Phocomelia

Etiology

While phocomelia is the most notable side effect of thalidomide, there have been several cases in the last 30 years of phocomelia associated with thalidomide use. However, today the cause of most cases is undetermined. Despite strict regulation worldwide, there have been several cases in the last 30 years of thalidomide attributed phocomelia. Underdeveloped countries and those endemic with leprosy where thalidomide occasionally remains in use, still report cases of defects caused by thalidomide exposures in pregnancy. Strict regulations in more developed countries have resulted in a dramatically decreased incidence of phocomelia within the general population.[3][4]

Aside from the teratogenicity of thalidomide, researchers have hypothesized that phocomelia is associated with anomalous origins of the subclavian artery, resulting in a disrupted vascular supply to intermediate limb segments.[5][6]

Epidemiology

The incidence and presentation of phocomelia were examined in 22,740,933 live births by Bermejo-Sanchez et al. in an effort to assess the prevalence of true phocomelia. Reports indicate that true phocomelia occurs in 0.62 live births per every 100,000 patients. Approximately half (53.2%) of the cases displayed isolated phocomelia, while 36.9% had additional major congenital abnormalities, and 9.9% of cases correlated with a clinical syndrome. 

The data shows that 55.9% of cases only involve one limb, while 40.2% of cases only involved two limbs. Only four cases of 141 had involvement of all four limbs. When comparing single upper extremities deficiencies, the left side was more commonly affected (64.9%) than the right.

When two limbs were involved, the upper limbs were involved 58.5% of the time compared to the lower limbs. The incidence of these findings was lower than what prior studies had reported, which is likely due to the care taken by this study, only to consider true phocomelia and not amelia or other limb truncation.[1][7]

Pathophysiology

In extremity development, the apical ectodermal ridge forms at the most distal end of the limb bud. This apical ectodermal ridge through its interaction with the underlying progress zone mesoderm subsequently determines appropriate longitudinal growth of the extremity, as well as differentiation of distal and proximal structures of the limb bud. Cell death due to apoptosis from any cause such as vascular insufficiency or drug toxicity that interrupts this relationship between the apical ectodermal ridge and the progress zone can result in phocomelia.[8]

History and Physical

Any time phocomelia is identified in a newborn, and given its correlation with thalidomide, practitioners should inquire about medications taken during early pregnancy. Additionally, children should undergo a thorough physical examination as one study reported that 36.9% of phocomelia cases have additional major malformations, with 9.9% of cases being attributable to various syndromes.[1]

Evaluation

When phocomelia is identified in a child, physicians should complete a thorough search for other associated abnormalities, as other defects are present in approximately half of the patients presenting with this limb anomaly. Particularly, practitioners should examine the musculoskeletal system, including the vertebrae, the intestines, and the heart, as dysfunction in these organ systems appears most frequently in conjunction with phocomelia.[1]

Treatment / Management

The most important management of a child born with phocomelia is to assess for other associated abnormalities, especially of the heart and intestines, and address them promptly and appropriately. Pediatric cardiologists and gastroenterologists should examine the child and recommend a treatment plan for any abnormalities encountered.

From the perspective of the hypoplastic limb, prosthetics may be of some use, but many without concomitant pathology can function quite well. Families of children who have severely hypoplastic extremities should work with therapists to help understand how to meet the unique needs of their children. And finally, caring for a disabled child can be traumatic for some people. Therefore, physicians should have a low threshold to recommend mental counseling services to assist in coping mechanisms that may be needed by both the parents and the child.

Differential Diagnosis

Bermejo-Sanchez et al. report that 9.9% of cases of phocomelia are associated with different syndromes. They appear here in order of decreasing prevalence[1]:

Roberts Syndrome: A rare autosomal recessive disorder caused by a mutation in the ESCO2 gene that manifests with severe limb malformations and craniofacial defects.[9]

Thrombocytopenia with radial aplasia (TAR): A rare autosomal recessive disorder related to the RBM8A gene that presents with thrombocytopenia and limb radial deficiency.[10]

Syndrome of severe limb defects, vertebral hypersegmentation, and mirror polydactyly: An autosomal recessive disorder resulting in severe limb hypoplasia with polydactyly and hypersegmentation of the spine.[11]

Prognosis

In one review study, there were 85 live births to every 24 stillbirths for children with phocomelia. When considering only cases of isolated phocomelia, there were 57 live births to every eight stillbirths.[1]

Complications

Children with phocomelia have a high stillbirth rate compared to the general population. Furthermore, children with severe limb hypoplasia may or will face problems with activities of daily life and mobility. For this reason, health care teams must be integrated to provide for more than just the medical challenges that present with phocomelia.