur. At birth, the infant was noted to have a saddle nose deformity as well as coronal cleft vertebrae in the lumbar spine.

Cases of sonographic prenatal diagnosis of Conradi–Hünermann syndrome have also been described in the literature. In one report, Tuck et al. (1990) described a 21-year-old primigravida with a known diagnosis of Conradi-Hunermann syndrome. She had ichthyosis; sparse, dry hair; and asymmetrical limb shortening. She had surgery performed on her right hip at 6 years ofage and subsequently had operations to lengthen her right femur at the age of 9 years. As an adult, she had short stature (144 cm) and a pronounced limp. When she became pregnant, sonographic survey of fetal anatomy was performed at 17 weeks of gestation and revealed a 3 mm asymmetry between the lengths of the right and left fetal femora and humeri. This asymmetry persisted on prenatal sonograms performed at 21, 24, 32, and 35 weeks of gestation. At birth, radiographs of her infant demonstrated epiphyseal stippling that was missed on prenatal sonogram. Physical examination also revealed a low nasal bridge, malar hypoplasia, and ichthyotic skin (Tuck et al., 1990).

As shown in the case above, the diagnosis of Conradi–Hünermann syndrome is more straightforward when it is known that one of the parents is affected. In one report, Pryde et al. (1993) described a pregnant woman, who herself had been diagnosed with Conradi–Hünermann syndrome at birth, who presented with scoliosis, punctate calcifications of the spine and femoral epiphyses, asymmetric limb shortening, postaxial polydactyly, cataracts, and irregular macular skin hyperpigmentation. In her first pregnancy, her fetus was noted to have asymmetrical short limbs, scoliosis, and mild ventriculomegaly. In her second pregnancy, at 16 weeks of gestation a 5 mm difference was noted between the right and left femoral lengths. At 32 weeks, severe polyhydramnios developed. At birth, the diagnosis was confirmed by the presence of a saddle nose, ichthyotic skin, and epiphyseal stipplings seen on radiographs. In this report, an affected fetus with a negative family history was also described. Prenatal sonograms were characterized by severe disorganization of the fetal spine observed at 18 weeks of gestation, represented by malsegmentation of the vertebrae along the entire length of the spine. No definitive scoliosis or short long bones was observed. At 21 weeks, the fetal profile demonstrated a flat nasal bridge. In addition, hyperechoic regions were observed at the femoral epiphyses that suggested premature calcification. In the same fetus, polyhydramnios was observed at 30 weeks (Pryde et al., 1993).

The diagnosis of rhizomelic chondrodysplasia punctata is easier to make than Conradi–Hünermann syndrome because of the severe shortening of the extremities in combination with premature ossification and stippling of the ephiphyses (Hertzberg et al., 1999). Since the condition is inherited in an autosomal recessive manner, there will be a negative family history for most cases. The prenatal sonographic findings reveal bilateral symmetric proximal shortening of the humeri and femora (less than the 3rd percentile for gestational age), along with marked epiphyseal echogenicity that suggests the presence of the punctate epiphyseal calcifications (Sastrowijoto et al., 1994). Additional fetal findings may include brachycephaly, hydrocephalus, scalp edema, hypertelorism, hypoplastic nose, and coronal clefts of the vertebral bodies. Bilateral cataracts have been detected by sonogram in a fetus with rhizomelic chondrodysplasia, type 1, at 30 weeks of gestation (Başbuğ et al., 2005). Congenital heart disease has also been reported in the rhizomelic form of chondrodysplasia punctata (Sastrowijoto et al., 1994).

Duff et al. (1990) described the sonographic diagnosis of rhizomelic chondrodysplasia punctata at 28 weeks of gestation in a woman with a previous affected infant. These investigators demonstrated stippling at the proximal end of the right humerus and both femurs over an 8-week period. The tibia consistently measured at the 20th percentile for gestational age, but both the femur and humerus were consistently at less than the 5th percentile. Over the period observed, a progressively more mottled appearance of the proximal end of the right humerus was demonstrated. The bone became more and more attenuated, irregular, and stippled in appearance, making it difficult to precisely define the end of it (Duff et al., 1990). In another report, a set of dichorionic twins was described, in which one was noted to have rhizomelic limb shortening at 25 weeks of gestation. In this fetus, the humeri were shaped like dumbbells and multiple hyperechoic foci were noted in the humeral epiphyses and the proximal femoral epiphyses. A 15-week sonogram was reanalyzed retrospectively; it revealed that the profound humeral shortening had previously been missed. Even at 15 weeks of gestation, flared humeral metaphyses and widened hyperechoic proximal ends of the humeri were visible (Gendall et al., 1994). After postmortem examination, the diagnosis of rhizomelic chondrodysplasia punctata was confirmed in this twin by demonstration of absent alkyl-dihydroxyacetone phosphate synthase activity in cultured skin fibroblasts.

Although two-dimensional ultrasound is adequate for diagnosis, at least one report exists that demonstrated enhanced resolution of pathologic findings in rhizomelic chondrodysplasia punctata using three-dimensional sonography and three-dimensional helical computer tomography (Ruano et al., 2004).

The differential diagnosis of conditions that result in limb shortening with punctate epiphyses is given in Table 99-1. The conditions include skeletal dysplasias, other genetic or metabolic disorders, disordersofvitamin Kmetabolism, and teratogens. To distinguish among the conditions grouped under the term chondrodysplasia punctata, fetal limb length must be measured. The humeri are the shortest in the rhizomelic form ofchondrodysplasia punctata. The presence of polydactyly may suggest the more mildly X-linked dominant form of Conradi–Hünermann syndrome (Poznanski, 1994). The major consideration in the differential diagnosis is to distinguish between the rhizomelic form of chondrodysplasia punctata and the milder, Conradi–Hünermann type.