Pfeiffer syndrome is an autosomal dominant craniosynostosis syndrome with characteristic anomalies of the hands and feet. Three clinical subtypes, which have important diagnostic and prognostic implications, have been identified. Type 1, the classic syndrome, is compatible with life and consists of craniosynostosis, midface deficiency, broad thumbs, broad great toes, brachydactyly, and variable syndactyly. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet, together with ankylosis of the elbows. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe, and the anterior cranial base is markedly short. Various visceral malformations have been found in association with type 3. Early demise is characteristic of types 2 and 3 (Cohen, 1993). Cohen and Barone (1994) further tabulated the findings in the 3 types of Pfeiffer syndrome.

Cloverleaf skull, or Kleeblattschaedel, consists of a trilobular skull with craniosynostosis. The condition shows pathogenetic variability and etiologic heterogeneity. The cause of isolated cloverleaf skull is unknown (Cohen, 2009). Cohen (1975) pointed out that Kleeblattschaedel is a component of many syndromes, e.g., it is found in some cases of Crouzon syndrome (123500), Pfeiffer syndrome (101600), and Carpenter syndrome (201000). Cohen (2009) listed 12 monogenic disorders with cloverleaf skull as a feature, including type II thanatophoric dysplasia (187601), which accounts for 40% of all cloverleaf skull syndromes. Cohen (2009) published photographs of cloverleaf skull in various syndromes.

Decreased fetal activity associated with multiple joint contractures, facial anomalies and pulmonary hypoplasia. Ultrasound examination may reveal polyhydramnios, ankylosis, scalp edema, and decreased chest movements (reflecting pulmonary hypoplasia).

The Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome (AARRS) is a rare autosomal recessive disorder characterized by severe malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. The disorder is believed to represent a defect of dorsoventral patterning and outgrowth of limbs (summary by Kantaputra et al., 2010). Overlapping limb reduction syndromes, less severe in nature, that are also caused by homozygous mutation in the WNT7A gene include Fuhrmann syndrome (228930), characterized by fibular aplasia or hypoplasia, femoral bowing, and poly-, syn-, and oligodactyly, and Santos syndrome (228930), characterized by fibular agenesis/hypoplasia, oligodactylous clubfeet, and anonychia/nail hypoplasia. Al-Qattan et al. (2013) stated that AARRS and Fuhrmann syndrome can be differentiated by the following features, which are seen only in AARRS: complete aplasia of 1 or both lower limbs, and absent elbow with radiohumeral synostosis. In addition, the number of digits per hand is 1 to 3 in AARRS, whereas there are 4 to 5 digits in Fuhrmann syndrome. 'Phocomelia' refers to an intercalary limb defect with the hand or foot being directly attached to the humerus or femur (absent zeugopod) or directly attached to the trunk (absent stylopod and zeugopod). AlQattan et al. (2013) stated that the limb defect observed in Schinzel phocomelia syndrome represents 'true' phocomelia, whereas the limb defect in AARRS is an 'apparent' phocomelia, in which there is absent ulna with radiohumeral synostosis. The authors described 3 radiologic features that define 'apparent' phocomelia: a single arm/forearm bone that appears too long to be the humerus alone; a thicker cortex at the area of the radiohumeral synostosis, with or without slight angulation at the site of synostosis; and the apparently single bone resembling the humerus proximally and the radius distally. The authors also noted that phocomelia is not a feature of the allelic disorder Fuhrmann syndrome (228930). Other distinguishing features of Schinzel phocomelia syndrome include normal nails and dorsal hand skin; distoproximal gradient of lower limb defects, without a resultant stick-like appearance; and a characteristic large cranial defect. AlQattan et al. (2013) concluded that Schinzel phocomelia syndrome and AARRS are distinct phenotypes.