Majewski's polydactyly syndrome

Overview

Majewski's polydactyly syndrome, also known as Majewski osteodysplastic primordial dwarfism type II (MOPD II), is an extremely rare and severe genetic disorder classified under the group of short-rib polydactyly syndromes. It is characterized by multiple congenital anomalies, including polydactyly (extra fingers or toes), severe short stature, skeletal dysplasia, facial abnormalities, and often visceral organ malformations. The condition is typically diagnosed in utero or shortly after birth due to the distinct clinical features.

Majewski's polydactyly syndrome is often fatal in the perinatal period due to respiratory failure from underdeveloped lungs, severe thoracic constriction, or associated organ anomalies. It is inherited in an autosomal recessive manner and falls under the broader spectrum of ciliopathies—disorders related to dysfunctional primary cilia, which play a vital role in embryonic development.

Causes

Majewski's polydactyly syndrome is caused by mutations in genes related to ciliary function, though the exact genetic etiology may vary depending on the subtype. Mutations affecting genes like NEK1, WDR35, and others involved in intraflagellar transport have been implicated in various forms of short-rib polydactyly syndromes.

The syndrome follows an autosomal recessive inheritance pattern, meaning both parents must be carriers of a defective gene copy for a child to be affected. In consanguineous populations, the likelihood of inheriting such recessive disorders is significantly higher.

Symptoms

Majewski’s polydactyly syndrome presents with a wide array of physical anomalies, many of which are identifiable prenatally. The most common clinical features include:

• Polydactyly: Presence of extra fingers or toes, often postaxial (on the outer side).

• Severe dwarfism: Intrauterine growth restriction leading to extreme short stature and skeletal underdevelopment.

• Short-rib thoracic dysplasia: A narrow chest cavity due to short ribs, often causing respiratory distress.

• Skeletal abnormalities: Short limbs, bowed long bones, and underossified skeletal structures.

• Facial dysmorphism: Including a small jaw (micrognathia), cleft lip/palate, low-set ears, and hypertelorism (wide-spaced eyes).

• Visceral organ malformations: Including cystic kidneys, liver fibrosis, or congenital heart defects in some cases.

• Brain anomalies: May include hydrocephalus or cerebellar abnormalities.

Due to the severity of these malformations, most affected infants do not survive beyond the neonatal period.

Diagnosis

Diagnosis of Majewski’s polydactyly syndrome is usually made through a combination of prenatal imaging, clinical evaluation at birth, and genetic testing. The key diagnostic steps include:

• Ultrasound (prenatal): Detects skeletal anomalies, polydactyly, and chest wall abnormalities as early as the second trimester.

• Physical examination (postnatal): Confirms the presence of characteristic dysmorphic features and skeletal abnormalities.

• Radiographic imaging: X-rays reveal short ribs, bowed limbs, and other skeletal dysplasias.

• Genetic testing: Molecular analysis using gene panels or exome sequencing can identify pathogenic mutations associated with short-rib polydactyly syndromes.

• Autopsy (in fatal cases): May help identify internal organ malformations and clarify diagnosis.

It is important to differentiate Majewski’s polydactyly syndrome from other syndromes in the short-rib polydactyly spectrum, such as Jeune syndrome, Ellis–van Creveld syndrome, and Saldino–Noonan syndrome.

Treatment

There is no curative treatment for Majewski’s polydactyly syndrome due to the severity and complexity of the congenital malformations. Management is primarily supportive and palliative. Treatment strategies may include:

• Neonatal intensive care: For infants born alive, respiratory support is often required due to underdeveloped lungs and thoracic constriction.

• Surgical intervention: Rarely considered, but may be attempted in cases of less severe malformations for cleft repair or limb deformity correction.

• Palliative care: Focuses on comfort measures in cases with poor prognosis.

• Genetic counseling: Essential for affected families, especially in populations where consanguinity is common, to understand inheritance risk and consider future reproductive options such as prenatal testing or preimplantation genetic diagnosis (PGD).

Due to the rarity of this condition, treatment is often guided by case reports and expert consensus rather than standardized protocols.

Prognosis

The prognosis for Majewski’s polydactyly syndrome is extremely poor. Most affected infants are stillborn or die shortly after birth due to complications from pulmonary hypoplasia and multiple congenital malformations. Survivors beyond the neonatal period are exceedingly rare.

Families affected by this condition should be offered ongoing psychosocial support and access to rare disease specialists. Advances in prenatal genetic diagnosis and molecular techniques may improve early detection and family planning decisions in the future.

Although the prognosis is bleak, increased awareness and research into ciliopathies may one day lead to better understanding and potential interventions for this and related disorders.