The short-rib polydactyly syndromes comprise a group of rare, generally lethal skeletal dysplasias. Much debate exists within the clinical genetics community as to the appropriate subclassifications, if any, for these conditions. Sonographic characteristics common to all the subtypes of the short-rib polydactyly syndromes include short horizontal ribs and long tubular bone changes that result in severe micromelia. Most of the conditions have associated polydactyly of the feet and hands. A variety of organ anomalies can also accompany this condition (de Sierra et al., 1992).

The short-rib polydactyly syndromes (SRPS) have been divided into four types. Type I SRPS (Saldino–Noonan syndrome) was first described in 1972 (Saldino and Noonan, 1972). It is characterized by extremely short bones with pointed and narrowed metaphyses. The ribs are also extremely short, causing compression of the developing lungs. This eventually results in severe pulmonary hypoplasia. Saldino–Noonan syndrome is also associated with more severe systemic abnormalities than exist in some of the other subtypes. These abnormalities include congenital heart disease, anorectal anomalies, and cysts in the kidneys. Polydactyly is present in more than 95% of cases of type I SRPS (Keating et al., 1989).

Type II SRPS (Majewski syndrome) was first described in 1971 (Majewski et al., 1971). These patients have very short ribs, severe pulmonary hypoplasia, micromelia, and polydactyly. A distinguishing feature of the syndrome is the presence of a median or midline cleft lip with or without cleft palate. These patients also have a very high frequency of central nervous system abnormalities (Lurie, 1994). The most common central nervous system abnormalities seen in Majewski syndrome include pachygyria, small cerebellar vermis, and absent olfactory bulbs (Martínez-Frías et al., 1993). Other central nervous system changes that have been demonstrated in type II SRPS include arachnoid cysts, agenesis of the corpus callosum, and arrhinencephaly (Prudlo et al., 1993). In addition to the midline cleft lip and cleft palate, patients with Majewski syndrome can have a cleft tongue, oral frenulae, natal teeth, and abnormalities of the epiglottis (Knapp et al., 1990).

Type III SRPS (Verma–Naumoff syndrome) was first described in 1977 (Verma et al., 1975; Naumoff et al., 1977). Patients with this subtype clinically resemble patients with type I because of the absence of cleft lip. These patients have the typical long narrow thorax with pronounced rib shortening, shortened long bones, and polydactyly. Their long bones can be distinguished from those in type I by the presence of the metaphyseal spurs (Figures 95-1 and 95-2). In addition to the presence of the spurs, there is a diagnostic shortening of the base of the skull. Patients with type III SRPS have small and poorly ossified vertebral bodies (Naumoff et al., 1977). The chondro-osseous histopathology is qualitatively similar in SRPS types I and III. The essential abnormality is a shortened or absent zone of proliferative chondrocytes with a loss of columnization (Sillence et al., 1987). In SRPS type II, shortening of the proliferative columns and irregularity in the columnization is not as marked as it is in types I and III.

Type IV SRPS (Beemer–Langer syndrome) was described in 1983 (Beemer et al., 1983). It clinically resembles type II SRPS, but the distinguishing feature is the general lack of polydactyly (Chen et al., 1994). Patients with type IV SRPS have the midline cleft lip, but the shape of the tibia differs significantly from that seen in the Majewski syndrome. Pathologic studies from patients with type IV SRPS reveal a disorganized physeal growth zone with a prominent zone of hypertrophy that is composed of closely arranged large chrondrocytic lacunae (Chen et al., 1994).

Although each has distinguishing clinical symptoms, much overlap exists between the subtypes of SRPS (Figure 95-3) (Sarafoglou et al., 1999). There aremultiple case reports in the literature describing patients with features of each subtype that defy definitive classification (Bernstein et al., 1985; Yang et al., 1991; Tsai et al., 1992; Wu et al., 1995). Debate in the literature persists as to whether or not this group of disorders represents one entity with a continuous spectrum of clinical manifestations (Sarafoglou et al., 1999). Controversy also exists about whether the different subtypes of SRPS are the result of point mutations occurring at different loci, different alleles at a single locus, or variability in the expression of the same mutant gene (Martínez-Frías et al., 1993). In one paper, Bernstein et al. (1985) argued that the SRPS subtypes represent a single entity with varying expressivity. It is hoped that when the mutant gene or genes responsible for this condition are identified, the controversy regarding classification will be settled by molecular analysis.

The SRPSs are extremely rare skeletal dysplasias. In the database of the Latin-American collaborative study of congenital malformations, representing 349,470 livebirths and stillbirths, no cases of short rib polydactyly were described (Orioli et al., 1986). In another report, evaluating the accuracy of prenatal diagnosis of skeletal dysplasias, there were eight cases of SRPS described in a study population of 226 stillbirths or fetuses with a prenatal diagnosis of skeletal dysplasia (Sharony et al., 1993). SRPS, therefore, is extremely rare in the general population but may represent 4% of fetuses evaluated in a perinatal center for a presumed skeletal dysplasia.

Prenatal diagnosis by two-dimensional sonographyhas been reported for all of the subtypes of SRPS. Three-dimensional sonographic studies have been described in types II and III (Viora et al., 2002; Chen et al., 2005). Prenatal sonographic studies appear to be highly accurate in the setting of a family history that is positive because of a previously affected child. Prenatal diagnosis has also successfully been performed even in the setting of a negative family history (Meizner and Bar-Ziv, 1985; Benacerraf, 1993).

Prenatal diagnosis of type I SRPS has been described both in the first and early third trimesters (Hill and Leary, 1998; Meizner and Bar-Ziv, 1989). In the case ascertained at 13 weeks, a narrow chest, micromelia, polydactyly, and anasarca were seen on transvaginal sonography (Hill and Leary, 1998). In the case ascertained in the third trimester, a singleton fetus was reported with a markedly narrow thorax, severely shortened long bones with pointed metaphyses, polydactyly on both hands, a markedly bulging forehead, a large ventricular septal defect, a small penis, severe polyhydramnios, mild hydrops, and hypoplastic vertebral bodies (Meizner and Bar-Ziv, 1989). The prenatal diagnosis of type II SRPS is characterized bypolyhydramnios, shortened long bones, and very short ribs extending less than halfway around the fetal thorax (Thomson et al., 1982; Gembruch et al., 1985; Benacerraf, 1993). This may give the heart a disproportionately large appearance within the thorax. In one report, the median cleft lip was visualized antenatally. In type II SRPS, the tibias have a diagnostic ovoid shape.

Prenatal diagnosis of type III SRPS consists of the typical findings of severe micromelia, narrowed thorax, short ribs, postaxial polydactyly, and severe polyhydramnios with mild edema (see Figure 95-1). The most useful diagnostic feature for discriminating type III from type I is that the ends of the long bones appear widened, with the presence of marginal spurs (see Figures 95-1 and 95-2). In addition, cases of type III SRPS demonstrate hypoplastic vertebralbodies with increased intervertebral spaces (Meizner and Bar-Ziv, 1985; Meizner and Barnhard, 1995). A fetus with type III SRPS has also been described with complete situs inversus and hypospadias (de Sierra et al., 1992). High airway obstruction due to epiglottal hypoplasia has been reported in type III SRPS (Golombeck et al., 2001; Chen et al., 2005).