Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.

Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean.

SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in SALL4 may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features).

X-linked spondyloepimetaphyseal dysplasia (SEMDX) is characterized by anomalies of the spine and the epiphyses and metaphyses of the long bones, resulting in short stature and osteoarthritic changes of the joints. Patients with SEMDX show rhizomelic shortening of the limbs and short limb-to-trunk ratio, significant bowing of the legs, waddling gait with lumbar lordosis, and brachydactyly (Cho et al., 2016).

Patients with Richieri-Costa-Pereira syndrome display a pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of the mandible, cleft palate/Robin sequence, absence of lower central incisors, minor ear anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability is also a common finding (summary by Favaro et al., 2011).

Lethal faciocardiomelic dysplasia is an extremely rare polymalformative syndrome. It was described only once, in 1975, in 3 affected males in a sibship of 13, from second-cousin parents. Patients were all of low birth weight, had microretrognathia, microstomia, and microglossia, hypoplasia of the radius and ulna with radial deviation of the hands, simian creases and hypoplasia of fingers I and V, hypoplasia of the fibula and tibia with talipes and wide space between toes I and II, and severe malformation of the left heart which may have been responsible for death of all 3 in the first week or so of life.

Female-restricted Wieacker-Wolff syndrome (WRWFFR) is an X-linked dominant syndromic form of neurogenic arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. Affected individuals have decreased fetal movements causing the development of contractures in utero and resulting in AMC and diffuse contractures involving the large and small joints apparent at birth. There is global developmental delay with difficulty walking or inability to walk, hypotonia that often evolves to spasticity, and variably impaired intellectual development with poor or absent speech and language. Dysmorphic facial features, including hypotonic facies, ptosis, microretrognathia, and small mouth, are seen in most patients. Seizures are uncommon; some patients have evidence of a peripheral motor neuropathy with distal muscle weakness. The level of X inactivation in lymphocytes and fibroblasts is often skewed, but may not predict the severity of the phenotype. Most cases occur sporadically; rare X-linked dominant inheritance has been reported in families (summary by Frints et al., 2019).